Summary of the 1st Schizophrenia International Research Society Conference oral sessions, Venice,...

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05 (2008) 289–383www.elsevier.com/locate/schres

Schizophrenia Research 1

Summary of the 1st Schizophrenia International Research SocietyConference oral sessions, Venice, Italy, June 21–25, 2008:

The rapporteur reports☆,☆☆

Roohi Abubaker a,1, Maaike Alaerts b,2, Ava-Ann Allman c,3, Jennifer Barnett d,4,Pauline Belujon e,5, Robert A. Bittner f,6, Thomas H.J. Burne g,7, Wiepke Cahn h,8,Steven Chance i,j,k, Sara Cherkerzian l,9, Renan deSouza m, Marta Di Forti n,10,Teresa du Bois o,11, Mar Fatjó-Vilas p,12, Melissa Green q, Demian Halpern r,13,John P. John s,14, Aaron Kemp t,15, Katja Koelkebeck u,16, Jimmy Lee v,17,

Daniel J. Lodge w,18, Panayiota Michalopoulou x,19, LaNina Mompremier y,20,Barnaby Nelson z,21, Jonna Perälä aa,22, Anna Rotarska-Jagiela ab,23,

Renata Schoeman ac, Katharine N. Thakkar ad,24,Giuletta Valuri ae,25, Shivarama Varambally s,26,

Clement Zai af,27, Lynn E. DeLisi ag,⁎

a Morehouse School of Medicine, Department OF Psychiatry, 720 Westview Drive, Atlanta GA 30310, United Statesb Applied Molecular Genomics Group, VIB Department of Molecular Genetics, University of Antwerp — Campus CDE, Parking P4,

Building V, Universiteitsplein 1, 2610 Antwerpen, Belgiumc O'Driscoll Lab of Clinical Neuroscience, Department of Psychology, McGill University, Stewart Biological Sciences Building,

1205 Dr. Penfield Ave., Montréal, Québec, Canada, H3A 1B1d University of Cambridge Department of Psychiatry, Box 189 Addenbrooke's Hospital, Cambridge CB2 2QQ, UK

e University of Pittsburgh, Dept of Neuroscience, A210 Langley Hall, Pittsburgh PA 15260, United Statesf Laboratory for Neurophysiology and Neuroimaging, Clinic for Psychiatry, Psychotherapy und Psychosomatic Medicine, Department of

Psychiatry, Goethe-University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germanyg Queensland Centre for Mental Health Research, The Queensland Brain Institute, The University of Queensland,

St Lucia, Queensland, 4072, Australiah UMCUtrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands

i Neuropathology, John Radcliffe Hospital, Oxford, OX3 9DU, UKj Department of Psychiatry, University of Oxford, The Warneford Hospital, SANE Prince of Wales Centre, Warneford Road, Oxford, UK

k Brigham and Women's Hospital/Harvard Medical School, Department of Medicine, United Statesl 1620 Tremont Street, OBC-3-034L, Boston, MA 02120, United States

m Centre for Addiction and Mental Health — 250 College St. R1/2 Toronto, Ontario, Canadan Institute of Psychiatry, Division of Psychological Medicine PO63, De Crespigny Park, Denmark Hill, London SE5 8AF, UK

o School of Health Sciences, University of Wollongong, Northfields Avenue, Wollongong NSW 2522, Australiap Unitat d'Antropologia, Facultat de Biologia. Universitat de Barcelona.Facultat de Biologia. Av. Diagonal 645, 2d floor. 08028 Barcelona, Spain

q School of Psychiatry, University of New South Wales, and Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, 2031, Australiar The Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel

s National Institute of Mental Health and Neurosciences (NIMHANS), PB No. 2900, Dharmaram P.O., Hosur Road, Bangalore 560 029, Indiat Psychiatry and Human Behavior, University of California, Irvine School of Medicine, UCIMC Neuropsychiatric Center,

101 The City Drive South, Orange, CA 92868-3298, United Statesu University of Muenster, Department of Psychiatry and Psychotherapy, Albert-Schweitzer-Strasse 11, 48149 Muenster, Germany

v Institute of Mental Health/Woodbridge Hospital, 10 Buangkok View, Singapore 539747, Singaporew Department Neuroscience, A210 Langley Hall, University of Pittsburgh, Pittsburgh, PA, 15260, United States

x Section of Schizophrenia, Imaging and Therapeutics, Department of Psychiatry, Institute of Psychiatry, King's College London,De Crespigny Park, London SE5 8AF, UK

0920-9964/$ - see front matter © 2008 Published by Elsevier B.V.doi:10.1016/j.schres.2008.08.015

http://dx.doi.org/10.1016/j.schres.2008.08.015

290 R. Abubaker et al. / Schizophrenia Research 105 (2008) 289–383

y Department of Clinical Psychology, Gallaudet University, Washington, D.C. 202-651-5540, United Statesz ORYGEN Research Centre, Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia

aa Department of Mental Health and Alcohol Research, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finlandab University of Cologne, Department of Psychiatry and Psychotherapy, Kerpenerstr. 62, 50924 Cologne, Germany

ac Department of Psychiatry, University of Stellenbosch, South Africaad Vanderbilt University, Department of Psychology, 409 Wilson Hall, 111 21st Ave., Nashville, TN 37203, United States

ae School of Psychiatry and Clinical Neurosciences, Neuropsychiatri Epidemiology Research Unit, M571, Level 3, MRF Building,Rear 50 Murray St, Perth WA 6000, Australia

af Neurogenetics Section, Centre for Addiction and Mental Health, R76 250 College Street, Toronto, Ontario, Canada, M5T1R8ag Department of Psychiatry, New York University Langone Medical Center, New York, NY 10016, United States

☆ Note: These summaries are written by each rapporteur to the best of their knowledge and interpreted by them based on what they heard at thecongress. In cases where individual researchers were quoted, rapporteurs were instructed to obtain permission for and to confirm accuracy of thestatements. However, neither the investigators who presented data, nor the editors of the journal, are responsible for any inaccuracies of the reporting.For confirmation, please see original publications by each speaker.☆☆ Each author contributed one or more sections and worked equally on this project.⁎ Corresponding author. Department of Psychiatry, New York University Langone Medical Center, 650 First Avenue, 5th Floor New York, NY

10016, USA. Tel.: +1 212 263 3406; fax: +1 212 263 3407.E-mail addresses: [email protected] (R. Abubaker), [email protected] (M. Alaerts), [email protected]

(A.-A. Allman), [email protected] (J. Barnett), [email protected] (P. Belujon), [email protected] (R.A. Bitner), [email protected](T.H.J. Burne), [email protected] (W. Cahn), [email protected] (S. Chance), [email protected](S. Cherkerzian), [email protected] (R. deSouza), [email protected] (M. Di Forti), [email protected] (T. du Bois),[email protected] (M. Fatjó-Vilas), [email protected] (M. Green), [email protected] (D. Halpern),[email protected], [email protected] (J.P. John), [email protected] (A. Kemp), [email protected] (K. Koelkebeck),[email protected] (J. Lee), [email protected] (D.J. Lodge), [email protected] (P. Michalopoulou),[email protected] (L. Mompremier), [email protected] (B. Nelson), [email protected] (J. Perälä),[email protected] (A. Rotarska-Jagiela), [email protected] (R. Schoeman), [email protected] (K.N. Thakkar),[email protected] (G. Valuri), [email protected], [email protected] (S. Varambally), [email protected] (C. Zai),[email protected] (L.E. DeLisi).1 Tel.: +1 404 218 8555.2 Tel.: +32 3 265 10 28; fax: +32 3 265 10 12.3 Tel.: +1 514 398 4916.4 Tel.: +44 1223 767037; fax: +44 1223 336968.5 Tel.: +1 412 624 7332; fax: +1 412 624 9198.6 Tel.: +49 69 6301 4864; fax: +49 69 6301 3833.7 Tel.: +61 7 3346 6371; fax: +61 7 3346 6301.8 Tel.: +31 8875 58180.9 Tel.: +1 617 525 7583; fax: +1 617 525 7746.

10 Tel.: +44 2078480100; fax: +44 2077019044.11 Tel.: +61 2 42214584; fax: +61 2 42214096.12 Tel.: +34 934021461.13 Tel.: +972 3 530 37 73; fax: +972 3 535 38 07.14 Tel.: +91 80 26995349/26995306; fax: +91 80 26564822.15 Tel.: +1 714 456 8690.16 Tel.: +49 2518356601; fax: +49 2518356612.17 Tel.: +65 63892000; fax: +65 63150548.18 Tel.: +1 412 624 7332; fax: +1 412 624 9198.19 Tel.: +44 207 848 0356; fax: +44 207 848 0287.20 Fax: +1 202 651 5747.21 Tel.: +61 3 9342 2800; fax: +61 3 9387 3003.22 Tel.: +358 947448660; fax: +358 947448478.23 Tel.: +49 221 478 87146; fax: +49 221 478 87702.24 Tel.: +1 770 330 2458; fax: +1 615 343 8449.25 Tel.: +61 8 9224 0288; fax: +61 8 9224 0285.26 Tel.: +91 80 26995349/26995306; fax: +91 80 26564822.27 Tel.: +1 416 535 8501x4883; fax: 1 416 979 4666.

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291R. Abubaker et al. / Schizophrenia Research 105 (2008) 289–383

Abstract

The Schizophrenia International Research Society held its first scientific conference in Venice, Italy, June 21 to 25th, 2008. Awiderange of controversial topics were presented in overlapping and plenary oral sessions. These included new genetic studies, controversiesabout early detection of schizophrenia and the prodrome, treatment issues, clinical characteristics, cognition, neuropathology andneurophysiology, other etiological considerations, substance abuse co-morbidity, and animal models for investigating disease etiologyand for use as targets in drug studies. Young investigators in the field were awarded travel grants to participate in the congress and one oftheir roles was to summarize the oral sessions and subsequent discussions. The reports that follow are the culmination of this workproduced by 30 young investigators who attended the congress. It is hoped that these summaries will be useful synopses of what actuallyoccurred at the congress for those who did not attend each session or were unable to be present. The abstracts of all presentations, assubmitted by the authors a few months prior, were previously published as supplement 2 to volume 102/1–3, June 2008.© 2008 Published by Elsevier B.V.

Contents

I. GENETICS SESSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292Searching for the genetic mechanism for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292Late breaking genetic findings: what is or is not a genetic risk factor?. . . . . . . . . . . . . . . . . . . . . . . 294Is COMT relevant? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Physiological mechanisms of schizophrenia phenotypes: genes and receptors . . . . . . . . . . . . . . . . . . . 298

II. EARLY DETECTION OF SCHIZOPHRENIA AND THE PRODROME. . . . . . . . . . . . . . . . . . . . . . . 299Predictors of psychosis: results from multi-site longitudinal prodrome studies in Europe and North America . . . 299The onset of psychosis, the prodrome and high-risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Visualizing early psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303The two hit hypothesis for pharmacotherapy in the prodrome: bench to bedside evidence. . . . . . . . . . . . . 304From vulnerability markers to disease — specific prediction of psychosis . . . . . . . . . . . . . . . . . . . . . 306Mapping transition to psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

III. TREATMENT ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309Plenary topic: advancing drug development in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . 309Symposium on drug development in schizophrenia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313Strategies to accelerate drug development for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316The prophylaxis and early management of psychosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318Dissecting the heterogeneity of antipsychotic drug response: new approaches to an old problem . . . . . . . . . 320Determining clinical outcome, quality of life and insight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321Time course of treatment response in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323Metabolics, metabolomics and antipsychotic treatment: recent studies in schizophrenia . . . . . . . . . . . . . . 327Pharmacologic and cognitive remediation strategies for improving cognition . . . . . . . . . . . . . . . . . . . 328Cognitive effects of second generation antipsychotic medications: experiences from first episode schizophrenia studies . 331The pathology and treatment of schizophrenia: a moving or fixed target? . . . . . . . . . . . . . . . . . . . . . 334The glutamate hypothesis is alive and kicking: treatment of negative symptoms and cognition in schizophrenia . 336Phosphodiesterases and schizophrenia: improving disease understanding and their potential as the nextgeneration of therapeutic targets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338

IV. CLINICAL CHARACTERISTICS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340Future classification of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340

V. COGNITION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342From visual perception to attention: recent advances in cognitive research in schizophrenia . . . . . . . . . . . . 342Visuo-cognition and emotion processing in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344Translational studies of working memory in schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

Mechanisms of working memory deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346Lateralization of brain activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346Working memory and dopamine function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347Neural systems approach to working memory deficits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

VI. NEUROPATHOLOGY AND PATHOPHYSIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349Glial cells and glia/neuron interactions in the pathophysiology of schizophrenia. . . . . . . . . . . . . . . . . . 349The underlying brain pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350

What can we learn from imaging?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353White matter disruption in psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355Integrity of brain pathways: functional and structural studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 357Evidence from electrophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359Neural synchrony as a pathophysiological mechanism in schizophrenia . . . . . . . . . . . . . . . . . . . . . 362Altered hippocampal activity as a pathophysiological basis for schizophrenia . . . . . . . . . . . . . . . . . . 365

VII. OTHER ETIOLOGICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366Experimental analysis of the maternal immune risk factor for schizophrenia . . . . . . . . . . . . . . . . . . . 366

VIII. SUBSTANCE ABUSE AND SCHIZOPHRENIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369The 1st episode of psychosis and substance abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369Cannabinoids and schizophrenia: potential mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371

IX. ANIMAL MODELS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372Updates in developmental models for schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372Further session on relevant animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376


I. GENETICS SESSIONS

Searching for the genetic mechanism for schizophreniaReported by Jennifer Barnett

This session focused on three main controversiescurrently fuelling the field: whether large-scale geneticassociation studies will help to find risk genes, whetherendophenotypes are worth pursuing, and whether thereare relevant gene–environment interactions.

The first three speakers were unanimous in theirviews that the current wave of large-scale genome-wideassociation studies (GWAS) will undoubtedly findgenes, though other methodologies will also beimportant. Michael O'Donovan (Cardiff, UK) notedimportantly that linkage and association studies may notuncover the same genes (though there may be someoverlap and neither is powerful to detect rare genes ofsmall effect). He cautioned that it is not clear what isconsidered replication in genetic studies, whetherreplication studies must use the same allele (whichmay itself be simply a proxy of a functional variant), orwhether confirmation at the level of the gene, regardlessof what aspect of the gene, is sufficient. He argued forevidence to be taken as the “balance of probabilities”,such that multiple strands of ‘softer’ statistical evidencemay be sufficient reason to invest further time andresources. He presented in press data from his group'sgenome-wide association study (GWAS) which usedless than 500 cases in the discovery stage but more than8000 cases and 13,000 controls for replication, with 6loci surviving both replication attempts. Interestingly,their finding with the highest significance, within thegene ZNF804A, also showed some association inanother independent schizophrenia sample and in the

Wellcome Trust Collaborative (WTCCC) bipolar data-set, suggesting that it may be associated with a broadpsychosis phenotype.

Phenotypes were a concern of the second and thirdspeakers, Pablo Gejman (Chicago, Illinois) and Nicho-las Craddock (Cardiff, UK). Gejman argued that whileGWAS has worked well for other complex diseases suchas type II diabetes, the lack of large genetic effects inschizophrenia could mean that schizophrenia is geneti-cally even more complex. One source of complexitymay be ethnic differences; while their recent study of4000 European Americans (Sanders et al., 2008) foundno convincing evidence for genetic association with 14candidate genes. New data (presented below) suggestssignificant effects of NRG1 and ERBB4 in AfricanAmericans, but not Americans of European origin.

Dr. Craddock argued that schizophrenia is not in anyway a special genetic case and that those who claim it isrisk increasing schizophrenia's stigmatization. He pointedout that even in the WTCCC study of seven diseases,bipolar disorder was not an outlier in terms of the distri-bution of association signals, and that it is this distribution,rather than just the top highest significant findings, thatshould be pursued. He gave the example of the GABRB1genewhich has a suggestive association to bipolar disorderin the WTCCC sample but a much stronger associationamong those who met criteria for RDC schizoaffectivedisorder, bipolar type. Using an iterative process his groupmoved from genome-wide analysis to address relatedgenes in the schizoaffective subgroup and found strongevidence implicating the GABAA system in these schizo-affective patients. Large-scale genetic association studieswill be worth our while, he concluded, but we shouldrealize that theymay also change our current concept of theclinical diagnosis of schizophrenia.


The next two speakers were charged with defendingthe use of endophenotypes, and provided complemen-tary evidence from cognition and imaging supportingthe utility of this approach. Katherine Burdick (GlenOaks, NY) pointed out that the original aim of theendophenotype approach was as an attempt to find newgenetic loci, which ultimately affect risk for schizo-phrenia. This is, with some notable exceptions (Freed-man et al., 1997) not how endophenotypes have in factbeen used: the typical study instead takes a candidategene and tests its effects on putative endophenotypes,attempting to replicate association and provide somefurther information about the biological function of thegene. Dr. Burdick showed evidence from her group'swork with DISC1 and dysbindin (DTNBP1) demon-strating that the same SNP markers or haplotypes affectrisk for both the clinical psychiatric disorder andcognitive function specifically. She argued that the useof cognitive endophenotypes provided additional bio-logical evidence that is then useful, for example, inguiding DISC1 mouse models.

Joseph Callicott (NIMH, Bethesda, Maryland) con-tinued this argument as he described how imaging dataprovided ‘value added’ physiological information aswell as one source of external validity supporting novelgenetic associations. He argued that prefrontal ineffi-ciency is an endophenotype that meets many ofGottesman and Gould's (2003) criteria for endopheno-types, though we do not yet know if it co-segregateswith illness within families. He cited Blokland et al.'s(2008) data demonstrating a heritability of 30% forprefrontal function on the N-back task, and suggestedthat digit symbol substitution may turn out to besimilarly useful. He added the argument that while theremay be no detectable genes for mental illness risk per se,there may well be detectable gene variations that are riskfactors for information processing as detected by thesemeasures.

While candidate genes may still have to prove theirvalidity, James Van Os (Maastricht, the Netherlands)reminded us that many environmental risk factorsincluding urbanicity, migration and cannabis use arealready established as elevating risk for schizophreniawith considerable effect sizes. He pointed out that muchof the additive genetic effects estimated from twin datacould be due to gene–environment interactions (G×E),that human data already demonstrates the importance ofthe environment in shaping brain development, and thatanimal work from Michael Meaney's group and othersshow epigenetic mechanisms by which postnatalenvironment can have profound interactions with geneexpression. Failing to take account of G×E can

massively dilute the power of a genetic associationstudy; and in his view, while we may still find risk genesby ‘brute force’, genotyping of thousands of samplesmay simply not be the most efficient use of researchfunds. Nor may it be the most effective way to helppatients, argued Kathleen Merikangas (NIMH,Bethesda, Maryland). The aim of G×E studies, sheoutlined, should be two-fold: to understand disease, andto find risk factors which we can treat or prevent. Weshould therefore use genetics to find susceptibilityenvironments, in which public health initiatives couldthen intervene. For example, the cognitive declineassociated with the APOE4 allele in Alzheimer's diseaseis greater in individuals with hypertension, a conditionwhich can itself be treated. Unfortunately, she cau-tioned, the scale of genetic association studies that willbe needed to detect G×E effects is enormous, and wemay wish instead to consider returning to extendedfamily samples which may prove more informativemeans of understanding G×E interaction and, ulti-mately, the biological systems that underlieschizophrenia.

As the discussant of above presentations, TimothyCrow (Oxford, UK) provided a skeptical counterpoint tothe relative unanimity presented thus far. He argued thatwe currently have a large body of literature of almost allfalse positive associations, and reminded the audience ofIoannidis (2005) who emphasizes that false positives aremore likely in the literature when samples and effectsizes are small, and when design, definition andoutcome are greatly flexible. Both epigenetic modula-tion and sites of high mutation, including copy numbervariants, may, he cautioned, ultimately prove moreimportant than the current set of candidate genes.

Brief comments from a distinguished panel ofspeakers then made a number of additional importantpoints. Raquel Gur (Philadelphia, Pennsylvania) empha-sized the need for parallel efforts in psychiatric geneticsand neurobiology that are accepted as complementaryand crucial to progress. Pamela Sklar (Boston, Massa-chusetts) echoed this as she called for psychiatricgeneticists to provide a united front in large multi-center international collaborations to move the fieldforward. The benefits of GWAS are as screeningtechnology, she argued, not to test specific hypothesesabout candidate genes; other methodologies will beneeded for the latter. Similarly, she suggested thatresearchers should cease arguing about what are themost appropriate phenotypes: there may be little point indebating their definition when it is clear that currentDSM-IV categories are highly heritable, measurable andcan be reliably diagnosed. Thomas Lehner (NIMH,


Rockville, Maryland) reassured the audience that NIMHis interested in funding a wide range of methods thatmay be appropriate to provide converging evidence, andAnil Malhotra (Glen Oaks, NY) requested that one ofthose methods be pharmacogenetics, which may offer amore important and immediate benefit to patients, forexample the case of clozapine-induced agranulocytosis.Robin Murray (Institute of Psychiatry, London, UK)reminded the audience that we are all responsible, viathe peer-review process, for the many false positiveassociations that have undoubtedly been published. Heargued that while most researchers would not “bet theirhouse” on a particular candidate gene, environmentalfactors show far larger effects and more consistentsupport, making the funding imbalance between geneticand environmental studies somewhat alarming. FinallySibylle Schwab (Perth, Australia) raised the question ofbiomarkers and systems biology approaches. Whilemultiple loci need following up, these should be done ina hypothesis-driven manner so that progress can bemade in understanding how genetic variants affectbiology.

Comments from the audience raised a number ofissues about the assumed genetic architecture ofschizophrenia and the utility of endophenotypes. Dr.Sklar suggested that endophenotypes play a role but arelimited by the expense in obtaining them, and by theirlow heritability. Dr. Lehner pointed out that theirusefulness depends not just on heritability but also onthe genetic architecture underlying them. Dr. Murrayclarified that endophenotypes are helpful only if they areon the pathway between gene and disease, not if they areepiphenomena of the disease. Kevin Mitchell (Dublin,Ireland) suggested that schizophrenia might be differentfrom other complex diseases because it reducesfecundity, arguing that a mutation selection balance istherefore more likely than common alleles. Drs Mal-hotra, Sklar and Kennedy argued that this was not thecase: low fecundity could be explained by a number ofgenetic structures including de novo copy numbervariants and low penetrant common variants, or by thebenefit to relatives of risk alleles. David Porteous(Edinburgh, UK) argued that low p-values are not theultimate goal for genetic research, and that independent‘proof’ could instead be provided by systems biology.Drs. Malhotra and Sklar agreed that p-values alone arenot enough but they are one source of convergingevidence, and help us to make choices when allocatingresources. Thus, this session brought together severaldifferent approaches toward understanding the geneticrisk for schizophrenia and displayed the state of ourunderstanding of the issues in 2008.

Late breaking genetic findings: what is or is not agenetic risk factor?Reported by Jennifer Barnett

This separate genetics session had reports of a broadrange of genetic techniques currently being applied instudies of schizophrenia, and included a considerableamount of new and as yet unpublished data.

Pablo Gejman (Chicago, Illinois) presented interimresults from the Genetic Association Information Net-work (GAIN) on schizophrenia, a GWAS in self-definedEuropean American (EA) and African American (AA)samples. The most highly significant association inapproximately 3000 EA samples, with a p-value ofapproximately 1e−6 was with the gene FAM69A andclose to it, RPL5, both loci that are implicated in a recentGWAS of multiple sclerosis. In 2400 AA samples, theirstrongest evidence for association was with two pre-viously reported strong candidate genes for schizophre-nia, NRG1 and its receptor ERBB4. The strength ofevidence for these two candidates in the AA samplecounters the argument that there are yet no true candidategenes for schizophrenia. Dr. Gejman noted that experi-ments which assess rare variation and adequately cover allgenes are currently feasible with custom made chip arraytechnology, but that a considerable amount of informationcan still be learned from the current commerciallyavailable standard arrays and common gene variation.

Pamela Sklar (Harvard/Broad Institute, Boston,Massachusetts), representing the International Schizo-phrenia Consortium, presented data on both structuraland sequence variation from their very large GWAS ofschizophrenia (n∼3400 cases and 3200 controls).Combining data from the Affymetrix 5.0 and 6.0 SNParrays, they found two regions which meet statisticalsignificance for genome-wide association. These are inthe HLA region, and on chromosome 1. Dr. Sklar thenpresented data from their large-scale survey of copynumber variants (CNVs) identified from the same datausing Birdseye, a hidden Markov model based approachwhich uses information from both SNP intensity dataand copy number probes. Concentrating their analysison large (N100 kb) and rare (b1%) CNVs, they find agreater amount of CNVs (OR=1.15), more CNVs thatintersect genes (OR=1.14), more ‘unique’ CNVs incases of schizophrenia compared with controls(OR=1.45; 15% of cases compared with 11% ofcontrols), and more CNVs that contain genes(OR=1.18), but no difference between cases andcontrols in the number of CNVs that do not containgenes (OR=1.09, p=0.16). They identified three lociwhere large deletions (N500 kb) were found


significantly more often in cases than in controls; theseincluded the well-documented 22q11 VCFS deletion(found in 13 cases and 0 controls), and two new regions:15q13 (9 cases and 0 controls) and 1q21 (10 cases and 1control). For both regions the affected individuals showsome cognitive impairment and one case with eachdeletion had epilepsy.

The session then switched to the inheritance ofcognitive endophenotypes. Timothea Touloupolou(Institute of Psychiatry, London, UK) presented astudy which aimed to quantify the genetic andenvironmental influences on possible cognitive endo-phenotypes, and to estimate the amount of geneticoverlap between schizophrenia and cognitive function.Dr. Touloupolou used a large study of concordant anddiscordant MZ and DZ twins to parse variance betweenschizophrenia and cognition into additive geneticeffects, and common and unique environmental influ-ences. Narrow heritability (A) estimates suggestedsignificant heritability for logical memory, visualassociative learning, and forward span, with eightother cognitive measures producing nonsignificantheritability estimates. Unique environmental effects(E) were significant for all cognitive measures, butcommon environmental influences (C) only significantfor one measure (forward digit span). High geneticcorrelations (in the range of 0.6–1.0) were foundbetween schizophrenia and some cognitive measures,including IQ and working memory, suggesting thatthese measures share a large amount of genetic variancewith schizophrenia.

Kevin Mitchell (Trinity College Dublin, Ireland)presented data from a developmental neurobiologyperspective on the effects of semaphorin and plexin-Agenes. Mice with mutations in these genes were shownto mimic aspects of schizophrenia: Sema6a mutantsshow abnormalities in cellular organization, limbic andcortical connectivity and sensory and motor circuitrythat parallel to some extent those found in schizo-phrenia. Functionally, these mutations produce corticalhyperactivation which can be reversed by a low dose ofclozapine. The behavioral phenotype includes impair-ments in object recognition, working memory, andsocial recognition. Sema6a knockout mice showhyperlocomotion which again can be reversed by alow dose of clozapine, but some of the behavioralphenotypes have less obvious human counterparts,including increased investigative sniffing and increasedobject exploration. Dr. Mitchell and colleagues havealso examined whether the SEMA6A, SEMA6B,PLXNA2 and PLXNA4 genes are associated withschizophrenia and find such evidence for the PLXNA2

and SEMA6B genes, the former of which has beenpreviously reported in the literature.

Comments from the audience questioned the extentto which prior candidate genes have been supported bythe latest GWAS studies. Dr. Sklar argued that many ofthe prior associations have involved different SNPs andhaplotypes not studied in the current large-scale GWAS,producing a practical problem of how many hypothesesyou would attempt to test for replication within GWASdata. She also pointed out that while there is currentlylittle evidence from GWAS for the previously reportedcandidate genes, such studies only have power to detectthe effects of common alleles. Rare alleles in candidategenes may be important, but GWAS are not designed todetect them. Dr. Gejman pointed out that in a complexdisease such as schizophrenia, a real effect with an ORof 1.4 would not be reliably detected given the currentGWAS sample sizes, and reiterated Dr. Sklar's argumentthat GWAS are not the appropriate experiment fortesting hypotheses about candidate genes. Dr. Mitchellpointed out that we have already discovered genes withvery large effects in individuals, but these are either notcommon or not present in all populations, whichprevents them from having major effects at thepopulation level. Ezra Susser (New York, NY) sug-gested that our efforts might be improved by collectingsamples from a wide range of ethnicities so as tounderstand genetic risk across populations. Collectingever-larger samples in one population runs the risk offinding further risk alleles which simply do not affectother populations.

It is clear that the large-scale association studies areonly in their infancy and that the results of recentanalyses and international collaborations are only nowcoming together. These data will need to eventually becombined with other types of genetic analyses to reachconclusions about the overall genetic mechanism forschizophrenia. The varying approaches illustrated in thissession were in support of this view.

Is COMT relevant?Reported by Mar Fatjó-Vilas

The catechol-O-methyltransferase gene (COMT) hasreceived much attention as a candidate gene because ofits role in metabolizing catecholamines at postsynapticsites and hence its role in neural functioning. COMTcontains a functional polymorphism that results in achange from Valine (Val) to Methionine (Met) at the158position of the protein sequence (position 108 in thesoluble form; Val158/108Met). The amino acid changeaffects the function of the enzyme. Individuals with the


Val/Val genotype have a fourfold increase of COMTenzyme activity in the brain compared to individualswith the Met/Met genotype (Chen et al., 2004).

This variation in COMT genotype has been sug-gested to play a role in the pathogenesis of psychosis.However, association studies in schizophrenia haveshown contradictory results and two recent meta-analyses failed to find significant association betweenthe COMT Val158Met polymorphism and schizophre-nia (Munafo et al., 2005; Fan et al., 2005). The reasonfor these inconsistent or elusive results may be theselection of phenotypes. Alternative strategies as the useof endophenotypes and/or the study of environmentalfactors interacting with gene variability could be usefulto disentangle the pathophysiologic role of the COMTgene. The present symposium was comprised of fivespeakers and aimed at understanding the relevance ofCOMT gene in relation to schizophrenia by thepresentation and discussion of recent results relatingthe COMT gene to i) schizophrenia vulnerability, ii)cognitive phenotypes, iii) cannabis interaction and iv)brain development.

The first presentation was a meta-analysis of thegenetic association between the COMT Val1/Metpolymorphism and six cognitive phenotypes by JenniferBarnett (Cambridge, UK). The first evidence for theeffect of COMT on cognitive function came from thestudy by Egan et al. (2001), describing the association ofthe Val1/Met genotype to performance on the WisconsinCard Sorting Test of executive cognition(WCST) amongschizophrenia patients, their siblings and healthycontrols. Since then, several studies have been devel-oped based on the premise that cognitive endopheno-types may help dissect the COMT contribution toschizophrenia vulnerability.

A meta-analysis of published associations (untilAugust 2007) between the COMT Val158/108Metpolymorphism and six measures of cognitive function(Trail Making Task, verbal recall, verbal fluency, N-Back, WCSTand IQ score) was presented (Barnett et al.,2008). After the exclusion of overlapping, matched orvelo-cardio-facial syndrome samples, results from atleast nine samples were included in the separate analysisof each cognitive phenotype. Meta-analytic techniquesmay be useful in obtaining more accurate effect sizeestimates and identifying potential moderating factors.The results of this meta-analysis question the role of theVal1/Met polymorphism on cognitive function. Theonly measure that appeared to be associated with COMTgenotype, without significant differences by ancestry,sex, average sample age, or patient status, was the IQscore. In view of these results, the speaker commented

that the effect of COMT on global intellectual function-ing seems to be real but small and that it would beimportant to include other SNPs in future genetic studiesto fully understand this association. She also discussedthe tendency to publish a lot of small positive studiesand few negative studies and to decrease the effect sizeswith later publication. Publishing these studies prema-turely, then may actually be hampering the under-standing of psychiatric genetics, rather than helping.Two comments were made from the audience: i) theinterest of including gene–environment studies infurther meta-analyses and ii) the necessity to workwith large datasets in order to analyse the effect ofstratification for different populations.

The second presentation was a confirmation of theinteraction between polymorphisms in the COMT geneand adolescent-onset cannabis use in a large sample ofpatients with schizophrenia by Ruud Van Winkel(Leuven, Belgium). Gene–environment interaction stu-dies have shown that the Val158Met COMT poly-morphism moderates the influence of adolescentcannabis use on developing adult psychosis (Caspi etal., 2005) and on the acute effects of cannabis (Henquetet al., 2006). Although the Val158Met is the moststudied SNP, several haplotypes exist across the COMTgene. Polymorphisms of the SNPs rs6269, rs4633,rs4818 and rs4680 form three common haplotypes thatcode for differences in COMT enzymatic activity andare associated with pain sensitivity (LPS: low painsensitivity haplotype shows the highest activity; APS:average pain sensitivity haplotype, HPS: high painsensitivity haplotype shows the lowest activity;(Nackleyet al., 2006). The main goal of Dr. Van Winkel's studywas to test the interaction between these haplotypes andadolescent-onset cannabis use in a sample of 505patients with schizophrenia. Significant or near-signifi-cant association between each SNP and monthlyadolescent-onset cannabis use before 16 years but notafter 18 years was described. Haplotype analysisshowed that homozygous LPS carriers were 3.2 timesmore likely to have smoked cannabis weekly before theage of 16 than homozygous APS carriers. Due to the lowfrequency of homozygous HPS carriers they were notincluded in the comparisons. These haplotypes thatmodulate protein expression have been poorly studied inschizophrenia. The findings of this study highlight theinterest of further analyses including this COMThaplotypic variation to understand its impact ondeveloping psychosis and interactions with cannabisuse. The audience expressed interest in the analysesincluding other substances, other stimulants of dopa-mine systems. Dr. Van Winkel responded that his study


included the analysis of other drugs such as ampheta-mines, cocaine or PCP, but none of them showed anyinteraction with COMT variants. The presenter was alsoasked about the possibility to replicate this study in othercountries and he answered that samples includingindividuals exposed to cannabis are needed; and hereminded the audience that Netherlands is not thecountry with the highest cannabis consumption.

The third presentation was a case–control study in alarge Japanese sample and a meta-analysis that showedno association of COMT variation with schizophrenia,by Okochi Tomo (presented by Nakao Iwata, Toyoake,Japan). Recent studies have shown that SNPs other thanVal158Met, and several haplotypes across the COMTgene influence enzyme activity. The authors presented agene-based case–control study between COMT andschizophrenia in Japanese large-samples (1118 patientsand 1100 controls). In addition, a meta-analysis about 5functional SNPs and a significant haplotype (rs737865–rs4680–rs165599) covering all published case–controlassociation studies up to August 2007 was alsopresented. Using linkage disequilibrium within theJapanese population (HapMap database) and after amutation scan of the whole exon and promotor region, atotal of 19 tag SNPs, including 6 functional SNPs, wereexamined. No association was detected between singleSNPs or haplotypes (2 or 3 markers haplotypes) andschizophrenia in the Japanese population. In addition,the meta-analysis did not show significant evidence foran association between Val158Met polymorphism andschizophrenia. An initial association between two SNPsand a three markers haplotype and schizophrenia wasobserved but it disappeared when one study wasremoved. The authors thus concluded that these resultsand previous meta-analyses (Fan et al., 2005; Munafo etal., 2005) show that the COMT gene is unlikely tocontribute to susceptibility for schizophrenia in theJapanese population. However, they also state that giventhe important role of COMT in the metabolism ofdopamine in the brain prefrontal cortex, new functionalSNPs in the COMT gene should still be studied.

The fourth presentation was another negative studyshowing a lack of influence of COMT Val1/Metgenotype on cognition in first-episode non-affectivepsychosis by Ignacio Mata (University Hospital Mar-ques de Valdecilla, Spain). The COMT Val158Metfunctional polymorphism has been associated withprefrontal cognitive abnormalities among patients withschizophrenia, healthy relatives and controls (Egan etal., 2001; Malhotra et al., 2002; Rosa et al., 2004).However, recent meta-analyses seem to question theseresults and suggest that the relationship between this

SNP and executive function is restricted to healthyindividuals but not to those with schizophrenia (Barnettet al., 2007). The study conducted by Dr. Mata et al.(2008), using an epidemiologically based sample of 130patients experiencing a first-episode of a non-affectivepsychosis, aimed to examine whether COMT Val158-Met genotype influenced cognitive performance inpeople with psychosis. The antipsychotic treatment ofthe included patients was randomly assigned, 42 werereceiving haloperidol, 42 olanzapine, and 46 risper-idone. At neurcognitive assessment the mean time oftreatment of patients was 10 weeks and the neurocog-nitive evaluation included the following six domains:General verbal ability, Attention and processing speed,Executive and perceptual organization function, VerbalMemory, Visual Memory and Motor Function. Nosignificant associations of any cognitive measure withCOMT genotype were observed. The authors suggestedthat the lack of significant findings in the present studycould be due to the interaction between COMT variationand antipsychotic treatment. Previous studies havefound no significant basal genotype effect on cognitiveperformance domain in unmedicated patients, whileafter 6 months of treatment with atypical antipsychotics,the effect was paradoxically observed (Bertolino et al.,2004; Woodward et al., 2007). Dr. Mata, answering aquestion about the mechanism by which the medicationinteracts with the COMT gene, explained that anti-psychotics interact with COMT-related prefrontal dopa-mine availability predicting cognitive performance. Hewas also queried about the effect of cannabis use and hereplied that their preliminary analyses did not show theinteraction of cannabis with COMT and neurocognitiveperformance.

The fifth presentation was about the influence of theCOMT genotype on corpus callosum development inadolescents born preterm by Matthew Allin (London,UK). The corpus callosum (CC) is the principal whitematter tract connecting the left and right hemispheres ofthe brain, and magnetic resonance imaging (MRI)studies have demonstrated that this structure is reducedin size and has abnormal morphological features inindividuals born preterm (Allin et al., 2006) and also inpatients with schizophrenia (Woodruff et al., 1995).Based on the fact that methamphetamine users have CCalterations (Axelrod, 1972) and on recent resultssuggesting that the COMT Val158Met polymorphismmay affect age-related differences in gray and whitematter density (Zinkstok et al., 2006), Dr. Allin's studyexplored the relationship between this variation in theCOMT gene and CC development in 32 individualsborn very preterm (VPT, born before 33 gestational


weeks). VPT individuals present more frequently lowIQ, conduct disorders and a higher risk for psychosisthan subjects born full term.

The following structural MRI and Diffusion TensorImaging (DTI) measures were obtained: longitudinalcross-sectional of the CC, at 14 and at 19 years; tract-specific Mean Diffusivity (MD) and Fractional Aniso-tropy (FA) of the CC, at 19 years. COMT genotypesinfluenced the total CC size at 14 years and at 19 yearsand the MD at 19 years. Specifically, carriers of the Met/Met genotype (related to a lower activity of the enzyme)showed the largest CC size and lowest MD; Val/Valhomozygotes showed the smallest CC and highest MD;and intermediate values in heterozygotes. Thus, theassociation of the COMT Met allele with greatergrowth and more organized microstructure of the CCin VPT individuals suggest that this genotype mayconfer resilience to the effects of perinatal white matterdamage.

An audience member suggested that future studiesinclude the 2′,3′-cyclic nucleotide 3′-phosphodiesterase(CNP) genes in analyses, as these are involved in thegenesis of the CC.

Physiological mechanisms of schizophreniaphenotypes: genes and receptorsReported by Melissa Green

In previous sessions on the status of genetic research,discussion converged on key unresolved issues. Forexample, in noting inconsistencies across variousGenome Wide Association Studies (GWAS), the needfor replication becomes paramount, despite logisticaldifficulties in facilitating such replication that mayrequire larger and larger sample sizes. Growingappreciation of the limitations of the GWAS approachhas thus seen increased focus on the genetic investiga-tion of cognitive and neurophysiological endopheno-types for psychosis. The current session thus focused onthe elucidation of neurobiological mechanisms of actionfor several genes implicated in schizophrenia, from boththe GWAS and endophenotype studies. The commonissue for each presentation was to progress in under-standing, from gene to mechanism, via the influence ofgenes or proteins on gene expression, neural function,and ultimately the information processing systemsrepresenting core disturbances in schizophrenia.

The first speaker was Shitij Kapur (Institute ofPsychiatry, UK), on the topic of D2 receptors. Thesignificance of D2 receptors is historically based on theaction of antipsychotic drugs, and the increase in D2receptors noted in post-mortem brain tissue, despite

largely negative results from genetic studies attemptingto link schizophrenia with D2 receptor genes. Morerecently the functional relevance of the “High” state ofD2 receptors, versus their “Low” resting state, has beenimplicated through evidence of a shift toward receptorsin the high state to be associated with psychosis. Dr.Kapur and colleagues have developed an agonistradioligand (11C-PHNO) for PET studies capable ofdistinguishing between High and Low states in theventral striatum of healthy participants, via binding withHigh state D2/3 receptors. Their recent application ofthis ligand to studies of schizophrenia attempted toestablish the status of D2/3 receptors in schizophreniapatients, and the impact of antipsychotic medication onthese receptors. It was found that although there is noincrease in active High state D2 receptors in drug-naïveschizophrenia patients, a group of patients treated withclozapine demonstrate significant up-regulation ofradiogland binding in the globus pallidus, an area richin D3 receptors. Subsequent use of Pramipexole as apharmacological challenge to this up-regulation showedthat the heightened binding signal can be displaced bythis D3-preferring agonist. These findings thus surpris-ingly implicate High state D3 receptor pathophysiologyin schizophrenia, especially within the globus pallidus,and suggest that future research should examine D3 up-regulating drugs for schizophrenia. One issue raisedwithin the subsequent discussion was whether the focuson striatal regions was limited: could there be evidencefor signal changes using 11C-PHNO in other regions (forexample, the thalamus)? This was not investigated andtherefore deserves further examination. Stafano Mar-enco (NIMH, USA) asked whether any evidence fromprimates supported the effects of antipsychotics on theup-regulation of 11C-PHNO by D3 receptors, but theseexperiments have yet to be performed.

The second speaker was David Porteous (Universityof Edinburgh, UK), reporting on the genetics andbiology of the DISC1 gene, from the arguablyprovocative stance that consideration of this geneshould move beyond its existence as a potentialcandidate. In keeping with the theme from previoussessions, Dr. Porteous asserted that it is highly likely thatDISC1 is involved in the pathophysiology of psychosis,based on over 25 positive linkage and associationstudies of DISC1 and schizophrenia, consistent associa-tion with neuroanatomical and psychophysiologicalendophenotypes such as hippocampal activation andvolume, working memory, reduced startle responseassociated with DISCI variants (Chubb et al., 2008), andevidence suggesting the role of DISC1 in neurodevelop-ment via interaction with signaling proteins (Millar


et al., 2005). The current use of mutant knock-out miceby Dr. Porteous and colleagues is now addressing thefunctional significance of DISC1 for psychosis, throughexamination of two ENU-induced mutations in mouseDISC1: Q31L and L100P. These studies implicate Q3ILin depressive-like behavior evidenced by abnormalmotor activity and its reversal with antidepressants.Administration of rolipam as a phosphodiesterase-4(PDE4) inhibitor did not reverse depressive behavior,and the Q31L mutants had lower PDE4B activity in linewith their resistance to rolipam. In contrast, L100Pmutations were associated with schizophrenic-likebehaviors, with particular psychophysiological conco-mitants that could be reversed with antipsychotics. Inconclusion, these findings provide a means of under-standing the functional significance of DISC1 mutationsfor psychotic disorders. Cynthia Shannon-Weickert(University of New South Wales, Australia) queriedwhy the association to DISC1 had been missed in largeGWAS. Dr. Porteus stressed the limitations of GWAS,i.e. that they reveal only the existence of a commonvariant relevant for schizophrenia, rather than thefunctional significance of allelic heterogeneity on anygiven gene. With the use of specific gene-targetedinvestigations, one can locate the dominant source ofsignal variation (such as that for DISC1, made up of 3SNPs) unable to be detected with GWAS.

The third speaker was Stephen Huffaker (NIMH,USA) reporting on a novel, primate-specific brainisoform of KCNH2 (a voltage-gated potassium chan-nel gene), and its role in cognition, hippocampalbiology, and schizophrenia. The delineation of theKCNH2 gene began with a family-based associationscreen, from which 10 genes were differentiallyexpressed in a large number of schizophrenia patients,as determined by microarray and genotyped haplotypetagging SNPs. Three genes within the microarray hadsignificantly associated haplotypes, with one passingBonferroni correction: the NOS3 haplotype block onKCNH2. These particular SNPs are associated withreduced hippocampal volume, overactivity hippocam-pal activity, poor cognitive performance and reducedspeed of processing in healthy control risk allelecarriers. Huffaker and colleagues have identified aprimate-specific novel isoform of the KCNH2 gene(Isoform 3.1) that is unique in structure and function,abundantly expressed in the human brain (althoughnotably, also expressed significantly in the humanheart), and importantly, expressed with over a 2-foldincrease in hippocampus in post-mortem material fromschizophrenia patients. The functional significance ofIsoform 3.1 over-expression is observed in hyperac-

tivity of primary cortical neurons that are resistant todepolarization, due to a rapidly deactivating K+current, and a high frequency non-adaptive firingpattern. While these findings suggest that the KCNH2gene may provide a novel target for psychopharmaco-logical therapeutics, it was questioned whether itwould be possible to design compounds to actspecifically on brain expression of this isoform (i.e.,that would not concurrently affect the expression ofIsoform 3.1 in the heart).

The final speaker in the session was AlessandroBertolino (University of Bari, Italy), whose presentationon the impact of variation in dopamine regulating geneson brain activity phenotypes in schizophrenia. Thispresentation began with the association between theCOMT gene and cognition via functional effects ondopamine catabolism in the prefrontal cortex (PFC), andthe differential effects of antipsychotics with variation inCOMT alleles. More recently the role of the D2 receptorgene (DRD2) and the dopamine transporter gene (DAT)in prefrontal cognition has been explored, includingpotential interactions between these and the COMTgene. While DAT and COMT have shown both additiveand epistatic modulation of prefrontal cortex andhippocampal activity during working memory (WM)and declarative memory tasks, novel SNPs on the DRD2gene have been associated with differential presynapticexpression of an isoform of this gene in human PFC andstriatum, and are associated with brain activity in theseregions during working memory (Zhang et al., 2007). Itwas noted that greater differentiation between allelecarriers on specific genes is achievable with moredifficult versions of WM tasks (e.g., higher n-back).These studies illustrated a method for examiningepistatic genetic modulation of neurocognitive pro-cesses as endophenotypes for psychosis.

II. EARLY DETECTION OF SCHIZOPHRENIAAND THE PRODROME

Predictors of psychosis: results from multi-sitelongitudinal prodrome studies in Europe and NorthAmericaReported by Barnaby Nelson

This symposium, chaired by Jean Addington (Cal-gary, Canada) and Joachim Klosterkötter (Cologne,Germany), included presentations based on two large-scale, multi-site studies of patients identified as being athigh risk for psychotic disorders due to symptomatologyand/or family history, i.e. in the putative prodromalphase of illness. The advantage of such studies is the


ability to pool resources and recruit large numberswithin a short period of time. The first of the two studieswas the North American Prodrome Longitudinal Study(NAPLS) study (N=888), which is a dataset thatcombines data collected across eight sites. The secondstudy was the European Prediction of Psychosis (EPOS)study, which consists of five European centers recruitingsubjects simultaneously (N=250).

Stephen Ruhrmann's presentation (Cologne, Ger-many) focused on clinical factors that predictedtransition to psychotic disorder in the EPOS sample.The rate of transition to psychosis was 14% at 12 monthsand 21% at 24 months. Ruhrmann presented a predictivemodel based on risk factors within the sample thatyielded an individual prognostic score of psychosis risk(an equation for each patient of the degree of risk ofpsychosis onset). This model demonstrated modest-good sensitivity, excellent specificity, and a highlikelihood ratio. This approach was derived from theclinical staging model used in other areas of medicine,and which has recently been discussed in relation topsychiatry by McGorry and others (McGorry, 2007;McGorry et al., 2007). The model presented byRuhrmann pushes predictive work in the ultra-highrisk (UHR) field forward by moving from generalpredictive variables to determining individual riskscores. However, this approach requires caution,because it is founded on having a high degree ofconfidence in predictive variables, which have to datebeen based on small–medium sample sizes. Indeed,Ruhrmann emphasized that the model he presentedbased on the EPOS data needs to be validated with anindependent sample.

Barbara Cornblatt (Glen Oaks, New York) presentedfunctioning data from the NAPLS study. One of thelimitations of assessing functioning in the UHRpopulation has been the fact that functioning measureshave been developed based on research with chronicpatients, rather than with young, prodromal patients.Cornblatt outlined the development of two functioningmeasures (the Social Functioning and Role FunctioningScales (Cornblatt et al., 2007)) that were used to capturedata collected across the different NAPLS sites and forfuture prodrome studies. The major findings were that inretrospective assessments, the UHR subjects in theNAPLS dataset were significantly impaired on bothsocial and role functioning compared to normalcontrols. Impaired social functioning was stable overtime, whereas role functioning fluctuated. There was nodifference in global role functioning or clinical GAFscores at baseline between cases who transitioned andthose who did not. However, social role scores were

lower for cases that transitioned to psychosis. Indeed,poor social functioning tripled the risk of transition inthe full NAPLS dataset. Cornblatt argued that these dataindicate that social functioning deficits are centralproblems in UHR patients, that they start prior topsychosis onset, and may be predictors of psychosisonset, particularly schizophrenia, and may be tied tocore cognitive deficits associated with schizophrenia.

Don Linszen (Amsterdam, the Netherlands) pre-sented neurocognitive data from the EPOS study.Questions of interest were whether the sample displayedneurocognitive impairment and whether neurocognitiveimpairment predicted psychosis onset. UHR patientsperformed worse than healthy controls across the batteryof neuropsychological tests but not as poorly as first-episode psychosis (FEP) patients. The only significantdifference between those who transitioned and thosewho did not was on verbal fluency tests. The dataindicated a positive correlation between verbal fluencyand mild hallucinations, social withdrawal anddecreased expression of emotion. Linszen concludedthat verbal fluency impairment may reflect a generalimpairment of intellectual ability and executive func-tioning, that it may be a predictive variable of prognosticoutcome for “at risk” patients, and may be associatedwith a subset of symptoms. Discussion drew attention tothe fact that the findings were divergent from previousfindings in the UHR population, which have tended toindicate that memory deficits, rather than verbal fluency,are present in UHR subjects who transition to psychosis.There was no clear reason why this discrepancyappeared in the current results. The issue of why verbalfluency deficits were interpreted as reflecting a generalintellectual disturbance rather than being an importantspecific deficit was also discussed. Linszen argued thatall neurocognitive tests have some learning effects apartfrom verbal fluency, and that it may therefore reflect amore basic deficit.

Finally, Larry Seidman (Boston, Massachusetts)returned to the NAPLS dataset. He outlined twomodels of neurocognitive deficits in schizophrenia.The first model is of a stable deficit from thepremorbid period into the prodrome, with a sharpdecline occurring at the first-episode of psychosis. Thesecond model is of a slow insidious decline inneurocognitive function. These models may reflectdifferent sub-groups of psychotic patients. TheNAPLS data indicated a general impairment in UHRpatients on neurocognitive tests. They indicated thatverbal memory and vocabulary were more impaired inUHR subjects who later transitioned compared to thosewho did not. The findings also indicated that family


history of psychotic disorder in UHR subjects,regardless of outcome, has a major impact oncognition. Questions that emerge from the data includehow well neurocognitive deficits individually and incombination predict longer-term outcome, the impor-tance of building additive models of risk andidentifying exactly when deterioration occurs, howneurocognitive measures contribute to early detection,and why there is variability in domains of impairmentacross different samples.

The symposium led to lively discussion. CherylCorcoran (New York, NY) highlighted the importanceof including biological variables in predictive models andthe role of proximal risk factors, such as stress andsubstance use. Alison Yung (Melbourne, Australia) drewattention to the discrepancy in transition rates between theEPOS and NAPLS studies at the 18-month point (17.1%versus 26.8%). Dr. Ruhrmann suggested that this may berelated to sample ascertainment: the NAPLS dataset wasbased on data collected at an earlier time point than theEPOS study, and more recent UHR cohorts have yieldedlower transition rates, possibly due to different referralpatterns and earlier detection (Yung et al., 2007). It wascommented that neurocognitive tests may not contributeto early detection efforts when used as a general screeningmeasure due to the lower base rate of psychotic disorder inthe general population compared to help-seeking UHRsamples. Dr. Seidman clarified that he was not proposingusing neurocognitive tests for this purpose, but rather thatcombining family history of psychotic disorder withparticular neurocognitive deficits may raise the index ofclinical suspicion. A final topic of discussionwas whetherprodromal programs have been assessed for cost effec-tiveness. Dr. Yung noted that there have been twoprodrome service cost effectiveness studies to date, bothof which have indicated that initial costs were quite high,but that costs for FEP patients who went through aprodrome service were ultimately cheaper than for FEPpatients who did not go through such a service.

The onset of psychosis, the prodrome and high-riskReported by: Giulietta Valuri

There were six presentations in this session on theonset of Psychosis: Gregor Berger (Melbourne, Aus-tralia), Maria de Grazia Dominguez Barrera (Maastricht,The Netherlands), Nikolaos Koutsoleris(Munich, Ger-many), Sara Cherkerzian (Boston, Massachusetts),Mary Clarke(Dublin, Ireland) and Charles Schulz(Minneapolis, Minnesota).

Dr. Berger discussed the neuroprotective propertiesof lithium, which has been found to have neuroprotec-

tive effects in the frontal cortex, hippocampus andstriatum of rats. In a previous study by Moore patientswith bipolar using lithium had an increase in gray matterby 30% (Moore et al., 1999). Dr. Berger used an open-label intervention study of 21 ultra-high risk (UHR)males (10 cases, 11 controls) from the PACE ClinicMelbourne, Australia to investigate whether the use oflow dose lithium may counteract microstructural brainchanges in individuals at ultra-high risk of psychosis.The study group was males 14 to 30 years of age fromthe Melbourne area, with no previous history ofpsychotic episodes, no organic disorders (i.e. epilepsy)and IQ of greater than 70. The interventions were lowdose lithium and supportive counselling only. Hippo-campal T2 relaxation time (HRT) was performed beforeand after the intervention and a difference was foundbetween the two groups. The cases had a reduced HRTand 30% of the variance of improvement could beexplained by being in the treatment group. Limitationsof the study were its small sample size, it was notrandomized, there were age differences at baseline andthe long recruitment period. Dr. Berger concluded that:low dose lithium does protect the hippocampus frommicrostructural brain changes in UHR patients fordeveloping psychosis and the reduced HRT correlateswith behavioral improvement, particularly reduction insuicidality and reduction in stress.

There were two comments from the audience. Thefirst comment was that a study using higher doses oflithium for mania looked at side effects and found nosignificant difference but they had no long-term data toshow this. The second comment was on the sample sizeand that it was too small to look at any predictors.

Dr. Barrera was examining the continuity from sub-clinical to clinical psychosis. A study found that in self-reported psychotic episode at 11 years had an OR of16.4 of having psychosis at 26 years of age. Thequestion Dr. Barrera was posing was: what happens inbetween/what are the mechanisms?

An 8 year prospective cohort study was conducted toassess the expression of psychosis in 845 adolescentsfrom the general population. Participants were assessed4 times, one at baseline (T0) and 3 follow upquestionnaires (T1, T2, T3). Transition from sub-clinical to clinical psychosis (i.e. T0–T2 to T3) wasexamined as a function of the level of prior persistence;was sub-clinical psychosis present never, once, twice orthrice at T0, T1 and T2.

Fifty-two percent were males, 61% of middle socialstatus. Sub-clinical transition decreased from T0 to T3.Two percent of the sample was in 2 higher levels ofpersistence. The odd of sub-clinical expression once


from T0 to T2 was 1.5, twice an OR of 5, at all three ORof 9.9.

Most psychotic expressions in sub-clinical psychosisare transitory and there is an increased risk ofdeveloping into clinical psychosis.

A question from the audience: Was persistencerelated to age? Dr. Barrera answered no. The samplewas aged between 14 and 17 years. Symptoms atbaseline slightly decreased over time.

Dr. Koutsoleris posed the following questions: domorphometric differences exist between at-risk mentalstate (ARMS) subjects and healthy controls (HC)? andare specific patterns of brain alterations associated withdifferent ARMS?

In a cross-sectional and longitudinal study ARMSsubjects clinical outcomes were monitored and followedup over 4 years. There were 20 early at risk (ARMS-E)subjects, 26 late at risk (ARMS-L) and 75 healthycontrols (HC). Fifteen subjects transitioned to psychosisand 18 remained healthy. The groups were found not tobe significantly different: HC and ARMS-L had more ofa difference, ARMS-E and ARMS-L had an inversecorrelation.

Is a neuroplastic process involved in transition fromthe early to the late ARMS of psychosis? Do ARMS-Eand ARMS-L differ regarding predictive validity?

Twenty-five percent of ARMS-E where asympto-matic at follow-up. Ten developed schizophrenia and 4schizo-affective in 6 months. Thus, Dr. Koutsolerisconcluded that there are different patterns of brainalterations associated with different ARMS.

Dr. Cherkerzian presented some results from the NewEngland family study which is a cohort study of womenand offspring of 17,741 pregnancies during 1959 to1966. The results presented were a follow-up study of208 psychotic (high risk) parents with 367 offspring and132 non-psychotic parents with 186 offspring. Thesechildren are now 40 years of age. This study waslooking at predictors, genetic and environmental, of age7 cognitive and behavioral functioning on the offspring.Cognitive included IQ, academic achievement, verbaland perceptual functions. The behavioral functioningwas aggression.

Cognitive functioning was significantly lower in thehigh risk offspring and a significant decrease in thoseexposed to prenatal inflammatory conditions. Thus, Dr.Cherkerzian concluded that genetic vulnerability forpsychosis and prenatal inflammation where indepen-dently associated with lower cognitive functioning evenby age 7; together they have an interactive effect; havingverbal/conceptual and behavioral inhibition impaired donot significantly predict psychosis in adult offspring;

and cognitive functioning was the only variable thatshowed a significant association.

Dr. Clarke discussion was on whether prenatalexposure to infection and parental history of schizo-phrenia could increase the risk of developing schizo-phrenia. There have been inconsistencies in results frompast studies. Most studies to date have been small in sizeand lack the power to look at the interaction betweengenetic liability and prenatal infection. It has beenshown that pyelonephritis (upper urinary tract infec-tions) have been associated with increased incidence ofschizophrenia among exposed offspring.

The study included 9596 women who receivedtreatment for an upper urinary tract infection duringpregnancy from 1947 to 1990. These offspring werecompared to their siblings, n=13,808. The studycalculated biological synergism, biological effects ofgenetic and environmental factors and if they aredependent on each other. The study showed a 1.5 oddsratio of exposure to pyelonephritis, 3.35 OR in the firsttrimester, 1.64 in the second trimester and 1.37 in thethird trimester. Both prenatal exposure to infection andparental history together showed an increased risk ofdeveloping schizophrenia later. The additive effect ofboth showed an even higher risk.

This was the first report showing genetic andenvironmental synergistic effects between prenatalinfection and familial liability. Dr. Clark concludedthat gene–environment interactions were important inthe causation of schizophrenia. Should also considerurbanicity.

A comment was made from the audience thatmaternal diabetes increases the risk of infection. Anaudience member asked; what factors were adjusted for?There were no additional information to control and nosmoking related information available. What aboutantibiotics? All women were hospitalised so more thanlikely they were treated with antibiotics.

Dr. Schulz was using multiple measurements to sortsubjects into different groups. He was using data fromThe Mind Clinical Imaging Consortium to test theirfirst-episode group. There are 75 neuropsychologicalvariables and 95 sMRI measures and the subjects had tohave all these tests so results could be used to correctlydistinguish patients from controls.

They used to types of analysis; stepwise lineardiscriminant analysis (LDA) and principal componentanalysis (PCA). LDA for neuropsychological variablesresulted in a sensitivity of 78.5% and specificity of85.1%; for structural MRI a sensitivity of 53.6% and sspecificity of 74.5%. Principal component analysisresulted in a sensitivity of 78.5% and specificity of


91.5% for neuropsychological variables and sensitivityof 69.9% and specificity of 72.3% for sMRI. When bothneuropsychological variables and sMRI were analyzedtogether LDA showed a sensitivity of 60.7% andspecificity of 72.3%, PCA showed a sensitivity of89.3% and specificity of 93.6%.

Results of the study are consistent with early studiesof adolescents in separating groups. The benefit of usingPDA and LDA over stepwise analysis is that it allowsmore variance to be included in the analysis. The betterperformance of neuropsychological measures alone mayreflect greater cognitive differences at an early stage ofillness.

Visualizing early psychosisReported by Anna Rotarska-Jagiela

Neuroimaging research has significantly contributedto our understanding of schizophrenia. However, whileprogress has been made in characterizing early stages ofthe disease, more research examining brain structure andfunction for risk factors is needed. The goal of thesymposium, chaired and co-chaired by Neeltje vanHaren and Wiepke Cahn (Utrecht, The Netherlands),was to introduce and integrate the newest findings fromanatomical and functional Magnetic Resonance Imaging(aMRI and fMRI), Single Photon Emission ComputedTomography (SPECT), Positron Emission Tomography(PET) and genetic studies examining first-episodeschizophrenia patients and those at increased risk fordeveloping psychosis.

Dr. Cahn (Utrecht, The Netherlands) presentedresults from a series of studies of morphologicalexaminations of first-episode schizophrenia patients atthe disease onset and over a five-year period. One yearafter the disease onset, progressive brain changes,including a whole-brain volume decrease of approxi-mately 3% and enlargement of lateral ventricles ofapproximately 7%, were detectable. In addition, theseanatomical changes were related to clinical and socialoutcome after two (Cahn et al., 2002) and five years(Cahn et al., 2006), with those patients who needed themost care and showed the most severe clinicalsymptoms having the most dramatic morphologicalbrain changes in the early stages of the disease. Inaddition, psychotic course of the illness was determinedby clinical interviews at inclusion, year one, two andfive, and total amount of time each patient showedpsychotic symptoms, remission or full recovery wasrecorded. Those patients, who had longer duration ofpsychosis also had most rapid decrease in total graymatter volume, and increased volume of the lateral and

third ventricles. In another study, a group of 107schizophrenia patients was examined to determinechanges in the PANSS score in relation to white andgray matter volumes. In the first year, gray matterdecreased most rapidly, while white matter volumeincreased. While positive PANSS scores decreased withtime, during the first year, negative symptoms weremore stable. In addition, there was a negative correlationbetween gray matter volume and positive and negativesymptom PANSS scores. The opposite was the case forwhite matter volume, where positive correlations topositive PANSS scores were found. Patients, whocontinued to be psychotic, had the largest increase inwhite matter volume. In conclusion, the results of theabove studies provide evidence for progressive brainvolume changes in the early stages of schizophrenia andthe severity of the observed anatomical abnormalitieswas related to clinical outcome and severity of clinicalsymptoms.

In the second talk, Birte Glenthoj (Copenhagen,Denmark) presented data from a study examining therelationship between extrastriate D2/3 binding potentials(BPs) and cognitive functioning and psychopathology intwenty-five first-episode, drug-naïve schizophreniapatients. Group comparisons of D2/3 BPs in the frontaland temporal lobes and the thalamus yielded nosignificant differences between control participantsand schizophrenia patients. However, males tended tohave increased BPs in the frontal lobes. In addition, BPsin male patients were positively correlated withincreased positive symptoms as measured by thePANSS. No similar correlations were found in femalepatients (Glenthoj et al., 2006). In the second study,correlation between BPs and attention and executivefunctioning were examined. In the frontal lobe,increased BPs were related to poorer response inhibitionand were related to positive symptoms. Increased BPs inthe temporal lobe were related to increased verbalfluency and better performance on the Trail Making testB.

Philip McGuire (London, UK), the third speaker,presented results of several studies of the at-risk mentalstate. The goal of these evaluations was to determinerisk factors from brain function and structure, whichwere specifically related to a transition to psychosis.Anatomical examinations of gray matter volumeshowed that the pattern of anatomical abnormalities inthe at-risk mental state was very similar to that observedin chronic schizophrenia patients, with abnormalitiesfound in the insula, superior temporal gyrus, cingulateand inferior frontal cortex (Borgwardt et al., 2007;Pantelis et al., 2003). Compared to those who did not


develop schizophrenia, patients who later developedpsychosis, had decreased gray matter volume in rightinsula, inferior frontal and superior temporal gyri(Borgwardt et al., 2007). After one year, progressivereduction in the gray matter volume was observed in leftparahippocampal, fusiform, orbitofrontal, cerebellar andcingulate cortex in patients who did transition intopsychosis, while those who did not had no significantanatomical changes (Pantelis et al., 2003). DiffusionTensor Imaging (DTI) showed a similar pattern ofresults whereby first-episode psychotic individuals weremost affected by disturbances in the integrity of whitematter fibers, followed by those with increased risk forbecoming psychotic. At-risk patients, who transitionedinto psychosis, had more severe abnormalities thanthose who did not develop schizophrenia.

fMRI examinations also provided evidence forimpairment of at-risk participants on a range of attentionand memory tasks. The observed impairments weresimilar to those of first-episode patients. Cognitiveabnormalities were further evaluated using a combina-tion of PET and fMRI and performance on a verbalfluency task. At-risk patients were significantlyimpaired. The observed abnormalities were related toincreased fMRI activation in the prefrontal regions andincreased dopamine functioning in the striatum, asmeasured by PET. fMRI activation correlated withincreased striatal dopamine. Moreover, an increaseddopamine level was associated with more severepsychotic symptoms. Another PET study focused onglutamate levels in the thalamus. The level of glutamatewas significantly reduced in the at-risk group andchanges in glutamate levels were correlated with graymatter volume decreases. To conclude, although most ofthe at-risk participants did not develop psychosis, theystill showed functional and structural abnormalitieswhich were strikingly similar to those observed inchronic schizophrenia patients. Those who transitionedto psychosis showed more severe abnormalities thatthose who did not.

Stephen Lawrie (Edinburgh, UK) presented datafrom the Edinburgh High Risk Study. A total of 200subjects at genetic risk for schizophrenia were includedin the study. The participants were studied on averagetwo and a half years before they developed schizo-phrenia. At the first scan, at-risk individuals showedsignificant decreases in gray matter density of the leftparahippocampal gyrus and bilateral anterior cingulatecompared to healthy controls. However, the observedpattern of abnormalities did not predict transition topsychosis (Job et al., 2003). One morphologicalpredictor, however, was increased prefrontal folding,

or the gyrification index, in those who did developschizophrenia (Harris et al., 2004a,b). In another study,white matter volume was examined (Harris et al., 2007).In the at-risk sample, white matter increased with age insubjects who developed psychosis, while the oppositetrend was observed in participants who remained well.In addition, white matter changes predicted transition topsychosis (Harris et al., 2007). Clinically, participantswho later developed psychosis showed increased levelsof anxiety and depression. Although many of the at-riskpatients used cannabis, no direct link between cannabisuse and onset of psychosis could be established, which,however, may be due to a relatively small number ofparticipants, who transitioned into psychosis (Owenset al., 2005).

Another study examined patients, who were psycho-tic at the time of the first examination. At the time of thesecond scan approximately half of them developedschizophrenia and half did not. The two groups differedin the gray matter volume of medial temporal andfusiform gyri (Job et al., 2006), which correspondedwith the findings of previous studies presented duringthis session. The high-risk population also presented arange of functional impairments, such as disturbance offunctional connectivity on fMRI during the Haylingsentence completion task (Whalley et al., 2005), whichpredicted transition to psychosis (Whalley et al., 2006).

Celso Arango (Barcelona, Spain) provided a sum-mary of the session. He stressed the importance ofstudies examining first-episode and high-risk partici-pants as they provide a unique opportunity for observingthe disease process, unconfounded by such factors asmedication, community isolation, and repeated hospita-lizations, all of which are associated with chronicschizophrenia. The results of the studies presentedduring this session suggest that schizophrenia may be anongoing process starting early during development andcontinuing after the onset of the disease. Anotherimportant aspect of the four presentations was the utilityof neuroimaging as a prognostic tool. Better character-ization of first-episode and at-risk mental states have apotential of providing clinicians with a longer windowof opportunity where they can intervene in the diseaseprocess and maybe even prevent the development ofchronic schizophrenia.

The two hit hypothesis for pharmacotherapy in theprodrome: bench to bedside evidenceReported by Teresa du Bois

This interesting translational session aimed to bringboth basic and clinical scientists together to discuss the


pathology and symptomatology of individuals in theprodromal phase of illness with a focus on currentpharmacotherapy used during this period in the hope ofdelaying symptom emergence and preventing thetransition into a psychosis.

From a neurobiological perspective, Cynthia Shan-non-Weickert (Sydney, Australia) focused on the role ofbrain-derived neurotrophic factor in brain maturationand its potential as a key molecule in the pathology andperhaps in the future, prevention of psychosis onset.Firstly, Dr. Weickert and colleagues found decreasedlevels of BDNF, as well as its receptor trkB, in theprefrontal cortex of patients with schizophrenia. Con-sidering the important role BDNF plays in braindevelopment, influencing processes such as synapto-genesis, neuronal differentiation and brain plasticity, anmRNA decrease of 25% is likely to be very biologicallysignificant. Moreover, when taking into account thedifferential expression of BDNF on distinct neuronalpopulations, these findings were magnified. For exam-ple, BDNF is most highly expressed on excitatoryneurons, and this specific population of neurons showedthe largest decrease in schizophrenia patients. Identify-ing what factors (e.g. gene–environment interactions)influence expression of BDNF and its receptor is thecurrent focus of Dr. Weickert's ongoing work.

In a cohort of subjects examined, those receivingantidepressant medication showed higher BDNFexpression in the prefrontal cortex compared to thosenot on antidepressant medication. Thus BDNF mayunderlie the therapeutic effects of these drugs. Whenlooking at the genetic structure of BDNF, it contains acoding exon as well as several alternative 5′ promotersthat can switch on under various environmentalconditions such as learning, stress, exercise andantipsychotic treatment. Dr. Weickert thus examinedwhether some alternative transcripts contributed to thedecrease in BDNF expression in schizophrenia. Of the5′ promoters examined, all were increased, notdecreased. To determine whether medication was aconfounding effect on these results, patients onantidepressant medication were then excluded fromanalyses, resulting in a decrease in the 2–5′ promoter(involved in learning). Future studies will aim todetermine how central a BDNF deficit is to schizo-phrenia pathology.

In contrast, the next presentation was from a clinicalperspective. Dr. Barbara Cornblatt (New York) focusedon pharmacotherapy during the prodrome in high riskindividuals, with the aim of reducing vulnerability andsymptomatology in these individuals. Within theRecognition and Prevention Program (RAP) she devel-

oped in New York, individuals at high risk ofdeveloping psychosis were followed over a 2.5 yearperiod. The working hypothesis was that schizophreniais programmed early in life, with a brain abnormalitythat leads to increased vulnerability for psychoticsymptoms. In the absence of psychosis there stillcould be disability in other aspects of functioning,such as cognitive and social deficits. A second, possiblygenetically induced mechanism around the time ofpuberty, she suggests, leads to more pronouncedsymptoms and onset of psychosis.

In the RAP program, subjects were considered athigh risk of developing psychosis if they displayed 5symptoms such as grandiose ideas, unusual thoughts,and perceptual abnormalities. Since most of theprodromal symptoms are cognitive or negative symp-tom-like, the idea of using antidepressants rather thanantipsychotic drugs evolved. Psychiatrists who had noknowledge of the study objective were asked to treatpatients based on symptoms. Individuals were followedfor 2.5 years. Of the 48 subjects included, 20 weretreated with antidepressants, 28 with antipsychoticdrugs. None of the patients on antidepressants went onto develop psychosis; however almost half of thepatients prescribed antipsychotic drugs developedpsychosis. Further analysis revealed that of the 12subjects that developed psychosis, 11 were non-compliant with their medication and antidepressantswere more adhered to than antipsychotics. Conclusionsfrom this study need caution, given that the treatmentswere not randomly allocated among groups, and thus thepossibility exists that the group treated with antidepres-sants differed from those treated with antipsychotics.Nevertheless, these results are of interest and could berelevant to the previous mention of an association ofantidepressants with increases in BDNF, as theincreased levels may be a stimulant for neuronal growthand viability even in the human adult brain, thuspossibly protecting against a psychosis.

In a separate 6 month study, the effects ofantidepressant treatment on prodromal symptoms werefurther investigated. Unexpectedly, antidepressantsimproved verbal memory, deficits in which are knownto be a predictor of psychosis, but had no effect on socialfunction, while antipsychotics did not improve eitherverbal memory or social functioning.

The next presenter, Maree Webster (Maryland),investigated the underlying neuroscience of the diseaseprocess by describing the normal expression of BNDFand trkB during development of the human brain.Mental illness often presents during late adolescence, atime when key processes such as maturation of synapses


are occurring. Currently there is not much informationabout how these processes are regulated at the molecularlevel. As mentioned previously, BDNF influencesimportant processes such as synaptogenesis, neuronaldifferentiation etc. so the changing expression of BDNFand other neurotrophins with age is of interest.

BDNF showed a particularly dynamic temporalexpression compared to another neurotrophin, NT3.The coding exon form of BDNF as well as the fulllength form of its receptor trkB both showed peakexpression in the prefrontal cortex of the young adult. Inthe hippocampus there were no temporal differences inexpression. In the inferior temporal gyrus, the infantbrain showed the highest expression of BDNF and trkB.However when examining which 5′ transcripts ofBDNF contribute to the developmental expressionpattern, those examined so far do not match what hasbeen observed for the coding exon. Therefore futurestudies examining the developmental expression ofnewly identified alternative transcripts for BDNF arewarranted.

The final speaker of the session, Christopher Pantelis(Melbourne, Australia) presented another study tracingprogression of brain changes in high risk individuals,including those who had gone on to develop a psychosis(40%). While decreased gray matter volume in thetemporal and cingulate cortices was observed in chronicschizophrenia, these changes were not observed at asignificant level in individuals at high risk of developingpsychosis. However, cortical thickness of the anteriorcingulate cortex was decreased in 1st episode schizo-phrenia and also detected in the high risk individuals,although not as extensively. In high risk individuals whodeveloped psychosis, decreased cingulate thicknesscorrelated negatively with negative symptoms. Thus,progressive change in the cingulate, while subtle earlyon, is likely to be taking place. Since stress is implicatedin schizophrenia pathogenesis, the pituitary gland sizewas also examined. The size of the pituitary wasincreased both before and after the onset of psychosis.An increase in ventricular size, consistently found instudies of chronic patients with schizophrenia, interest-ingly was not apparent prior to onset of illness. Thus theneuroimaging studies show that pathology in specificbrain regions change dynamically during differentphases of psychosis. Some brain changes do not becomeevident until the onset of illness, while other changes arepresent at least from the prodrome phase onwards. Earlyintervention has the hope of possibly ameliorating thesechanges.

To test whether certain compounds can delay orprevent brain changes, patients were given omega-3

fatty acids or lithium. Evidence was provided by MRSstudies that suggested that omega-3 fatty acids sig-nificantly increased glutathione (an antioxidant thoughtto be neuroprotective) in the medial temporal lobe andthat lithium also had beneficial effects by significantlylowering MRS T2 relaxation times in the hippocampusof 1st episode patients.

In summary, the most important question is whetherindividuals in early stages of a prodromal syndromeshould be treated with pharmacotherapy and if so, withantipsychotic drugs or compounds such as antidepres-sants or neuroprotective agents. Some evidence from Dr.Cornblatt's study suggests that antidepressants mayhave superior efficacy. This could be related to BDNFdeficits and the increase in BDNF following antide-pressant therapy. As noted by Dr. Pantelis, perhapstreatment needs to be phase dependent. At early phases:antidepressants, omega fatty acids, or lithium; at laterstages (i.e. chronic schizophrenia), then antipsychoticdrugs.

From vulnerability markers to disease — specificprediction of psychosisReported by LaNiña Mompremier

Although the etiology of schizophrenia remainsuncertain, research has made great strides at determiningvulnerability markers for the disease. Today, the strategyis to further understand what precedes the adult disorderin order to predict or prevent its development. Newtechnologies make it possible to study multiple timepoints across the lifespan for vulnerability and riskfactors for schizophrenia.

In this symposium, chaired by Larry Seidman ofBoston and Mary Cannon from Dublin, Dr. SaraCherkasian (Boston) focused on prediction of schizo-phrenia with genetic markers. According to Cherker-zian, studies show higher rates of psychosis inrelatives of females than relatives of males. Thus,X-chromosome linkage may be associated with thedevelopment of schizophrenia. She went on todescribe an epidemiological study that suggestedpotential X-chromosome linked genetic mechanismsfor schizophrenia transmission. Fathers were morelikely to transmit psychosis to their daughters andmothers more likely to transmit psychosis to theirsons. You would expect a 100% transmission fromfather to daughter and 50% from mother to son, butthe transmission effects might be reduced by inactiva-tion of X-chromosomes, reduced pentrance of thegene, X–Y homologous genes, or multifactoral geneeffects.


Dr. Tyronne D. Cannon presented environmentalrisks to neonates. In cases of fetal distress, the brainreleases Brain Derived Neurotropic Factor, BDNF, aspart of its neuroprotective response to insults, such afetal hypoxia. Fetal hypoxia or deficient oxygenation offetal blood is “one of the strongest environmentalrisk factors for schizophrenia” (Van Erp et al., 2003). Itis thought that hypoxia regulates the over/underexpression of many genes during critical stages ofdevelopment (Schmidt-Kastner et al., 2006). Evidencesuggests that fetal hypoxia may be an early predictor ofschizophrenia onset. This effect may be produced by aninteraction between hypoxia and predisposing genes.Further, hypoxic associations with D2 receptors anddecreased hippocampal volume may also be relevant tothe development of schizophrenia (Decker and Rye,2002).

In addition, polymorphisms of the BDNF gene havebeen associated with schizophrenia in some studies(Chao et al., 2007; Shoval and Weizman, 2005). In astudy by T Cannon and colleagues, the BDNF levels incord and maternal blood samples of a Philadelphiacohort was tested. “Birth hypoxia was associated with asignificant increase in BDNF in cord samples, whileamong cases, hypoxia was associated with a significantdecrease in BDNF”. Findings suggest that those laterdeveloped schizophrenia may not have had enoughBDNF protection during hypoxic insults. The subse-quent discussion included topics such as improvingantenatal care for mothers whose infant experienceshypoxia, as well as improvements in reducing cases ofhypoxia. Dr. Cannon emphasized that poor prenatal careis a factor influencing hypoxia and in infants of motherswith schizophrenia that makes causation even harder todetermine.

Dr. Larry Seidman discussed detection of schizo-phrenia beyond the fetus. This study comparedpremorbid neuropsychological functioning in personswith schizophrenia with normal controls, and non-psychotic siblings. Neuropsychological functioning inpersons who later developed schizophrenia and theirsiblings was significantly impaired. Most discriminatingwere attention, working memory and verbal conceptualability measures. Further, a meta-analysis of studies wasconducted revealing an approximate 7-point IQ deficitin those with schizophrenia. Cases with affectivepsychosis and their siblings had less neurocognitivedeficits than non-affective psychosis.

Dr. Mary Cannon's described extending the workdone on adults reporting psychotic symptoms to studiesthat follow children who later develop schizophrenia.Children at age 11–12 were asked about psychotic-like

symptoms. These symptoms are rarely asked of childrenthis age. Yet, 35% of the children answered “yes” to atleast one of the psychotic-like symptom questions on aself-report rating measure. The children who endorsedtwo or more items were interviewed, particularly thosethat endorsed the question of “hearing voices.” Thesefindings stress the importance of screening youngchildren for psychotic-like symptoms to predicting thedevelopment of psychosis.

In summary, birth cohort prospective follow-upstudies such as those presented in this session providemuch needed information about the pre-morbid andprodromal states. This information can then be used inthe detection of high-risk populations for the possibilityof early prediction and treatment so that the course ofschizophrenia may be altered. In the review of thesestudies, the question that becomes most salient isdetermining the interplay between genes and theenvironment.

Mapping transition to psychosisReported by Panayiota Michalopoulou

This session chaired by Phillip McGuire (UK) andMichelle Tansella (Italy) “Mapping Transition topsychosis” provided audience members the opportunityto hear the latest structural, functional and molecularbrain neuroimaging research findings in individuals athigh risk of psychosis. Professor Phillip McGuire, chairof the session, underlined in his introduction thatneuroimaging is a potentially powerful tool to explorethe neurophysiological basis of the early stages ofpsychosis. He also stressed that investigation of subjectsat the beginning of illness allows researchers tominimize confounders, such as duration of illness andlong-term treatment with antipsychotics. All researcherswho presented their findings during this session,identified individuals at high risk to develop psychosis(i.e. “at Risk Mental State”, ARMS) based on theclinical high-risk strategy. This strategy assesses thepresence of clinical features such as attenuated psycho-tic symptoms or schizotypal traits, brief limited inter-mittent psychotic symptoms (BLIPS) or a recent declinein functioning, which are significantly associated withthe onset of psychotic disorder.

The first talk by Stefan Borgwardt was entitled “Graymatter abnormalities and cognitive function in subjectsat risk for psychosis: longitudinal perspectives” andfocused on gray matter abnormalities and their associa-tions with cognitive dysfunctions in ARMS subjects.The study had a cross-sectional and a longitudinalphase: A) Cross-sectional phase: 1) 35 ARMS subjects


2) 25 Subjects with first-episode of psychosis (FEP) 3)22 Healthy Controls B) Longitudinal phase: Individualswith ARMS were followed up for 2 years andcomparisons were made between B1) 12 ARMSsubjects, who developed psychosis and B) 23 ARMSsubjects, who did not develop psychosis. The research-ers hypothesized that the severity of gray matterabnormalities would reflect the severity of psychoticillness, i.e. ARMS individuals would show gray matterabnormalities similar to the FEP patients, but to a lesserdegree and that ARMS who developed psychosis wouldshow decreased volumes in certain brain regions.Indeed, ARMS subjects had smaller volumes in leftsuperior temporal gyrus, posterior cingulate and pre-cuneus compared to controls, and FEP patients had alsosmaller volumes of these regions compared to healthycontrols. Therefore, these reductions may reflectpsychosis vulnerability. ARMS subjects who developedpsychosis had smaller volumes in right superiortemporal gyrus, insula and inferior frontal gyrus.Based on evidence from neuropsychological studiessuggesting that ARMS subjects manifest deficits inworking memory, the researchers also investigated theassociation between gray matter volume and workingmemory performance in ARMS subjects and foundcerebellar and frontal associations. The need toinvestigate the clinical significance of brain changesbefore and during transition and the need for long-itudinal studies was stressed by Dr. Borgardt. Clarifica-tions about the statistical methods used for thecorrelations between brain volumes and workingmemory performance were asked from the audience.The issue of white matter abnormalities in these subjectswas also raised from the audience and Dr. Borgwardtsaid that their team will certainly expand the research towhite matter abnormalities in this population.

The talk of Dr. Paul Allen was entitled “Abnormalverbal encoding and recognition in individuals at highrisk of psychosis”. This was an fMRI study in 18 ARMSand 22 healthy individuals, based on evidence indicatingstructural and functional impairments of the regionsimplicated in memory formation and retrieval from a)neuropsychological studies suggesting that people athigh risk for psychosis show impairments in verbalmemory and learning compared to healthy controls. Inaddition people at high risk who later develop psychosisperform more poorly than those who do not become illon verbal memory tests and b) structural MRI studies inpeople at high risk for psychosis, which showed smallerleft and right hippocampi compared to healthy controlsand also smaller right medial temporal and bilateralfrontal regions.

The hypotheses tested were: a) The At Risk MentalState (ARMS) individuals would show impairedperformance on verbal memory compared to controlsand b) ARMS individuals would demonstrate alteredactivation of memory-related regions in the medialtemporal and prefrontal cortices. The fMRI paradigmused was the Deese-Roediger-McDermott (DRM) FalseMemory Paradigm, which has two phases: i) encodingphase and ii) recognition phase (the more you encodethe more likely you are to recognize a LURE word as anold word). Behavioral results: 1) All subjects mis-recognized more LURE words as OLD as it wasexpected and 2) ARMS subjects recognized more novelwords as OLD (recognition accuracy) Neuroimagingresults: During both encoding and recognition ARMSsubjects showed altered activation in medial temporallobe and prefrontal cortex relative to controls. Dr. Allenconcluded that “In ARMS individuals prior to the onsetof psychosis behavioral and neurofunctional alterationsare apparent during verbal episodic memories processes.Such alterations may represent vulnerability for thedevelopment of psychosis”. An interesting discussionabout the interpretation of the study findings followed.A member of audience suggested that the task used inthis study did not reflect problems with the episodicmemory but rather with meta-memory of the ARMSsubjects. In addition, another member of the audiencesuggested that based on the findings of the study, analtered lateralization input in the memory system couldaccount for these findings and not an altered memorysystem itself. The issue of whether the seemingly oldage of the ARMS individuals in this study (21–38 yearsin this study) can affect the rate of transition to psychosiswas also discussed. The difficulties of both thedefinition of the “at risk mental state” and therecruitment of this population were underlined by Dr.Allen.

The talk by Dr. Oliver Howes was entitled “Dopa-mine and the onset of psychosis” and presented amolecular imaging investigation in ARMS individuals.Molecular imaging studies have provided evidence forincreased synaptic availability of dopamine andincreased presynaptic dopamine synthesis in the stria-tum of psychotic patients and presynaptic dopamineabnormalities in the striatum appear to be relativespecific to psychosis. The dopaminergic function duringthe prodromal phase of psychosis has not been studiedand the present molecular imaging study investigatedthe striatal dopaminergic function in unmedicatedARMS subjects (n=24), first-episode patients (n=7)and healthy controls (n=12). The findings of the presentstudy suggested that dopamine synthesis capacity in the


striatum and especially the associative striatum isincreased in people at ultra high-risk for psychosis.Interestingly, the increased capacity of dopaminesynthesis is also associated with the severity ofsymptomatology in ARMS subjects and neurocognitivefunction as measured by semantic verbal fluency. Inaddition, striatal dopaminergic dysfunction appearedsimilarly disturbed in ARMS and FEP patients. Theparticularly marked elevation of dopamine in theassociative striatum found in this study raised thequestion of a potential specific association of thisparticular functional subdivision of striatum withschizophrenia. Dr. Howes replied that dopamine levelswere indeed increased in the associative striatumrelative to the sensimotor and limbic subdivisions,however these findings cannot be considered conclusiveof such a specific association.

The talk by Paolo Fusar-Poli was entitled “Dopami-nergic modulation of prefrontal functioning duringexecutive and mnemonic tasks in ARMS subjects: acombined PET-fMRI study” Twenty-two ARMS sub-jects and 17 healthy controls undergone PET scanning,which showed an increase in their striatal dopaminerelative to healthy volunteers. The researchers concludedthat increased dopamine may underlie the emergence ofthe prodromal symptoms. Apart from increased striataldopamine, the prodromal phase has also been associatedwith prefrontal abnormalities. Averbal fluency and anN-back task were used to delineate the task-inducedprefrontal abnormalities in the same ARMS subjectsrelative to controls. Dr. Paolo Fusar-Poli concluded histalk stressing that the combination of imaging techniquesin the prodromal phase of psychosis may have thepotential to delineate related pathophysiological pro-cesses and clarify their causal relationship.

A study on “Linguistic and pragmatic deficits inpatients with schizophrenia” was also presented duringthis session by Dr. Paolo Brambilla. The aim of thisstudy was to examine verbal communication impair-ments in patients with schizophrenia and investigate thepossible relationship between language dysfunction andanatomical correlates in 37 patients with schizophreniaand 37 healthy volunteers. Patients with schizophreniaproduced significantly less words on the narrative taskand were less fluent on the conversational task relativeto controls. Speech fluency correlated significantly withgray matter of left superior temporal gyrus in controlsbut not in patients. Patients also showed poorer syntacticdiversity skills and impaired syntactic abilities at areceptive level. Complex syntax directly significantlycorrelated with left Heschl gyrus (HG) and in worddiversity inversely significantly associated with right

HG patients with schizophrenia but not in controls.Members of the audience posed questions about anypossible l correlations of the speech abnormalities withthe negative symptoms of schizophrenia. Dr. Brambillainformed the audience that no such correlation couldhave been done because BPRS rather than PANSS wasused. The choice of brain regions of interest was alsodiscussed. It was argued that HG is involved in speechrather than verbal fluency and that Broca's region wouldbe another plausible choice.

III. TREATMENT ISSUES

Plenary topic: advancing drug development inschizophreniaReported by Aaron S. Kemp

The plenary lecturer, Steven M. Paul (Eli Lilly andCompany) was introduced by session chair John M.Kane (Glen Oaks, New York). Dr. Paul is a distin-guished psychiatrist who formerly served as theScientific Director of the Intramural Research Programat the National Institute of Mental Health (USA) and iscurrently the Executive Vice President for Science andTechnology for Eli Lilly and Company and President ofthe Lilly Research Laboratories. Dr. Paul noted that hislecture would cover three general topics: 1) Challengesof drug development from a pharmaceutical company'sperspective, 2) Alzheimer's disease as a prototype forneuropsychiatric research and development (R&D), and3) glutamate receptors as a target for the development ofnovel antipsychotics.

Dr. Paul began with an in-depth discussion of forcesthat are impeding industrial development of new drugs,including: soaring R&D costs, too few new chemicalentities (NCEs) in the pipeline, much longer develop-ment times, shorter exclusivity due to patent issuancewell before the drugs reach market potential, increasedsafety concerns and pricing pressures. Dr. Paul statedthat the collective impact of these forces is evidenced bythe fact that there were only 19 new drugs approved bythe Food and Drug Administration (FDA) in 2007, thefewest since 1983. Despite massive industrial invest-ment in R&D (over $50 billion in 2007 compared withabout $3.5 billion in 1983) very few NCEs are making itto market. Taken in consideration with the fact that theremay be no patent-protected psychiatric drugs in just afew short years, Dr. Paul suggested this indicates there isan “Ice Age” coming, thus raising the question, “Willthis industry evolve fast enough to stave off extinction?”

Among the strategies that Dr. Paul recommended toboost R&D productivity and overall confidence in target


compounds prior to clinical testing was the concept oftailored therapies: “Developing the right drug for theright patient at the right time.” Accordingly, hesuggested that the use of disease-specific biomarkersis critical, particularly when considering the problem ofpatient heterogeneity. Specifically, he stated that beingable to subgroup or stratify patients on the basis ofbiomarkers that might predict treatment response oradverse event profile will be incredibly important toincrease the probability that the drugs will be effective.Additionally, he suggested that pharmacodynamic orneuroimaging biomarkers might also serve as surrogateendpoints and guide the optimization of dosing prior tolaunching costly efficacy trials.

As a model of how this basic approach has beenapplied effectively in the development of neuropsychia-tric treatments, Dr. Paul then turned to a discussion ofAlzheimer's disease (AD). Providing a detailed reviewof the basic etiology, genetic risk factors, and patho-physiological biomarkers that have been identified, henoted that it is this fundamental understanding of thedisease process that has precipitated promising advancesin targeting new treatments for AD. Specifically, Dr.Paul described how formulation of the “amyloid cascadehypothesis” has led to a variety of new disease-modifying treatment approaches (e.g., γ- and β-secretase inhibitors, apolipoprotein E modulators,methods to promote amyloid clearance, genetic animalmodels with cognitive impairments, amyloid biomar-kers, and innovative ways to discover drug targets usingcombinatorial chemical, high-throughput, roboticscreening). Dr. Paul asserted that following a similarmodel of R&D (i.e., identifying genetic, proteomic, andimaging biomarkers) would certainly stimulate innova-tive new treatment approaches to schizophrenia, as well.

As an example of a novel approach to the treatmentof schizophrenia, Dr. Paul concluded his lecture with arapid overview of the work conducted at the LillyResearch Laboratories focusing on metabotropic gluta-mate 2/3 (mGlu2/3) receptor agonists. In particular, thecompound LY2140023 (a prodrug of the mGlu2/3receptor agonist LY404039) has advanced to Phase IIdevelopment. Although he cautioned that the dosage ofthis drug has not yet been optimized, Dr. Paul reportedthat early results from a 4-week trial among acutely illpatients with schizophrenia have shown preliminaryindications of efficacy comparable to olanzapine onPANSS scores and cognition, with no indications ofsignificant weight gain, extrapyramidal symptoms, orhyperprolactinemia, and low incidences of other adverseevents. In closing, Dr. Paul referred the audience torecent work by Javier González-Maeso, Stuart Sealfon,

and colleagues at Mount Sinai, showing that a G-protein-coupled heterodimer complex of 5-HT2A andmGlu2 receptors may subserve the hallucinogenic/psychotomimetic effects of drugs like DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) or LSD(lysergic acid diethylamide). Given that post-mortemanalyses have shown up-regulated 5-HT2A and down-regulated mGlu2 receptors in untreated patients withschizophrenia, these findings may provide an intriguingtheoretical basis for the putative antipsychotic effects ofmGlu2/3 receptor agonists. Among those that Dr. Paulalso acknowledged for their pioneering work develop-ing mGlu2/3 receptor agonists at The Lilly ResearchLaboratories were Darryle Shoepp, Ann Kingston,Gerard Marek, David Lodge, Ann Dantzig, JamesMonn, Sandeep Patil, and Bruce Kinon.

Following his plenary lecture, Dr. Paul was joinedon-stage by a group of 7 highly respected internationalexperts in the treatment of schizophrenia for a paneldiscussion entitled, “Pharmacologic treatment develop-ment: What has held us back and where do we go fromhere?” Prior to fielding questions from the audience,each of the 7 panel members was given 5 min tosummarize additional topics for the discussion.

The first panelist was Peter B. Jones, from theUniversity of Cambridge (UK), who discussed implica-tions from the Cost Utility of the Latest Antipsychoticsin Severe Schizophrenia (CUtLASS) studies from theUK. Taken in conjunction with results of the ClinicalAntipsychotic Treatment Intervention Effectiveness(CATIE) study conducted in the US, Dr. Jones indicatedthat the CUtLASS results have raised serious questionsabout the perceived superiority of second-generationantipsychotics. In particular, Dr. Jones noted that havinga younger generation of psychiatrists with little or noclinical experience prescribing and managing first-generation antipsychotics may present a troubling lossto the potential well-being of some patients who mightrespond just as well (or better) to these older medica-tions. In closing, Dr. Jones cautioned that cliniciansmust be vigilant not to allow industrial imperatives toexert undue influence over prescribing practices; thatindependent evaluations must be conducted in parallelwith industry-sponsored trials; and that “real-world”functional outcomes must remain a central focus despitethe value of biomarkers as surrogate endpoints in thedevelopment of new treatments.

Additional concerns regarding the need to optimizedosing parameters of currently available drugs wereraised by Robin Emsley from the University ofStellenbosch (South Africa). Dr. Emsley pointed outthat there are still a lot of unknowns relating to the


clinical optimization of antipsychotic medications,particularly considering the common practice of pre-scribing these drugs in combination. Dr. Emsley alsostated that one of the greatest challenges in maintainingimprovements is medication adherence. Whether youdevelop a better drug or not will not matter if the patientis not going to take it on a routine basis. Accordingly,he suggests that the industry should focus on thedevelopment of alternate delivery mechanisms such aslong-acting injectable formulations, patches, orimplants. Dr. Emsley stated that this may be funda-mental to achieving optimal outcomes.

The next panelist, Stefan Leucht of TechnischeUniversität München (Germany), mentioned five pointsregarding the adequacy of clinical trial methodologies todetect clinically meaningful results. Dr. Leucht statedthat the most important problem to be overcome is theextremely high drop-out rates in current trials. Evenwith the most advanced mixed-effects statistical models,he cautioned that the validity of results are unclear withsuch high drop-out rates. The second issue Dr. Leuchtraised was the need for greater standardization ofoutcome measures, particularly in terms of whatpercentage of change is to be regarded as “clinicallymeaningful”. Relating to outcome assessment, he alsomentioned that the lack of “hard” outcomes, such as areroutinely applied in other medical fields, remains alimitation in schizophrenia trials. The fourth point wasthe need for more studies focusing exclusively ontargeted symptoms in order to isolate specific effects.The fifth issue of concern raised by Dr. Leucht pertainedto an inherent publishing bias which limits the exposureof negative findings to the broader scientific community.

John M. Kane, of Glen Oaks and the Albert EinsteinCollege of Medicine (US), presented an overview ofissues relating to selection bias and quality of assess-ments in clinical trials. Dr. Kane pointed out thatresearch sites have financial incentives based on thenumber of participants enrolled, thus providing thepotential for conscious or unconscious inflation ofbaseline ratings, which tend to truncate around studyentry criteria. This can result in abnormally high placeboresponse rates, which has become an increasing problemas evidenced by a greater number of failed antipsychotictrials. Dr. Kane noted that one potential solution to thisproblem is to find methods to increase interraterreliability⁎⁎, such as the use of centralized assessmentsby independent raters. Considering the current industrialimperative to develop better medications with anemphasis on sensitivity to subtle effects, Dr. Kaneconcluded that overcoming such methodological issuesis critical.

⁎⁎ Dr. Kane disclosed a potential conflict ofinterest — i.e. participating in a company to developsuch a product.

Wolfgang Fleischhacker, from Medizinische Uni-versität Innsbruck (Austria), posed the question ofwhether placebo-controlled trials are really necessary.Dr. Fleischhaker pointed out that, while still consideredthe “gold-standard” in clinical psychopharmacology, theplacebo-controlled trial is rarely employed in most othermedical fields. As mentioned by Drs. Leucht and Kane,the problems of high drop-out rates and increasedplacebo response may limit the clinical relevance andoverall validity of the results. Dr. Fleischhaker notedthat employing alternate study designs could resolvesuch problems. Two alternative design options that Dr.Fleischhacker discussed were noninferiority studies andmodified placebo-controlled trials utilizing multipletreatment arms with a short placebo phase followed byre-randomization of placebo-treated subjects to an activetreatment arm.

Dieter Naber, from the Universitätsklinikum Ham-burg-Eppendorf (Germany), opened his talk by suggest-ing the ambition/premise/belief that ONE drug may befound to improve positive symptoms, negative symp-toms, and cognition and be uniformly efficacious acrosspatients for acute treatment and long-term care isactually a delusion. Dr. Naber also commented that,while an industry-sponsored clinical trial may establishthat Drug A works better than Drug B, this does notdiscount the possibility that a given patient may stillrespond better to Drug B. The final point that Dr. Naberraised for discussion was that the perspective of thepatient is critical to whether they will stay on a givendrug. While the clinician may like a certain drug becauseof its pharmacologic profile, we must bear in mind thatthe blockade of dopamine decreases reward mechanismsthus patients do not want to take the drugs. As they arethe one's that must take them everyday, it is theirperspective on which we must focus when developingnew treatments.

The final panelist, Stephen Marder of the Universityof California Los Angeles (US), noted that oneinterpretation of the results of recent studies, such asCATIE, CUTtLASS, CAFE (Comparison of Atypicalsfor First-Episode Psychosis) and EUFEST (EuropeanFirst Episode Schizophrenia Trial), is that the limitationsof second generation antipsychotics may have alreadybeen reached. Reiterating comments by Dr. Paul, Dr.Marder suggested that new treatment mechanisms (otherthan the traditional focus on dopamine antagonists) mustbe explored by both academia and industry. As negativesymptoms and cognitive impairments are two of the


major determinants of functional outcome and neitherimproves substantially with dopamine antagonists, Dr.Marder suggested that these symptoms must be thetarget for the development of better treatments. Dr.Marder also recommended the exploration of the effectsof drugs within a rehabilitation context, to findtreatments that may enhance the effectiveness ofpsychosocial interventions or standardized behavioralparadigms, by incorporating these programs into thedesign of clinical trials. In addition to also noting theneed for new animal models and better biomarkers tofuel development, Dr. Marder mentioned the need for anew generation of academic clinical trialists who “lovethe idea of trying out new drugs”. Dr. Marder closedwith the hope that meeting these needs will lead to a newera of innovative drug development that may actuallychange the course of treatment for this disorder.

Following the brief talks by the panelists, Dr. Kaneopened the discussion to questions from the audience.The first question was from Patrick McGorry, from theORYGEN Research Centre (Australia), who noted that,although recent open trials may not have shown a clearadvantage of second-generation antipsychotics (SGAs)in terms of efficacy, these drugs may still holdsignificant advantages in terms of tolerability. So,while not undermining the need for developing newtreatments, he asked if the panelists felt that SGAs werebeing “sold short”, particularly in terms of the issue Dr.Naber broached concerning the importance of thepatient's perspective. Dr. Naber mentioned in hisresponse that the “quality of life” assessments used inrecent studies may not have provided adequate sensi-tivity to measure such a subjective difference betweenfirst and second generation treatments, but that anecdo-tal reports have shown a clear advantage for SGAs inthis regard, so perhaps better measurement methods tocapture such differences are needed.

Henry Nasrallah, of the University of CincinnatiCollege of Medicine (USA), had several questions thatstimulated interesting discussions. He agreed that there isa great need for increased standardization of measure-ment instruments, as mentioned by Dr. Leucht, butquestioned how one could standardize remission criteriawhen clinicians do not usually apply formal scales on aroutine basis. Dr. Leucht replied that his emphasis was onthe need for increased standardization of measuresapplied in scientific investigations but agreed that theapplication of such measures to the clinic is an issue, aswell. Dr. Kane suggested working with colleagues in thefield to stimulate a move toward the use of brief ratingscales to better quantify changes and supplement clinicaldecisions in routine psychiatric practice.

Dr. Nasrallah also asked Dr. Paul whether the GABAsystem was being targeted for potential drug develop-ment and why neural plasticity had not received moreattention as a viable target, as well. Dr. Paul respondedthat a lack of interest in GABA may be attributable toearlier studies showing very little efficacy with high-dose benzodiazepines (allosteric modulators of GABA).Nonetheless, he stated that there are several GABAreceptor subtypes that are being explored and that hethought Merck had a GABAergic compound in late-phase development with potential antipsychotic effects.Dr. Paul also agreed that neural plasticity was a veryimportant avenue of exploration but that the field wasstill “too new” to offer clear paths for safely modulatingplasticity. He mentioned that Lilly had identifiedglutamatergic compounds that increase neurotrophicfactors which will be explored further and predicted thatplasticity will be an important focus in the future,particularly for affective disorders, but also in schizo-phrenia, as well.

Larry Alphs, of Ortho-McNeil Janssen ScientificAffairs (USA), commented that perhaps the nosologyand associated methodologies (i.e., measurement scalesand response criteria) that are currently being employedmight be antiquated and inadequate for exploring newtreatment approaches to schizophrenia. Several of thepanelists (Drs. Naber, Marder, and Fleischhaker) con-curred with this perspective and agreed that there is anurgent need to reconsider the bases for the clinicalconcepts that are being measured with available scalesand whether the common method of gauging “percentresponse” has any relevance to “real-world” outcomes.Dr. Marder also commented that current scales mighthave very little correspondence with fundamentalpsychopathologic processes and that there should bemore emphasis placed on understanding (and measur-ing) how changes in neurobiological biomarkers (e.g.,prefrontal activation) manifest clinically.

Another intriguing discussion followed an issueraised by Robert Zipursky, of McMaster University(Canada), who asked whether the results discussed fromrecent open trials could potentially lead to a resurgencein the usage of first-generation antipsychotics (FGAs),and if so, were there concerns among the panelists thatthis would also increase incidences of tardive dyskinesia(TD). Dr. Kane pointed out that this issue has become afocal point of debate and that there is currently a lack oflongitudinal data to accurately evaluate the incidence ofTD with low to moderate doses of mid-potency FGAs,although it does appear that SGAs confer a reduced riskof TD by as much as 1/5th that seen with FGAs. Dr.Jones noted that the key findings from the CUtLASS


studies are not about one group of medications beingany “better” than another group, but that it is possible forclinicians to do well with any drug so long as they areallowed to tailor its uses with individual patients. Healso agreed that TD is a crucial issue that must be betterunderstood, but cautioned that we must not slip into theshorthand of differentiating between SGAs and FGAsbecause it is more important to ensure that all drugs are“used well” (i.e., in a way that minimizes side effectsand optimizes outcome). Dr. Fleischhaker concurred andalso noted that prescribing practices following CATIEdid not reflect an increase in FGAs, so fears of a largeresurgence of these drugs may be unfounded.

Additional issues which stimulated discussions were:the potential use of “item banks” to develop betterassessment methodologies, which was brought up byGeorge Awad from the University of Toronto (Canada);the need for better measures to assess psychosocialfunctioning, which Dr. Marder mentioned are currentlyunder development in response to a question from CarolRobertson-Plouch of Eli Lilly and Company (US); thenecessity to examine the safety of new treatments inchildren without relying on translation of results inadults to infer safety, as mentioned by Celso Arangofrom the Universitario Gregorio Marañón (Spain); theneed for naturalistic studies to understand the interactionof medications with the substances of abuse that manypatients also take, raised by Christian Schenk of theUniversity of British Columbia (Canada); the impor-tance of overcoming the stigma that injectable formula-tions should only be used as a last resort or haveotherwise punitive connotations, which was raised byJohn R. Hayes of Eli Lilly and Company (US); and aquestion of whether addressing the heterogeneity ofpatient samples by finding better ways to stratifybiologically defined subgroups may be more importantthan focusing resources on endlessly refining measure-ment instruments or clinical trial methodologies, whichwas posed by Werner Rein of Sanofi-Aventis (France).

Symposium on drug development in schizophreniaReported by Demian Halperin

This symposium, Co-chaired by Jonas Eberhard andCarol Tamminga, offered a multi-disciplinary overviewof drug development in schizophrenia, from basic andclinical development to regulatory and businessconsiderations.

In the first lecture of the symposium, Gary Pisano,Professor of Business Administration at Harvard Schoolof Business, addressed several questions related toeconomics and productivity of drug R&D in schizo-

phrenia: What do we know about drug R&D productiv-ity and how could it be improved? What are the specificimplications for schizophrenia drug R&D? The speakersuggested that productivity could be increased byspending more on basic research, by providing greaterincentives for companies to do R&D, by relaxingregulatory rules, by enhancing collaboration betweenacademia and industry, and by increasing the govern-ment's involvement. Contrary to the common heldbelief that small biotechnology firms are more flexibleand productive than the big Pharma, the speakerpresented data showing that this is not the case. Mostsmall biotech companies have lost money with verylittle to show in terms of productivity. To answer thesecond question about increased productivity, GaryPisano described three requirements of productivity: theability to manage profound uncertainty due to thecomplexity of human biology, the ability to integrateacross disciplines involved in drug development, andthe ability to learn from experience. The first require-ment can hardly be fulfilled because the financing ofmost biotech companies is by its nature a short-termarrangement with uncertainty. The second requirementhas the problem of “islands of expertise”, i.e. compart-mentalization of knowledge within disciplines and littlechance for integration. Finally, learning from experienceis difficult as most biotech companies are short lived anddo not have a chance to accumulate knowledge. Thelecturer emphasized these three fundamental aspectsproposing to re-think funding strategies, to promoteindustry-wide consortia on key science problems and toencourage sharing of data in the industrial sector. Thistheory was then applied to schizophrenia, a disease,which involves long lead times and high uncertainty,multiple interacting bodies of knowledge, and cumula-tive advances, i.e. most of the knowledge accumulatesafter years of use of the drug. Because information, evenin the form of “bad news” is the engine which drives amolecule from basic discovery to the market, theimplementation of information feedback loops fromclinicians to specialists of clinical development, dis-covery research and basic research was then proposed asa potential challenge to the existing paradigm. In thefinal part of the presentation, the notion of informationproductivity which involves the concept of “informationregime” (or how much we reduce uncertainty by howmuch we spend), was then addressed by Gary Pisano,who views drug development in schizophrenia as a“weak” information regime, because most of theinformation that is generated about a drug comes afterits approval. The lecturer concluded by saying that untilproductive basic research has succeeded to shift the


information regime from “weak” to “strong”, it is criticalto systematically capture whatever information isgenerated across the entire development cycle andimplement mechanisms for information sharing andcross discipline learning.

In the second lecture, Anders Pedersen, VP for DrugDevelopment, Lundbeck, described the main challengesthat drug development is facing in the field ofschizophrenia. The lecturer reminded us of the impor-tance of schizophrenia in terms of socioeconomicburden, and reviewed key-elements of drug develop-ment in schizophrenia: serendipity of first-generationantipsychotics (FGA), late description of extrapyrami-dal symptoms (EPS) in the initial open-label studies onFGA, the rapid effect on hallucinations and delusions ofFGA, and the advent of second-generation antipsycho-tics (SGA) in an attempt to solve the issue of EPS.Anders Pedersen then addressed the following dilemma:first, the focus on treatment of positive symptoms hasnot changed functional outcome; second, discoveryplatforms for antipsychotics have only produced drugswith similar mechanism of action, with no drug clearlyshowing superior efficacy; third, there are no predictorsfor choice of drug for individual patients. Thus, inpractice, treatment of patients with schizophrenia isbeing optimized by switching between availablecompounds without any guidelines for when and howto do it. The lecturer then emphasized the importance ofthe effect of a drug on each individual, rather than thestudy-population effect, taking as an example the resultsof a retrospective, single-arm, cross-over study onsertindole which showed a clear clinical deteriorationof certain individuals after discontinuation of the drugand an amelioration of symptoms when it wasreinstituted. Dr. Pedersen described two hurdles thathave to be addressed in schizophrenia drug develop-ment: (1) safety as it pertains to QT prolongation, and(2) formulary listing and price negotiations. He alsoproposed a focus on improving outcome, not onlypsychotic symptoms, but by treating cognitive impair-ment and negative symptoms and addressing partialresponse seen with all compounds, as well as affecting alarge group of patients. Finally he proposed a focus onthe pre-acute phase and post-acute phase, i.e. theprevention of schizophrenia in high risk populations(genetic, environmental risk), on the prevention ofpassage from prodrome into first-episode, on theprevention of chronicity during initial stages of disease,on achieving recovery (more than reduction of symp-toms), and on more efficient relapse prevention. Inconclusion he suggested that potential risks of treatmentshould be balanced by risk of not treating or under-

treating a disease and that a regulatory and developmentpathway is needed for pre- and post-acute treatmentsfocusing on early intervention and relapse prevention.

Ravi Anand, CEO, Anand Pharma Consulting,presented his work on Placebo Response in antipsycho-tic trials. According to him, many of the arguments thathave been proposed to justify the decreased drug-placebo difference in schizophrenia trials observed from1992 to 2007 cannot be considered valid arguments.Indeed, antipsychotics have not reasonably lost efficacyin these years, nor has the study population changed, butrather it is the placebo response that has increased overthe years. By a comparative analysis of later trials versusearlier trials, he showed that in later trials, there is atendency for a greater discontinuation rate, greater lostof follow-up, and lower compliance in the active druggroup compared to earlier trials. Furthermore, later trialshave failed to separate the active drug from placebo, andhe demonstrated a higher placebo response in the USAprivate investigator centers as compared to non-USAcenters and USA traditional investigator centers. Otherissues, linked to trials design, could be accounted fordifferences in treatment response in earlier versus latertrials. These could be related to episode duration, tobaseline severity of illness, to differences in concomi-tant medications, to the duration of the wash-out period,or to the effect of hospitalization. A more detailedassessment of these parameters then confirmed that theplacebo response is higher when the episode of illnesshas lasted for more than 4 weeks (a worsening ofsymptoms in placebo-groups has been noted in trialswith very recent onset of decompensation), andconfirmed a potential influence of baseline severity ofillness. Ravi Anand then summarized the commonfeatures of trials with a clear separation between placeboresponse and active drug response: patients werehospitalized because of the disease and not for thepurpose of the study; episodes had been lasting for lessthan 4 weeks; severity scales comprised a minimalBPRS of 42, a CGI-S rated moderately severe or at least2 core symptoms rated as moderately severe; noconcomitant benzodiazepine, antidepressant, anxiolytic,mood stabilizer or antipsychotic use were allowed;break-through symptoms were treated with injection ofsodium amatol and insomnia with chloral hydrate; ahigh drop-out rate due to lack of efficacy, especially inplacebo groups, was observed; a mean change inplacebo showed worsening; and there was no paymentto patients and caregivers. Conversely, in the amper-ozide (USA) trial where the placebo group showedimprovement compared to baseline, benzodiazepineswere allowed, there was no requirement concerning the


duration of the episode, patients rated “moderate” couldbe included, and the drop-out rate due to lack of efficacyin placebo group was low. In conclusion, Ravi Anandsaid that the two main issues to consider are that use ofcommercial sites appears to reduce drug-placebodifference, and that change in methodology may havecontributed to observed reduction in effect size, and anincrease in placebo improvement. Separation betweenplacebo and active drug could thus be favored by a goodmethodological approach: episode shorter than 4 weeks,a seven day wash-out period, exclusion of benzodiaze-pines and other antipsychotics, use of fewer centers andgreater number of patients.

The next speaker, Michael Davidson, Professor ofPsychiatry at the Medicine School of Tel-AvivUniversity, addressed the issue of cognitive impair-ment in schizophrenia as a target for pharmacologicalintervention. The first questions that he raised werewhether antipsychotics affect cognitive performance inschizophrenia and whether there is a differencebetween FGA and SGA. Based on the conclusions oftwo meta-analysis and two trials, he concluded thatantipsychotics do improve cognitive performances inschizophrenic patients, and that there is no differencebetween FGA and SGA after 2 or 6 months oftreatment. However the effect-size for cognitiveimprovement is small (0.3–0.5) and this improvementcould be due to practice effects. Dr. Davidson thensummarized what is known about cognitive impair-ment in schizophrenia: subtle cognitive impairment issometimes already present at adolescence in futureschizophrenia patients; this cognitive impairmentpersists throughout life; it is present in other familymembers and is not specific to schizophrenia, but ratheris related to mental illness in general. Dr. Davidsonthen provided other relevant information: the observedcognitive impairment is general, rather than specific; itis not due to a degenerative process; and it could be theresult of multi-factorial genetic and environmentalinteractions. He concluded that the MATRICS cogni-tive screening battery of tests is a reasonable means forassessing cognitive domains because it takes intoconsideration factors such as lack of motivation or pooreducation. He then reviewed the pharmacologicalstrategies that have already been employed to improvecognition, emphasizing that manipulation of a singleneurotransmitter level does not necessarily affect aprocess in which several neurotransmitters are in-volved. In addition, he stated that the presence ofpsychosis and cognitive impairment in the sameindividual might reflect a random association (ratherthan a causal association), and therefore, interventions

which enhance cognitive performance in below-average individuals should also improve cognitiveperformance in schizophrenia, and vice-versa. If themild to moderate cognitive impairment of schizophre-nia represents a continuum with normal cognitiveperformance, non-specific interventions to enhancecognition might also benefit schizophrenic patients.

Susanna Del Signore, CNS Group Leader, EuropeanMedicines Agency (EMEA), concluded this session bygiving a regulatory perspective on clinical development inschizophrenia. After a brief description of the EMEA, shepresented the legal and regulatory framework for market-ing authorization, insisting on the importance of pediatriclegislation and the need for data regarding pharmacoki-netics, efficacy, safety (short and long-term), and ageappropriate formulations. The existing guidelines forconducting clinical trials in schizophrenia were thendiscussed: the study-population should be composedsolely of patients with a diagnosis of schizophreniaaccording to DSM-IV/ICD-10; placebo-controlled trialsare required to show the efficacy of a new product; aspecific study in patients with predominant and persistentnegative symptoms stable over the last 6 months, withplacebo and classic antipsychotic arms is required.Further requirements are the presence of at least twoconfirmatory three-arm trials on acute exacerbation and atleast one trial demonstrating maintenance of effect.Susanna Del Signore then acknowledged that data arestill awaited on the efficacy of antipsychotics in thetreatment of cognitive impairment, for which two long-term double-blind placebo controlled pivotal studies arerequested, with the stipulation of a functional outcomeand the possible use of the MATRICS battery. She alsoacknowledged the need for treatment of severe aggressionin patients with Alzheimer's disease and the spread of off-label use of typical and atypical antipsychotics in thegeriatric population, which is more at risk for cardiovas-cular and metabolic effects. The question of a biomarkersqualification process was then raised. This procedure hasbeen recently set up and is currently under publicconsideration. In conclusion, the main points of thislecture were: the need still exists for new antipsychotics(i.e. for children and elderly patients, improved long-termsafety profile, cognitive symptoms); the need for avail-ability of guidance documents to assist applicants in thedevelopment of new antipsychotics; the need for theavailability of a biomarkers qualification procedure; andthe necessity of synergy between stakeholders forbuilding new methodologies and these challengingindications.

Dr. Shitij Kapur, the final discussant, underlined thecore-message of each participant, saying that Dr. Pisano


encouraged sharing information between stakeholders;Dr. Pedersen made us aware of problematic hurdles inclinical development of antipsychotics; Dr. Ananddiscussed the problem of the placebo effect; Dr.Davidson raised the question of a possible randomassociation between psychotic symptoms and cognitiveimpairment in a given individual; and Dr. Del Signoreacknowledged the interest in a biomarkers qualificationprocedure.

Strategies to accelerate drug development forschizophreniaReported by Aaron S. Kemp

As indicated in the plenary lecture by Steven M. Paul(Eli Lilly and Company), in order to overcome theobstacles impeding a new generation of antipsychoticsreaching the clinic, it is imperative that the pharmaceu-tical industry adopt novel methods to optimize dosingand identify efficacy signals earlier in development,stratify subjects on the basis of putative response profilesor side-effect risk, and make wise use of availablebiomarkers across all phases of the research anddevelopment (R&D) process. Accordingly, the presenta-tions at this session were directly focused on methodol-ogies to rapidly meet such needs. Session chairs LarryEreshefsky and Steven G. Potkin introduced therelevance of the session topic and the accompanyingneed to forge collaborative alliances between academiaand industry in pursuit of innovative R&D solutions toquicken a third generation of antipsychotic development.

The first speaker, Vicki L. Ellingrod (University ofMichigan), provided a concise but engrossing overviewof several recent developments in the rapidly emergingfield of pharmacogenomics that may provide criticallyimportant biomarkers to guide antipsychotic R&D.Included in her review were studies examining theutility of variants associated with dopamine receptors(Taq1A, -141 C Ins/Del, and -241 A/G; either alone oras diplotypes) and catechol-O-methyltransferase(COMT 158 Val/Met) in predicting therapeutic responseto various antipsychotic medications. Dr. Ellingrod alsodiscussed findings from her own lab showing that type 3metabotropic glutamate receptor gene (GRM3) variantscould predict negative symptom improvement followingtreatment with olanzapine. Additionally, Dr. Ellingroddiscussed Eli Lilly's new metabotropic glutamatereceptor (mGluR) agonist, LY404039. As this com-pound is delivered through the metabolism of prodrugLY2140023, Dr. Ellingrod noted that certain metabolicphenotypes may also play an important role in theidentification of putative responder profiles.

In addition to predictors of treatment response, Dr.Ellingrod also discussed the search for pharmacoge-nomic biomarkers for metabolic complications (e.g.,weight gain, insulin resistance, etc.), often associatedwith the use of atypical antipsychotics. She reviewedfindings showing some potentially important relation-ships between antipsychotic-induced weight gain andvariants of brain-derived neurotrophic factor (BDNF 66Val/Met) and serotonin receptors (HTR2C -759 C/T).Additionally, Dr. Ellingrod provided details regardingher work showing a relationship between the methyle-netetrahydrofolate reductase (MTHFR) 677 C/T variantand predisposition to metabolic syndromes associatedwith atypical antipsychotics. In closing, Dr. Ellingrodrecommended an informative website (www.fda.gov/cder/genomics/) for anyone interested in the FDA'sperspective on pharmacogenomics, and suggested thetremendous utility that pharmacogenomic biomarkerswill have for predicting therapeutic response and side-effect risk in order to develop treatments that can finallyfulfill the promises of “personalized medicine”.

The next presenter, Larry Ereshefsky (CaliforniaClinical Trials/Parexel), provided an overview offundamental R&D requirements to move a targetcompound from the benchtop to the market anddescribed studies demonstrating the “proof of concept”utility of a novel method known as “CSF Dynabridging”to identify biomarker indicators of optimal dosingschemes and corroborative evidence for drug action,prior to launching costly multi-center trials. Dr.Ereshefsky also noted that “Patient Bridging” studiesyield valuable information to supplement findings fromhealthy volunteer studies. For many classes of therapiesfor schizophrenia they result in substantially differentfindings for maximal tolerated dose (MTD), andminimal intolerated dose (MID). These Patient Bridgingand Dynabridging studies provide an important transla-tional link between animal/in vitro work and patients,and explore the differences between healthy volunteersubjects and those with the target illness.

The Dynabridging techniques described by Dr.Ereshfsky entail the collection of continuous or repeatedtimed interval sampling of cerebro-spinal fluids (CSF),via an indwelling catheter in the lumbar sac, in parallelwith plasma samples in order to model pharmacokinetic/pharmacodynamic (PK/PD) relationships relevant toproof of pharmacologic effects, safety, and dosing. Dr.Ereshefsky noted that studies of novel mGluR agonistsrequiring prodrugs to deliver across the blood-brainbarrier have used the Dynabridging technique to identifyoral doses that deliver concentrations exceeding theIC50s for h-mGlu-2 and h-mGlu-3 receptors. These

http://www.fda.gov/cder/genomics/

http://www.fda.gov/cder/genomics/


techniques also allow for the development, validation,and application of biomarkers facilitating ‘go-no-go’decisions for novel therapies.

Dr. Ereshefsky also noted that experimental medicinecan provide additional information to facilitate the“bridging” from pre-clinical (animal model) findings totarget patient populations. Illustrations included a CSForal glycine loading study providing a ‘benchmark’ forthe development of gly-t-1 inhibitors, and assessinggene expression targets by proteomic screens obtainedat baseline and post-treatment. Patient studies in PhaseIB are usually used to assess MTD but, when combinedwith surrogate/biomarker data (e.g., behavioral, cogni-tive, polysomnography, quantitative EEG, and neuroi-maging), can also provide early indicators of CNSeffects that guide dose selection for Phase II “proof ofconcept” studies. While too detailed to summarizeherein, Dr. Ereshefsky's description of the many studieson which he has employed these techniques provided anappreciation that innovative methods such as these maydramatically enhance confidence in the target compoundand optimal doses to be applied in later-phase trials, thusmaximizing the possibilities of detecting the potentialclinical efficacy of new antipsychotic treatments.

The value of specific neuroimaging biomarkers indetermining the optimal dosing to maximize clinicalresponse and minimize side effects was discussed bySteven G. Potkin (Irvine, California). Among theneuroimaging measures discussed, Dr. Potkin describedthe results of several studies on which he has appliedpositron emission tomography (PET) to gauge thedopamine (D2) receptor occupancy profiles of severalinvestigational antipsychotic compounds. Not only havesuch studies helped to identify appropriate dose levels toreach target D2 occupancy, but they have also providednew information regarding the duration and neuroana-tomical regions of D2 occupancy that may be critical toachieving optimal effects of antipsychotic treatments.

In addition to the use of PET, Dr. Potkin alsodiscussed the value of studies providing multiplemeasures of convergent validity, including the use ofvolumetric and functional magnetic resonance imaging(vMRI and fMRI), magnetic resonance spectroscopy(MRS), quantitative electroencephalography (qEEG),genetic screening, and neurocognitive assessments.Following discussion of one such study conducted athis site, Dr. Potkin reviewed some of the challenges inconducting such multi-modal studies across multiplesites. As principal investigator of the FunctionalBiomedical Informatics Research Network (FBIRN),which was funded by the National Center for ResearchResources (NCRR) to develop analytic tools and data-

exchange infrastructures to facilitate multi-site fMRIresearch, Dr. Potkin was able to provide a uniqueperspective on how these challenges are currently beingovercome. In conclusion, Dr. Potkin noted that neuroi-maging biomarkers are applicable across all phases ofdrug development, from early CNS signal-detection ordose-finding studies with relatively small sample sizesto large multi-site studies as an add-on providingmeasures of convergent validity for antipsychoticclinical trials.

Stephen R. Saklad (Austin, Texas) presented anoverview of how drug formulation technologies andnovel delivery mechanisms are also critical to ensuremaximal efficacy and minimal side-effect profiles forantipsychotic medications. As appropriate selection ofthe route of administration can directly impact risk–benefit ratios, tolerability, patients' adherence, and riskof relapse, the full range of available mechanisms mustbe carefully considered. Among the strategies formodifying delivery mechanisms that Dr. Saklad dis-cussed were oral dissolving tablets, controlled- orextended-release oral dosing (e.g., using enteric coat-ings, wax matrix, polymers, or osmotic release),intramuscular or parenteral dosing (e.g., using anesterified agent in oil, slowly dissolving suspensions,or implants), transdermal patches, and aerosolizedsmall-particle inhalation technologies. For each ofthese mechanisms, Dr. Saklad provided a brief reviewof the relative advantages or disadvantages anddiscussed several recent (successful and unsuccessful)attempts to apply them to the delivery of antipsychoticmedications. Dr. Saklad noted that changes in thepharmacokinetics by method of delivery might haveimplications on the context in which the medication maybe used most appropriately. For example, aerosolizedinhalation may allow a much more rapid response whichmay be more appropriate for acute stabilization, whereaslong-acting, extended-release formulations may havebetter applicability for the maintenance of stability. Suchconsiderations will be important in the development ofnew antipsychotic medications and should be exploredearly in the R&D process.

The session was brought to a conclusion by thediscussant, Robert Alexander (GlaxoSmithKline), whoprovided an overview of the relevance of the presenta-tions from a pharmaceutical company perspective. Dr.Alexander noted that drug development traditionallyprogresses at a glacial pace for a variety of reasons,including the enormous complexities of in-house dataprocessing. As such, nurturing collaborative allianceswith academic researchers who understand the implica-tions of the findings they generate is crucial. Dr.


Alexander also stated that one of the most importantstrategies to accelerate R&D is not having to repeat astudy, so having it done right the first time is alsocrucial. Dose selection, for example, is absolutelycritical to do correctly and early to ensure that costlyefficacy studies do not fail simply due to inadequatedosing regimes or improper formulation. Accordingly,Dr. Alexander reiterated comments by Dr. Potkinregarding the importance of PET to establish that thedrug is entering the brain at a level that is comparable tothe efficacious levels observed in pre-clinical models.

Similarly, early studies are important to determineMTD; however, Dr. Alexander stated that such studieshave traditionally represented a very primitive processand that the Dynabridging techniques that Dr. Ere-shefsky and colleagues have developed provide muchneeded enhancements to that process, yielding far richerPK/PD information than traditional MTD studies canprovide. Dr. Alexander also pointed out that the choicesof formulation that Dr. Saklad reviewed has importantimplications regarding both PK/PD effects and medica-tion compliance and that patients' perceptions concern-ing mode and frequency of administration also needs tobe taken into consideration earlier in the process ofdevelopment. Finally, Dr. Alexander also commentedthat the pharmacogenomic biomarkers discussed by Dr.Ellingrod have very intriguing implications for patientselection and genetic screening to stratify patients, andthat rapid turn-around of such pharmacogenomicscreens will improve the logistical constraints toapplying these methods in meaningful ways. Inconclusion, Dr. Alexander commented that “makingthe most” of the data obtained at each stage beforemoving on to the next stage is the most effective way toaccelerate development of antipsychotic medicationsand the presentations all provided innovative means toachieve that objective.

The prophylaxis and early management of psychosisReported by Barnaby Nelson

This symposium, chaired by Wolfgang Fleischhacker(Innsbruck, Austria) and John Kane (Glen Oaks, NY),addressed the prophylaxis and early management ofpsychotic disorders, with particular focus on pharma-cological interventions. The first speaker, RobertFindling (Cleveland, Ohio), reviewed interventionresearch for children and adolescents with psychoticdisorders. Until recently, there has been a paucity ofrigorous psychopharmacological research on this patientgroup, and non-pharmacological interventions have notbeen researched at all. Although there have been many

open label case reports, only two randomized controlledtrials have been reported. The general outcome of thisresearch is that there appears to be some benefit oftreatment with antipsychotics, that the proportion oftreatment-resistant patients is greater in children andadolescents than in adults, and that there are moretreatment-related side effects. The industry-sponsoredstudies have consisted mainly of three-arm designs: aplacebo arm, a minimally effective dose arm, and amaximally tolerated dose arm. Results generallyindicate that both active treatments are superior toplacebo, and that differences between the minimallyeffective dose and the maximally tolerated dose arms donot differ with regard to symptom reduction but do withregard to side effects.

Dr. Findling referred to the preliminary analysis of astudy that compared three second generation antipsy-chotics. There were high rates of serious adverseevents, including suicidality and one completedsuicide. A safety monitoring board reviewed thestudy, resulting in one of the treatment arms (Olanza-pine) being discontinued due to the side effect ofsubstantial weight gain.

Dr. Findling concluded that child and adolescentintervention studies have finally been conductingrigorous trials with decent sample sizes and emphasizedthe need to accumulate more data, including cross drugcomparisons and longer term outcome data, and closelymonitor side effects, particularly metabolic and weightgain effects. Discussion focused on the wide age rangeincluded in the studies, the use of antipsychotics forconduct disorder, and poor rates of adherence in thispopulation.

Stephan Ruhrmann (Cologne, Germany) reviewedpharmacological interventions in patients in the puta-tively prodromal phase of psychotic disorder. Thechallenge of intervening in this phase of disorder hasbeen to find appropriate treatment strategies, withtolerability and acceptability to young people. Thefirst study of this type, conducted by McGorry et al.(2002), found that a specific intervention of combinedlow-dose risperidone and cognitive-behavior therapy(CBT) was superior to needs based intervention inreducing rates of transition to psychotic disorder inultra-high risk (UHR) patients over 6 months, but thatthis effect only remained for treatment-adherent patientsat the 12 month follow-up point. McGlashan et al.'s(2006) placebo-controlled double-blind trial of olanza-pine resulted in a trend-level difference in transitionrates at 12 months. This study may have failed to reachstatistical significance due to the small number ofsubjects treated.


In contrast to the traditional UHR approach, theGerman prodrome research group make a distinctionbetween the early and late prodrome. The earlyprodrome is defined using family history and basicsymptoms criteria and the late prodrome using attenu-ated psychotic symptoms and brief limited intermittentpsychotic symptoms (BLIPS) criteria. Ruhrmannreported a pharmacological study of amisulpride versusneeds-based intervention with patients in the lateprodromal phase. At the 12-week point medium effectsizes were evident between the treatment groups onvarious symptom measures in favor of the amisulpridetreatment group. The preliminary analysis of 12-monthtransition rates found a 5.3% transition rate in theamisulpride group versus 21% in the needs basedintervention group.

Dr. Ruhrmann emphasized the importance of recruit-ing large sample sizes for prodromal intervention studies,and that multi-site trials are critical. A seven-center RCTcomparing aripiprozole, placebo and CBT has recentlybegun in Germany. The aim is to recruit 380 at-riskpatients over 30 months. Given the declining rates oftransition to psychotic disorder in the UHR population,benign interventions may be suitable for this group.Positive results from a recent Vienna-based study has ledto a new international multi-center trial using omega-3fatty acids in UHR patients (NEURAPRO), due tocommence shortly. Finally, Dr. Ruhrmann suggestedstrategies for developing individualized prognostic scoresfor at-risk patients, based on the combination of riskfactors present in a given patient. Such an individualizedrisk index would assist with deciding on interventionstrategies for individual patients.

Discussion focused on the value of moving towards aneuroprotective approach with the at-risk population,the side-effects of neuroleptics in this population, andrecent data indicating the possible value of antidepres-sants in this population, although no controlled trials ofantidepressants have been conducted to date.

Wolfgang Fleischhaker reported data from theEUFEST study. The rationale for the study was basedpartly on concern in the field regarding the translation offindings from large RCTs of antipsychotic medicationsinto everyday clinical practice. Some obstacles thatprevent translatability include the fact that the trials aregenerally short, the samples are quite selective (about90% of patients seen in everyday clinical practice do notmeet RCT inclusion criteria), and dosages have tendedto be in favor of second generation antipsychotics.Therefore, EUFEST included patients who met routineclinical criteria for psychotic disorders and treated themin a naturalistic treatment setting.

EUFEST was a randomized open trial of 500 first-episode psychosis (FEP) patients conducted acrossmultiple sites in Europe and Israel. Low dose haloper-idol (1–4 mg) was compared with a group of secondgeneration antipsychotics over a one-year treatmentperiod. The outcomes of interest were retainment in thestudy and rates of rehospitalization. Discontinuationrates were higher in the haloperidol group than in thegroup receiving second generation antipsychotics, afinding which held for each individual drug in thesecond generation antipsychotic group. In terms ofsymptom outcome, initial analyses indicated no differ-ence between the drugs on PANSS total scores. Therewas an advantage for second generation drugs overhaloperidol for functioning and overall clinical improve-ment measures. After one year, 60% of patients were onthe same drugs they were initially randomized to,indicating moderately high levels of satisfactionamongst patients with their pharmacological treatment.

Discussion drew attention to the fact that antipsy-chotic drug research has become quite emotionallyladen, with biases operating in favor of either secondgeneration or typical antipsychotics. Another discussionissue was the role of long acting injections ofantipsychotics. Although the EUFEST data indicategood outcomes for oral medications, discontinuationrates were still a problem, so the results do not discounta possible role for long-acting injectables.

The final speaker was Patrick McGorry (Melbourne,Australia), who presented 12-month outcome data froman RCT conducted with a UHR sample at the PACEclinic in Melbourne. Three treatments were compared:risperidone+CBT versus placebo+CBT versus placebo+supportive therapy. As previous trials indicated thattreatment had not been provided for long enough,treatment was delivered for twelve rather than sixmonths. The primary outcome of interest was transitionto psychotic disorder, with secondary outcomes beingsymptom and functioning levels. 115 patients wererecruited to the trial over a five-year period. Baselinedata indicated substantial impairment in the UHR group,with 90% of the sample receiving current DSM-IVAxisI diagnoses, mainly mood disorders, and with significantlevels of suicidal and self-harming behavior andsubstance use. Outcome data indicated no significantdifference in transition rate between the treatmentgroups at 12 months, although the placebo+supportivetherapy group displayed a higher transition rate (21.8%)compared with the other two groups (10.7% and 9.6%).It was later suggested that a lack of power may havebeen responsible for this difference not reachingstatistical significance. In terms of symptom and


functioning outcome, all treatment groups improved,with no significant difference between the groups.

The overall transition rate in this trial was lower thanin previous UHR research. The declining transition ratesin UHR samples may be due to a lead time bias(identifying patients earlier in the course of symptoms),a length time bias (identifying more “false positives”earlier in the course of symptoms), or a sampling effectdue to changing referral patterns and broader youthmental health services (i.e., including patients who areUHR positive but with a lower base rate of risk forpsychosis than in earlier cohorts; Yung et al., 2007).Reinforcing Dr. Ruhrmann's point from earlier in thesymposium, Dr. McGorry argued that the resultsindicate the importance of a staging model in psychiatry,with treatment being most effective when introducedearly in the course of disorder and relatively benigninterventions possibly being sufficient at this stage.

The issue of antidepressant use in the trial wasaddressed after the presentation. Although no differencewas found between treatment groups in antidepressantuse, transition rates are yet to be analyzed in relation toantidepressant use. The issue of adherence to psycho-logical treatment was also addressed. The analysisindicated some “leakage” between the cognitive-beha-vior and supportive therapy arms, which suggests thevalue of using different therapists for different psy-chotherapy modalities in intervention studies.

Dissecting the heterogeneity of antipsychotic drugresponse: new approaches to an old problemReported by Renan Souza

Although antipsychotic drugs have been utilized intreating schizophrenia since the 1950s, there arecurrently no clear criteria by which to predict anti-psychotic treatment response or to select the optimaldrug that will have the best efficacy and minimal sideeffects. Approximately 10–20% of patients do notrespond to antipsychotic drug treatment, and anadditional 20–30% do respond early on but eventuallyrelapse; others develop serious side effects that causethem to discontinue medication altogether.

George Awad (Toronto, Canada) presented an over-view of response heterogeneity and prediction ofoutcome. Response prediction has been the mainresearch interest for his group for over 30 years.Historically, prediction of treatment response has beenan important goal in psychiatry. Assumptions that thecriteria for improvement, recovery and all other factorspertaining to prognosis were vague and disorderly werenoticed even before the introduction of chlorpromazine

in the 1950s. Two decades later, clinical practicebrought important knowledge showing that chronicillness would be likely to remain chronic; people are notlikely to do better after treatment than they did prior toillness when they were at their best before and, ingeneral, those who responded in the past are likely torespond in the future. Although these conclusions mightsound pessimistic, they stimulated further research ondrug response. Some methodological issues pertain tothis field, such as drug response specificity, patients'selection, follow-up time, response time course, out-come choice, response definition, appropriateness ofmeasuring tools and lack of adequate conceptual drugresponse and prediction. Outcome of schizophrenia wasgenerally the result of, as yet, not clearly understoodinteraction of biological and non-biological processesproducing the “natural course” of illness, which getsfurther complicated by the impact of treatment. A“predictor” was defined as an indicator of variousoutcome dimensions, through an unclear relationship,which depends on the particular definition and oper-ationalization of outcome/response. Accordingly, it canchange by altering definitions, i.e. that the scientificstatus of the predictor is not that of a determinant, butrather a statistically defined risk factor. Two importantpredictors were highlighted: early symptom change anddysphoria. Early symptom change (up to 48 h after thebeginning of treatment) was a good predictor accordingto work published by Dr. Awad's group two decades agoand it seems to be supported by some recent data. On theother hand, patients who develop dysphoria present witha lower dopamine D2 binding ratio and changes inmotor and cognitive symptoms.

Richard Keefe (Chapel Hill, North Carolina) reportedsome neurocognitive results on 1331 patients from theClinical Antipsychotic Trial of Intervention Effective-ness (CATIE) sample and methodological issuesregarding accessing cognition in first-episode psychoticpatients. His group previously showed that patientstaking atypical antipsychotic had a better cognitiveprofile than patients who were on typical agents. Manymethodological issues were found in studies reviewedby his group, such as many non-randomized studies,large dosing of the atypical comparator, the phenotypeused (composite scores or individual measures), smallsamples, missing data, practice and placebo effects. Insupport of the idea that composite scores were a betterprimary cognitive outcome than individual measures fortreatment trials (assuming that there are seven primarydomains of cognition in schizophrenia that are relevantto functional outcome and also could be potentiallytreated in cognitive enhancement trials), the CATIE


sample showed a correlation among all of the sevencognitive domains, suggesting that there is no particularcognitive impairment that it is unrelated with othercognitive impairment. After two months of treatment,no significant correlations were found in neurocognitivecomposite score changes among the five tested drugs(pherphenazine, risperidone, olanzapine, quetiapine andziprasidone). After eighteen months, pherphenazineshowed greater neurocognitive improvement than theatypical agents. The European EUFEST results (after6 months), in comparison, showed no differences oncognition between typical and atypical drugs. In general,cognitive improvement appears greater in studies offirst-episode patients than those of chronic patients. Animportant point raised was that the Brief Assessment ofCognition in Schizophrenia (BACS), that evaluates fourout of the seven domains previously mentioned, hasshowed similar sensitivity to the longer seven batteryand takes approximately 30 min to administer.

Philip Szeszko (Glen Oaks, USA) included in thedrug response prediction scenario an interesting topic:structural neuroimaging. It was shown that betteroutcome related to larger putamen volume and whitematter increases in dorsal posterior regions. Further-more, brain asymmetry has been associated with fullrecovery in first-episode schizophrenia patients. On theother hand, poorer outcome has been associated withventricular enlargement and smaller gray mattervolumes in temporal, occipital and prefrontal regions.Using 45 healthy volunteers and 39 first-episodeschizophrenia patients (25 responders and 14 non-responders), his group examined the relationshipbetween cortical surface morphology and treatmentresponse, hypothesizing that patients who are non-responders to antipsychotic treatment would have apattern of more severe cortical gray matter deficitscompared to responders. Patients were treated eitherwith risperidone or olanzapine. It was reported graymatter thinning in some cortical areas (lateral ventralfrontal, lateral occipital, medial ventral frontal andmedial occipital) in both hemispheres in the non-responder patients. Their findings were consistent withsome prior data showing positive symptom improve-ment associated with changes in orbital frontal andoccipital brain activity.

Following the neuroimaging field, but at this timeexploring functional imaging, Carol Tamminga (Dallas,Texas) presented some findings on regional brainactivity affected by antipsychotic drugs. It was shownthat these drugs increase regional cerebral blood flow(rCBF) in basal ganglia and thalamus, but decrease it inprefrontal cortex. In the medial temporal lobe (MTL),

antipsychotics decrease the abnormal rCBF present inschizophrenia and elevate the task-activated fMRIBOLD signal. An interesting association between limbiccortex activity and psychosis was observed. Overall, inpatients with schizophrenia who are medication free,MTL perfusion is increased and activation is decreased.Antipsychotic drugs correct the perfusion increase andthe activation decrease to a large extent by a mechanismthat may be mediated by dopamine D1 and D2 receptorsand acetylcholine release.

The genetic component of drug response predictionwas present by Anil Malhotra (Glen Oaks, NY).Pharmacogenetic strategies may offer important infor-mation to create treatment individualization, although,the current available data is controversial. Most of thepharmacogenetic studies on antipsychotic drug responsewere conducted with clozapine. It has been shown thatsome relevant candidate genes determining treatmentresponse are such genes as those for dopamine D2, D3and D4 receptors, serotonin 2A and 2C receptors and theserotonin transporter. Some polymorphisms of the D2dopamine receptor that presented significant associationwith drug response have been shown to be functional.Some of these polymorphisms have been associatedwith weight gain. Two relevant issues were raised. First,which population should be used in pharmacogeneticstudies: chronic patients or drug-naïve patients in orderto detect the differences in drug effect. Second, as hasoccurred with dopamine D2 receptor results, there is noway to assume that the personalized medicine concepthas been reached, as different drugs present the sameresults (no drug specificity). More recently, Dr.Malhotra's group has performed a whole genomeassociation study in relation to drug response using 62non-responders and 100 responders. Five genes forassociation with treatment response have reached asignificance level below 5×10−6: a gene located onchromosome 3p related to axonal cell adhesion; one onchromosome 19q, a SNARE related gene; one on 8q, acannabinoid receptor; one on 5q, a lipid transporter; andone on 8p, a protein phosphatase subunit.

Determining clinical outcome, quality of life andinsightReported by Jonna Perälä

This Oral Communication session was led by RobinEmsley (Stellenbosch, South Africa) and Alex Hofer(Hamburg, Germany). Dieter Naber (Hamburg, Ger-many) introduced the topic. Quality of life andfunctioning are becoming important components ofthe outcome of schizophrenia. Subjective values and


needs of patients are increasingly respected. Treatmentgoals have extended from decreasing psychotic symp-toms to also improving the subjective quality of life ofpatients and to obtaining remission.

Recently, the Remission in Schizophrenia WorkingGroup proposed symptomatic remission criteria and alsopointed to the lack of data regarding functionalremission and quality of life in schizophrenia. Theseissues have been studied in post-hoc analysis of datafrom German patients in the Schizophrenia OutpatientHealth Outcomes (SOHO) study, where rates andpredictors of symptomatic and functional remission, aswell as adequate subjective well-being/quality of lifehave been assessed in a large cohort of patients withschizophrenia. Subjective Well-being Under Neurolep-tic Treatment Scale, short version (SWN-K) (Naberet al., 2001) was used to assess the subjective well-being. SWN-K, assessing the past 7 days, is found to besensitive to treatment changes in schizophrenia and hasbeen well correlated with commonly used Short-Form36. It is a self-rating scale with 6 response categoriescovering 20 statements on 5 subscales. The correlationof SWN-K with objectively rated PANSS was onlymoderate at 6 weeks and increased to 0.7 at 12 monthsfollow-up. Different factors were found to affect thesubjective and objective ratings.

Subjective well-being on antipsychotics and positiveattitude to treatment may be also associated withremission and contribute to the adherence amongchronic patients. Subjective well-being of patientsreceiving combination of antipsychotics was comparedto those on monotherapy in a cross-sectional survey of78 outpatients with schizophrenia as presented by JanLibiger (Prague, the Czech Republic). SWN, DrugAttitude Inventory (DAI-30), PANSS and scales ofadverse events were completed. Symptomatic remissionwas evaluated. They found that patients with the lowertotal dose of antipsychotics and those treated withmonotherapy felt subjectively better on treatment thanpatients on higher dose of an antipsychotic or oncombination of antipsychotics. SWN scores were higherin those who were in symptomatic remission. However,surprisingly no significant relationships between sub-jective satisfaction with and attitudes to treatment werefound.

Martin Lambert (Hamburg, Germany) presented ameta-analyses by Agid et al. (2003) and Leucht et al.(2005), showing that a substantial amount of theantipsychotic response begins in the first two weeks oftreatment and accumulates over time. This suggests thatif good outcome is to be obtained with a particular drug,the level of symptoms will lower within the first two

weeks. However, there are many open problems andquestions still to be answered: data are mostly frominformed consent studies lacking severely impairedpatients and thus could be biased. Are there predictorsfor compliance and outcome? Are there predictors formore multidimensional outcome, where several differ-ent measures of outcome could be combined?

The relationship of early subjective effect ofantipsychotic medication and multidimensional out-come was then presented. In a prospective, non-randomized observational study, 727 outpatients withschizophrenia were treated with antipsychotic medica-tion. Early response (20 points increase) in SWN-Kscale distinguished between patients with or withoutlater subjective wellbeing — remission and overallsymptomatic and functional response. A subject waslikely to be a non-responder, if a fast response in SWN-K was not found. In this study, early response in SWN-Kfrom baseline to week 4 was the best predictor for thecombined outcome in schizophrenia at 3 years.

Poor insight is highly prevalent in schizophrenia, andoften affects the compliance and the outcome. Poorinsight has been associated with psychopathology e.g.high levels of psychotic symptoms and depression, andshowed a correlation with cognition, especially withexecutive function (Aleman et al., 2006).

Anthony David (London, UK) presented a study of 14patients with good insight for having schizophrenia(SAI-E score 15–28), 12 with poor insight (SAI-E 3–9),and 28 healthy controls matched for age, gender andnationality. He andDr. Bedford studied whether denial ofillness in schizophrenia was reflecting motivatedunawareness by measuring perceptions of the desir-ability of schizophrenia-related trait-adjectives andmental illness exposure preferences in schizophrenicpatients with contrasting attitudes towards their illness.They also studied if poor insight was associated withineffective self-reflection by measuring the SRE (Self-Referent Effect). They concluded that poor insight inschizophrenia is contributed to by cognitive impairment,psychopathology and mood. In this study patients withpoor insight showed some evidence of implicit aware-ness of the consequences of disclosure, implying thatpublic disavowal of illness may be partly motivated andunder conscious control. Their implicit memory ofmental illness-related traits was intact, but they showedimpaired processing of mental illness traits in relation tothe self, which is unlikely to be motivated or “con-scious”. The challenges and aspects of future studies andinterventions on poor insight were discussed.

Merete Nordentoft (Copenhagen, Denmark) pre-sented a study of the five-year outcome of schizophrenia


spectrum psychosis in the OPUS-trial, where 547individuals with first-episode patients were randomizedto an intensive early intervention program (OPUS) andstandard treatment. The OPUS treatment consisted ofassertive community treatment with flexible frequencyof contacts, family involvement, practical help andsocial skills training. The intensive treatment period wasfor two years. Follow up was at one, two and five years.Register base information at five-years were obtainedfor all the subjects.

At 1- and 2-year follow up, the subjects in the OPUStreatment had less positive and negative psychoticsymptoms, and comorbid substance misuse, betteradherence to treatment, and more satisfaction withtreatment. However, these differences were equalized atfive years (Bertelsen et al., 2008). Even though, asignificantly smaller proportion of the OPUS-treatmentgroup than the standard treatment group were living insupported housing (4% and 10%) and the number ofhospital bed days were 17% lower, no significant effectson other social outcome measures on depression,suicidal behavior or mortality was found. (Petersen etal., 2005; Bertelsen et al., 2007). The long-term effect ofthe intensive treatment, and the role of supportive,assertive and compensatory treatment, psychoeducation,and other aspects are being further explored in theExtension Trial OPUS II.

Education and employment are important compo-nents of functional outcome. Supported employmentcan increase the rate of competitive employment forindividuals with severe mental illness. However thefocus has thus far been on chronically ill individuals,even though most of the young people with recent onsetschizophrenia, who have been in the midst of theireducation at the time of their initial psychotic episode,and are often eager to return to school or work. KeithNuechterlein (Los Angeles, California) presented resultsof a randomized controlled trial of supported employ-ment and education. 69 recent-onset patients withschizophrenia were randomized to have IndividualPlacement and Support (IPS) and Workplace Funda-mental Module (WFM) or traditional vocational reha-bilitation. The IPS model of supported employmentextended to supported education to adapt it toindividuals with a recent first-episode of schizophrenia.While the first six months included intensive treatment,the following 12 months were less frequent. (Nuechter-lein et al., 2008). The results of trial showed, that IPS-WFM had a striking impact on initial rate of return to(83% versus 41% by six months) to work or school. At18 months, the subjects in IPS-WFM group were morelikely to be in competitive work or school (72% versus

42%), and spent significantly more weeks there (42 and26 weeks). There also seemed to be a delay in use offunds for disability, but a larger sample is needed toexamine this further. The findings support other findingsshowing that employment and education appears tohave a very notable impact on work recovery early in thecourse of schizophrenia.

The conclusions from this session were that whenevaluating the effects of antipsychotic drugs, otherpsychopharmacological or psychosocial treatments, theassessment should not include only psychopathology orobjective measures of outcome, but also systematicevaluations of the patients' perspectives of treatmentsuccess, subjective wellbeing and quality of life. Inpatients, no more acutely psychotic and without relevantcognitive deficits, their perspective, which is not alwayscorrelated with clinician opinion, can be explored withself-rating scales. Subjective wellbeing in the earlystages of treatment response may be a good predictor forthe combined outcome in schizophrenia. Subjects onmonotherapy and with lower dose of antipsychotics feltsubjectively better on treatment. Finally, subjectivequality of life and well-being were found to be stronglyrelated to compliance and to remission. In the earlycourse of schizophrenia, intensive, flexible and suppor-tive treatment models like Assertive Community Treat-ment seem to be better and cheaper than standardtreatments. Thus, the “Adapting Individual Placementand Support” program in patients with recent-onsetdisorder may be a very effective way to help them returnto school or work.

In summary, the presentations and the discussions inthis session highlighted the importance of furtherstudying different predictors and components of clinicaloutcome and remission. Subjective wellbeing andquality of life, as well as functional status are importantcomponents of outcome in addition to psychopathology,while several factors like compliance and poor insightare linked to them.

Time course of treatment response in schizophreniaReported by Shivarama Varambally and John P. John

This session, chaired by Dr. John M. Kane (GlenOaks, USA) and Dr. Stephen Leucht (Munich, Ger-many), evoked considerable amount of interest andgenerated some very active discussions. The talkscovered the following topics: (a) prediction of anti-psychotic non-response; (b) receptor changes linked toantipsychotic response; (c) time course of early treat-ment response; and (d) the delayed-onset hypothesis ofantipsychotic action. Dr. Kane introduced the theme of


the session and moderated the proceedings along withco-chair, Dr. Stefan Leucht, who in fact, delivered thefirst talk.

Dr. Leucht initiated his talk on early prediction ofantipsychotic non-response with a slide depicting thehighly controversial issue of time course of onset ofaction of antipsychotic medications. The ‘delayed onset’hypothesis is that there is a clear lag of several weeks toeven months between starting the drug and experiencingany antipsychotic effect, whereas the ‘early onset’hypothesis contends that the onset of action isimmediate, but more time is required for improvementto accumulate to a point where clear improvement canbe seen.

A meta-analysis by Agid et al. (2003) with 53 studiesand 8177 patients showed that the strongest reduction insymptoms occurred after the first week itself. Areplication and extension of the analysis beyond4 weeks using original patient data was done to ruleout the possibility that artificial inflation of baselinescores to meet the studies' inclusion criteria might haveled to the drop after 1 week. It found that BPRSreduction at week 4 was greater than BPRS reduction atweek 4 to 51 in all cases. Dr. Leucht also cited severalstudies that showed separation of antipsychotic drugsfrom placebo as early as 24 h after initiation oftreatment, controlling for non-specific sedation andgeneral symptoms. These findings therefore, clearly ruleout the ‘delayed onset’ hypothesis of antipsychoticaction.

Dr. Leucht then presented the question of how longshould one wait before considering an antipsychoticineffective. The expert consensus guidelines (Kane etal., 2003) mentions that in the event of little or no initialresponse, one should wait for approximately 2.5–5.5 weeks, whereas if there was partial response initially,an approximate wait period of 4.5–10 weeks may bedesirable. A number of older correlational studies hadshown that early (1–2 weeks) response predicts later (4–12 weeks) response, but cut-offs were not provided.Therefore a test showing the degree of non-response at1–2 weeks needed to predict later non- response (e.g. at4–12 weeks), with as high sensitivity, specificity,positive and negative predictive power as possible,would be a potentially useful advancement. With thisobjective, Dr. Leucht and colleagues used sensitivity —specificity analyses and receiver operator curves in alarge database of 1708 participants in antipsychotic drugtrials to find out what percentage BPRS cutoff at twoweeks would make a response at four weeks unlikely.The main result was that no change or worsening at twoweeks (=0% BPRS reduction) predicted no-response at

4 weeks defined as less than 25% BPRS reduction, withgood specificity and positive predictive value. Thisresult was replicated in another sample of 1306 patientswith schizophrenia. Considering that the 4-week cut off,i.e., less than 25%, is very stringent, it can be inferredfrom the results of the study that patients who do notderive benefit from a given treatment at 2 weeks shouldbe given the option of deriving the benefits of a changeof treatment. Moreover, a reasonable strategy to befollowed in clinical practice could be to have a 4-weekcut-off of 50% in acutely ill, non-refractory populationsand 25% for treatment resistant populations. UsingPANSS scores, more than 20% reduction at week 2predicted more than 40% PANSS reduction at week 8with a specificity of 89%.

Dr. Leucht then summarized the findings and gavesome directions for future research in this area. Researchhas consistently shown that early non-response doespredict later non-response, although the exact modelsand results varied. Therefore, in order to find outwhether an early switch in treatment does really improveoutcome, there is a need for prospective studies in whichearly non-responders are either kept on the same agent,or switched to another agent or an augmentationstrategy, to find out whether an early switch in treatmentdoes really improve outcome. However, one of thepotential limitations of this design would be that earlynon-responders have a low likelihood of later response,irrespective of the treatment they receive.

Robin Emsley's (Stellenbosch, South Africa) talkextended the relationship between early response(2 weeks) and short-term outcome (4–12 weeks),proposed by Dr. Leucht, to longer-term treatmentoutcome (2 years). Dr. Emsley commenced his talk bystating that early symptom changes may be a morereliable way of predicting longer-term response, asopposed to demographic variables, which have hadlimited success as putative response predictors. Dr.Emsley then described a number of recent studies inwhich this approach was adopted and the relationshipbetween early response (1–2 weeks) and later response(4–6 weeks) had been well established. However, theassociation between early treatment response andlonger-term treatment outcome still remained unclear.Given this background, Dr. Emsley and colleaguesundertook their study to examine the time course ofearly treatment response and its relationship to remis-sion in first-episode schizophrenia with the followingobjectives: (1) does early response accurately predicttreatment outcome?; (2) if so, how early?; (3) can thepredictive power be increased by adding other vari-ables? i.e. generation of a predictive model.


Dr. Emsley and colleagues examined the symptomimprovement pattern over the first 6 weeks of treatmentand its relationship to remission in three separate studiesin first-episode cohorts who were followed up for atleast two years. Remission was defined according to therecently described operational criteria by Andreasenet al. (2005). In the first study, 57 subjects were treatedwith low doses of haloperidol according to a fixedprotocol. The second study was a multinationalrandomized controlled trial in 555 patients treated witheither risperidone or haloperidol. The third studyinvolved 50 patients treated with risperidone long actinginjection. In all these studies, it was found that theprognostic divide emerges early. Most subjectsresponded rapidly to antipsychotic treatment, althoughunlike multi-episode patients there was a subset thatresponded more slowly. Treatment response in the firstsix weeks (particularly at 2 weeks) was stronglycorrelated with remission status later in the studies.The two strongest predictors of remission were shorterduration of untreated psychosis (DUP) and treatmentresponse at 6 weeks. The potential predictor variables,which were significantly different in remitters and non-remitters (best subsets model), were DUP less than1 year, neurological soft signs (NES) score, depressionscore, and change in PANSS total score at 6 weeks.These variables were 81% accurate for predictingremitters and 84% correct in predicting non-remitters.

Dr. Emsley concluded that early treatment responseis generally rapid and robust in first-episode schizo-phrenia, and strongly predicts long-term (2 years)outcome. Given the above findings, Dr. Emsleysuggested that a useful guideline to follow in clinicalpractice is to consider earlier switching to alternatestrategies, those patients who have not responded at6 weeks and who have associated neurological softsigns, long DUP (N1 year) and low depression scores(Emsley et al., 2006).

In response to a question regarding the presence ofdepressive symptoms at baseline and its effect onoutcome, Dr. Emsley mentioned that patients who haddepressive symptoms at baseline had a favorableoutcome, whereas those patients with persistent depres-sion or who had emergent depression during the courseof the study fared poorly. He also clarified that otherbaseline symptoms, including positive, negative anddisorganization symptoms did not seem to havepredictive value for outcome. In reply to a query onthe approach to patients who did not respond at 6 weeks,Dr. Emsley pointed out that clozapine is generally usedvery late in many of these non-responding patients, andit may benefit them if it could be tried at an earlier stage.

Dr. Shitij Kapur (London, UK) continued from wherethe previous speakers left with an objective to expand onthe neurobiology of early treatment response. Specifi-cally, Dr. Kapur's talk focused on the following crucialquestions: (1) how quickly does true antipsychotic effectbegin? (2) how quickly does receptor occupancy establishitself? (3) Does D2 occupancy relate to patients gettingbetter? (4) What does this mean for preclinical models?

Since the earlier speakers had already addressed theissues related to early antipsychotic response, Dr. Kapuraddressed the subsequent questions regarding howquickly D2 occupancy occurs and what is the relation-ship between early D2 occupancy and early response. InPETstudies, wherein single doses of antipsychotics weregiven to human volunteers, 60%D2 occupancy occurredas early as the 3rd day. The antipsychotic responserelated to D2 occupancy on the 3rd day is measurable by2nd to 3rd week. In a recent study by Dr. Kapur andcolleagues wherein they examined the relationshipbetween striatal (11C-raclopride) and extrastriatal (11C-FLB) D2 occupancy measured at 48 h and early responsein BPRS and PANSS positive symptoms (14 days), thedata showed that striatal occupancy predicted responsein PANSS positive symptoms (no relationship tonegative or disorganization symptoms), while extra-striatal occupancy did not relate to symptom improve-ment. Dr. Kapur noted that more than 95% of the currentpreclinical models reflect single dose treatment only andhave not attempted to model the response to antipsycho-tics in humans, which occurs in a more gradual fashion.The few exceptions that have attempted to do so havefocused on biological outcomes like genes, depolariza-tion etc., but not on the behavioral outcome. In an effortto model the antipsychotic response in humans, Dr.Kapur and colleagues examined the effect of immediate,transient and continuous occupancy (as measured withex-vivo 11C-raclopride) induced by typical (haloperidol)and atypical (olanzapine) in animal models (ConditionedAvoidance Response, CAR). While the animal modelsmirrored the human findings in that they showed animmediate onset and subsequent growth of antipsycho-tic-like response, longer-term continuous D2 occupancyled to progressive loss of response by around day 12,despite the fact that the drug levels remained constant—a kind of relapse. This phenomenon was shown to berelated to the development of D2 upregulation. Whetherthis phenomenon mirrors the loss of antipsychoticefficacy in humans on long-term antipsychotic treat-ment, remains to be studied. Dr. Kapur speculated thatthere could a learning process that would accompany D2occupancy and that the loss of efficacy could be a resultof the same.


Dr. Kapur concluded his talk by summarizing theexisting data from the bench to the bedside, which suggestthat there is a direct and causal role of D2 occupancy ininvoking early response; there is continuity between earlyand late response; and the response continues to growwhile occupancy remains stable. However, at least inanimal models, subsequent compensatory responses bythe brain (D2 upregulation) may lead to loss of efficacy.

In response to a question whether the D2 upregula-tion hypothesis could be a signal of the return of the“supersensitivity psychosis” hypothesis, Dr. Kapurresponded by saying that chronic treatment wouldindeed lead to a change in D2 receptors, and it ispossible that the supersensitivity psychosis could berelated to underlying D2 upregulation. If indeed it isproved to be so, then, that opens up an avenue forpharmacologically reversing this phenomenon to obtainclinical benefit. Dr. Kapur also added that it is stillunclear whether, at the optimum doses of antipsychoticsthat are routinely used, D2 upregulation occurs or not.Therefore, an important consideration here is that “dosematters”. He went on to suggest that this could be animportant question for future research.

Dr. Kane brought up the issue of whether the CARmodel and the amphetamine psychosis model haveequal relevance for human behavior. Dr. Kapurresponded by saying that the CAR model may nothave face validity with regard to symptoms of schizo-phrenia; however it has got good predictive validity withrespect to efficacy and therefore, is an equally relevantmodel to study response to antipsychotics. Prof. Kanefurther asked whether reintroduction of antipsychoticfollowing drug withdrawal resulted in faster receptorchanges, in response to which Dr. Kapur highlighted animportant methodological issue in assessing receptorchanges in such patients. He mentioned that sincepatients who are withdrawn from an ongoing antipsy-chotic regimen are the ones who have not responded totreatment, it is difficult to make inferences regarding D2receptor changes in those patients who are re-introducedto an alternate antipsychotic.

Dr. Bruce Kinon (Eli Lilly and Company, Indiana-polis, Indiana) presented the results of a study aimed atprospectively studying early responders and non-responders to look at improvement in symptoms andfunctional outcome. Dr. Kinon alluded to recent datathat have suggested that the onset of antipsychotic drugaction is much earlier than previously thought, withsignificantly more clinical improvement seen within thefirst 2 weeks than in any other 2-week period thereafter.

In the HGMN study by Dr. Kinon and colleagues,20% improvement in PANSS positive symptoms at

2 weeks on risperidone 2–6 mg was used as a cut-off todistinguish patients as early responders versus earlynon-responders. The early responders continued onrisperidone, while the non-responders were eithercontinued on risperidone or switched to olanzapine(10–20 mg). The primary objective was to determinewhether early response is associated with bettersymptom improvement. The secondary objective wasto see if early non-responders to risperidone experiencedgreater improvement in symptoms at endpoint whenswitched to olanzapine. The results showed that earlytreatment responders demonstrated better symptomimprovement than early non-responders, and theproportion of early responders achieving response atendpoint was significantly higher. Early treatmentresponders also had shorter time to remission andachieved better functional outcomes. Among baselinecharacteristics, early responders had higher PANSSscores at baseline but lesser previous episodes. Theyshowed greater reduction in depression scores andgreater improvement in functional outcomes than non-responders receiving risperidone. Thus the study foundthat early non-response is a robust predictor ofsubsequent non-response. Dr. Kinon and colleaguesalso found that early non-responders to risperidone didexperience a greater improvement in symptoms atendpoint when switched to olanzapine, although not asmuch as the early responders. This may be related to theimprovement in depression scores in olanzapine treatedpatients.

Dr. Kinon concluded by reiterating the potentialvalue of identifying non-responders early in treatment toenable clinicians to consider alternative treatments toprovide the earliest most effective treatment for thesepatients, thereby cutting down on the higher treatmentcosts of non-responders.

During the general discussion, Dr. Leucht mentionedin response to a question regarding what happens toearly responders over time, that equally important areother factors such as duration of illness prior to theinitiation of treatment. With regard to early respondersthey are likely to be early responders in future as well.Dr. Kane added that there is a paucity of studies in thisarea, and that definite inferences cannot be drawn at thispoint.

There was a question regarding what constitutes theideal duration of new drug trials and whether 2–4 weekstrials would be enough, in the light of Dr. Kapur's PETfindings. Dr. Kapur answered by saying that for proof ofprinciple, regarding whether the drug is better thanplacebo, only a 3 week trial is required; in such ascenario, there is the definite advantage that we will get


a more representative sample of schizophrenia subjects,given the short duration of the trial. Once it isestablished that the drug is better than placebo, thelater ‘real’ trials for efficacy in schizophrenia should bearound 6 months, rather than 6–12 weeks as is thegeneral practice at present. Dr. Kapur later clarified thatfor the initial trial, the duration of 3 weeks should befrom the day that the optimum dose of the drug isreached.

In response to another query, Dr. Kapur mentionedthat the extent of receptor upregulation due to clozapineand quetiapine could be related to the abruptness of thewithdrawal of the drug. With quetiapine and clozapine,the dissociation of the drug from the receptors takes only72 h as opposed to around 5–7 days for risperidone.

With regard to symptoms at baseline that predictearly response, Dr. Kinon mentioned that positivesymptoms at baseline indeed predicted early response.There was also a suggestion from the audience thatbaseline metabolomic parameters should be looked at inearly responders and non-responders.

Dr. Kapur lamented that despite currently being morethan 50 years after the introduction of antipsychotics,the field is still unable to provide definitive answers tothe simplest of questions that the practicing clinicianmight have regarding the time course of response toantipsychotics and the factors that may influence thesame. He hoped that the ongoing research into thefactors influencing drug response would provide a betterunderstanding of these issues in the near future.

Metabolics, metabolomics and antipsychotictreatment: recent studies in schizophreniaReported by Jimmy Lee

Metabolic disorders in schizophrenia have taken onincreased importance over the past decade with newinformation that patients with schizophrenia are also atrisk for weight gain and a metabolic syndrome leadingto a reduced lifespan.

It was thus appropriate that this symposium startedwith epidemiological findings from Sweden, presentedby Dr. Urban Osby (Stockholm, Sweden). He showedthat the standardized mortality ratio (SMR) for peoplewith schizophrenia of cardiovascular deaths in Stock-holm County from 1973 to 1995 was 2.2; that is, therewere 306 excess deaths from cardiovascular causescompared with that in the general population.

Dr. Osby presented data on time trends from 1970 to2003, and revealed that SMR for schizophrenic patientshad increased over time. This contrasted with thegeneral population where benefits in healthcare were

seen and people were generally living longer. Aquestion posed to Dr. Osby was whether this increasedtrend was due to atypical antipsychotic medications, andif the deinstitutionalization movement in Sweden hadled to poorer medical care and consequently highermortality rates. He replied that atypical antipsychoticcould have contributed to higher SMR, but this neededfurther investigation. Dr. Osby also agreed thatdeinstitutionalization could be a contributory factor,and added that there was a reduction in hospitalizationdays since the 1970s for patients with schizophrenia. Dr.Henry Nasrallah (Cincinnati, Ohio) commented thatresults from the CATIE (Clinical Antipsychotic Trials ofIntervention Effectiveness) study revealed that 30% ofdiabetic patients with schizophrenia were not treated,62% of those with hypertension were not on anti-hypertensive medications and 90% of schizophreniapatients with hyperlipidemia were not on statins.

Dr. Ruud Van Winkel (Kortenberg, Belgium) pre-sented data on glucose dysregulation in 3 monthsfollowing antipsychotic treatment in a naturalistic studyof 183 subjects with schizophrenia. Clozapine, olanza-pine and quetiapine were associated with new onsetglucose abnormalities. Clozapine was significantlymore deleterious with more than 50% of subjects startedon clozapine in 3 months experiencing glucoseabnormalities.

Dr. Van Winkel went on to present findings fromanother study, examining metabolic status in schizo-phrenia and schizoaffective subjects compared withthose with bipolar disorders. He found that subjectsdiagnosed with schizoaffective disorder had higher ratesof metabolic syndrome when compared to subjects withbipolar disorder. These findings were not attributablewholly to medications. He concluded that there could bea diagnosis specific vulnerability to metabolic distur-bances and those subjects with schizoaffective disordercould be particularly at risk.

Dr. Nasrallah focused on another topic in thesymposia that was potentially controversial. He positedthat weight gain was an indicator of therapeutic efficacyand added that this was not a new finding but had beenobserved since the 1950s. In the past, regular andcontinuous weighing of patients was a means to measureimprovement. In addition, there were studies to suggestthat elevated serum insulin in non-diabetic subjects wasassociated with better psychopathology profiles.

Dr. Nasrallah showed data from the CATIE study,and focused on correlation between total PANSS scoreand weight gain at 3 months. He found a significantnegative correlation between the 2 variables across alldrugs at not only 3 months, but also at 6 and 18 months.


Specifically looking at the ziprasidone group within theCATIE, the sub-group that demonstrated most improve-ment also had the highest weight gain. He furthercommented that this posed a dilemma to clinicians.

Dr. Rohan Ganguli (Pittsburgh, Pennsylvania) addedthat even if weight gain was associated with goodclinical response, it might not be a good thing. Dr.Nasrallah agreed that weight gain should be managedbehaviorally, and suggested that metabolic dysregula-tion could confer a survival advantage by improving apatient's cognition. He said that elevated glucose helpsmemory, and that insulin could have antidopaminergicactions, but clarified that this was entirely speculative.Dr. Rima Kaddurah-Dauok (Flint, Michigan) commen-ted that there were membrane structural abnormalitiesobserved in brains as well as red blood cells of patientswith schizophrenia, and suggested that schizophreniacould be a whole body disorder.

Dr. Kaddurah-Dauok was the next speaker andfocused on the emerging field of metabolomics. Shebegan by explaining that metabolomics is the study ofthe metabolome and the building blocks of biologicalpathways. It gives researchers a way of looking at thedisease in an integrated global way, and aids in theidentification, quantification, and study of the flux ofbiochemical molecules. It could also provide anopportunity to study gene–environment interactions.She elaborated on the metabolomic process, fromsample collection to preparation and creation ofbiochemical databases, to eventual bioinformaticsanalysis. Dr. Kaddurah-Dauok emphasized the impor-tance of bioinformatics support in correlating thebiochemical data with disease outcome and drug effects.She posited that schizophrenia could be distinct frombipolar disorder, and even other psychiatric disordersbiochemically, and she further suggested that biochem-ical databases of the various psychiatric disorders couldbe generated and compared to identify these differences.She added that biochemical profiles could be used as away to subtype schizophrenia, and could be combinedwith genetic studies. The biochemical platform createdcould also be used to measure different neurotransmitterpathway metabolites.

She presented results from a recently publishedstudy, where the metabolome of subjects with schizo-phrenia treated with olanzapine, risperidone and aripi-prazole were compared. The study revealed that subjectshad lowered phosphatidylethanolamine levels and base-line and that they were increased post-treatment with all3 drugs. However, elevated triacylglycerols and reducedfree fatty acids were observed in subjects treated witholanzapine and risperidone, but not with aripiprazole.

She suggested that metabolomics could thus identifybiomarkers of clinical utility, to separate drug respon-ders from non-responders and those who would bebetter placed on one drug rather than another. She wasasked if metabolomics could be used to predict obesityin patients treated with second-generation antipsycho-tics, to which she replied that it was possible. Shecommented that total biochemical changes at baselineand post-treatment could be compared to identifymarkers that could predict weight gain. Dr. Nasrallahadded that there are early warning signs such asconsiderable weight gain in the first 2 weeks ofantipsychotic treatment.

A participant asked if there were any studies thatlooked at the impact of exercise and diet in schizo-phrenia. Dr. Van Winkel replied that he tried toimplement these measures in his clinical work but theresults were not spectacular, as it was difficult tomotivate the patients to lose weight. Dr. Nasrallahagreed that these measures might help reduce weightgain but it would be difficult for patients to adhere to theregimen. However, he commented that exercise hadbeen shown to stimulate hippocampal regeneration, andcould help improve the cognition of patients withschizophrenia.

Dr. Marc De Hert (Kortenberg, Belgium) led thediscussion by highlighting that patients with schizo-phrenia and severe mental illnesses are at risk of dyingprematurely from cardiovascular causes, and thatscreening of these risk factors could improve generaloutcome. He suggested that metabolomics provide apromising tool to study illnesses and treatments, and tostudy gene–environment interactions as well.

Pharmacologic and cognitive remediationstrategies for improving cognitionReported by Ava-Ann Allman

Cognitive deficits are considered one of the corefeatures of schizophrenia (Meltzer, 1999). Numerousstudies to date have shown that these impairments arepresent in medication-naïve patients (Saykin et al.,1994), do not improve with a reduction in positivesymptoms (Meltzer, 1999), are reliably present in themajority of patients (Heinrichs and Zakzanis, 1998) andare stable and lifelong (Rund, 1998). Perhaps moststrikingly, cognitive function is strongly associated withfunctional outcome in patients with the illness.

Because of the importance of cognitive function inoutcome, a great deal of research is being conducted onhow to improve this area of dysfunction in the illness.The current session looked at both pharmacologic and


cognitive remediation strategies for improving cognitionin these patients. It opened with Dr. Harvey whoprovided a framework within which to discuss the topic.While he agreed that disordered cognition played animportant role in functional outcome, he emphasized thefact that many mediating variables were important toinvestigate, including income, social support andmotivation. Indeed, in a recent study with the CATIEgroup, the strongest predictor of unemployment inpatients was not neuropsychological functioning, butwhether they received disability benefits, followed bythe race of the participant (Rosenheck et al., 2006). Healso noted that there is sometimes a difference betweencompetence and performance, such that impaired out-come does not necessarily mean impaired ability inpatients. As many measures depend on self report,which may be affected by symptomatology in thepatients, one cannot always depend on these to measurea skill set. Therefore, it is critical that one understandsthis distinction when attempting to determine andunderstand the causes of disability in the real world.He concluded by stating that while it was important toimprove cognitive performance in this population, itwould not necessarily guarantee an improvement inoutcome if mediating variables were not also addressed.

The following presentation focused on pharmacolo-gic approaches to improving cognition. Dr. Marderopened by emphasizing the need for an ordered approachto studying the effect of different drugs on cognition inschizophrenia by following the recommendations fromthe NIMH.FDA conference (Buchanan et al., 2005). Hethen went on to summarize a number of studies lookingat the impact of different classes of drugs on cognitivefunction. In general, studies appeared to conclude thatthere was no additional benefit of second generationcompared with first generation antipsychotics on cogni-tion. Given these findings, Dr. Marder went on to discussthe need to look beyond antipsychotics for cognitiveimprovement by examining drugs that work on otherneurotransmitter systems. Targets of particular interesthave been the ά7 nicotinic andNMDA receptors. Resultshave been mixed, showing none or small improvement.However, he also expressed hope in a current study thatwas looking at using a GABA ά2 partial agonist toimprove cognitive function in this population.

To conclude, Dr. Marder raised the notion that theremay be drugs that are having a positive impact inpatients, but if the patients aren't engaged in variousactivities then there would be no way to know. Inaddition, he emphasized the importance of combiningpharmacological and psychosocial approaches inaddressing cognitive deficits.

An audience member asked about co-morbid ADHD,and if any work had been done on treating these patientswith stimulant medications. The potential use ofatomoxetine in these cases was discussed, but Dr.Marder was unaware of studies that had specificallyexamined this issue. In a similar vein, the potential forampakines in treatment was raised. While there hadbeen one study using CX516 which showed noadvantage for the drug over placebo, it was noted thatthe drug was of very low potency. Finally, it was askedwhether, given the data, we should even bother lookingat drugs as a potential way to treat cognitive deficits. Dr.Marder felt that this was premature, given that it is anemerging field and the few studies that have been donehave been underpowered. In addition, there have beenno studies that included psychosocial approaches as anoutcome amplifier.

The next two presentations by Dr. Alice Medalia(New York, NY) and Dr. Till Wykes (London, UK) werefocused on cognitive rehabilitation in schizophrenia. Dr.Medalia presented neuropsychological approaches tothe issue, while Dr. Wykes presented the costsassociated with it and the relative benefits.

Dr. Medalia opened with a review of the basicprinciples of cognitive remediation, which consist ofbehavior-based techniques to improve cognitive func-tioning in patients with impairments. There were anumber of different approaches discussed along withtheir relative effectiveness. For example, some programsfocus on computer based tools whereas others focus onverbal/paper pencil tools, with computer based programshowing larger effect sizes. Frequency of the interven-tion has also been examined, with programs rangingfrom 2–3 times per week to 4–5 times per week, withevidence showing no added benefit for more than 2sessions per week. As expected, programs that promotestrategy development in their clients as opposed to adrill and practice approach have been shown to havehigher effect sizes. Finally, she underlined the impor-tance of motivation, and the necessity of any program totake it into account. High levels of intrinsic motivationresult in greater self esteem and engagement in theprocess, and programs that provide motivationalinstruction (versus generic instructions) lead to anincrease in clients appreciating the utility of performingthe tasks.

The Neuropsychological Educational Approach toCognitive Remediation (NEAR) program that wasdeveloped by Dr. Medalia and her colleagues was thendescribed. The program uses a combination of strategydevelopment and drill/practice approaches. Becauseschizophrenia is known to impact motivation, the


program uses a number of techniques known to promotelearning by increasing intrinsic motivation and taskinvolvement. Tasks are completed on the computer andthen participants take part in bridging groups, whichallow the tasks to be placed into the context of the realworld. There is an emphasis on individualized trainingand sessions are held 2–3 times per week.

A question from the audience focused on thesubjective impression of the participants, wondering ifthey found that it made a difference in their functioningand if “booster sessions” would be helpful in maintain-ing any potential gains. Dr. Medalia responded that aftercompleting the program patients report feeling morecompetent, which is a cornerstone of motivation. Aswell, she and her colleagues are currently examining theutility of these “booster sessions”.

Dr. Wykes then discussed the cost and effectivenessof cognitive rehabilitation therapy (CRT) in schizo-phrenia. She began by presenting data showing that thecosts of caring for patients who have schizophreniaand cognitive deficits was much higher than forpatients with no cognitive impairment. These costswere wide ranging, from direct costs such as medica-tion and hospitalization to more indirect costs includ-ing reduced financial independence as a result ofunemployment. The ability of CRT to reduce thesecosts was thought to lie in improving employment aswell as social functioning, which in turn would promotedecreased dependence on social programs and increasedindependence.

Two recent randomized control trials looked at theeffectiveness of CRT in older (average age of 36) andyounger (average age of 18) groups of men as measuredby cognitive, social and symptomatic improvements.The control group received treatment as usual (TAU)while the experimental group received CRT in additionto TAU. Outcome variables were measured at baseline,three months later, immediately after treatment, and atfollow-up, which was 3 or 6 months after completingtreatment. In order to take part participants needed toexhibit cognitive difficulties in memory or cognitiveflexibility, have a diagnosis of schizophrenia and bestably medicated.

In the older group there was a significant advantagefor CRT in terms of memory at both time points aftertreatment and a significant improvement in cognitiveflexibility at 6 months post-treatment. There was also animprovement in self esteem and symptomatologyimmediately after therapy, but this was lost at follow-up. Both groups showed a decrease in costs over thecourse of the study, and while there was an advantage tothe CRT group it was not significant. In the younger

group, there was a significant improvement in cognitiveflexibility both immediately after treatment and atfollow-up, but no effect on other outcome measures.

In addressing the primary issue of cost effectivenessof CRT, one must take into account the cost of providingthe service and balance it against the potential effec-tiveness of the intervention in reducing the costs of carefor the patient. The studies discussed above, as well assome previous studies, suggest that while there is littledoubt of the cost effectiveness of CRT immediately aftertreatment, this is no longer evident approximately6 months after the intervention. However, any changesin symptomatology and functioning, while they may notdirectly impact health care or societal costs, can beinvaluable to the patients and their families. In addition,even small changes in cognitive function may lead to animprovement in skills learning.

The final presentation in the session was from Dr.R. Penadés (Barcelona, Spain), who discussed improv-ing patient functioning with cognitive remediationtherapy. He began by reviewing studies which foundthat post-CRT, patients showed an improvement inobtaining competitive jobs, as well as increased abilityto deal with interpersonal problems and increasedquality of satisfaction with their relationships.Although these improvements have been relativelyrobust, very few studies have looked at the underlyingmechanisms that led to these changes. One studycomparing CRT and Cognitive Behavioral Therapy(CBT) found that CBT resulted in only a slight, non-specific improvement in working memory whereasCRT led to a significant improvement in verbal andnon-verbal memory, as well as executive function. Inaddition, those who showed results with CRT showedan associated improvement in social functioning,which was still present 6 months later (Penadeset al., 2006). Another study comparing CRT andTAU found that an increase in the ability to generateschemas, as well as an increase in executive functionperformance played a role in improved social function-ing. Finally, the specific skills to be targeted wereaddressed. A recent meta-analysis showed that CRT inconjunction with psychiatric rehabilitation had astronger effect on psychosocial functioning than CRTalone. In addition, CRT programs that use strategycoaching have been shown to be ore effective thanthose that use a drill and practice approach. Dr.Penadés concluded by that although CRT is effective atimproving both cognition and functioning, programsneed to target aspects of executive function, focus onstrategy coaching and metacognition and considerincluding additional skills training.


In response to a question from the audience, Dr.Penadés emphasized that the content of CRT is not asimportant as the way in which the intervention isapproached. One must determine what area of function-ing one would like to improve, and build upon theexisting skills of the individual.

Dr. Richard Keefe (Chapel Hill, North Carolina) thenled the discussion, opening with a reflection on theseeming disconnection between the ineffectiveness ofdrugs in treating cognitive deficits in schizophrenia andthe relatively robust effects of CRT. However, he thennoted that there had been a lack of multi-site studiesconducted using CRT, and wondered if the effectivenessof the intervention would hold up. Finally, he posed thequestion of whether or not CRT and drugs could be usedin conjunction to improve cognitive performance, asmany drug studies are done in deprived cognitiveenvironments, which he likened to using steroids withdoing any exercise.

Dr. Keefe then asked the panel about a medium scalepilot study that was being initiated through theSchizophrenia Trials Network that would assess thepossibility of a multi-site clinical trial of CRT. Heinquired about the feasibility of such a project, and whatkey features, if any, could not be compromised. Dr.Penadés responded that above all, therapists must bewell trained in administering the intervention, and theremust also be a clear operational definition of good socialoutcome. Dr. Marder asked about dosage issues,wondering what is the length of time and frequency ofadministration that would be ideal, to which Dr. Medaliaproposed twice a week. Dr. Wykes cautioned thatbecause CRT is such an umbrella term, multi-site studieswill be tricky, as the intervention is heavily dependenton the site. Dr. Keefe proposed a meeting to discuss acommon approach, similar to the NIMH FDA con-ference, but Dr. Wykes replied that while such a meetinghad been held there was very little resolution reached.

A question regarding the heterogeneity of thefindings was posed, with an audience member wonder-ing if factors needed to be more clearly defined at theoutset of studies. Dr. Wykes proposed that samples bestratified according to the time since onset of the illness,perhaps dividing patients into those less than versusthose more than 5 years after onset, as the more recentonset patients may be trying to maintain their existingrelationships while the more chronic patients are tryingto create new relationships. The impact of CRT onnegative symptoms was also discussed, with Dr.Medalia commenting that if amotivation is considereda symptom then the impact is huge, and Dr. Wykespointing out that even though some patients are almost

catatonic, and many patients have had little success withprior interventions, these individuals can still beengaged and be successful in the program.

Cognitive effects of second generationantipsychotic medications: experiences from firstepisode schizophrenia studiesReported by Sara Cherkerzian

“First episode (FE) schizophrenia cohorts offerseveral distinct advantages for the study of theeffects of second generations antipsychotics (SGAs).First, they do not have long and complex histories ofantipsychotic and adjunctive treatment, which mightconfound examination of variables of interest.Second, such patients have not received long periodsof institutional care, with possible ramifications formotivation and volition. Third, first episode patientsare known to have relatively good symptomaticresponses to medication, suggesting that interven-tions at this stage in course may have optimal effectsand, implicitly, that there is plasticity in some neuralsystems relevant to schizophrenia." (introduction byDr. Terry E. Goldberg, Glen Oaks, NY)

Neurocognition is impaired in persons with schizo-phrenia and is a strong predictor of poor functionaloutcome. Since cognitive status is a strong predictor ofillness outcome, both industry and government have hadstrong incentive to focus on developing new drugtreatments to target these neurocognitive domains.Several studies indicate that atypical, or secondgeneration antipsychotics (SGA), provide a greaterbenefit for neurocognitive improvement in personswith schizophrenia compared with the typical, or firstgeneration antipsychotics (FGA); however, the effect ofthese SGAs on neurocognitive outcome remains con-troversial. FE schizophrenia subjects (FES) may providethe advantages listed above in the study of SGAs, and inthe symposium, several experts in the field togetherprovided a critical examination of the methodology ofthe SGA studies and its impact on our understandingSGA efficacy in the improvement of neurocognition inpersons with schizophrenia, and how early interventionin these people can perhaps lead to better long-termfunctional outcome.

The typical paradigm used in studies of SGAs beginswith the testing of the agent(s) in acutely admitted FEschizophrenia subjects who are generally more respon-sive and/or adherent to treatment than chronic subjectswith multiple episodes of the disease, and thereby mayprovide a broader, less biased, range of outcomes with


SGA treatment. Dr. D.G. Robinson (Glen Oaks, NY)discussed his 4-month longitudinal randomized study oftwo different SGAs – olanapine versus risperidone – inn=112 FE subjects (2006). Consistent with results fromother studies of antipsychotic medication treatment inFES subjects, Robinson and colleagues found signifi-cant improvement in positive symptoms for both SGAtreatment arms. Though the investigators found a smalladvantage in clinical outcomes for risperidone, studieson multiepisode subjects such as the CATIE trial foundthe advantage in olanzapine. An important notehowever, is that studies based on multiepisode subjectsmay not serve as an optimal basis for treatmentdecisions in FES persons who have no known treatmentresponse. In terms of the negative symptoms in theRobinson study, similar improvements seen for thepositive symptoms were not found. There were onlymodest improvements in avolition–apathy and asoci-ality–anhedonia but not among the other symptomdomains such as parkinsonism and akathisia.

Dr. Robinson continued his talk on improvement andintervention in disease outcome with a discussion aboutlong-term outcomes in other domains impaired inpersons with schizophrenia, particularly role function-ing, social adjustment, and cognition. For his discus-sion, Dr. Robinson focused on his long-term study(2004) of recovery in n=118 FES subjects in treatmentfor 5 years using the UCLA recovery criteria. Theyfound about half of the subjects met symptom remissioncriteria for 2 or more years, approximately one-fourthmeeting adequate social vocational functioning criteriafor 2 years or more, and only about 14% who met bothcriteria for 2 or more years. The severity of cognitivefunctioning at baseline was correlated with worse long-term outcomes. Dr. Robinson used these findings tohighlight the need to develop better early inventions forFES subjects for improved long-term quality of life.

Dr. Keefe's presentation began with the discussionthat while SGAs have been identified across severalstudies as providing an improvement over FGAs oncognition in persons with schizophrenia, there areseveral methodologic issues to consider, issues thatinclude no randomization into treatment arms, switchingto SGA treatment after use of fairly large doses of FGAs(and thus reflecting perhaps an improvement from FGAextrapyramidal symptoms and anticholinergic treat-ment, both of which impair cognition), short durationof treatment, and small sample sizes. The 18-monthCATIE (Clinical Antipsychotics Trials of InterventionEffectiveness) trial was a study designed to investigatethe relative effects of SGAs versus FGAs on neurocog-nitive function addressing the limitations of previous

studies, and it was based on multiepisode subjects(n=1460) and using several SGAs and the FGA,perphenazine (2007). This study began with anextensive neurocognitive battery at Phase I (n=817).Baseline analyses were performed using structuralequation modeling providing a composite score foreach subject, and small, albeit significant, improvementin neurocognitive composite scores across all domainswere found after two months of treatment across alltreatment groups, with no significant differencesbetween the different groups, including the FGA. Theresults were similar at 6 months; however, post-hocanalyses at 18 months suggested greater neurocognitiveimprovement with perphenazine compared with olanza-pine and risperidole. This finding may have to do withthe fact that the CATIE study used a FGA that isconsidered to have less extrapyramidal side effects andanticholinergic treatment than haloperidol which hasoften been used as the FGA treatment in studies, but Dr.Keefe also suggested that a placebo or practice effectmay be involved using the example of a study ofdonepezil and placebo in a sample of subjects withschizophrenia stabilized using SGAs.

Dr. Keefe and colleagues also initiated the CAFÉ(Comparison of Atypicals in First Episode Psychosis)study which is a randomized, double-blind trial of theSGAs olanzapine, quetiapine, and risperidone in n=224FES subjects in which cognition was measured atbaseline, 12 and 52 weeks, and all-cause treatmentdiscontinuation was a primary endpoint. Neurocognitivescore were calculated similarly as in the CATIE trial andincluded the Brief Assessment of Cognition in Schizo-phrenia (BACS) battery as well. While at weeks 12 and52 there was significant improvement in neurocognitionand functional outcome for all treatments, there were nodifference between SGAs in the trial, and cognitivechanges were modest and consistent with practice and/or placebo effects.

Most studies comparing SGAs and FGAs have beenconducted on subjects with chronic schizophrenia whoare not neuroleptic-naïve, subjects who may respondmuch differently to treatment than FESs as previouslydiscussed by Dr. Robinson. Another methodologicallimitation of several of the studies in the field is that theyhave been financed by the pharmaceutical industry andhave used highly selected samples. Both of these issueswill affect the generalizability of the optimal treatmentrecommendations in real-world clinical practice. EUF-EST (European First Episode Schizophrenia Trial), asan independently designed and financed study,addresses such limitations. The EUFEST study pre-sented by Dr. S. Galderisi (Naples, Italy) is a large


European study of FES subjects and their cognitiveresponse to SGAs. In this randomized, multinationalstudy of n=498 FES subjects, neurocognitive changeswere examined after six months of treatment withamisulpride, olanzapine, quetiapine, and ziprasidole andcompared with subjects following treatment on lowdoses of haloperidol. In an effort to keep as close toclinical practice as possible, subjects taking concomitantdrugs such as benzodiazepines and antidepressants werenot excluded in the study. A large battery of neurocog-nitive tests were administered to the FES subjects aswell as to n=200 healthy individuals. Neurocognitiveassessment was performed on n=457 FES subjects atbaseline and n=331 after 6 months. As with the studiesdescribed by Drs. Robinson and Keefe previously,similar improvement in cognition was observed acrossall treatment arms with no significant differencesbetween them.

As mentioned previously, cognitive impairment is amajor cause of poor functional outcome in persons withschizophrenia, and as a result has been recognized as animportant treatment target in drug development. Tradi-tional neuropsychological measures have been usedacross studies to determine neuroleptic efficacy. Usingan alternative approach, Dr. J. Sweeney (Chicago,Illinois) used a battery of translational cognitiveneuroscience tasks based eye movement paradigmswith known robust sensitivity to drug effects in animalstudies to examine their utility for assessing neurocog-nitive outcomes of antipsychotic treatment. Suchtranslational neuroscience methods can complementthe traditional clinical neuropsychological approachwith its greater sensitivity and discrimination toevaluating cognitive effects of antipsychotics and theirreciprocal integration of clinical testing with animalmodels.

Dr. Sweeney recruited 30 FES (DSM-IV) subjectsprior to treatment with risperidal and an equal number ofmatched controls and studied them using a battery ofneuropsychological tests as well as a series ofoculomotor neurophysiology paradigms at baselineand then again at 4–6 weeks, 26 weeks, and52 weeks. The model system of eye movement controlis a useful tool for studying motor and cognitiveprocesses with minimal practice effects as seen with thetraditional neuropsychological measures and that aresuitable tasks for functional brain imaging. For thisstudy, Dr. Sweeney and colleagues focused on apredictive saccade paradigm, a serial reaction timetask assessing procedural learning, as they rely upondorsal–striatal circuitry, systems that are also affectedby the D2 blockade associated with antipsychotic

medications. Using this paradigm, Sweeney and collea-gues identified increases in visually guided saccadelatencies at the first follow-up. These latencies were thenstable over time in the FES group in the form of slowedresponse initiation and reduced accuracy of responses,consistent with psychomotor slowing. In contrast to pre-treatment measures, FES subjects also demonstrated adecrease in the accuracy of the predictive but notsensory-guided responses. On the oculomotor delayedresponse test of spatial working memory, performancewas impaired before risperidone treatment, but wasfurther and persistently impaired after treatment initia-tion, consistent with observations in animal modelswhich suggest that risperidone may exert this effect byaltering modulary functioning in the prefrontal D1receptors.

There have been several studies that indicate SGAssignificantly improve cognition in persons with schizo-phrenia; however, new data from studies that includehealthy controls raise the possibility that cognitiveenhancement with SGA treatment may be an artifact, orpractice effect, of serial assessments of neurocognition.Dr. Goldberg discussed this issue using the example ofhis NIH sponsored study of 104 FES, largely drug-naïve, subjects randomized to either olanzapine orrisperidone in a blinded trial on key measures ofcognition measured at baseline, six and sixteen weeks.The study also included a healthy control group ofn=84 subjects thus allowing the investigators tomeasure practice, or training, effects over repeatedneurocognitive assessments. The investigators found nodifferential drug effects, and of the 16 neurocognitivemeasures, only visual memory for designs and trail-making speed exhibited greater rates of change thanthose observed in the healthy control group suggestingvalid cognitive enhancement in these domains. Thecomposite effect size for the FES group (0.36) found inthis study is consistent with those from industry-sponsored trials; however, the healthy control group –a group critically most often excluded in the design ofdrug trials that attempt to demonstrate neurocognitiveenhancement – showed similar improvement, suggest-ing that the observed cognitive improvements, otherthan the two listed above, are confounded by practiceeffects. This practice effect may be argued against, giventhe cognitive impairment in persons with schizophrenia;however, data indicate that these people are indeed ableto demonstrate a practice effect suggesting thatprocedural learning systems are intact. While the abilityof persons with schizophrenia to demonstrate a practiceeffect may seem advantageous, Dr. Goldberg notes thatsuch learning is not generalizable to real-life situations


given that the effect is paradigm specific. Dr. Goldbergalso discussed means to minimize practice effects by useof multiple trials and oculomotor neurophysiologyparadigms as discussed by Dr. Sweeney.

The pathology and treatment of schizophrenia: amoving or fixed target?Reported by Renata Schoeman

The current debate whether schizophrenia is aneurodevelopmental or a neurodegenerative disorderwas further explored in this session. Despite strongevidence in support of the neurodevelopmental hypoth-esis (e.g. cognitive impairments, minor physicalabnormalities, premorbid risk factors and susceptibilitygenes), the clinical deterioration, including decliningfunction and cognitive abilities soon after the onset ofthe illness, is indicative of a neurodegenerative process.However, these two processes do not have to bemutually exclusive and it is possible that they maypredominate at different stages of the illness.

Brian Dean started this session by giving anoverview of genes linked to schizophrenia, morespecifically those associated with the prefrontal cortex(Brodman area 46). In previous restriction fragmentdifferential display (RFDD), 153 genes were identifiedwith 33% having increased expression in the prefrontalcortex. These genes could be grouped into families, e.g.for energy metabolism and signal transduction. Genevalidation studies followed (Dean et al. Aust.N.Z.J.Psychiatry 41.4 (2007): 308–320) in which changes inlevels of gene expression in the dorsolateral prefrontalcortex were identified. Using restriction fragmentdifferential display (RFDD), it was discovered that 30genes are altered by RFDD with symptom specificityrelated to duration of illness (DUI). In those with a DUIless than 7 years, 15 genes were identified which wereassociated with positive symptomatology. However,with a DUI of more than 7 years, genes were associatedwith expression of negative symptoms. There is alsofurther evidence for disease specificity of gene expres-sion, e.g. Musclebind Protein (MBNL) and protocad-herin 17 (PCDH17), which is overexpressed inschizophrenia, but not in bipolar mood disorder.Furthermore, MBNL overexpression is restricted to ashort DUI. It therefore appears that changes occur ingene expression with transition from acute to chronicillness. Dr. Dean continued to discuss findings from atranspacific collaborative study “Changes in geneexpression profiles in subjects with schizophrenia ofvarying duration of illness”. In this study the HumanGenome U133 Plus 2.0 array (Affymetrix), which

combine both SNP and CNV genome-wide coveragein a single assay, was used to profile genome-wide RNAexpression patterns in the prefrontal cortex of schizo-phrenic subjects at different stages of illness, andcompared to age- and sex matched controls. DUI wasarbitrarily decided on according to available tissue toform a reasonable cohort. With a short DUI (less than7 years), heatmaps were able to cluster schizophrenicsubjects separate from controls. This was not evident inintermediate DUI (10–16 years) and long DUI (morethan 22 years) subjects. Pathways predominantlyaffected also differed according to DUI, e.g. changesin genes involved in gene transcription, metal ionbinding (short DUI), inflammatory pathways (inter-mediate DUI) and calcium signaling (long DUI). Therewas also evidence of the glycosphingolipid pathways(linked to lipid rafts and myelination) to be particularlyaffected in early onset of the illness. Lipid rafts arepresent in all cell membranes and interact with NMDAreceptors and sigma 1 receptors. Antipsychotics andantidepressants also concentrate in lipid rafts. It there-fore appears that most changes in cortical geneexpression differences occur in tissue from subjectswho were early in the illness (b5 years from initialdiagnosis) at death. However, changes in gene expres-sion that include signal transduction, lipid metabolismand protein transport/metabolism occurs at all stages.These results support the hypothesis that schizophreniais a progressive, evolving disorder. The results should becompared to changes in gene expression in other chronicdisorders such as diabetes mellitus. It is also necessaryto investigate further cohorts of different DUI (e.g.2 years). The complicated expressive pathways of genessuch as DISC1 and COMT may cloud the results of themicroarray and due to exquisite regional specificity ofthe genes, it would be a major task ahead to workthrough the whole brain, gene by gene.

Lynn DeLisi (New York, NY) started her presenta-tion with a comprehensive overview of evidence forprogressive structural brain change in schizophrenia.The concept that schizophrenia is a degenerative braindisease exists in the literature since Kraepelin definedDementia Praecox as a disorder, with only partiallyreversible damage, that progressed, from early signs intodementia. This was followed by a century of observa-tions using technology such as pneumoencephalography(showing the first evidence of ventricular enlargement)and CT scans. During the past 30 years, evidence hasaccumulated for structural changes in schizophrenia, forexample increased lateral ventricle size, non-localizeddecreases in gray matter volumes, decreased integrity ofwhite matter, regional volume decreases in frontal and


temporal lobes (especially the superior temporal gyrusand the hippocampus), decrease in the normal asym-metry of the brain, caudate enlargement, and develop-mental abnormalities (such as cavum septumpellucidum and size and shape changes of the corpuscallosum). However, since the early 1990s, a contro-versial debate has ensued as to whether schizophrenia isa neurodevelopmental disorder. Dr. DeLisi describedschizophrenia as a “lifetime disorder”, where defectivegenes influence brain growth and development beforethe onset of the illness, and then have an influence of thebrain aging process, whereby progressive brain changesignificantly greater than in health controls occursthroughout one's lifetime. This progression variesamong individuals and is sporadic. However, it maybe used to determine early signs of illness prior to itsclinical presentation. DeLisi continued to discussfindings from the Stony Brook First Episode Psychosisfollow-up study (1988–2000). This was the firstcontrolled serial imaging study and followed 87 patientsover a period of 10 years (90% of the cohort had outcomedata available; DeLisi et al., 1995, 1997, 2004).Although ventricular enlargement was a consistentfinding in this cohort of patients, when the enlargementoccurred varied greatly among subjects. Past literatureand findings are varied and are not without methodolo-gical problems (for example lack of a control group, orthe use of only one imaging slice). A focus of DeLisi'swork, as well as other centers throughout the world, is todevelop markers using Magnetic Resonance Imaging(MRI) that will detect individuals at high risk for thedevelopment of schizophrenia (the so called “at-riskmental state”). The NYU/NKI Genetic High Risk study(2007), DeLisi's more recent work, examined whitematter integrity using Diffusion Tensor Imaging (DTI) ofwhite matter connections and evidence of atrophy bymeasuring an apparent diffusion coefficient (ADC).They confirmed decreased fractional anisotropy (FA)and an increased Apparent Diffusion Coefficient (ADC)in the left frontal gyri. When these changes occur is notyet clear, but there is an indication that people at genetichigh-risk for schizophrenia show evidence of subtlestructural changes of a progressive brain disorder leadingto schizophrenia. However, there is evidence that similarprogressive changes occur in other disorders, such asbipolar mood disorder and Alzheimer's disease. Ven-tricular enlargement is also a “fluid” condition, forexample in alcoholism and anorexia nervosa, whereshrinkage and enlargement can occur at different stagesof the disease. It therefore appears that structural changesare non-specific, but that the rate, place and timing of thechanges appear to be specific to schizophrenia. We now

have reached a period in which the influence ofneuroleptics on structural changes and the developmentof third generation neuroprotective drugs should beexamined.

Patrick McGorry, of the ORYGEN Research Centre,Melbourne (Australia), presented a series of studiesincluding clinical trials in prodromal and first-episodepsychosis, longitudinal follow up studies of first-episode psychosis, and neurobiological studies, tomotivate the use of the clinical staging model inpsychiatry. The concept of staging is borrowed fromclinical medicine in which different stages of a disorderwarrant different interventions. Current diagnosticmodels in psychiatry still have difficulty guidingtreatment and predicting outcome. Staging could restorethe utility of diagnosis, promote early intervention andorganize research data into a coherent clinico-patholo-gical framework. Interventions could be evaluated interms of their ability to prevent or delay progressionfrom earlier to later stages of disorder. Previouslongitudinal studies were heterogeneous, includingpatients with multiple episodes and chronic illness.Few longitudinal first-episode psychosis (FEP) studiesof more than 24 months have been done. FEP can evolveover time into different clinical phenotypes, e.g. majordepression, bipolar mood disorder, or schizophrenia.The lack of baseline refusal data could have contributedto sampling bias. The EPPIC (Early Psychosis Preven-tion and Intervention Centre) study aimed to addresssome of these issues, and to describe long-termfunctioning and clinical outcome of FEP. EPPIC is anaturalistic, prospective longitudinal study whichincluded 723 FEP patients between the ages of 14 and30 years, who were recruited over several yearsbeginning in 1989. The median follow-up durationwas 7.2 years, with data available on 651 patients (484whom were interviewed). Seventy-four patients werenot contactable and 128 refused follow-up evaluations.At baseline, DSM III/ DSM IV-TR diagnoses wereschizophrenia (57.5%), schizoaffective disorder (9.4%),affective psychosis (24.7%) and other psychotic dis-orders (8.4%). The mean age at follow-up was28.7 years. 50.2% of patients with schizophreniaachieved remission (Andreasen et al., 2005). Over aperiod of 2 years, 20.2% of patients were ill intermit-tently, 32.1% were chronically ill, and 40% were not ill.At follow-up 77.5% of patients were on treatment, and3.7 patients were inpatients. In comparisonwith previousstudies, the outcome of the EPPIC study seems better, forexample current employment 39.2% (19–29% in pre-vious studies), employment over previous two years57% (versus 37%), and suicide rate 2.3% (versus 10–


11%). Remission rates in other studies, depending oncriteria used, were 37–59% with 29–50% of those withschizophrenia achieving remission. This is similar to thefindings in EPPIC. The strengths of EPPIC is the largeand representative sample, the inclusion of multiple FEPdiagnoses and standardized assessments (SANS andBPRS). Limitations are variation in FEP treatmentreceived, the follow-up after 2 years were not controlled,and the investigators were unable to apply duration ofremission criteria (6 months). Low admission rates donot seem to have been influenced by bed-availability, butMcGorry explained that alternatives, for examplecommunity beds, were available. At the time of thestudy no specific interventions were done to promotevocational outcome, however, case-management couldhave contributed. IPS based support may be of benefit.Although 90%of the sample remitted, only 50%worked.It appears that specialized early intervention treatmentmay improve vocational functioning and symptomaticremission. Cost-effectiveness data is available on asubset of the study. Over the 7 years of follow-up, $2500per capita per annum has been spent (compared to $5000per capita/annum in historical control groups). It seemsthat although initial outsets are more, the pay-off of earlyintervention is good. However, to influence policymakers, cost-effectiveness analysis is not sufficient andmomentum and pressure from consumers and commu-nities are needed to facilitate change. According toMcGorry “clinical staging with a restructure across andwithin diagnostic boundaries with the explicit operatio-nalization of criteria for extent and progression ofdisorder should be actively explored in psychiatry as aheuristic strategy for the development and evaluation ofearlier, safer, and more effective clinical interventions,and for clarifying the biological basis of psychiatricdisorders”.

Stephen Marder (Los Angeles, California) concludedthe session by discussing “Differing targets for theshort-term management of acute episodes and long-termfunctional impairments of schizophrenia”. He built onthe preceding talks' arguments regarding the “evolu-tion” of schizophrenia over time and the importance ofstage-specific and early intervention. Previous researchshowed that different symptomatic domains followeddifferent time courses. For example, positive symptomsprogress from premorbid, to prodromal, to acute andthen to chronic symptoms. However, negative symp-toms do not follow this pattern, but also seem to bepresent in the prodromal stage (e.g. Hafner and Now-otny, 1995). Cognitive impairment seems to be presentlong before the onset of positive symptoms. In apopulation based study of 555,326 Israeli adolescents

(Reichenberg et al., 2005), there was clear impairment inactual and expected IQ, as assessed by reading andspelling skills, between adolescents that went on todevelop schizophrenia, and those who did not. Schizo-phrenia cases' estimated IQ was 0.18 below, and theactual IQ 0.49 standard scores below those of thehealthy cohort. In another restrospective study ofpremorbid cognitive functioning, Fuller et al. (2002)found patients with schizophrenia to have a decline incognitive abilities (especially reading, language, sourcesof information and mathematical abilities) by the 11thgrade. Cognitive differences can be detected as early asgrade 1 and the pattern and average of cognitiveimpairment in FEP and chronic patients seem to besimilar. There is no convincing evidence for cognitivedecline during the 1st 5 years of illness. Whethertreatment changes the course of schizophrenia is stillopen to debate. Bleuler (1978) followed 208 patientsover a period of 20 years. 20% of these patients had amild/moderate “end state” of disease. He also found adecline in “catastrophic cases” and described these casesalso as a “clinician illusion” due to clinicians working inhospitals being exposed to more severe cases. We nowknow that remission rates of FEP are higher and that theshorter the duration of untreated psychosis, the better theoutcome. Patients also deteriorate more rapidly after theage of 74 years. Marder proposed that multipleneuropathological processes play a role in differentgroups of symptoms and patients and that the disease ismore “active in the prodromal and early course of theillness. Patients with schizophrenia are vulnerable tolosses in gray matter and connectivity.

Dean raised the question of whether schizophreniacould be considered a “syndrome”, with completelydifferent underlying processes. Further research toimprove our understanding of schizophrenia and theunderlying neuropathological processes, will enable thedevelopment of specific interventions aimed at prevent-ing the onset of psychosis, limiting deterioration of thepatients, and improving their functioning and quality oflife.

The glutamate hypothesis is alive and kicking:treatment of negative symptoms and cognition inschizophreniaReported by Jimmy Lee

Schizophrenia has been viewed primarily as adopaminergic disorder, and most antipsychotic medica-tions available have dopaminergic antagonism proper-ties of varying potency. Increasingly, observations andstudies have implicated other neurotransmitter systems


in the pathogenesis of schizophrenia, notably theserotonergic as well as glutamatergic systems.

The symposium started with Dr. Daniel Javitt(Orangeburg, NY) reminding the participants thatphencyclidine and ketamine, both glutamate antago-nists, produces schizophrenia-like symptoms in indivi-duals who consume them. This observation ledresearchers to hypothesize the involvement of theglutamatergic system in schizophrenia, and that mod-ulating the system will lead to improvement insymptoms. Dr. Javitt also pointed out that whiledopaminergic neuronal projections are to the limbic,frontal and basal ganglia regions, N-methyl-D-aspartate(NMDA) receptors were diffusely distributed through-out the whole brain. NMDA receptors are believed toplay a role in gain control, integration and sensorymemory systems.

His presentation then focused on sensory processingdeficits in schizophrenia, highlighting the mismatchnegativity deficits observed in schizophrenia. Dr. Javittpostulated that these processing deficits could result inemotion identification deficits. He also presentedfunctional neuroimaging data that demonstrated visualcortex involvement in schizophrenia, correlating withvisual processing deficits.

Dr. Louise Verrall (Oxford, UK) noted that schizo-phrenia susceptibility gene studies thus far convergeupon signaling at the NMDA receptor synapse. Shehypothesized that NMDA receptor hypofunction was animportant feature in schizophrenia and that its modula-tion could be therapeutically beneficial. Glutamatefunctions as an agonist at the NMDA receptor, and D-serine and glycine are known co-agonists at the samereceptor. Reduction of availability of co-agonists couldlead to hypofunction of the receptor complex.

Dr. Verrall focused her presentation on D-serineregulation, specifically the roles of serine racemase(SRR), D-amino acid oxidase (DAO) and alanine-serine-cysteine transporter 1 (Asc-1). SRR is involved in thesynthesis of D-serine from L-serine, and its proteinexpression was found to be increased in post-mortemschizophrenia brains, specifically in the frontal cortex.DAO degrades D-serine, and increased DAO mRNAexpression has been found in the cerebellum ofschizophrenic brains, with corresponding raised proteinexpression. In addition, antipsychotic administrationappears to have no effect on DAO activity. Asc-1modulates re-uptake of D-serine, and it was found to bereduced in schizophrenia with no significant changes tomRNA expression. Dr. Verrall posits that this down-regulation of Asc-1 could be a homeostatic mechanismin response to lowered D-serine levels. Dr. Antonio Vita

(Milan, Italy) asked if there was any correlation withseverity of disease and Dr. Verrall added that her groupnoted that increased DAO activity was correlated withduration of illness. The presentations thus far hadconcentrated on highlighting the role of glutamatergicdysregulation on a molecular, neurophysiological andimaging level. The speakers than moved on to treatmenttrials.

Dr. Javitt presented a summary of the clinical trialswith NMDA agonists and calculated an effect size of0.5. He then presented data on a 4-week open label D-serine dose escalation study, from 30 to 120 mg/kg/d,examining psychopathology using the total PANSSscore, and neurocognition measured by the MATRICS(Measurement And Treatment Research to ImproveCognition in Schizophrenia) neurocognitive battery. Hefound improvement in composite neurocognition mea-sures at doses 60 mg/kg/d and above, and specifically inworking memory, verbal learning and attention.

Dr. Mark Weiser presented preliminary data on a 16-week randomized, placebo-controlled trial on schizo-phrenic subjects stabilized on antipsychotic medication.Each subject received either 2 g of D-serine per day or aplacebo. The primary outcome measures were negativesymptoms, measured using the SANS, and cognition,measured with the MATRICS battery. Out of 195subjects randomized, 149 completed the trial. Therewere no differences in negative symptom scores, orMATRICS composite scores. There were no differencesin individual cognitive domains. Both groups hadimprovement in PANSS total scores, equal number ofdropouts and no subjects suffered from nephrotoxicity,an adverse event associated with D-serine. Dr. Weiserwent on to discuss the possibility of publication bias inexisting literature as a reason for the optimism generatedby the trial results. He also highlighted a significantplacebo effect in negative symptom improvement. Dr.Vita asked why was there such a high placebo effect, towhich Dr. Weiser replied that it could be due to thesubjects entering the trial all hoping to see improvement,and their anxiety to get better. Dr. Weiser also added thatthe dosages achieved in this trial were far lower than thatin rat models where biological effectiveness was seen at10-fold higher serum levels of D-serine.

Dr. Guochuan Tsai presented data on a trial involvingsarcosine. Sarcosine is an inhibitor of the sodiumdependent glycine transporter (GlyT1), and Dr. Tsaihad demonstrated recently that it improves positive,negative and cognitive symptoms when used incombination with antipsychotics. Therefore, the trialcompared sarcosine against D-alanine (a glycine siteagonist) and D-serine. Results from the trial showed that


sarcosine was superior to D-serine. In addition, sarcosinewas used as monotherapy in acutely ill schizophrenicsubjects and demonstrated better efficacy againstplacebo, especially in antipsychotic-naïve subjects. Dr.Tsai was asked if any studies were done combiningNMDA agonists with atypical antipsychotics, and hereplied that there were and that D-cycloserine combinedwith clozapine appears to have a worse, rather thanbetter outcome. He was also asked if efficacy of theagonists was dependent on the stage of illness of the trialsubjects; to which he agreed that drug-naïve subjectsresponded better to sarcosine, perhaps implying thatearlier stage treatment would have a better outcome. Dr.Javitt was asked for his opinion on indications for D-serine treatment; to which he replied that negativesymptoms and cognitive deficits would make interestingdrug targets. He added that D-serine or related agonistscould also be used in the prodromal stage of illness,possibly to restore neuronal plasticity.

Dr. William Deakin (Manchester, UK) led thediscussion and began with the statement that glutamatemarked the “renaissance of therapeutic optimism”. Heagreed that impaired NMDA function possibly leads tosymptom production, but asked if this impairment is aprimary abnormality. He added that any geneticevidence of glutamate involvement was tenuous andweak at best. He suggested that the search forbiomarkers and functional imaging tools should focuson the glutamate pathway.

Phosphodiesterases and schizophrenia:improving disease understanding and their potential asthe next generation of therapeutic targetsReported by Maaike Alaerts

The cyclic nucleotides cAMP and cGMP areimportant second messengers involved in intracellularsignal transduction in all types of cells throughout thehuman body. To ensure that these two moleculescorrectly communicate diverse extracellular signals toa complex set of tertiary messenger and effector systemsto trigger unique responses, their production, accumula-tion and destruction is tightly regulated and localized inspecific subcellular microdomains, enabling the cell tolimit time and space of signal activity. Cyclic nucleotidephosphodiesterases (PDEs) are the enzymes thatdegrade cAMP and cGMP and thus have a crucial rolein controlling this cyclic nucleotide signaling. There are11 different PDE families, with each family typicallyhaving several different isoforms and each isoformhaving several different splice variants. It is notsurprising that these PDE isozymes are differentially

expressed in different cells and localized in distinctmicrodomains in the cells to modulate distinct signalingpathways. In the brain, a structure specialized in cell-to-cell communication, the regulation of second-messengersignaling, is probably most sophisticated and expressionof PDEs is particularly high. This has led to investiga-tions into the contribution of specific PDEs to CNSdisorders and into their potential as targets for selectivedrugs for the treatment of psychiatric and neurodegen-erative disorders (Menniti et al., 2006). In this sessionthe possible roles of PDE4, PDE9 and PDE10 inpsychiatric disorders and their promising potential astherapeutic targets were discussed by Ben Pickard(Edinburgh, Scotland), Frank Menniti (Pfizer, Groton,Connecticut), James O'Donnell (Memphis, Tennessee)and Nick Brandon (Wyeth, Princeton, NJ).

The PDE4 family, consisting of 4 members A/B/C/D,is involved in the specific degradation of cAMP. TheDrosophila learning and memory gene Dunce ishomologous to PDE4. Accordingly, in humansPDE4A, PDE4B and PDE4D are mainly expressed incortex, hippocampus and striatum, brain regionsimplicated in memory and cognition. Activation ofNMDA receptors that induce cAMP signaling oractivation of MEK that stimulates ERK signaling, bothlead to increased phosphorylation of CREB and play animportant role in memory. NMDA receptor antagonistsand MEK inhibitors induce memory deficits, which canbe reversed by PDE4 inhibition with Rolipram, asshown in different behavioral tests in mice and rats.Rolipram is a specific PDE4 inhibitor that has not onlybeen shown to facilitate long-term memory, but also tohave antidepressant and antipsychotic activity (O'Don-nell and Zhang, 2004; Kanes et al., 2007). Themechanism and the role of the different PDE4 subtypesin these diverse effects are being investigated. BothPDE4B and PDE4D knock-out mice show antidepres-sant like behavior and a proliferation of neuronal cells inthe hippocampus (Zhang et al., 2002; Siuciak et al.,2008; Zhang et al., 2008). The mice deficient in PDE4Dalso show enhanced long-term memory and specificdownregulation of PDE4D4 showed improved memoryin rats. Hippocampal neurogenesis is thought to mediatethe effects of chronic treatment with Rolipram onmemory formation and depression. More evidence for arole of PDE4B in psychiatric disorders comes fromgenetic studies. The PDE4B gene has been found to bedisrupted by a translocation breakpoint in two relatedindividuals with psychosis (Millar et al., 2005) andassociation has been found between SNPs in the geneand schizophrenia (Pickard et al., 2007; Fatemi et al.,2008; Numata et al., in press). Moreover, the scaffold


protein disrupted-in-schizophrenia 1 (DISC1), which isan important genetic risk factor for schizophrenia andbipolar disorder, has been shown to interact dynamicallywith PDE4B (Millar et al., 2005). DISC1 also binds theother PDE4 isoforms and it turned out that theirinteractions are quite complex and dependent on bothDISC1 and PDE4 isoforms. Increased cAMP levelscause release of PDE4D and PDE4C, but not PDE4Band PDE4A from full-length DISC1. The finding thatDISC1 has two binding sites that PDE4 isoforms bind incommon, while it possesses additional N-terminal sitesspecific for PDE4B, is probably related to this (Murdochet al., 2007; Millar et al., 2007). DISC1 missensemutations located within these specific PDE4B bindingsites and interfering with the binding, give rise tophenotypes related to psychiatric disorders in mice.Q31L mutants show a depressed phenotype and respondto the antidepressant Bupropion but not to Rolipram,while L100P mutants show a schizophrenic phenotypeand respond to both the antipsychotic Haloperidol andRolipram (Clapcote et al., 2007). Altered DISC1-PDE4B interaction may thus underlie the symptoms ofsome cases of schizophrenia and depression andmore generally, genetic variation in either DISC1 orPDE4 that alters their coexpression, dynamic associa-tion and thereby cAMP signaling may predispose topsychopathology.

PDE9 is a cGMP specific PDE and is widelyexpressed throughout the brain. NO is an importantactivator of soluble guanylylcyclase (GC) and theformed cGMP activates cGMP dependent proteinkinases (cGKs) and different types of cyclic nucleotidegated ion channels. This signaling cascade has beenlinked to membrane excitability, modulation of neuro-transmitter release and synaptic plasticity, the cellularbasis for learning and memory (Feil and Kleppisch,2008). Certain postsynaptic effects induce retrogradesignaling with NO as messenger, causing a presynapticcGMP rise and changes leading to long-term potentia-tion (LTP) or long-term depression (LTD). PDE9 isthought to play an important role in regulating thissynaptic plasticity. Genetic deletion or pharmacologicalinhibition of PDE9A in mice results in elevation ofcGMP levels in the brain, enhanced hippocampal LTPand improved spatial memory and object recognition.One important player in hippocampal LTP is thehippocampal-VTA (ventral tegmental area) functionalloop that controls the entry of information into long-term memory (Lisman and Grace, 2005). Noveltysignals from the hippocampus to the VTA, get integratedwith other information and cause firing of thedopaminergic VTA neuronal projections to the hippo-

campus, which enhances LTP. But PDE9 does not seemto have an effect on this dopamine pathway. Furtherinvestigations showed that PDE9 plays a role indifferent glutamate pathways. Glutamate acts onNMDA and AMPA receptors, ion channels that incooperation enhance excitatory post-synaptic potentialsleading to LTP. Activation of 5HT2A receptors in theprefrontal cortex (PFC) excites glutamatergic pyramidalcells in deep cortical layers and activates a glutamatergicrecurrent network (Béïque et al., 2007). PDE9 isexpressed in these pyramidal projection neurons incortical layer 5 where it regulates an actively turningover pool of cGMP and in PDE9 knockout mice thepsychedelic effects of the 5HT2A receptor agonistmescaline are inhibited. The striatum gets glutamatergicinput from cortical layer 5 and PDE9 inhibitionstimulates the highest rise in cGMP there (∼300%),but there is no effect on striatal behavior such ascognitive processes involving executive function.Visual recognition memory is correlated with AMPAreceptor endocytosis and LTD in the perirhinal cortex(Griffiths et al., 2008). PDE9 is highly expressed in thisarea and PDE9 inhibition augments object recognition.So PDE9 seems to play a role in these glutamatepathways, but to really understand the mechanism, moredetailed knowledge on the expression of this isoform inneuronal cell types, subcellular localization and regula-tion of the PDE9 sensitive cGMP pool is needed.

PDE10 is a dual cAMP/cGMP PDE that is highlyexpressed in the medium spiny neurons in the striatumand also shows low expression in hippocampus andcortex (Seeger et al., 2003). The striatal medium spinyneurons are the principal input site for widespreadcortical information that is integrated in the basalganglia circuit to plan and execute relevant motor andcognitive reactions. A disruption of this cortico-basalganglia signaling is believed to contribute to thepsychotic symptoms and cognitive deficits of schizo-phrenia. Inhibition of PDE10A with papaverineenhances striatal output by increasing activity in thecGMP and cAMP signaling pathways and has beenshown to have anti-psychotic properties and thepotential for improvements in cognition (Siuciak et al.,2006; Menniti et al., 2007). Wyeth and Elbion enteredinto a partnership to identify small molecule PDE10inhibitors that effectively treat the positive and negativesymptoms and the cognitive deficits in schizophrenia,while current antipsychotics only treat the positivesymptoms. Using a battery of behavioral tests for miceto identify effects on the three types of symptoms, twocompounds were found with satisfying effectivenessand few undesirable side effects. Further biochemical


investigations showed that PDE10 inhibition leads toincreased phospho-CREB and phospho-ERK, known tounderlie synaptic plasticity and thus learning andmemory. The findings that PDE10A is expressed in apunctuate pattern, which might point to interaction withscaffolding proteins, and that PDE10A2 translocates tothe cytosol upon PKA phosphorylation while PDE10A2inhibition causes re-insertion in the membrane, showthat subcellular localization of PDE10 is important fornormal enzyme function, and a better biological under-standing is needed to unravel the mechanism of action ofPDE10 inhibition.

In conclusion, PDEs have crucial roles in normalbrain functioning, may contribute to dysfunction in CNSdisorders and exciting results are awaited for treatmentof these disorders by inhibition of specific PDEsubtypes.

IV. CLINICAL CHARACTERISTICS

Future classification of schizophreniaReported by Demian Halperin

Robin Murray (London, UK) began this session byaddressing the question of whether minor psychoticsymptoms in the general population are relevant toschizophrenia. In a large survey on mental health in theUK, correlates of minor psychotic symptoms in thegeneral population were examined and found to be thesame as in schizophrenia cohorts (low verbal IQ, loweducation, urbanicity, cannabis, life events, neuroticsymptoms, ethnic minority), thus suggesting thatpsychosis is at the extreme end of a continuum. Thenecessity of treatment at a certain point in thiscontinuum imposes the need for a categorical distinc-tion. He then examined the notion of an overlap ofschizophrenia with affective psychoses, recalling theKraepelinian dichotomy between schizophrenia andbipolar disorder and emphasizing that this dichotomymay involve a certain amount of misdiagnosis and an inbetween category which is schizoaffective disorder. Toaddress the question of whether dimensions are betterthan categorical diagnoses, Dr. Murray reported theresults of two studies in which the five usual symptomfactors of the psychotic state (mania, reality distortion,depression, disorganization, and negative symptoms)were distributed in schizophrenia and psychotic mooddisorder according to rating scale scores. The maniascore was shown to be a good distinguisher of psychoticmood disorder, whereas disorganization and realitydistortion were rather good distinguishers of schizo-phrenia. Negative symptoms and depression were

shown to less distinguish between schizophrenia andpsychotic mood disorder. After regression of clinicalfactors on diagnosis and dimension scores, dimensionscores were found to be slightly better than categoricaldiagnoses. However, using both provided more clinicalinformation than either alone. This result thus suggeststhat the next version of DSM and ICD classificationsystems should consider using both dimensional scoresand categories in the formulation of diagnoses. Finally,the question of risk factors was raised. Dr. Murray beganby showing evidence that developmental deficits are notsimilarly distributed among pre-schizophreniform andpre-manic individuals. He then showed a 50% overlapof candidate genes for both schizophrenia and bipolardisorder and said that copy number variations mayexplain some of the further developmental impairmentfound specifically in schizophrenia. He concluded byproposing that the next version of DSM (DSMV-V) andICD (ICD-11) could replace the term psychosis with theterm “Dopamine Sensitisation Disorder of the Associa-tive Striatum (DSDAS)”, that this, he predicted, will beroutinely diagnosed by neurochemical imaging, and thatdifferent genes and different environmental factors willhave been mapped onto the 5 symptom factors and thedevelopmental dimension of DSDAS.

James Van Os (Maastricht, The Netherlands) beganhis lecture by explaining the current dissociationbetween the four main aspects of the diagnosticconstruct: the psychosis phenotype, the diagnosisvalidity, its usefulness and its acceptability. He thenanalyzed each of these aspects. Regarding the pheno-type, psychosis has been shown to be developmental(high expression of the disease between the age 15 and35). Subclinical psychoses have been found to be highin the 23–24 y/o population with a 15.7% cumulativeincidence of delusions and 4.6% cumulative incidenceof hallucinations. Also urbanicity has been shown toequally influence the risk for psychotic disorders as wellas subclinical psychoses which itself is a strongpredictor of clinical transition to psychosis withinthree years. Different configurations of symptoms maylead to different courses, behaviors, distress and need forcare. This, according to Dr. Van Os, is the basis for adimensional approach in which psychotic disorder is anoutcome at the end of a continuum comprising commonand transitory subclinical psychoses and rare andpersistent clinical psychoses. Jim van Os then discussedthe notion of diagnosis validity. This notion involvesspecific symptoms, specific causes/correlates, specificoutcomes and specific treatment or response. Regardingsymptoms, he showed no strong contrast or specificitywith as example an overlap of the distribution of manic


symptoms in non-affective psychosis and manic psy-chosis. To discuss the specificity of etiology, he showedno genetic specificity. In terms of outcome, a differentcourse can be seen in bipolar disorder and schizo-phrenia, with cognitive deterioration starting at onset ofthe disease in the latter. He then described the currentcategories (schizophrenia, schizoaffective disorders, andbipolar disorder) as “fuzzy sets” and asked whether thesolution could come from a dimensional approach. Healso asked whether it is possible to distinguish primaryversus secondary negative symptoms because of thedifficulty in clarifying whether these symptoms are aresult of positive symptoms, affective symptoms,cognitive impairment, and extrapyramidal side effectsof antipsychotics, social exclusion, environmental orprofessional deprivation. In a study on intensity andvariability of emotions, a potential influence of bluntedaffect was invalidated. In the last part of the lecture, Dr.Van Os discussed the usefulness of “diagnosis”. Heproposed a switch from the current categorical approachto a dimensional approach according to the majorsymptoms of the disease. The dimensional approach hasbeen shown to be superior to the categorical approach interms of therapeutic usefulness and prognostic useful-ness, but the higher benefit could be obtained by theconcomitant use of these approaches. The proposeddimensional approach could somehow resemble theapproach of metabolic syndrome which is also com-posed of major symptoms forming a continuum betweenthe “normal” and the “pathologic” (obesity, dyslipide-mia, glucose intolerance, prothrombotic state, proin-flammatory state), thus requiring a dimensional axis inaddition to the categorical axis (diabetes, cardiovasculardisease, etc). This model could be applied to the“general psychotic syndrome”. He concluded byacknowledging that the term “schizophrenia” shouldbe modified because misuse of medical terms have anegative impact due to medical reification and beha-vioral pseudo-validation.

Dr. Jaeger (Munich, Germany) discussed the issue ofcourse of schizophrenia as a potential criterion forclassification. First he briefly recalled the nosologicalmodel of Emil Kraepelin, and the key-elements for theestablishment of diagnosis validity; clinical description,laboratory studies, delimitation from other disorders,follow-up studies and family studies. He then presentedthe current challenges for classification in psychiatrywhere the validity of diagnosis is low, perhaps due tolack of specificity of neurobiological findings fortraditional diagnostic entities and continuous distribu-tion of psychopathological symptoms. He also presentedthree nosological models of functional psychoses: the

dichotomous concept, the continuous spectrum modeland the multiple-entities model. Dr. Jaeger presented theresults of his study on the predictive validity of ICD-10diagnoses and the comparison with the dimensionalapproaches. This study is a 15-year follow-up study onfunctional psychoses. Course types were divided intosingle-episode, episodic, and chronic courses. Therewere no significant differences between ICD-10 andDSM-IV in terms of distribution of course typesaccording to diagnoses. A logistic regression modelwas applied for the prediction of a dichotomousoutcome variable. The model I (categorical) had ICD-10 diagnoses as predictor variables and the model II(dimensional) had psychopathological and demographicdata as predictor variables. A dependent variable waschronic versus non-chronic course. The predictivevalidity of the categorical model was 78% and thepredictive validity of the dimensional model was 77%.In conclusion, he acknowledged the considerablepredictive validity of the ICD-10 and DSM-IV diag-noses and questioned the superiority of the dimensionalmodel. He also proposed a multidimensional diagnosticapproach comprising syndromes, course types andetiology.

The fourth lecture of this symposium was presentedby Silvana Galderisi (Naples, Italy). She discussed thetopic of deficit schizophrenia and its validity as acategorical subtype of schizophrenia. She proposedabolishing the term “schizophrenia” and replacing it by“idiopathic psychosis”. According to her, clinicalheterogeneity within schizophrenia may reflect differentetiopathogenic mechanisms and the identification ofvalid categorical subtypes might advance scientificknowledge and development of more specific symptomclusters. She defined the major features of the diagnosisof deficit schizophrenia as follows: at least two of thefollowing symptoms (restricted affect, diminished emo-tional range, poverty of speech, curbing of interests,diminished sense of purpose, diminished social drive);symptoms enduring in the precedent 12 months andduring periods of clinical stability; symptoms notsecondary to factors other than the process of thedisease itself. She then gave us an overview of the majorclinical differences between deficit and non-deficitschizophrenia, such as more negative symptoms, morefrequent insidious onset, worse long-term outcome,more frequent resistance to antipsychotics, more severeneurological impairment, and less dysphoria, suspi-ciousness, hostility, suicidal ideation and substanceabuse, and worse premorbid adjustment, a prevalence of15 to 25%, and a high rate of agreement between initialand follow-up diagnoses. In an attempt to validate the


deficit schizophrenia subtype, she presented differencesin risk factors, in brain imagery results, and inneurocognitive profiles. Regarding risk factors, it wassaid that there is a greater risk of schizophrenia inrelatives of probands with deficit schizophrenia. Also,more severe social withdrawal has been shown in non-psychotic relatives of probands with deficit schizophre-nia. An association between male sex and deficitschizophrenia has been found, and there is a double-dissociation regarding season of birth where anassociation between summer birth and deficit schizo-phrenia has been found in various studies. Regardingbrain imaging, no decrease of prefrontal volume and noenlargement of the ventricles has been observed indeficit schizophrenia (as opposed to non-deficit schizo-phrenia). Also, there seem to be no abnormality of P300in deficit schizophrenia. Concerning cognition, adifferent set of cognitive impairments has been foundin deficit schizophrenia, namely social cognition, globalcognition and language. Dr. Galderisi summarized themain differences between deficit versus non-deficitschizophrenia as follows: more negative symptoms,more treatment resistance, worse premorbid adjustment,different risk factors, no neuroanatomic abnormalities,no P300 abnormality and different neurocognitivedeficits. She concluded by saying that so far researchhas failed to prove that deficit schizophrenia representsthe severe end of the psychosis continuum, but has notdisproven the claim that it may be a valid categoricalsubtype within the syndrome of schizophrenia.

In the discussion that followed Dr. Van Os was askedhow in practice, he would combine the categorical anddimensional approaches. Jim van Os answered that the“general psychotic syndrome” (categorical approach)could be viewed as stable in time, whereas thedimensional approach would allow variations in time.Dr. Jaeger was asked whether he favors keeping thecurrent categorical diagnoses. He responded positivelyand proposed to add to it an etiologic classification.Dr. Galderisi was asked whether it is possible todistinguish primary versus secondary negative symp-toms. She answered that it is the most difficult issue withdeficit schizophrenia, and that one has to rely on variousinformation from multiple sources, and that it is usuallynot possible to reach a conclusion after the firstinterview with the patient because the negativesyndrome requires longitudinal assessments. Also,medication changes have to be taken into account. Shewas also asked what she thinks of the “acceptability” ofthe term “deficit schizophrenia”. She responded thatprobably the acceptability would be low and proposedthe term “primary enduring negative syndrome”. She

was also asked whether deficit schizophrenia could beconfounded with developmental disorders, for exampleautism. She answered that the clinical picture in autismis totally different, with a greater lack of verbalcommunication and social interactions. Regardingdevelopment disorders in general, she said that it isnot totally possible to exclude this hypothesis becausepoorer premorbid adjustment in the deficit syndromereflects a very early developmental process that isoccurring.

V. COGNITION

From visual perception to attention: recentadvances in cognitive research in schizophreniaReported by Katja Koelkebeck

In recent decades, the general opinion seemed to bethat schizophrenia patients display deficits only in high-cognitive level abilities, with the visual system not beingcompromised. The current opinion, though, is muchdifferent from that assumption. During the oralpresentations it became clear that also basic levelfunctions show disturbances in schizophrenia patients.These basic-level functions encompass, for example, theability to integrate stimuli, the function of center-surround interaction, detection accuracy, inhibition ofreflexive saccades as well as voluntary saccade initia-tion, spatial perception of hemi eye-fields and differentareas of attention (alertness, orientation and executivecontrol). These functions seem to be severely disturbedand consecutive symptoms often occur before onset ofillness, as well as in close relatives and patients withschizophrenia spectrum disorders. The core deficits inattentional domains are hypothesized to be based ondysfunction in various brain regions and discussed to beeither bottom-up or top-down deficits.

Pamela Butler (Orangeburg, NY) was the firstpresenter and talked on impairment of perceptualorganization of “similarity” and “proximity” in schizo-phrenia. She presented a model of disturbance of low-level perceptual organization and visual cortex deficitsin schizophrenia patients and presented a visual task thattests visual grouping based on proximity in space andsimilarity in color. A grouping threshold was observed;later, the stimuli were additionally masked. Theschizophrenia patients had significantly higher thresh-olds in perceiving grouping differences. The datashowed impairments for perceptual organization basedupon spatial relationships and feature similarities.Schizophrenia patients seemed to have deficits in low-level perceptual organization. The results imply


impaired lateral connections within cortical areasinvolving the peripheral magno- and parvocellularvisual cell systems, maybe also the glutamate signalingsystem.

Dr. Butler further discussed whether basic levels ofgrouping are disturbed and what might be the stimulusduration needed for organizing and grouping. One wayto further investigate this issue might be animal models,and some research on rat models was presented. Ratsshowed a higher threshold for stimulus perception whengiven ketamine. One possible explanation for thisNMDA-antagonist effect might be a disruption ofintegrating information across the cortex (Kurylo andGazes, 2008). In sum, schizophrenia patients neededmore intrinsic organization and greater time to dis-criminate simple forms using two basic principles ofgrouping: proximity and similarity.

Yue Chen (Boston, Massachusetts) reported on basicinhibitory control deficits in visual motion processing inschizophrenia. He stressed that in this disorder, thechallenge in research is to find closer links to specificneuromechanisms. Thus, he presented data on specificvisuo-neurophysiological tasks activating spatial pro-files of neuroresponsiveness, particularly on visualmotion processes. The main paradigm of his recentresearch is the so called “center-surround interactiontask” as well as the “three-flash illusion task”. Centralstimulus action will be attenuated by outer stimulusinterference, but the responsiveness depends on thedirection of the general movement of the dots. Inschizophrenia, his research group observed a greaterperception shift opposite to the general direction of thestimuli. These findings suggest greater surround sup-pression in patients. In the three-flash illusion task,similar results were yielded. While healthy controlsperceived two quickly-sequenced light-flashes as threeflashes, schizophrenia patients perceived only the tworeal flashes. Again, a stronger surround suppression wasfound in patients when compared to healthy controls.The pattern of the results seems to provide evidence foraltered basic inhibitory control of visual motionprocessing in schizophrenia.

Raquel Gur (Philadelphia, Pennsylvania) introducedan fMRI task in her presentation challenging very basalfunctions of visual attention, sensory processes anddecision-making. Participants were required to push abutton when they saw a certain stimulus. Withoutinforming participants, distracter stimuli were pre-sented. Patients were very disturbed by distracter stimuliand brain activation in the posterior brain regions washigher in patients during distracter stimulus presenta-tion. Patients and also close family members seemed to

have difficulties focusing on targets and neglectingdistracter stimuli (Gur et al., 2001a,b). Gur supposedthat these deficits might be due to a failure to activatefocusing mechanisms, to pay close attention and to agreater distractibility by non-introduced stimuli. Similarauditory deficits have been shown in a recent study byWolf et al. (2008). The question was raised whether thedeficits described are due to attentional difficulties only,although those deficits seem to occur earlier in visualprocessing. The current design tests bottom-up effects;the next step would be to investigate combinations ofbottom-up and top-down deficits. In summary, schizo-phrenia is associated with increased processing ofdistracter stimuli. This effect can be found with visualand auditory stimuli.

Michael Wagner (Bonn, Germany) stressed in hispresentation “Antisaccade deficits in subjects eithergenetically or clinically at risk for schizophrenia” thatoculomotor system disturbances in schizophreniapatients are considered to be endophenotypes for theillness, especially oculomotor inhibition and initiationdeficits. In recent studies a correlation between geneticloading and antisaccade task performance has beenreported (Petrovsky et al., 2008). Hence, deficits insocial and neurocognitive performance might becaused by genetic susceptibility, and antisaccadetasks might be one factor of endophenotype research.In Dr. Wagner's present study with a high number ofparticipants, antisaccade task performance wasobserved in first-degree relatives of schizophreniapatients and high risk subjects. Increased antisaccadelatencies and error rates were found in relatives ofschizophrenia patients. Relatives with high geneticload and subjects with brief psychotic episodesperformed worst. According to Cannon et al. (2002)antisaccade effects are consistent with brain volumeloss, also frontal dysfunction has been discussed.However, antisaccade task performance was notcorrelated to psychopathological symptoms, althoughthere were only mild symptoms observed in theparticipants of this study. Dr. Wagner argues thatantisaccade abnormalities are most likely not specificto schizophrenia spectrum disorders, but, this mightnot be relevant if genetic models are to be developed.In summary, antisaccade measures seem to be relatedto current clinical risk definitions; these putativeendophenotypes will allow testing of candidate genesfor their effects at symptom level.

James Danckert (Waterloo, Canada) discussedthe right parietal cortex and the neglect syndrome inschizophrenia. He presented recent work of hisresearch group dealing with left-spatial hemineglect in


schizophrenia patients. These deficits are apparent forexample when patients are asked to bisect a line in thecenter. Although healthy controls too have a physiolo-gical shift to the left, schizophrenia patients show abigger effect. In addition, schizophrenia patients havepoor motor imagery abilities (Cavézian et al., 2007).The findings of these recent studies were stronglyinfluenced by symptoms; especially when patientssuffered from passivity phenomena, the effects werebiggest. A recent volumetric study underlines thesefindings by showing reduced gray matter in the rightparietal cortex (Maruff et al., 2005). Dr. Danckertsuggested a dysfunctional symbiosis between the brainhemispheres as well as a hypo-rightward orienting and adysfunction in the right or left frontal cortex. Poorgeneration and use of efference copies and visualfeedback are hypothesized; maybe even poor workingmemory is involved. Recent research on the question”Do we need to choose sides?” has been summarized ina review article by Danckert and Ferber (2006).

In her study of visual attentional networks and theirclinical and therapeutic implications Isabelle Amado(Paris, France) presented data on the “AttentionalNetworks Test” (ANT). It combines a cued reactiontime task and a flanker paradigm and evaluates theefficiency of the orienting and alerting networks as wellas conflict-solving. For a theoretical background,Amado cited Posner's (2008) hypothesis that attentionis not a single, but a complex mechanism consisting ofthree attentional components (executive control, orien-tation, alertness). A new version of the ANTwas used toexplore interactions between networks in schizophreniapatients, siblings and healthy controls. Patients showedreduced reaction times and greater alert effects.Furthermore, alertness seemed to be influenced bytone cues. COMT/Met-alleles increased reaction times.Especially for high negative scores in the PANSScognitive remediation seems to be valuable, but thereduction effects were small. Still, reinforcements byattentional engagement can influence cognitive controlin schizophrenia. New paradigms were developed tosubdivide early information processes into more basicunits. The issue was raised, whether these attentionaldeficits are specific for schizophrenia-spectrum dis-orders or if they are unspecific markers of psychiatric orneurological illnesses. It seems that while the quest forspecificity has its merits, it is most important to findsensitive measures of general attentional pathways thatmight be translated to animal models.

Why do we then need so many levels of attentionaldeficits? Maybe the eagerness to transfer tests intoanimal models easily influences our ambitions to

investigate the most basic attentional functions. None-theless, we have to be cautious to over interpret data,since so far we can not be sure if we really are measuringbasic effects or combined effects of various functionstaken together. Still, these recent findings lead towardthe development of more specific tests and deepen ourunderstanding of basic visual attentional deficits inschizophrenia.

Visuo-cognition and emotion processing inschizophreniaReported by Katja Koelkebeck

Disturbances of emotional visual stimulus processingin schizophrenia were the main topic of this session.Patients suffer from a lack of social communicationskills, and the reduced capacity of emotional visualstimulus processing might be one of the central deficitsof schizophrenia. As the basic mechanisms of facialprocessing deficits are not fully understood, the speakerstried to elucidate this problem and presented their recentresearch.

Cynthia Shannon-Weickert (Sydney, Australia) wasfirst to present her study, “Reaction to emotional facesduring adolescence is influenced by sex steroid levels inthe monkey”. The focus of her research group is themolecular developmental neurobiology of schizophre-nia. In a previous study on schizophrenia patients, thepresenter showed that estrogen is able to modify humanemotions and cognition (Weickert et al., 2008). Changesin the sex hormone receptor ESR1 might be responsiblefor steroid hormone abnormalities in schizophreniapatients. Thus the brain of patients with schizophreniamight fail to respond normally to the pubertal surge insex steroids due to genomic or transcriptional changes inthe receptor. Also, lower steroid hormone receptormRNA has been found in the hippocampus (Perlmanet al., 2005).

In her talk, Dr. Shannon-Weickert presented data onbehavioral changes in monkeys to social stimulidepending on testosterone levels in the blood. Theresearch group performed a task during which castratedand non-castrated monkeys had to retrieve a treat fromin front various photographs. The photographs showedunfamiliar monkeys with emotional facial expressions.Non-castrated monkeys had shorter latencies reacting tostimuli with fearful expressions than compared to thecastrated group. There was no difference in latencywhen placed in front of a fear-invoking plastic snake.Results may hint at higher sensibility of specificbehavioral responses, e.g. to emotional faces, to latematurational changes in sex steroids. The data suggest


genomic influences in social cognition and provide agood basis for research on human social cognition.

The presentation “Facial emotion identification andexpression in schizophrenia: Lessons from imageanalysis of brains and faces” by Raquel Gur (Philadel-phia, Pennsylvania) focused on the neural correlates ofdisturbed emotion processing in schizophrenia patients.As schizophrenia patients show less facial expression,an emotional faces fMRI-task, displaying basic emo-tions, was applied to a sample of schizophrenia patients.While patients showed reduced limbic activity, theamygdala was over-activated when false answers weregiven. Flattening of affect correlated with higheramygdala response to fearful faces. Thus, these datashow functional abnormalities in brain areas related tofacial emotional stimulus processing in schizophreniapatients.

In an attempt to solve the question “Are visuo-cognitive deficits a vulnerability marker for schizo-phrenia? Evidence from first-degree relatives of schizo-phrenia probands” Carmel Loughland (Sydney,Australia) presented her findings on restricted scanpaths in schizophrenia patients processing emotionalstimuli. The study observed schizophrenia patients aswell as first-degree relatives and focused on distur-bances of scan paths and their basic mechanisms (e.g.information sequencing, retention, integration). In taskperformance, patients showed restricted scanning offacial stimuli and poor recognition accuracy. Relativesdisplayed similar deficits in an attenuated form.Schizophrenia patients and their relatives seemed to beaccurate at identifying congruent (automatic) emotions(e.g. happiness) but displayed greater difficulty withmore complex emotions (e.g. fear, anger). This might bedue to a higher social meaning or impact on limbicfunction of these stimuli. Patients and to some extenttheir relatives were likely to misattribute disgust foranger and surprise for fear, which might have an impacton their social behavior. Furthermore, patients usedinflexible adaptive strategies and did not adapt theirperformance to easier tasks when needed. For futureresearch, Loughland recommended looking for repeti-tive strategy issues (patients using fixed responsepatterns) and genetic factors that underlie face proces-sing deficits.

Patricia Bestelmeyer (Edinburgh, Scotland) asked inher presentation “Scan path data on healthy twins andpatients” whether spatial factors a genetic marker forschizophrenia. Her research focuses on face and voicereception in schizophrenia patients as impairments ofscanning processes have been proposed as partlyresponsible for patients' disturbance in social interaction.

Bestelmeyer reported about normal scanning beha-vior of healthy controls and stated that in schizophreniapatients, these abilities seem to be disturbed. Patientsshow fewer fixations, longer fixation periods andsaccade durations, longer peak velocity and smallersaccade amplitudes as compared to healthy controls(Bestelmeyer et al., 2006). These deficits are not onlyspecific to faces and seem to occur in bipolar patients,too. Twin studies have shown that the distribution offixations may be genetically determined and might thusbe a biomarker for psychoses. Bestelmeyer concludedthat spatial and not temporal deficits might be markersfor the illness.

In the last report of the session, “Remediation offacial emotion processing deficits in schizophrenia”,Melissa Green (Sydney, Australia) talked about abnor-mal visual attention in schizophrenia patients. Thisabnormality might result in a reduction of life qualitydue to poor interpersonal relationships. Dr. Green's coreresearch interest is the interaction of cognition andemotion in psychosis, with respect to the effect ofregulation processes and the delineation of cognitiveendophenotypes in psychotic disorders. The Micro-Expression Training Tool (METT) was used to improvedeficits of schizophrenia patients. After training ses-sions, there was a significant improvement in recogni-tion accuracy. The training group showed more eye-movement to the core features of faces (e.g. eyes, nose,and mouth). The effects were visible even one weekafter training. The METT might be promising forstandard care, because of the one-off, self-administeredtraining.

In the discussion, the question was raised whether theimprovements might be specific to facial recognition orif they generalize to broad visual attention. As there aredifferent networks of socially-implicated brain regions,the effect might be specific to faces. The potential utilityof clinical and neuropsychological predictors of suc-cessful social-cognitive remediation and relationshipswith real-world functioning are currently being eval-uated. The identification of a robust behavioral markerassociated with schizophrenia would be of great benefit.

In summary, visual attention to facial stimuli seemsto be disturbed in schizophrenia and has been discussedas causative of social communication difficulties.Authors have proposed these deficits as vulnerabilitymarkers and have presented behavioral, functional andneurophysiological data to support this notion. More-over, the possible genetic basis of hormonal influenceson behavior has been discussed and future animal andhuman research models have been highlighted. Finally,possible options for remediation have been examined.


Translational studies of working memory inschizophreniaReported by Katy Thakkar

Deficits in working memory were first identified inschizophrenia in the early 1990s (Park and Holzman,1992), and these findings, motivated by single-unitrecording data in the monkey prefrontal cortex (PFC)during a delayed response task (DRT; Kojima andGoldman-Rakic, 1982; Funahashi, Bruce & Goldman-Rakic, 1989, 1991), have spurred a considerable amountof research. Dr. Sohee Park (Nashville, Tennessee)began the symposium by presenting data illustrating themarked increase in number of peer-reviewed articlespublished on working memory and schizophrenia,comprising nearly half of all studies of cognitivefunction in schizophrenia in 2007. This line of researchhas been fruitful, as working memory deficits seem to bea stable marker of disease, present in first-degreerelatives, provide a parsimonious explanation for thewide variety of cognitive and social deficits inschizophrenia, and have implications for behavioraland pharmacological interventions. Drs. Sohee Park andHenrik Walter (Bonn, Germany) were the Chairpersonand Co-chairperson, respectively, of the session.Presentations were given by Drs. Natasha Matthews(Nashville, Tennessee), Manaan Kar Ray (Peterbor-ough, UK), John Sweeney (Chicago, Illinois), andHenrik Walter, and Drs. Gillian O'Driscoll (Montreal,Canada) and Sohee Park led the discussion followingthe oral presentations.

Among the most prevalent themes of the presenta-tions were: identifying specific phases of workingmemory deficits, lateralization of brain activity relatedto working memory processes, relationship betweenworking memory and dopamine and effects of anti-psychotic treatment, and using a neural systemsapproach to study working memory deficits.Mechanisms of working memory deficits

Dr. Matthews discussed the issue of mixed findingsof task-related hypo- and hyper-frontality duringworking memory tasks in schizophrenia and suggestedthat clarification may come through investigations ofcomponents of working memory and consideration ofthe types of errors that patients make. In a previousspatial working memory DRT, Lee and colleagues(2008) asked subjects to rate their confidence in theirresponse following each trial. Thus, trials wereclassified based on their objective and subjectiveaccuracy (true correct trials, correct guesses, falsememory trials, and true error trials). They found thatpatients had more false memory trials (they reported

being confident of incorrect trials more frequently),and patients activated prefrontal regions more duringfalse memory trials than true error trials. Anothermajor finding was that while healthy control subjectsshowed increased right PFC activation during delayperiod of the correct trials, schizophrenic patientsshowed increased left PFC activation during thecorrect trials.

Dr. Matthews presented data from a subsequentphonological verbal working memory paradigm, whichfound the same effect: patients had more false memorytrials and activated a fronto-parietal network duringthese trials. Moreover, there was no difference inactivity between false memory trials and true correcttrials. These data were interpreted as indicating thatduring false memory trials, patients were holding arepresentation in working memory during the delayperiod, suggesting that encoding processes are particu-larly impaired in schizophrenia. Schizophrenic patientsalso showed reduced hemispheric asymmetry during thedelay period of the verbal working memory task; whilehealthy subjects showed increased left PFC activationduring the maintenance phase of the DRT, schizophrenicpatients showed more rightward asymmetry during thecorrect trials. Dr. Matthews speculated that increasedfalse memory could result from reduced encodingaccuracy or impaired selection of items for encoding,and future directions of research should focus onmechanisms by which working memory deficits areoccurring.

Dr. Woodward commented on the use of con-fidence ratings and noted that it is possible thatconfidence ratings themselves may be altered in thepatients. Dr. Potkin questioned the assumption thatthe similar pattern of neural activity during falsememory and true correct trials reflects an encodingdeficit. Dr. Matthews responded by referring to thebehavioral data, where patients more often reportedbeing confident of trials in which they respondedincorrectly, indicating that patients were also report-ing holding a representation in memory. However, sheacknowledged that the fMRI data were not enough toconclude a deficit in encoding processes, but at thevery least highlighted the importance of consideringthe types of errors that subjects make on workingmemory paradigms.Lateralization of brain activity

Dr. Manaan Ray's talk addressed differences inlateralization of brain activity during verbal and spatialworking memory paradigms between schizophreniapatients and controls. He presented data to address hishypothesis that “there is a generic [working memory]


circuit, which recruits additional specialized regions forverbal and spatial processing.” Few studies to date haveinvestigating within-subject differences in patterns ofneural activity during spatial and verbal workingmemory tasks. In one study in healthy controls, Rayet al. (2007, 2008), used a spatial and verbal N-back taskduring fMRI, and found a left lateralized fronto-temporal network of regions that showed greateractivation during the verbal working memory taskthan the spatial working memory task. There were noareas with increased activity during the spatial workingmemory task, which they interpreted as spatial workingmemory tasks recruiting a more general bilateralnetwork of regions and verbal working memoryprocesses recruiting additional left lateralized regions.

Dr. Ray then discussed implications of functionallateralization for language acquisition. He argued thatlateralization provides a closer circuit for more efficientprocessing and that left lateralization provides furtherefficiency due to the comparative thickness of thearcuate fasciculus, the pathway connecting the areas ofthe brain involved in the generation and understandingof language. He presented data supporting a relationshipbetween the failure to inhibit the right hemisphereduring verbal processing and language deficits inschizophrenia. To test his hypothesis that there is lessstrongly left lateralized activity during a verbal workingmemory task in patients with psychotic illness, heconducted the same verbal and spatial working memoryfMRI study in patients with schizophrenia. All groupswere practiced until they reached a set accuracy level, sothere were no differences in accuracy or reaction timebetween patients and controls for either of the workingmemory tasks. Across groups and working memorydomains, he found a similar pattern of bilateral fronto-parietal activation. Across both domains, he found asimilar pattern of reduced right fronto-parietal activity inpatients with schizophrenia. He also found an increasein right hemispheric interference, resulting in a differentpattern of laterality. Moreover, in patients he found anincrease in activity in a region associated with verbalprocessing the during spatial working memory task. Toconclude, he claims deficits in both (1) a bilateral fronto-parietal shared network, resulting in a working memorydeficit across domains, and (2) a left lateralized fronto-temporal adjunct network for verbal working memorydue to a relative increase in right hemispheric activityand an increase in spatial activity in regions associatedwith verbal processing, resulting in language-relatedpsychotic symptoms.

Some audience members asked about the matchedbehavioral data, suggesting that the differences in

activation might be practice effects, or that the righthemisphere might be compensating to achieve equalperformance.

Dr. Matthews also addressed different patterns oflateralization during working memory. Lee and collea-gues (2008) also found an increase in left frontal activityand decrease in right frontal activity during a spatialworking memory task. Dr. Matthews also discussed datafrom a verbal working memory study revealing a loss oflaterality in schizophrenia, which she speculated may bedue to neural inefficiency or use of a different cognitivestrategy.Working memory and dopamine function

Dr. Sweeney began his talk by emphasizing theutility of adapting paradigms from animal research tobuild translational links, and he discussed the role ofdopamine and effects of antipsychotic administrationon working memory based on neurochemical studies innonhuman primates. He reviewed the finding of spatialworking memory performance varying as an invertedU-shaped function of D1 levels in PFC; that is, toomuch or too little D1 receptor activity impairsperformance. Although the clinical efficacy of anti-psychotics is associated with blockage of D2 receptors,they also reduce D1 receptors (Lidow et al., 1997) andthus are associated with decrements in spatial workingmemory performance in non-human primates (Castneret al., 2000). These deficits can be reversed with D1co-administration. Similarly, Reilly et al. (2006) foundthat patients with schizophrenia were more impairedon a spatial working memory DRT after treatment withrisperidone, and only recovered marginally afterpharmacological treatment initiation. In order todetermine whether directing covert attention awayfrom the remembered location during the delay periodwould differentially disrupt patients' performance, afollow-up study was conducted in which the sameoculomotor DRT was conducted with an additionalattention manipulation component (Reilly et al., 2007).Subjects were presented with letters at a parametricallymanipulated rate during the delay period. They foundthat directing covert attention from the rememberedlocation was more disruptive to patients following6 weeks of antipsychotic administration, whichsuggests that treatment impacts working memoryperformance more so in the context of increased at-tentional demands.

Dr. Sweeney concluded by highlighting the advan-tage of applying paradigms used in nonhuman primateresearch to models of human disease. The robust findingof a relationship between dopamine in the monkey PFCand spatial working memory performance has clear


implications for the development of antipsychoticmedications in targeting specific cognitive processes.Neural systems approach to working memory deficits

Dr. Henrik Walter spoke about using a neural systemsapproach to investigating working memory deficits inschizophrenia and looking beyond regional effects inPFC. He discussed three functional networks andstudies supporting a deficit in the interplay amongregions within the network in schizophrenia.

He began by presenting data from an fMRI verbalworking memory study (Walter et al., 2007), whichconsisted of three difficulty levels. They found greateractivation in the default mode network for low difficultytrials versus high difficulty trials (i.e. there was lessdeactivation in the default mode during easier trials).Deactivation of the default mode is thought to reflect re-allocation of resources away from task-extraneousregions to those more relevant to the cognitive task(Drevets and Raichle, 1998). In controls and depressedpatients, they found a pattern of fronto-temporalcoupling such that as prefrontal activity increased,temporal activity decreased. However, patients withschizophrenia did not exhibit this same pattern, indicat-ing a deficit in coordinated activity between frontal andtemporal regions in patients. Contrary to prior findings,there was no evidence for hypoactivation in PFC inpatients with schizophrenia, nor any evidence for aninverted-U shaped pattern in PFC, in which patientsshowed hyperactivation at low difficulty levels andhypoactivation at high difficulty levels. They did find aninverted-U shaped pattern in striatum as a function ofdifficulty, but only in patients. One audience memberquestioned the reduced deactivation of the default modenetwork in patients, presenting a possibility that it couldbe an effect of differences in task difficulty as patientsgenerally perform worse on the task.

Dr. Walter discussed these findings of reduceddeactivation of the default mode network in patientswith schizophrenia during a working memory task inrelation to difficulties in social functioning. Regionscomprising the default mode network have also beenimplicated in theory of mind tasks, in which subjectsmust infer the mental states of other agents. In priorstudies, activity in these regions has been found toincrease parametrically with the amount of socialcommunication in an inference task (Walter et al.,2004; Ciaramidaro et al., 2007). However, schizophre-nic patients with paranoid symptoms do not show thesame amount of differential activation with increasingsocial communication; they activate these regions lessthan controls on the trials that involved the most socialcommunication, but activate these regions more than

controls when only a simple physical inference isrequired. Dr. Walter interpreted these results aspotentially resulting from overattribution of mentalstates for physical causality, which questions whetherpatients with schizophrenia have hypo- or hyper-theoryof mind.

Dr. Walter also presented data supporting abnormal-ities in the fronto-striatal system in schizophrenia. Inboth healthy individuals and patients with schizophre-nia, increased ventral striatum activation is associatedwith expectation of greater reward. They also found thatventral striatum activity is greater when the reward is notexpected, and this modulation of activity is morepronounced in patients than controls in the left nucleusaccumbens. However, he found that activity in inferiorfrontal gyrus was not modulated as a function of thesalience of reward in patients, as seen in healthycontrols. Moreover, as modulation of IFG activity byreward salience decreased, anhedonia scores increasedin schizophrenia. Dr. Walter used this data to support amodified theory of dopamine dysfunction in schizo-phrenia, with increased mesolimbic and decreasedprefrontal dopamine levels.

Dr. Walter concluded by proposing a broaderapproach to studying schizophrenia, using more generalneuropsychological tests, taking a genome-wideapproach to investigating genetic causes of disease,and considering multiple brain systems in neuroimagingstudies.

Dr. O'Driscoll began the discussion, noting thatcognitive outcome measures are moving towards afixed battery, for example, the MATRICS (Measure-ment and Treatment Research to Improve Cognition inSchizophrenia) initiative. However, cognitive researchseems to be using a more fine-grained approach. Inlight of this, she asked the committee whether therewas room for such a battery. Dr. Sweeney respondedby referring to these two approaches as “two tectonicplates”. He noted that neuropsychological batteries areimportant for treatment targets, but more refinedmeasures are also needed, to assess how drugs affectcognition, for example. Dr. Walter noted that thesebatteries are only clinically useful if they are strongenough to extract meaningful information from singleindividuals. Dr. Nuechterlein responded thatMATRICS is looking for more specific measures, butthere are no cognitive neuroscience paradigms that arespecific, psychometrically-refined, or time-efficientenough. He posed this as a future challenge fortranslational research.

Another audience member noted Dr. Sweeney'sresults of the effect of drug treatments on working


memory performance. He asked whether, given thesedrug effects, more care needs to be taken in interpretingworking memory related activations in individuals withschizophrenia, since most patients are taking antipsy-chotic medication. Dr. Sweeney emphatically agreedthat drug effects must be closely considered as they acton the neurotransmitter systems as well as on vascularsystems, which has implications for interpreting theBOLD signal. He suggested more research withprodromal and unmedicated patients to avoid theseantipsychotic effects, and Dr. Park also suggested moreresearch with healthy people with schizotypal traits,unaffected family members who are free of medication,and bipolar patients who are receiving the sameantipsychotic medications.

One audience member questioned how much can beinferred from the animal literature, based on the validityof the assumption that humans and nonhuman primatesare using the same cognitive processes. Dr. Sweeneyresponded that it is important to use tasks that don'trequire elaborate cognitive processing and commentedthat with increasingly complex tasks, you lose thevaluable link to the animal literature.

VI. NEUROPATHOLOGY ANDPATHOPHYSIOLOGY

Glial cells and glia/neuron interactions in thepathophysiology of schizophreniaReported by Steven A. Chance

Historically, the investigation of gliosis, normallyassociated with acquired neural injury, has been pivotal indebate about the aetiology of schizophrenia. The absenceof gliosis has been thought to indicate a neurodevelop-mental origin and a static rather than a neurodegenerativedisease course. Although the earliest study reported thepresence of gliosis (Stevens, 1982) subsequent efforts didnot replicate this finding. Consequently, despite someinconsistencies between the different histopathologicalmethods of detection, the recent consensus has been thatreactive gliosis is absent in schizophrenia. However,increasing evidence from brain imaging suggests thatschizophrenia is not neuropathologically static during itsclinical course. At the same time, modern stereologicalmicroscopy indicates alterations in the numbers of gliacells and accumulating molecular studies find changedgene expression associated with the late maturing processof myelination. The different glial cell types have adiversity of functions including myelination, the regula-tion of glutamate, and a contribution to the immunologicalresponse. Thus glia cells are candidates for involvement in

several current hypotheses of the pathophysiology ofschizophrenia. Session VII discussed recent progressintegrating glial findings into what is otherwise a very“neuron-centric” field of theories.

Steven Arnold (Philadelphia, Pennsylvania) pro-vided an overview of the three main groups of glialcells: astrocytes are the most common, providingstructural support as well as many neurochemicalfunctions including uptake and release of neurotrans-mitters, microglia respond to brain injury and infection,oligodendrocytes fabricate the myelin sheath aroundaxons. The role of astrocytes in glutamate regulationwas taken up by Daniel Kondziella (Göteborg, Sweden).Astrocytes transform glutamate into glutamine for useby neuronal cells. In so doing they remove glutamatefrom the synaptic cleft and help to prevent glutamateneurotoxicity that is otherwise so damaging andconstitutes a key part of the glutamate hypothesis.Magnetic resonance spectroscopy enables imaging ofthe relationship between astrocytic and neuronalmetabolism and provides a window on the glutamate–glutamine cycle that appears to be impaired inschizophrenia. Furthermore, an extended period ofcortical hyperglutamatergia is associated with cognitivedeficits, negative symptoms and the transition fromacute to chronic schizophrenia. It was suggested thatmanipulation of glutamate metabolism using MK801will alter levels of glutamate and glutamine and may beused to stall the transition to the chronic illness state.

Sabine Beretta (Milan, Italy) explored the functionalsignificance of the extracellular matrix (ECM) thatsurrounds the cell bodies and neural processes.Consisting of different components, the regulation ofneuropil space around cells appears to be altered inschizophrenia, with associated abnormalities of celldensity and gray matter volume. A key component ofthe ECM is chondrotin sulfate proteoglycans (CSPG)that is expressed by some astrocytes. CSPG functioncontributes to neuronal migration, synaptic maturationand stability (including glutamatergic, GABAergic anddopaminergic synapses), and CSPGs are a majorcomponent of perineuronal nets — especially selectiveto parvalbumin containing cells. Both cell adhesionmolecules and neuregulin interact with CSPGs. Largeincreases in CSPG expression are found in some brainregions in schizophrenia. CSPG increase and accom-panying change in perineuronal nets may particularlyaffect late developmental processes.

The burgeoning Diffusion Tensor Imaging literatureindicates abnormalities of myelinated white matter.The effects of neuregulin expression on the myelin-producing oligodendrocytes was discussed by Joseph


Buxbaum. Neuregulin deficits have been associatedwith decreased oligodendrocyte numbers and reducedmyelin. The interaction between the NRG1-ERBB4signaling pathway and expression of the PTPRZ1 geneimplicates PTPRZ1 as a putative susceptibility gene.Manipulation of PTPRZ1 in mouse models results inaltered expression of myelin genes, as well as change indopamine gene expression and glutamate transmissionand synapse structure. However, as pointed out inquestions from the audience, the change in neuregulinisoform expression in human schizophrenia may not fitwith the model.

Therefore, as always, open questions remain whilehypotheses advance. To return to one such question ofwhether schizophrenia involves a neurodegenerativeprocess, Steve Arnold reported on the effect ofschizophrenia on microglial cells (which constituteroughly 20% of glial cells). Microglia have a mesench-ymal developmental origin different from other glialcells. They are replenished in adulthood and proliferatewith injury, secreting inflammatory, anti-inflammatoryand neurotrophic factors. Most post-mortem studieshave reported no change in glial numbers; however,Steve Arnold proposed an alternative approach thatemphasizes change in microglial activation rather thannumber by assessing the activity-dependent morphologyand protein expression. No differences were found inschizophrenia, although microglial activity is difficult tocharacterize due to its variation across the lifespan.

Further discussion pursued alterations in cell numberand density with reference to the macroscopic effects inMRI studies and the role of antipsychotic medication. Theoverall message fromSession VII is clear— do not ignoreglia; the schizophrenia story is not just about neurons. Inaddition, the work ties in to a challenge emerging frommuch neuropathological literature; that is the detection ofpathognomonic abnormality against a dynamic back-ground of lifetime variation and medication effects. Evenif a glial neurodegenerative response is not detected, itseems that disruption of the glutamate–glutamine cycle, orchanges in perineuronal nets in late development, oraltered myelination are likely to have ongoing effectsbeyond early development. The prospect of interventionssuch as the suggested stalling of the transition to thechronic illness state will emerge frombetter understandingof this progressive component of the disease process.

The underlying brain pathologyReported by John P John and Shivarama Varambally

This session, chaired by Dr. Kelvin Lim (Minneapo-lis, Minnesota) and Dr. Celso Arango (Madrid, Spain),

contained six interesting talks on brain morphometryand spectroscopy in schizophrenia encompassing thefollowing topics: (a) brain glutathione levels; (b)longitudinal study of cortical thickness; (c) associationof fibroblast growth factor 2 with hippocampal volume;(d) cortical folding; (e) orbitofrontal sulcogyral patternand (f) relationship between learning potential andneuronal integrity of the anterior cingulate cortex. Dr.Lim and Dr. Arango introduced the theme of the sessionand moderated the proceedings.

Dr. Stephen Wood (Melbourne, Australia), the firstspeaker of the session, presented the findings of amagnetic resonance spectroscopy (MRS) study thatexamined brain glutathione concentrations in first-episode psychosis. Glutathione, being the main anti-oxidant in the central nervous system, plays a major rolein protecting the brain from oxidative stress. Previousstudies carried out in chronic schizophrenia subjects hadreported reductions in glutathione in CSF and post-mortem brains, especially in the medial prefrontalregions (Do et al., 2000). Dr. Wood and colleaguescarried out their MRS study in a sample of 30 first-episode psychosis patients (70% male) compared to 18age- and sex-matched healthy controls using a GE 3Tesla LX Horizon machine. A short echo (30 ms) MRSacquisition using a PRESS sequence was employed.

In contrast to the previous findings in chronicschizophrenia patients, Dr. Wood and colleaguesfound that their sample of first-episode psychosispatients had significantly higher brain glutathione levelsin both hemispheres. Their findings were not attribu-table to gender, diagnosis, treatment status, duration ofillness, or smoking status. Interestingly, Dr. Wood andcolleagues found that there was a correlation betweenincreased brain glutathione and lack of sensitivity totopical niacin, which is dependent on arachidonic acidavailability. Oxidative stress in schizophrenia is asso-ciated with reduction in arachidonic acid level, whichwould probably explain the niacin insensitivity. It wasobserved that the increase in brain glutathione waspresent only in those patients who did not have thenormal response to topical niacin. Dr. Wood concludedthat the increase in brain glutathione in niacin-insensitive patients with first-episode psychosis coulddefine a sub-group experiencing oxidative stress. Thelongitudinal pattern and regional specificity as well asthe relationship of glutathione levels to symptoms,neurocognition and clinical outcome need to beexplored in future studies.

During the discussion, in response to a queryregarding the relationship between duration of untreatedpsychosis (DUP) and glutathione concentration, Dr.


Wood clarified that the study sample had a very shortmean DUP; and thus it is difficult to make anyinferences in this regard. This could be an interestingaspect to be looked into in future studies with largersample sizes.

Dr. Neeltje Van Haren (Utrecht, Netherlands)presented the findings of a longitudinal study of corticalthickness in schizophrenia. This study was undertakento address the contentious issue of static versusprogressive nature of morphometric abnormalities inschizophrenia. Dr. Van Haren and colleagues performedbaseline (T0) scans in 159 schizophrenia patients and158 healthy individuals on a 1.5 T Philips NT scanner,of whom 96 patients and 113 control subjects underwentrescanning after an interval of approximately five years(T5). The groups were comparable with respect to sex,age at MRI, handedness, height, follow up duration,years of education and parental level of education;however, schizophrenia patients had a significantlylower level of education than comparison subjects.Gray–white–CSF segmentation was carried out usingan in-house software, CLASP, which employs a surfacedeformation algorithm with a 20 mm FWHM smoothingkernel. Changes in cortical thickness were measured bysubtracting the cortical thickness at follow-up from thethickness at baseline.

Significant cortical thinning, especially of the lefthemisphere, in the temporal region (superior temporalgyrus and inferior temporal gyrus), cingulate gyrus,frontal pole, Wernicke's area and occipital regions wasnoted at 5-year follow-up. There was a relativereduction of thinning noted in the right hemisphere,limited to the posterior temporal and parietal areas.Further, cortical thickness at 5 years showed a negativeassociation with exposure to typical antipsychotics andvice versa with atypical antipsychotics. Dr. Van Harenconcluded that these findings are in line with earlierlongitudinal volumetric and voxel-based morphometrystudies suggesting progressive changes in schizophreniapatients particularly in the frontal and temporal areasregions (van Haren et al., 2007, 2008).

During the discussion, there was a query as towhether the present study replicated previous reports ofgray matter volume increase linked to atypical anti-psychotics. Dr. Van Haren clarified that there was noactual increase in cortical thickness in the atypicalantipsychotics subgroup, but, a smaller decrease wasnoted in comparison to the typical antipsychoticssubgroup. A clarification was sought whether thepatients who showed an increase in gray volume asevident from the scatterplot, constituted a sub-groupexposed to atypical antipsychotics such as clozapine, to

which Dr. Van Haren replied that there were nodifferences in gray matter volume between the treatmentsubgroups. In response to another clarification regardingthe use of a 20 mm FWHM smoothing kernel, Dr. VanHaren mentioned that a higher order kernel is needed forstudy of cortical thickness.

Dr. Steven Bakker (Utrecht, The Netherlands)commenced his talk by introducing the relevance offibroblast growth factor (FGFR) genes, referring torecent evidence from their laboratory, regarding theirassociation with schizophrenia (Jungerius et al., 2007).The fibroblast growth factors are a large family ofproteins comprising more than 25 factors and 4receptors having diverse functions, principally that ofmediating neuronal differentiation through cAMP.Previous studies have revealed that FGF2 and itsreceptor FGFR1 may play a role in mood disordersand schizophrenia, given its functions including axonbranching, oligodendrocyte maturation, remyelinationand neuroprotection from environmental insults. FGFfunction in the hippocampus is of special interestconsidering that the neuronal expression of FGF2 isrestricted to the hippocampus. Increased blood levels ofFGF2 are found in medicated schizophrenia patients andvice versa in major depressive disorder. With thisbackground, Dr. Bakker and colleagues investigated theassociation of FGF2 and FGFR1 with hippocampalvolume in 72 schizophrenia patients and 90 controls.Hippocampal and intra-cranial volumetry was carriedout on MRIs that were acquired on a 1.5T scanner.Fifteen haplotype-tagging single nucleotide polymorph-isms (SNPs) in FGF2 and FGFR1 were genotyped on anIllumina Bead Station. The effect of genotype on totalhippocampal volume was determined usingUNPHASED software, with age, gender and intracranialvolume as covariates. Fifteen markers were studied;two SNPs with low minor allele frequencies wereexcluded and the remaining was in Hardy WeinbergEquilibrium in controls. FGF2 SNP rs308379 (uncor-rected p=0.003) was associated with hippocampalvolume in patients, but not in controls (post-hocp=0.6). In the light of this disease-specific associationbetween FGF2 and hippocampal volume, Dr. Bakker andcolleagues concluded that the FGF2 dysfunction in thehippocampus may result in increased susceptibility toenvironmental insults due to impaired neuroprotectiveeffects of FGF, causing subtle alterations in myelination,possibly leading on to the dopamine imbalance under-lying schizophrenia. Considering that FGF2 and FGFRgenes are good candidates to be included in gene xenvironment studies, they plan to undertake a compre-hensive study of FGF and interacting genes in 300


schizophrenia patients. During the discussion, Dr.Bakker clarified the possible etiological link betweenthe FGF2 SNP and schizophrenia, saying that the SNPdoes not lie in the coding region and therefore, it may nothave a function of its own; instead, it could be a markerof a neighboring disease-related gene.

Dr. Jani Penttila (Paris, France) introduced the topicof her presentation by alluding to brain maturationalprocesses occurring in utero as well as duringadolescence, of which cortical folding is an importantcomponent. She presented slides illustrating the processof cortical folding occurring during 26–35 weeks ofgestation. Adult schizophrenia has been shown to beassociated with alteration of cortical folding, possiblyreflecting neurodevelopmental deviance (Cachia et al.,2008). Temporal regions that surround the superiortemporal and collateral sulci are known to continueundergoing maturational changes throughout adoles-cence in healthy development (Gogtay et al., 2004).Given the above background knowledge, Dr. Pentillaand colleagues set out to study cortical folding measuresincluding global sulcal indices (an estimate of theoverall folding surface buried in the sulci) for eachhemisphere and local sulcal indices for the superiortemporal and collateral sulci using BRAINVISA soft-ware in 51 early onset schizophrenia patients (27M: 24F,average age 16.5 years, age of onset 15.1 years, andduration of illness 1.4 years) and 59 healthy controls(29M: 30F, average age 16 years) with the following apriori hypotheses: reduction of overall cortical foldingapplies also to early onset schizophrenia; and early onsetschizophrenia would involve prominent structuraldeviations in the superior temporal and collateral sulci.

Dr. Pentilla and colleagues found that, relative tohealthy individuals, early onset schizophrenia patientshad significantly lower global sulcal indices in bothhemispheres (schizophrenia = 1.26; healthy con-trols=1.97) and a lower local sulcal index in the leftcollateral sulcus. She concluded on the basis of thesefindings that reduced hemispheric sulcification is afeature of schizophrenia that is evident during the earlyyears of the illness that reflects underlying neurodeve-lopmental deviance. Further, patients with early onsetschizophrenia may additionally have a local aberrationin the region near the left collateral sulcus (parahippo-campal gyrus, lingual gyrus and entorhinal cortex).

During the discussion, Dr. Stephen Murray soughtDr. Pentilla's opinion on whether she considered thecollateral sulcal findings as a neurodevelopmentaldeviation or a feature of the illness itself. Dr. Pentillafelt that only longitudinal studies of cortical folding cananswer this question. Dr. Van Haren commented on the

remarkable similarity between their own findings in theleft temporal region and the findings of the present studyand, and queried whether these changes could be theresult of slowing of maturation or a sudden stop inmaturation. Dr. Penttila felt that since there was norelationship of cortical folding that they could find withage, it might indicate a process of slow maturation.

Dr. Motoaki Nakamura (Yokohama, Japan) began histalk with an introduction to the orbitofrontal cortex(OFC), an area that is described as a major part of the‘social brain’ in humans. He then went on to elaboratehow studying the sulco-gyral pattern of the OFC couldbe important in examining evidence for neurodevelop-mental deviance in schizophrenia The sulco-gyralpattern of the OFC, which shows substantial inter-individual variability, has been classified by Chiavarasand Petrides (2000) into types I, II and III. In an earlierstudy (Nakamura et al., 2007), Dr. Nakamura andcolleagues had reported that the type III sulco-gyralpattern was overrepresented in schizophrenia subjects, asopposed to the type I pattern in healthy control subjects.The type III pattern was found to be associated withpoorer socioeconomic status, cognitive dysfunction,more severe symptoms, impulsivity and smaller intra-cranial volumes. However its longitudinal stability anddisease specificity to schizophrenia were not known.With this objective in mind, Dr. Nakamura andcolleagues studied the OFC sulco-gyral pattern usingMRI in 44 patients with first-episode schizophrenia, 50patients with first-episode affective psychosis, and 50age- and gender-matched controls, employing Chiavarasand Petrides' (2000) classification.

Healthy controls were found to manifest almost theidentical sulcogyral pattern reported by Chiavaras andPetrides (2000), and that in the previous study by Dr.Nakamura and colleagues in normal subjects (Nakamuraet al., 2007). The first-episode schizophrenia patientsshowed a sulco-gyral pattern quite different fromcontrols, especially in the right hemisphere, similar tothat reported earlier in chronic schizophrenia patients.The sulco-gyral pattern in the patients with first-episodeaffective psychosis was not different from that incontrols, thus suggesting the specificity of sulco-gyralpattern abnormalities to schizophrenia. Dr. Nakamuraconcluded that the findings provide evidence fordisease-specific alteration in the orbitofrontal sulcogyralpattern distribution in schizophrenia, possibly reflectingsusceptibility to schizophrenia, but not to affectivepsychosis. The OFC sulco-gyral pattern may begenetically controlled irrespective of race and gender,as the spatial pattern was similar to the earlier results ofChiavaras and Petrides (2000) in a Caucasian sample.


During the discussion another group studying thesulco-gyral pattern of the anterior cingulate region drewparallels between their findings and those of the presentstudy. Dr. Nakamura mentioned that he and hiscolleagues are currently looking at the OFC sulco-gyral distribution in relation to paracingulate–cingulatesulcal patterns. Another point that was discussed was thepotential significance of the sulco-gyral patterns asendophenotypes of schizophrenia.

Dr. Patricia Ohrmann (Muenster, Germany) presentedthe findings of a study that attempted to link learningpotential with endogeneous brain metabolites in schizo-phrenia. She gave an introduction to the dynamic versionof the Wisconsin Card Sorting Test (WCST) (Wiedl etal., 2004), which was used to classify the subjectsaccording to their learning potential into non-retainers,learners and high-achievers. N-acetyl aspartate (NAA), aputative marker of neuronal integrity that is almostexclusively found in neurons, as well as the excitatoryneurotransmitter glutamate, have been shown to bepositively correlated to cognitive functioning in healthysubjects and in various neuropsychiatric conditions. Dr.Ohrmann and colleagues attempted to link the learningpotential as investigated using the dynamic WCST, withneuronal integrity and function as reflected by NAA andglutamate, in localized brain regions. N-acetyl aspartateand glutamate were estimated using single voxel protonspectroscopy (1H MRS) of the dorsolateral prefrontalcortex (DLPFC) and the anterior cingulate cortex (ACC)in 43 schizophrenia patients and 37 matched healthysubjects, classified according to their learning potential.N-acetyl aspartate was found by Dr. Ohrmann andcolleagues to be significantly reduced in the ACC ofnon-retainers, when compared to learners and highachievers in the schizophrenia group as well as the high-achiever control subjects. Learning potential was foundto be positively correlated with NAA-level and gluta-mate levels in the ACC in schizophrenia patients,whereas in healthy controls it was positively correlatedwith the NAA-level in the DLPFC. Dr. Ohrmannsuggested that these findings might imply that there aredifferential neuronal network systems mediating execu-tive functioning in schizophrenia and healthy subjects.Further neuronal functionality in discrete brain areas canbe linked to learning potential in both schizophrenia andhealthy subjects. The correlation between learningpotential and glutamate in the ACC provides indirectsupport to the hypothesized relationship between pre-frontal glutamatergic hypofunction and cognitiveimpairment in schizophrenia.

During the discussion Dr. Stephen Wood (Mel-bourne, Australia) raised the possibility that the

association between NAA and learning potential in theACC in the learners and high achievers amongschizophrenia patients could in fact be due to a lack ofreduction of NAA in those patients, as opposed to areduction of NAA in the non-retainers. Dr. Ohrmannagreed that this indeed is a possibility. Further, inresponse to Dr. Arango's clarification regarding theobjective behind dividing the subjects into 3 artificialgroups, Dr. Ohrmann mentioned that the attempt was tolook at the issue using categorical and dimensionalapproaches, both of which have their advantages andlimitations.

In conclusion, this well-attended and enlighteningsession showcased six streams of research exploring theunderlying brain pathology in schizophrenia. Severalimportant findings such as aberrant cortical folding,disease-specific alteration of the orbitofrontal sulco-gyral pattern, role of hippocampal fibroblast growthfactor dysfunction, progressive frontal and temporalcortical thinning in schizophrenia having a differentialrelationship with typical and atypical antipsychotics,link between brain glutathione levels and oxidativestress in first-episode psychosis and relationshipbetween NAA in ACC and DLPFC with learningpotential were presented. The discussions that followedtouched upon the potential significance of these findingsin elucidating the underlying brain pathology ofschizophrenia and ideas for future research along theselines.

What can we learn from imaging?Reported by Wiepke Cahn

The goal of this interesting plenary session, chairedby Rene' Kahn (Utrecht, The Netherlands), was todiscuss neuroimaging as a tool in schizophreniaresearch. Where are we now, what is the future andwhat are the pitfalls of neuroimaging research onschizophrenia?

The first of nine speakers was Celso Arrango(Madrid, Spain) who gave an overview of results thathave come from neuroimaging research. Increasinglyadvanced neuroimaging technology has enabled pro-gress to be made toward the understanding of braindevelopment, how the brain works, what drugs do in thebrain, about the neurobiology of symptoms, cognitionand other pathological dimensions and lastly has led toconsist data suggesting that patients with schizophreniahave reduced brain volumes of several structures. Inaddition, neuroimaging may be more informative fordefining endophenotypes for the syndrome of schizo-phrenia and can then be used as the phenotype for


genetic studies. Dr. Celso then discussed neuroimagingresearch in early-onset psychosis, which has shown lessgray matter is a risk factor for psychosis in children andadolescents and that children with psychotic symptomshave progressive changes in gray matter greater thanexpected in normal brain development (Thompson et al.,2001).

The second speaker, Tyrone Cannon (Los Angeles,California), presented studies on the use of neuroima-ging-based phenotypes to identify genes that predisposeto schizophrenia. He put forward the “Watershed Modelof Genetics of Complex Traits” (Cannon and Keller,2006), an analogy in which pathways lead from genesthrough to different levels of endophenotypes. Some ofthe gray matter deficits present in schizophrenia appearto be heritable, but its significance is unclear. Post-mortem literature shows increased cell packing density,reduction in branching of neurons and reduced dendriticbranching. Thus, it would be interesting to examinegenes that influence these processes and use neuroima-ging to look at how gene variants affect brain structure.He put forth the notion that DISCI would be a goodcandidate gene, although there are probably severalother genes influencing brain volume in schizophrenia.

Nitin Gogtay (Bethesda, Maryland) talked aboutchildhood-onset schizophrenia (COS) in which graymatter loss is an exaggeration of normal development,progresses in the parieto to frontal direction andbecomes circumscribed in prefrontal and temporalcortex with age. This progression is diagnosticallyspecific, as bipolar children do not show the same graymatter decreases. If healthy siblings of COS patients areexamined, progressive gray matter deficits are alsodetectable, but gray matter appears to normalize overtime (Gogtay, 2008). In healthy siblings of COSchildren a greater cortical thickness was associatedwith a higher global functioning and gray matter deficitsfound in COS patients who showed clinical remission atdischarge had a thicker cortex at admission than thosewho did not. Thus, gray matter loss in COS is likely tobe genetically determined and related to functionalabnormalities.

Hilleke Hulshoff Pol (Utrecht, The Netherlands)stated that structural brain changes represent an activepathophysiological process of unknown etiology, asthese abnormalities in schizophrenia are consistentlypresent, are progressive in first-episode patients and alsoin chronic patients, and are related to the illness course.In schizophrenia a 3% gray matter decrease is foundwith a 0.5% decrease per year, which is consistent withthe result of post-mortem studies of schizophrenia(Hulshoff Pol and Kahn, 2008). The progressive brain

volume changes also appear to be genetic, with aheritability factor of at least 50%. She concludes that it iswell-established where the brain structural changes arelocated in schizophrenia, but it is time to study whatactive pathophysiology underlies these brain changesusing new imaging methods, such as DTI, MTR, fMRIand ultra high field imaging.

Eva Meisenzahl (Munich, Germany) began herpresentation by mentioning that preparatory work forthe DSM V/ICD 11 has begun and that potentially theKraeplinian Dichotomy between schizophrenia andaffective disorders will be relinquished. She noted thatevidence from genetic epidemiology points to a clearoverlap between these entities and posed the question ofwhether this is also true for imaging findings. In a largeMRI study hippocampal volume and gray matterreductions were found to be greater in schizophreniaas compared to major depressive disorder, but depressedpatients shared reductions in the left temporal andthalamic region with schizophrenia patients. She con-cluded that comparative brain imaging will provideimportant information about specificity and diversity ofthe pathophysiological mechanisms.

Peter Falkai and his team (Göttingen, Germany) foundthat exercise (cycling versus table tennis) could reversehippocampal atrophy in patients with schizophrenia.WithMRS-Spectrum they examined the basis of this volumeincrease and found an increase of NAA/creatin quotientsin those patients who cycled versus those who did not,which suggests that there could be an improvement inneuronal integrity through exercise (Pajonk et al., 2008).It was suggested that, as hippocampal volume reduction isnot associatedwith a significant loss of neurons, that thereis a disturbance of microconnectivity (synaptopathy),although as of yet, we are unable to visualize synapticprocesses with in vivo brain imaging.

Christopher Pantelis (Melbourne, Australia) pre-sented neuroimaging data that show loss of lateralityand sulcogyral pattern alterations, consistent with adevelopmental defect during the second prenataltrimester. There are also progressive changes duringthe onset of a psychosis in ultra high-risk subjects andventricular changes in early psychosis of patients withschizophreniform disorder. Furthermore, there is evi-dence in favor of anomalies in late/ongoing neurodeve-lopmental trajectory such as cortical surface retraction inearly psychosis. The notion of different “hits” at variousdevelopmental stages implies the need to study braindevelopmental trajectories (different regions of thebrain) that might change dynamically over time. Inaddition, there is a need to study genes relevant to brainmaturation (Pantelis et al., 2007).


Steven Lawrie (Edinburgh, Scotland) discussed thenecessity of multi-center brain imaging studies, asthousands of brain scans are needed to tease apartenvironmental and genetic effects. Most existing MRIstudies are small, based in one imaging center and donot necessarily cover representative samples of subjectsfrom the general population. Multi-center imagingstudies could generate large datasets relatively quicklyand are complementary to clinical research networkinitiatives. Nevertheless, several technical and metho-dological issues need to be addressed before multi-scanner data can be validly combined to increase studypower. He presented an initial multi-center calibrationfMRI study and concluded that within and betweenscanner variances are less than within and betweensubject variances. Thus, multi-center MRI studies willlikely increase the study power at minimal extra cost.

The last speaker, Philip McGuire (London, UK),talked about the clinical applications of neuroimaging.Although research has provided a wealth of informationabout brain structure and function in schizophrenia,there has been very little influence on clinical practice.In first-episode psychosis routine MRI scanning is noteven recommended in the UK. Preliminary data werepresented of a PET study in subjects with an at riskmental state. Unfortunately, the presynaptic dopaminelevel was unable to predict the transition to psychosis.He stated that longitudinal imaging might be morepredictive, but serial scanning might be a problembecause of limited imaging facilities and capacity. Thus,ideally a single scan would be best, but integrating thedifferent imaging modalities with genetic and clinicalneuropsychological information will lead to greaterpredictive power.

White matter disruption in psychosisReported by Clement Zai

Strong evidence exists for connectivity deficits inschizophrenia. Dysconnectivity between the two hemi-spheres of the brain, the cortical and medullar regions,as well as that between the frontal and temporal lobeshave been proposed. These deficits may be shared withother neuropsychiatric disorders with some commonclinical features, including bipolar disorder. The degreeof white matter disruption may correlate to schizo-phrenia symptom severity. Finally, part of the whitematter phenotype may be genetically determined. Thissession highlights the current status of this area ofresearch.

Dr. Paolo Brambilla (Udine, Italy) presented data onstructural MRI and neuropsychological endophenotypes

(executive functions, and interhemispheric communica-tion) in chronic schizophrenia and bipolar disorderpatients recruited in Verona, Italy. Diffusion weightedImaging (DWI) was conducted on all four main lobes(frontal, temporal, parietal, occipital), as well as fourregions of interest within the corpus callosum: genu,anterior body, posterior body, and splenium, bymanually positioning these regions of interest (ROIs).Bilateral white matter differences, as seen by anincreased Apparent Diffusion Coefficient (ADC), wasobserved in all four main lobes in schizophrenia patientscompared to controls. All four regions of interest withinthe corpus callosum were found to have increased whitematter changes (ADC) in chronic schizophrenia (N=72)compared to controls. A possible correlation was foundbetween ADC in the genu and positive symptomseverity measured by the BPRS. The ADC was alsoincreased in thalamic white matter in the patients.Preliminary results on bipolar patients (N=24) showedwhite matter disruption to be significant only in theanterior body and splenium of the corpus callosumcompared to controls. Results from the Poffenberger'stest, a visuomotor reaction time task that assesses braininterhemispheric communication, also were presented.Schizophrenia patients (N=25) had delayed right-hand(not left-hand) response compared to controls (N=41),but the results were not significant in first-episode(N=27) or bipolar (N=18) patients.

Marek Kubicki (Boston, Massachusetts) presentedDTI data on the cingulum bundle and uncinatefasciculus and their involvement in the neuropathologyof schizophrenia. Dr. Kubicki began by comparing thedifferent types of analyses that can be performed onDTI: (1) voxel-based morphometry (VBM) that has theadvantage of being automatic and fast producing data onthe entire brain at once, but assumes lack of anatomicalvariability, (2) region of interest analyses (ROI), whichis simple and fast, but low resolution limits itsapplication, and (3) tractography, which can followwhole structure/tracts with greater sensitivity, but tractscan be interrupted/disturbed by noise, and intersectingtracts decrease fractional anisotropy.

Since there appears to be loss of normal connectivitybetween the frontal and temporal lobes (Wernicke,1906; Friston and Frith, 1995; McGuire and Frith, 1996;Weinberger et al., 1992), and a myelin abnormality isobserved in schizophrenia in the prefrontal cortex(Uranova et al., 2004; Hakak et al., 2001), Dr. Kubickifocused on these pathways. Both uncinate fasciculus(UF) and cingulum bundle (CB) connect the frontal andtemporal lobes. UF is involved in decision-making,social behavior, autobiographical memory, while CB,


with longer connections, is involved in attention,emotions. A review of 25 DTI studies of schizophreniafound no consistency in location or fiber tracts affected.However, the resolution or lack of specified location inprevious studies might have prevented an accurateoverview.

UF white matter abnormalities were present, indi-cated by a lack of fractional anisotropy (FA) lateralasymmetry in chronic schizophrenia, as well as reducedFA in schizophrenia spectrum and first-episode schizo-phrenia (Nakamura et al., 2005), but not in bipolardisorder. CB white matter abnormalities were observedonly in chronic schizophrenia with reduced FA, and notin schizotypal personality disorder, first-episode schizo-phrenia, or bipolar disorder.

Abnormalities in DTI tractography were consistentwith the ROI observations of Nestor et al., 2007. FAalong the CB tract correlated with attentional processing(Stroop test, only in patients), alertness and visualorienting (Attentional Network Test, only in patients),and executive functioning (Wisconsin Card Sort Testnon-preservative errors). It was noted that FA along withCB correlated negatively with age in schizophreniapatients but not in controls. No overall difference ofmean FA was observed in UF, but a closer inspectionrevealed decreased FA around areas of highest FA alongthe tracts (Nestor et al., 2007).

Dr. Wobrock (Göttingen, Germany) was the nextspeaker. He presented data showing a bilateral,progressive decrease in frontal lobe volume in patientswith schizophrenia compared with healthy controls(N=54). The pattern appeared to be attributed todifferences in gray matter, and not white matter volume.His present work included tracing of the anterior limb ofthe internal capsule (ALIC) in MRI slices, whichshowed bilateral, progressive decrease in ALIC volumeand relative maximal cross-sectional areas from healthycontrols, to non-schizophrenic family members, toschizophrenic family members (Wobrock et al., 2008).The presence of the NRG1 Icelandic schizophrenia riskgene haplotype appeared to influence ALIC size in thatits presence was associated with decreased volume inschizophrenic family members.

The possible functional consequences of ALICdifferences were investigated using MRS (magneticresonance spectroscopy) and neuropsychologicalassessments. Error rate in the Subject Ordered PointingTask (SOPT), which assesses frontal lobe neurocogni-tive performance, negatively correlated to the relativeALIC volume in family members with schizophrenia,less so in family members without schizophrenia, andthe two variables were not correlated in healthy controls.

ROI volumetric measurements of hippocampus, ven-tricles, and ALIC in first-episode schizophrenia patientsfound that the relative left ALICmaximal cross-sectionalarea was decreased in patients with bad outcomecompared to those with stable outcome, while neitherthe hippocampus nor the ventricle volumes revealedsignificant differences between groups.

Dr. McIntosh (Edinburgh, Scotland), speaking onevidence of shared structural dysconnectivity in bipolardisorder and schizophrenia, addedmore genetic data to theneuroimaging session by also studying people withdifferent NRG1 alleles. Previously, his group found areduction of FA in the ALIC in schizophrenia and bipolarpatients as well as their relatives compared to matchedcontrols (McIntosh et al., 2005, 2006). They also reportedearlier a genetic component to ALIC white matter density.ALICVBMandROIwere reduced in peoplewith a higherrisk for schizophrenia compared to controls. Individualswith the T/T genotype of the putative functionalpolymorphic SNP243177 in the NRG1 gene experiencedless activation during performance of the HaylingSentence Completion Test (Hall et al., 2006), reflectingpossible disrupted frontotemporal connectivity. Wholebrain (especially ALIC) white matter density (VBM) wasdecreased in SNP243177 T/T genotype carriers comparedto carriers of the other genotypes (McIntosh et al., 2007).The genetic findings were consistent with a recent paperby Winterer et al. (2008) that reported an association ofwhite matter disruption in the medial frontal cortex withalleles of another, SNP221533, of the NRG1 gene.Therefore, risk to schizophrenia and bipolar disorder isassociated with abnormal cortical function and disruptedwhite matter connectivity. Questions remaining includethe functional significance of SNP221533 variants, aswellas NRG1's role in white matter function.

Dr. Monte Buchsbaum (New York, NY) presentedwhite matter brain-imaging studies of schizotypalpatients, schizophrenia patients, non-schizophreniacontrols, bipolar-I patients, bipolar-II patients, andnon-bipolar controls (N=17 per group) that exploredthe two threshold severity spectrum model/concept.They found BA22 (left temporal lobe) to be decreasedonly in schizophrenia patients, and not in schizotypalpatients or controls. Temporal white matter wasincreased in bipolar-II patients, but not in bipolar-Icompared with control subjects. PFC volume and graymatter showed a decrease in both schizophrenia andschizotypal patients compared with controls. BA25(cingulate) appeared to be affected in affective disordersonly. Overall, schizophrenia spectrum patients appearedto have a frontal and temporal lobe spectrum of severity,while bipolar spectrum disorder patients appeared to


have a cingulate deficit, but not temporal, consistentwith less cognitive changes in bipolar disorder.

In summary, the results presented in this sessionprovide support for white matter changes in the corpuscallosum, the largest interhemispheric commissuralpathway, the anterior limb of the internal capsule, aswell as the uncinate fasciculus and cingulum bundle inboth schizophrenia and bipolar disorder patients. Thedegree of change in the corpus callosum correlates toschizophrenia symptom severity. This anomaly isconsistent with deficient interhemispheric communica-tion assessed by the Poffenberger's test. The internalcapsule, particularly the anterior limb, is also a candidatebrain region showing changes in both schizophrenia andbipolar disorder patients. This change is also present infamily members of the probands, with white matterdensity negatively correlated to the genetic risk. Geneticrisk influences the association between ALIC volumeand frontal neurocognitive performance in the SubjectOrdered Pointing Task. Part of the genetic risk can becontributed to by variations in the schizophreniacandidate gene Neuregulin (NRG1). The frontotemporalconnection via UF and CB also appear to be affected inschizophrenia and bipolar disorder.

During the session, several important issues werementioned that need to be considered in future schizo-phrenia imaging studies. First, different equipment,analytical methodologies, and parameters (VBM, ROI,tractography) can influence findings, preventing a com-prehensive review and meta-analysis of white matterresults. Second, antipsychotics and antidepressants havebeen shown to alter the levels of brain derivedneurotrophicfactor (BDNF). They can potentially confound imagingresults. Third, investigating spectrumdisorders (not treatedwith neuroleptics) may help elucidate whether regionalwhite matter changes are causative or epiphenomena.Similarly, investigating bipolar disorder may uncovershared white matter abnormalities that are associated withshared clinical symptoms (presence of psychotic or moodsymptoms), as well as unique white matter changes thatcorrelate to specific symptoms or diagnoses (i.e. presenceof cognitive deficits). Finally, the effects of NRG1, as wellas other gene variants (such as those of DISC1 andDTNBP1) on brain structure and functioning should beexamined further.

Integrity of brain pathways: functional andstructural studiesReported by Panayiota Michalopoulou

This session was co-chaired by Gina Kuperberg(Boston, USA) and Hilleke Hulshoff Pol (Utrecht, The

Netherlands) and focused on the latest research findingsin functional and structural imaging of brain pathwaysimplicated in the pathophysiology of schizophrenia.Three fMRI and an equal number of structural MRIstudies examining patients in various stages of schizo-phrenia (i.e. prodromal phase, first-episode, early andchronic) of the disorder were presented.

The first fMRI research by Dr. Kelvin Lim wasentitled “Altered functional connectivity in schizophre-nia: a small world network analysis of resting fMRI” andgave the audience the opportunity to hear about a novelapproach for the assessment of the functional integrityof brain networks in schizophrenia. The study was basedon a “small-world network model”, according to whichthe human brain is described as a large complex networkcharacterized by properties assuring that the braingenerates and integrates information with high effi-ciency: a) is economical, i.e. has maximum a number ofconnections with minimum wiring costs b) supportsparallel processing of information, i.e. both segregatedand distributed processing and c) is fault tolerant. Themain hypothesis was that brain networking in schizo-phrenia is characterized by disruption of the small-worldtopological properties. To test this hypothesis, restingfMRI data from 29 patients with schizophrenia werecollected and the cerebrum was divided into 90 brainregions for the analysis of brain connectivity. The resultsof this study indicated abnormalities in all small-worldtopological properties described above and the research-ers concluded that small world abnormalities point to adeficit in functional connectivity in schizophrenia. Thecomparison of small-world network analysis with DTIdata in patients with schizophrenia as well as theexamination of network properties during task-inducedactivation in the future could supplement our knowledgeabout how the brain functions in schizophrenia. The“know-how” of this sophisticated method intrigued theaudience as questions regarding the definition of therange of thresholds and frequency scales for the smallworld metrics were addressed to the speaker.

The second fMRI research presentation was by Dr.Sukhi Shergill (London, UK) who focused on the role ofsensory pathways in the emergence of certain positivepsychotic symptoms. Such symptoms (i.e. auditoryhallucinations, passivity phenomena) are associatedwith misattribution of the actions of the patient to anexternal source. Cognitive models propose that thelabelling of an action as “one's own” depends on amatch between the predicted and the actual conse-quences of an action. According to this model, if thepredicted and actual sensory consequences are discor-dant, as when one's arm is passively moved by someone


else, the movement is labelled as externally generated.Patients with schizophrenia show a difficulty inperceptual differentiation between self-produced andexternally produced actions e.g. tactile stimuli, but theneural basis of this phenomenon has not beeninvestigated. To this end, the present fMRI study useda task, where subjects could apply a force with theirright index figure or not and could perceive it with theirleft index figure or not. Interestingly, self-generatedforces elicited less activation attenuation within the rightsomatosensory cortex relative to healthy individuals.The present study provided support for the presence of adysfunctional sensory mechanism in the sensory cortexof schizophrenia. Questions about the clinical relevanceof this finding and the possible association of thesomatosensory cortex activation with passivity phenom-ena were raised by the audience. The small number ofthe patients with passivity phenomena in the sample,however, did not allow the examination of thisassociation according to Dr. Shergill. The suitability ofmotor actions to assess the predictive mechanisms inschizophrenia and the possible modality specificityeffects were also discussed with the audience. Dr.Shergill said that “language or even thought isconsidered a proxy for motor command”, therefore thefindings of fMRI studies using motor action tasks areapplicable to studies like the present one. Reducing thecomplexity of the process studies enables investigationsthat can understand the components of more complexdeficits.

The third fMRI study, presented by Dr. MarcoPicchioni (London, UK), was an examination of thefunctional patterns in medial temporal and frontal lobesduring the prodromal phase and first-episode insubjects. Evidence from structural neuroimaging studiessuggests that regions in the frontal and temporal corticesare possible sites of progressive volume change over theearly course of the disorder. Object working memorytasks reliably engage frontal and temporal cortices andwere therefore used as probes of medial temporal andfrontal lobe activity in subjects at high risk forpsychosis. 16 subjects at high risk for psychosis, 10first-episode of psychosis subjects and 14 healthycontrols were studied using fMRI during an objectworking memory task. Object working memory taskelicited greater activation in medial and inferiortemporal cortex in the subjects at high risk for psychosisand the first-episode subjects relative to healthy controlsat the delayed phases of the task. Of note is that theresults of the study were not related to poor taskperformance as subjects who did not perform well wereexcluded from the analysis. These results suggest an

inefficiency or compensatory mechanism that may relateto the vulnerability of psychosis. The issue of thepsychometric properties of the task was raised by theaudience. Specifically, the ability of the object workingmemory task to measure aspects of working memory,attention and/or stimuli processing was discussed. Inaddition the specificity of the association of thehyperactivation pattern with the transition or thepredisposition to psychosis was also discussed. “Theassociation of psychosis with patterns of hyper- or hypo-task related activation is an over simplification, as thetailoring of task difficulty level can induce overactivityto compensate for the deficits in patients with schizo-phrenia” conclude Dr. Pichionni.

The first structural MRI studies were presented byDr. Sanjiv Kumra (Minneapolis, Minnesota), whousedDiffusion Tensor Imaging (DTI) to examine thestructural integrity of white matter in adolescents withearly onset schizophrenia. The study of this populationoffers a unique opportunity to examine regional anddisease-specific late abnormal brain development inschizophrenia. 23 patients with schizophrenia from thisrare population underwent DTI and the comparison oftheir neuroimaging data to those of healthy volunteersshowed that the patients have lower white matterintegrity in the left inferior longitudinal fasciculus.

The second structural MRI presentation was by Dr.Rene Mandl (Utrecht, The Netherlands), who focusedon the investigation of structural and functional integrityof white matter during the early stages of schizophrenia.He used a combination of two techniques DTI and MTR(magnetic transfer ratio), which measures myelination.Neuroimaging data from 40 patients and 40 healthysubjects were compared. Despite the lack of structuralabnormalities in the uncinate fasciculus, increasedmyelination was found, which suggests increasedcommunication speed between the anterior temporaland inferior frontal cortices. The specific association ofthe findings with illness phase was discussed and theneed for longitudinal studies in the field was stressed.

The third structural MRI presenter, Dr. Marion Plaze(Paris, France) focused on the neural substrate of thespatial location for auditory hallucinations. The a priorihypothesis was that this substrate would involve thesame brain regions as normal auditory spatial proces-sing, i.e. superior temporal or inferior parietal regions.The researchers used 2 morphometry approaches in 15patients with schizophrenia and internal auditoryhallucinations, 12 patients with schizophrenia andexternal auditory hallucinations and 20 healthy controls.Patients with external hallucinations had decreasedwhite matter volume in the right posterior superior


temporal gyrus. In addition, 3D analysis of the sulcus inthis region showed a displacement of the junctionconnecting the right superior temporal sulcus to itsanterior branch, the angular gyrus. These findingssuggest early neurodevelopmental impairment in thecortical folding process in patients with schizophrenia.The audience raised questions about the consistency ofthe subdivision of hallucinations into whether they areperceived as internal or external. According to Dr. Plaze,patients in the internal hallucination group had neverexperienced external hallucinations in the course of theirillness. Likewise, the external-hallucination group hadnever experienced internal hallucinations. The necessityof longitudinal studies was stressed by Dr. Plaze.

Evidence from electrophysiologyReported by John P. John

This session, chaired by Dr. Daniel Javitt (Orange-burg, NY), had four interesting talks on evoked potentialstudies in schizophrenia encompassing the followingtopics: (a) neural deficits in comprehending emotionalinformation; (b) longitudinal evaluation of P50 suppres-sion; (c) nicotinic modulation of P50 amplitude; and (d)mismatch negativity and prepulse inhibition. Dr. Javittintroduced the theme of the session and moderated theproceedings.

Dr. Gina Kuperberg (Boston, Massachusetts) spokeon emotional discrimination deficits in schizophrenia,focusing on the late positive or emotional reactivecomponent of the event-related potential (ERP) asopposed to the earlier components. Patients withschizophrenia have a decreased ability to discriminateemotional stimuli and this has been found to be linked tocompromised social competency and functional out-come in schizophrenia. However, the source of emo-tional discrimination deficits in schizophrenia andwhether it results from decreased response to emotionalstimuli or increased response to neutral stimuli isunknown. Patients with negative symptoms oftenshow a blunting of emotional responsivity, whereaspatients with paranoid delusions have demonstratedelevated or inappropriate emotional responses (Holtet al., 2006; An et al., 2003). Emotional recognition,emotional evaluation, regulation and emotional discri-mination are the function of the emotional neuralcircuitry which possibly comprise, among other brainregions, the dorsolateral prefrontal cortex, orbitofrontalcortex and the amygdala. However functional localiza-tion of this circuitry is limited by the fact that fMRI usesa subtractive method, and cannot tell us whether theemotional recognition abnormality is due to increased

responsivity to neutral stimuli or decreased responsivityto emotional stimuli. Event-related potentials aresensitive to different stages of emotional processing,with the late positive component (LPC) correspondingto emotional discrimination.

In a study of emotional evaluation and socialcognition through language, Dr. Kuperberg and collea-gues measured ERPs as 18 schizophrenia patients and18 demographically-matched controls made emotionalvalence judgments about two-sentence descriptions ofsocial situations. Emotional valence was conferred by apleasant, unpleasant or neutral critical word (CW) in thesecond sentence that was presented word by word, e.g.,“Sandra's old boyfriend stopped by her apartment. Thistime he brought a rose/gun/letter with him”. Criticalwords in scenarios classified as negative (versus neutral)evoked a smaller late positive component (LPC) effectin patients than controls. Similarly, CWs in scenariosclassified as positive (versus neutral) evoked a smallerLPC effect at posterior sites in controls with no sucheffect seen in patients. Dr. Kuperberg and colleaguesinferred that the group differences arose because theLPC to negative and positive CWs was smaller inpatients than controls, but there was no such differencein the LPC to neutral CWs. Within the patient group, themagnitude of the LPC to both the negative and positive(versus neutral) words inversely correlated with theseverity of the negative symptoms, while the magnitudeof the LPC effect to negative (versus neutral) wordscorrelated with the severity of delusions. On the basis oftheir findings, Dr. Kuperberg and colleagues concludedthat schizophrenia patients showed selective neuralabnormalities to emotional information during thecomprehension of social vignettes, with delusions andnegative symptoms showing characteristic deficits.

Dr. Bodil Aggernaes (Copenhagen, Denmark) pre-sented P50 suppression data from a longitudinal study offirst-episode, antipsychotic-naïve schizophreniapatients. Reduction of P50 evoked potential amplitudein a conditioning-testing task provides a measure ofsensory gating. Healthy subjects show a robust reduc-tion in their P50 amplitude in response to the testingversus the conditioning stimulus (P50 suppression),whereas schizophrenia patients show an impairedsuppression of the P50 response. Medication statushas been a common confound that limits the findings ofprevious studies (Light et al., 2000). Dr. Aggernaes andcolleagues investigated P50 suppression in antipsycho-tic-naïve, first-episode schizophrenia patients to avoidthe confounding effects of psychotropic medicationswith a hypothesis that schizophrenia subjects wouldshow a deficit in P50 suppression. Further, considering


that atypical antipsychotics like clozapine have beenshown to reverse this deficit, they also attempted toinvestigate whether 6 months of treatment withquetiapine would normalize the P50 suppression deficit,with the hypothesis that the P50 suppression deficit canbe affected by treatment with an atypical antipsychoticdrug.

Dr. Aggernaes started her presentation by giving anoutline of the overall design of their project, whichinvolved studying first-episode antipsychotic-naïvepatients with clinical signs of schizophrenia, who arediagnosed following a SCAN interview and baselinephysical and laboratory assessments. As per the studyprotocol, the subjects underwent PANSS, NRI/fMRIscan, PET scan, psychophysiology experiments (PPI,P50, P300, PN and MMN) and neuropsychologicalassessments, which were all repeated at 6 monthsfollowing treatment with quetiapine. 38 schizophreniasubjects and 39 matched controls underwent theCopenhagen Psychophysiological test battery compris-ing hearing test, PPI, auditory P50 suppressionparadigm, P300, PN and MMN. In the P50 paradigm,the conditioning stimulus was administered 500 msprior to the test stimulus with a 10 s inter-trial interval.At baseline, the ratio scores (T/C) reduced in patientscompared to controls. Patients showed a significantreduction in P50 suppression compared to healthycontrols at baseline, indicating that sensory gatingdeficits are present at an early stage in the developmentof schizophrenia. The gating deficit persisted at follow-up despite 6 months of treatment with the atypicalantipsychotic drug quetiapine, indicating that quetiapinedoes not restore sensory gating. Dr. Aggernaes andcolleagues plan to analyze the P50 suppression data inrelation to neurocognitive, structural and geneticfindings.

During the discussion there was an interestingclarification and suggestion from the audience regardingrelating possible normalization of the P50 deficit inclinical responders versus non-responders to seewhether the normalization was restricted only to theresponders. Dr. Aggernaes responded by saying that sheand her colleagues would be addressing this issue infuture analyses.

Dr. Bruce Turetsky (Philadelphia, Pennsylvania)initiated his talk by referring to the utility of impairedP50 auditory sensory gating, assessed in a paired-clickparadigm, as a putative endophenotype for schizophre-nia, which in turn is thought to reflect perturbednicotinic acetylcholine activity (White and Yee, 2006;Adler et al., 1992). Genetic linkage analysis hasdemonstrated an association between P50 gating and

the α7-nicotinic acetylcholine receptor subunit onchromosome 15. However, the assessment of P50 gatingas a trait marker is confounded, in patients, by acutesymptomatology, the use of atypical antipsychoticmedications and nicotine addiction. Dr. Turetskypointed out that there is disagreement about the natureand extent of the P50 abnormality; while someinvestigators have reported a failure to suppress theP50 response to the second of 2 paired clicks, othersfound reduced P50 response to the first click.

With an objective to studying the short-term effect ofnicotine on P50 suppression, Dr. Turetsky and collea-gues carried out two experiments. In the first study theyassessed 13 unaffected first-degree relatives of patientswith schizophrenia and 16 controls subjects in astandard P50 evoked potential paradigm. All subjectswere non-smokers with no Axis I psychiatric disorders,history of substance dependence or recent history ofsubstance abuse or any medical condition or treatmentthat could compromise brain function. 9 relatives and 14controls were reassessed within the next 2 weeks afterrandomized double-blind application of transdermalpatch containing 7 mg nicotine versus placebo. Theassessment was done after the patients were monitoredfor 4 h following the application of the patch. Serumcotinine levels, which were measured at beginning andend of the session, were found to be higher in thenicotine group as compared to placebo, as expected.Average EP waveforms were generated for bothconditioning and test stimuli. P50 amplitude wasmeasured at vertex (Cz) and the P50 gating ratio (i.e.,test amplitude/conditioning amplitude). The relativeshad increased P50 gating ratios at baseline (1.01 versus0.37); however this reflected reduced 1st click ampli-tude (1.75 µV versus 2.64 µV), not increased 2nd clickresponse (1.18 µV versus 1.14 µV). Repeat testingreplicated the group P50 ratio difference, but nicotinehad no effect on P50 gating. However, there was asignificant group×drug interaction for both 1st and 2ndclick. Nicotine increased P50 amplitude in familymembers and decreased it in controls, relative to placeboas was shown in a scatterplot.

In the second experiment, Dr. Turetsky and collea-gues assessed 16 healthy subjects, all of whom werecurrent smokers (N15 cigarettes per day) and whounderwent randomized double-blind application oftransdermal patch containing 21 mg nicotine versusplacebo, using the standard P50 evoked potentialparadigm. Subjects were randomly assigned to one oftwo groups: (a) abstinent— refrained from smoking for12 h prior to arrival and (b) active — maintained theirnormal smoking habit prior to arrival. Abstinence was


confirmed by respiratory carbon monoxide level. Therelationship between P50 amplitude and nicotine isconsistent with an inverted U-shaped curve. The effectof nicotine in unaffected family members mirrors theeffect seen in chronic smokers who are experiencingshort-term abstinence. In the absence of other potentialconfounds, reduced P50 amplitude appears to be a morerobust marker of schizophrenia vulnerability thanabnormal P50 gating. Although P50 gating is increasedwith nicotine, this effect is observed for both healthycontrol subjects and unaffected family members ofschizophrenia patients. A differential effect of nicotineamong those at genetic risk for schizophrenia is foundonly for P50 amplitude. The relationship between P50amplitude and nicotine is consistent with an inverted U-shaped curve, with schizophrenia risk shifting one'sposition on this response curve to the left. P50 amplitudemay therefore be a more specific marker of nicotinicagonist effects, which could be used to identifyindividuals with functional nicotinic deficits and theability of new potential therapeutic agents to amelioratethis deficit.

During the discussion, in response to a questionregarding whether an attempt was made in the study tolink the effect of nicotine on other measures of cognitiveperformance, Dr. Turetsky replied that the subjects alsounderwent assessment using a cognitive battery, theresults of which are currently being analyzed. It waspointed out that there have been studies that have lookedat cognitive performance in smokers with schizophre-nia, whose cognitive deficits following a period ofabstinence, reversed with 21 mg of nicotine. Dr.Turetsky observed that since the present study was onrelatives of schizophrenia patients, it was difficult tofind adequate numbers of smokers among the relativesto constitute an adequate sample in this study design,given the declining rates of smoking in the UnitedStates.

Dr. Ulrich Schall (Newcastle, Australia) presentedthe results of an event-related study carried out in acommunity mental health service dedicated to theassessment and treatment of young people at increasedrisk of psychosis, or in first-episode. The typical patientswho seek consultations at this service would be seenwhen “something's not quite right”. The ultra-high risk(UHR) vulnerability group was identified using theComprehensive Assessment of At Risk Mental State(CAARMS; Yung et al., 2004) based on the combina-tion of a trait risk factor, i.e. a family history ofpsychosis in first degree, a significant deterioration inglobal functioning as measured by 30% drop in GAFscore and/or presenting with attenuated or a brief history

of psychotic symptoms. Dr. Schall and colleaguesstudied mismatch negativity (MMN) and sensorimotorgating based on prepulse inhibition (PPI) recorded from10 healthy control subjects and 72 referrals to theircenter for the identification of UHR.

Dr. Schall explained briefly the physiological basis ofMMN. He then showed a review of the effect of durationof illness in schizophrenia, which has a significantinverse effect on the amplitude of MMN. In the presentstudy, MMN was derived as subtraction wave forms ofevent related potentials (ERPs) to (1) frequent short(50 ms) or (2) long-duration (100 ms) standard tonesminus ERPs to infrequent long or short-duration devianttones, respectively. PPI was recorded as eye blinkresponses to startling white noise stimuli, eitherpreceded by a non-startling acoustic prepulse at120 ms prepulse-to-startle stimulus intervals or not intwo conditions: (1) as a passive listening task and (2) asa two-tone discrimination task on the prepulse.

Although not significant, the largest MMN ampli-tudes were recorded in controls compared with equallyreduced MMNs from 20 referrals meeting criteria forfirst-episode psychosis and 40 UHR. Significantlyreduced MMN was recorded in 5 UHR individualsmaking a confirmed transition to schizophrenia one yearafter UHR identification in comparison to 12 UHRindividuals who did not. Sensorimotor gating discrimi-nated controls from all referrals when recorded in theprepulse discrimination task but not between referralgroups not did it identify those making a transition.Amplitude of MMN correlated significantly with graymatter volumes in schizophrenia patients especially inthe superior temporal gyrus and prefrontal cortex. Dr.Schall and colleagues inferred that reduced MMNappears to be associated with prodromal schizophrenia.

Dr. Schall inferred from the results of the study thatattention modulation of sensorimotor gating (PPI)discriminates clinical population from healthy controlsubjects. Sensorimotor gating (PPI) does not discrimi-nate UHR versus FES and does not predict transition toschizophrenia. Course of illness (i.e., prodromal andearly versus late stages) is associated with MMN deviantproperties (i.e., duration and intensity versus frequencydeviants; Todd et al., 2008). Reduced MMN amplitudesto frequency deviants are associated with fronto-temporal gray matter reduction in schizophrenia andpoor socio-occupational functioning. Reduced MMN toduration deviants discriminates FES from healthycontrol subjects. Dr. Schall concluded that thesepreliminary data suggests that MMN reduction toduration deviants predicts transition to schizophrenia.However, one of the limitations of this study was that


there were only 5 subjects in the UHR group; howeverhe was confident that the MMN reduction noted even inthis small group indicated that there was an effect oftransition to schizophrenia on MMN.

In summary, this well-attended and interestingsession brought together three important event-relatedpotential research streams that constitute evidence forthe underlying pathophysiological mechanisms inschizophrenia. The important findings that werereported include differential neural abnormalities toemotional information during the comprehension ofsocial vignettes in patients with delusions versusnegative symptoms, potential validity of P50 suppres-sion deficit as a trait marker for schizophrenia, reducedP50 amplitude as a marker for nicotinic deficitsunderlying schizophrenia and MMN reduction toduration deviants as a marker for transition to schizo-phrenia in UHR individuals.

Neural synchrony as a pathophysiological mechanismin schizophreniaReported by Robert A. Bittner

The synchronization of neuronal oscillations appearsto be an important mechanism for the coordination ofdistributed neuronal activity in the brain (Singer, 1999).A large body of evidence from electrophysiologicalrecordings in animals and humans as well as EEG andMEG studies indicates that synchronous oscillatoryactivity in the theta-, alpha-, beta- and gamma-band isassociated with cognitive functions such as attention,working and long-term memory, sensory-motor integra-tion and also with consciousness. In his short introduc-tion chair Peter Uhlhaas (Frankfurt, Germany),highlighted these findings and their significance forschizophrenia research. Disturbances of oscillations andneuronal synchrony could not only offer a parsimoniousexplanation for important aspects of the clinicalphenotype, e.g. hallucinations and disorganized think-ing, but also for a number of cognitive impairments thatcharacterize schizophrenia. Thus, elucidating the under-lying neuroanatomical, neurochemical and neurophy-siological alterations could give valuable insights intoits pathophysiology (Uhlhaas et al., 2008) and providethe foundation for the development of novel treatmentinterventions.

This was the central theme of the first presentation byDavid Lewis (Pittsburg, Pennsylvania). Post-mortemstudies by his group and other researchers have identifiedabnormalities in distinct subtypes of cortical GABAergicinterneurons in schizophrenia which might have detri-mental effects on neuronal oscillations (Lewis et al.,

2005). Fast spiking parvalbumin (PV)-containing chan-delier cells which form a network linked by both chemicaland electrical synapses in themiddle layers of cortex seemto influence oscillatory gamma-band activity via inhibi-tory synaptic input on the axon initial segments ofpyramidal neurons. In prefrontal PV-positive neurons ofpatients mRNA expression of the GABA synthesizingenzyme glutamic acid decarboxylase 1 (GAD67) isreduced. The resulting decrease in extracellular prefontalGABA levels should lead to reduced gamma-bandactivity and impairments in workingmemory. This notioncould be supported by a PET study using [11C]Flumazenil, which showed that higher capacity toincrease extracellular GABA predicts greater gamma-band power during the performance of a workingmemory-cognitive control task (Frankle et al., 2008).Additionally, in patients with schizophrenia a significantreduction of prefrontal gamma-band power during theperformance of the same task was reported (Cho et al.,2006). Other neuroanatomical alterations – decreased PVexpression, reduced GABA transporter 1 (GAT1) expres-sion and up-regulation of post-synaptic GABAA α2receptors–may be compensatory attempts to augment thepresynaptic release of GABA and the duration ofinhibitory postsynaptic potentials (IPSPs) respectively.In another class of interneurons, cholecystokinin (CCK)-containing basket cells, GABA synthesis seems to bereduced in a similar fashion. Like chandelier neurons theyregulate the output of pyramidal neurons primarilythrough GABAA receptors containing the α2 subunitbut target pyramidal cell bodies and proximal dendrites.

These findings led to the hypothesis that counter-acting reduced GABA input at perisomatic GABAA α2receptors while preserving the critical timing ofinhibition provided by chandelier and basket cell inputmight increase gamma oscillations in schizophrenia andameliorate cognitive deficits. This hypothesis could beconfirmed in a randomized, double-blind, placebo-controlled proof of concept trial. MK-0777 – a positiveallosteric modulator of GABAA receptors containing theα2 subunit – was given for four weeks as an add-ontreatment to clinically stable males with chronicschizophrenia on atypical antipsychotic medication.Compared to the placebo group, patients receivingMK-0777 showed increased prefrontal gamma oscilla-tions during working memory performance and sub-stantial improvement in cognitive function. While formost of his presentation Lewis had focused on changesin prefrontal cortex he emphasized that this was onlyone part of the whole picture. He closed by showingrecent data that indicate that alterations in GABAergicinterneurons are conserved across cortical regions —


even in primary visual cortex (Hashimoto et al., 2008).He emphasized that while changes in gamma oscilla-tions induced by MK-0777 had been confined toprefrontal cortex, this might have been an effect of theworking memory task employed. It remains to be seen,whether similar effects can be observed for corticalnetworks supporting other cognitive functions.

Dorea Vierling-Claassen (Boston, Massachusetts)also focused on alterations of GABAergic neurotrans-mission. She combined empirical data with mathematicmodeling in order to link basic neurophysiology withclinical findings and to investigate the effect of alteredinhibition on gamma and beta oscillations. Auditoryentrainment was studied in patients with schizophreniaand matched controls using MEG. In response to both20 and 40 Hz click-train stimuli, controls had a stronger40 Hz response than patients who instead showed apreference for a 20 Hz response in both conditions(Vierling-Claassen et al., 2008). In order to explain thisresult she pointed out post-mortem findings by Lewisand others of reduced GAT1 expression in GABAergicinterneurons. Because of slowed GABA reuptake thisshould increase the duration of IPSCs. The resultingextended inhibition rather than weaker inhibition due todecreases in GAD67 expression and GABA synthesismight underlie the shift to a 20 Hz response.

This hypothesis was explored with a simplified neuralnetwork model consisting of 15 excitatory (E) and 15inhibitory (I) neurons with four types of synapses: E-to-I,I-to-E, E-to-E and I-to-I. In this model an IPSC decaytime of 8ms lead to a pure 40 Hz response to 40 Hz click-train stimuli. Extending IPSC decay time to 28 ms andadding noisy input resulted in a mixed mode responsewith both a 20 and 40 Hz component similar to thepatient response. Removal of the I-to-I synapses from themodel lead to a loss of the 20 Hz component. A strongerdrive could override the extended inhibition and alsoeradicate the skipping of responses responsible for the20 Hz component. This might explain why previousstudies did not observe a significant 20 Hz response to40 Hz click-train stimuli in patients (Kwon et al., 1999).

Thus, the model response patterns of patients couldbe explained by extended inhibition. Based on theseresults Vierling-Claassen made the following predic-tions: Prolongation of IPSPs produced by PV-positiveinterneurons – possibly due to a reduction of GAT1 –leads to reduced gamma-band activity in schizophrenia.Since chandelier cells do not have I-to-I synapses, GAT1levels should also be reduced in other classes ofinterneurons. She proposed that in the next step thesepredictions derived from mathematical modeling shouldbe tested in animal models.

Peter Uhlhaas presented a series of EEG and MEGstudies on perceptual organization using Mooney faces,pictures of from which all shades of gray have beenremoved. Their perception relies on the Gestalt principleof closure in order to group stimulus elements into acoherent object representation. It is also associated withlong range synchronization in the beta and gamma-band(Rodriguez et al., 1999). Patients with chronic schizo-phrenia are significantly impaired in their ability tosuccessfully detect Mooney faces among scrambledcontrol stimuli. In an EEG study they also demonstratedreduced phase synchrony in the high beta-band (20–30 Hz) (Uhlhaas et al., 2006). To investigate distur-bances of gamma-band activity in the frequency rangeabove 60 Hz, MEG was used because of its greatersensitivity to high frequency oscillations. Compared tocontrols, chronic patients showed reduced evoked andinduced oscillatory activity in the high gamma-band.Beamforming analysis revealed areas around the lateraloccipital complex as the source of this deficit. Incontrast patients showed stronger oscillatory activity inthe 30 to 40 Hz range. In first-episode, medication-naïvepatient's high frequency gamma-band oscillatory activ-ity was also reduced. However this deficit was lesspronounced with mean power falling in betweencontrols and chronic patients. These data indicate thatdisturbances in gamma oscillations are already presentat illness onset and are not the result of antipsychotictreatment. They also suggest that this deficit mightbecome more pronounced during the course of theillness.

The same perceptual grouping paradigm was alsoused to investigate changes in oscillatory activity andphase synchrony during human development. EEG datafrom over 60 healthy subjects in the age range from 6 to21 years indicated a marked increase in oscillatoryactivity – particularly in the gamma-band (55–75 Hz) –with increasing age. Patterns of phase synchrony duringlate childhood and early adolescence (6–14 years) werecharacterized by greater involvement of frontal electro-des, whereas in adults (18–21 years) phase synchronywas primarily observed among occipital and parietalelectrodes. In late adolescence (15–17 years) phasesynchrony was strongly diminished. This was inter-preted as evidence for a critical period at the transitionfrom adolescence to adulthood, during which corticalnetworks undergo substantial reorganization. Consider-ing the typical time of onset during early adulthood,disturbances of these maturation processes might play arole in the development of schizophrenia.

Corinna Haenschel (Frankfurt am Main, Germany)addressed the question of how impairments of low- and


high-frequency oscillatory activity contribute to workingmemory dysfunction, a central cognitive deficit in schizo-phrenia. Disturbances of oscillatory activity were investi-gated with EEG in adolescents with a recent onset of thedisorder and controls. Participants had to encode up to threeabstract visual objects into working memory and after adelay period compare them to a test stimulus. In patientspronounced deficits in oscillatory activity were observedduring all phases of the task. During the encoding of visualinformation, they showed reduced evoked oscillatoryactivity in the theta-, alpha- and beta-band over posteriorelectrodes. During the later maintenance phase of the task,induced oscillatory activity in the gamma-band overanterior electrodes was stronger in patients for a workingmemory load of two items. However, patients failed tosustain this level of gamma-band activity for a workingmemory load of three items, where gamma-band powerdropped below the level of controls. During retrieval,evoked and induced anterior theta- as well as inducedposterior gamma-band activity was significantly reduced.In controls but not in patients, evoked posterior beta-,alpha- and anterior theta-band activity during encodingpredicted the number of successfully encoded items.Whereas the number of encoded items was negativelycorrelated with evoked beta and theta oscillatory activity, itwas positively correlated with evoked alpha activity.

These findings correspond well to ERP and fMRIdata of the same subjects (Haenschel et al., 2007) andconfirm that neurophysiological changes in schizophre-nia can already be found during the early stages ofworking memory encoding. However disturbances ofneuronal oscillations were also present during main-tenance and retrieval. Haenschel particularly pointed outthe reduction of maintenance related induced gammaactivity which was seen several seconds into the delayphase. This might lead to growing behavioral impair-ment with increasing delay length. Overall, widespreaddifferential disturbances of both low and high frequencyoscillations during the different working memorysubprocesses seem to give rise to working memorydysfunction in schizophrenia. Haenschel suggested thatthe equally widespread alterations of GABAergicinterneurons which are observed both in areas asso-ciated with early sensory as well as areas subservinghigher order cognitive functions may be one of the keyreasons for the extent of these abnormalities.

Miles Whittington (Newcastle, UK) brought anumber of other neurotransmitters into playmost notablyglutamate. He primarily addressed the question to whichdegree the broad spectrum of changes in cortical rhythmsin schizophrenia might be explained by hypofunction ofthe NMDA receptor. To address this question he

examined changes in the gamma (30–50 Hz) and highbeta or beta2-band (20–30 Hz) resulting from ketamine-induced NMDA-receptor blockade in different areas ofrat cortex. In schizophrenia lower global synchrony hasbeen reported for oscillations in both the gamma(Spencer et al., 2003) and the beta2-band (Uhlhaas etal., 2006). While there is little evidence for overallpower changes in the beta2-band, for the gamma-bandboth positive and negative findings have been reported.One explanation could be that changes in gamma-bandpower in schizophrenia may be area or task specific.The former hypothesis was supported by his results.After ketamine infusion in rat cortical slices heobserved an increase in gamma-band power in theauditory cortex and a decrease in the entorhinal cortexbut no changes in other brain arease, e.g. hippocampus,parietal and prelimbic cortex. Interestingly, beta2-bandpower decreased in the hippocampus but in increased inparietal and prelimbic cortex. The mismatches in localpower produced by ketamine could also disrupt globalsynchrony, which seems to require the correspondenceof both oscillatory frequency as well as oscillatorypower between different brain areas. NMDA receptorblockade resulted in complex spatiotemporal disruptionof cortical activity, indicating that the ketamine modelmight be good at explaining a wide range of changes inneuronal synchrony and oscillatory activity found inschizophrenia (Roopun et al., 2008).

In the second part of his presentation, Whittingtonfurther explored the properties of beta2 and gammaoscillations. Blocking gap junctions completely disruptedboth types of oscillations. However, blocking GABAA

andAMPA receptors only diminished gamma oscillationswhile it left beta2 oscillations unchanged. Both rhythmswere also differentially affected by input from cholinergicneurons. This supports the notion of beta2 and gammaoscillations being two distinct rhythms with differentfunctions and origins. Indeed, while gamma oscillationsare generated by interneurons in the more superficialcortical layers, beta2 oscillations seem to originate from anetwork of pyramidal cells linked by gap junctions incortical layer five (Roopun et al., 2006).

As Whittington pointed, by changing just a singleparameter massive, distributed effects on gamma- andbeta2-band power could be observed. This underscoresthe nonlinear dynamics of cortical oscillations. It mightalso present researchers with considerable challenges onthe way to the development of pharmacological agentswhich adjust individual parameters like NMDA drive orcholinergic modulation in just the right way toeffectively counter the disruption of neuronal synchronyfound in schizophrenia.


Altered hippocampal activity as apathophysiological basis for schizophreniaReported by Daniel J. Lodge

There is significant evidence for altered hippocampalfunction in the pathophysiology of schizophrenia, basedlargely on structural and functional human imaging data.Thus, a decrease in hippocampal volume is one of themost consistent findings in patients with schizophrenia(Nelson et al., 1998). In addition to structural deficitsthere are numerous functional imaging studies reportinga significant reduction in hippocampal activation duringtask performance in schizophrenia patients (Heckerset al., 1999). These data are consistent with impairmentsin memory processing that are a hallmark of the disease(Heckers et al., 1999). Taken together, these data haveled to the suggestion that hippocampal activity isreduced in the schizophrenia patient. The one caveatwith this proposition is that such studies focus primarilyon changes in hippocampal activity during taskperformance that do not necessarily reflect the baselineactivity of the structure. The ‘altered hippocampalactivity as a pathophysiological basis for schizophreniapsychosis' session integrated information from bothbasic and clinical studies to provide evidence forelevated baseline hippocampal activity at rest as apotential underlying pathophysiology for psychosis inhuman schizophrenia subjects. Furthermore, aberrantstress and HPA functioning in ultrahigh risk people wascorrelated with the transition to psychosis.

Evidence for baseline hippocampal hyperactivity inhuman schizophrenia patients was provided by DoloresMalaspina (New York, NY) and colleagues almost adecade ago (Malaspina et al., 1999). Specifically,baseline hyperperfusion of the medial temporal lobewas reported using SPECT imaging in human schizo-phrenia patients (Malaspina et al., 1999). More recently,techniques with higher spatial resolution have providedevidence for increased regional cerebral blood flow(H2015-PET: Medoff et al., 2001; Tamminga andHolcomb, 2005) and increased regional cerebral bloodvolume (dynamic susceptibility contrast MRI: Mala-spina) at rest in schizophrenia patients. Furthermore,these studies have demonstrated that the enhancedbaseline activity, in unmedicated patients, is primarilyrestricted to the more limbic, anterior hippocampus(Medoff et al., 2001; Tamminga and Holcomb, 2005), inparticular the CA1 and subicular subregions of thehippocampus (Malaspina). Moreover, the hyperactivitywithin these hippocampal subfields is highly correlatedwith clinical measures of psychosis and delusionssuggesting that aberrant hippocampal activity may be

a key anatomical substrate involved in the positivesymptoms of schizophrenia (Malaspina and Tamminga).The increase in regional cerebral blood flow in theanterior hippocampus observed in drug free patients wasreversed by chronic treatment with both typical(haloperidol) and atypical (clozapine) neuroleptics(Medoff et al., 2001; Tamminga and Holcomb, 2005).

Taken together there is increasing evidence forbaseline hippocampal hyperactivity in schizophreniapatients, and it is suggested that this pathologicallyenhanced baseline may result in an inability to recruitthe hippocampus during task performance. Indeed,Carol Tamminga (Dallas, Texas) presented data demon-strating a deficit in the activation of the perirhinal cortex(a medial temporal lobe structure) in schizophreniapatients presented with novel images. Furthermore,using a task requiring patients to flexibly utilize data,control individuals display robust hippocampal activa-tion, whereas schizophrenia patients fail to activate thehippocampus. These data demonstrate that while there isevidence for hippocampal hyperactivity in schizophre-nia, this aberrant activity results in hypo-functionality,i.e. an inability to recruit the hippocampus during taskperformance.

At present, the cause for this hyperactivity isunknown. However, recent data from Tony Grace andcolleagues (Pittsburgh, Pennsylvania) have demon-strated a decrease in inhibitory parvalbumin-containinginterneurons throughout the prefrontal cortex and ventralhippocampus of the MAM G17 model. Moreover, thiswas correlated with an enhanced baseline firing rate ofthe population of hippocampal neurons recorded in vivoin anesthetized rats. The reduced expression of parval-bumin-containing interneurons was further associatedwith a reduction in coordinated neuronal activity duringtask performance in freely moving rats. More specifi-cally, MAM treated rats display deficits in mPFC andventral hippocampal oscillatory theta- and beta/gamma-band responses to a conditioned tone that is associatedwith an impaired behavioral expression of latentinhibition in MAM treated rats. Thus, it was proposedthat a decrease in intrinsic GABAergic signaling may beresponsible, at least in part, for the baseline hippocampalhyperactivity and hypofunctionality, observed duringtask performance.

The consequence of an elevated baseline activity isnot entirely known; however, an association betweenhippocampal activity and ascending dopamine functionhas been demonstrated (Floresco et al., 2003; Lodge andGrace, 2007). More specifically, the ventral subiculumof the hippocampus can modulate dopamine neuronpopulation activity (i.e. the number of neurons tonically


active) and this is correlated with an altered dopamineefflux in the nucleus accumbens (Floresco et al., 2003).Given that the positive symptoms of schizophrenia havebeen previously correlated with dopamine hyperfunc-tion and evidence for hyperactivity within the hippo-campus, it was suggested that increases in hippocampalactivity such as that observed in schizophrenia patientsmay result in an augmentation of DA system responsiv-ity. Indeed, recent findings presented by Tony Graceinvestigating the MAM G17 rodent model of schizo-phrenia have demonstrated a significantly highernumber of spontaneously active VTA dopamine neuronscompared to control rats. This was attributed tohyperactivity within the ventral subiculum since TTXinactivation of the ventral hippocampus normalized theaugmented dopamine neuron activity as well asreversing the behavioral hyperresponsivity to ampheta-mine administration. Given that the hippocampus doesnot project directly to the midbrain dopamine neurons, ithas been suggested that the ventral subiculum of thehippocampus can modulate dopamine transmission via amultisynaptic pathway involving the nucleus accum-bens and ventral pallidum. Consistent with this hypoth-esis, Dolores Malaspina (New York, NY) presented datademonstrating that the increase in cerebral bloodvolume observed in the hippocampus of schizophreniapatients was highly correlated with activity in thenucleus accumbens. Thus, it appears that the hippo-campal hyperactivity observed in rodent models as wellas in human schizophrenia patients may actually drivethe dopamine hyperfunction and associated psychosis.

In addition to regulating memory processes anddopamine neuron activity, the hippocampus also plays amajor role in inhibition of the hypothalamic-pituitary-adrenal (HPA) axis response to stress (Herman andMueller, 2006). More specifically, hippocampal activityhas been shown to negatively regulate ACTH andcorticosterone release via indirect projections to theparaventricular nucleus of the hypothalamus (Hermanand Mueller, 2006). Thus it is possible that a tonicincrease in hippocampal activity may result not only in adecrease in circulating plasma cortisol, but also anatypical regulation of HPA functioning. Indeed, anassociation between HPA axis functioning and thetransition to psychosis has been recently demonstratedby Patrick McGorry and colleagues (Thompson et al.,2007a,b). More specifically, ultra high-risk patients whodevelop psychosis have significantly lower circulatingcortisol levels at baseline when compared to those whodid not develop a psychotic episode. Interestingly,increased levels of plasma cortisol were more highlycorrelated with greater levels of depression and anxiety,

symptoms that were more severe in the non-transitioninggroup at the time of the test. In addition, the occurrence ofminor daily events or ‘hassles' are strongly correlatedwithplasma cortisol levels, whereas the more stressful lifeevents are not. Similar findings were presented in a studyof patients at the time of first psychotic episode. Morespecifically, a decrease in circulating cortisol levels and ahigher level of dexamethasone suppressionwere observedin first-episode patients. Moreover, this group also had atrend for impaired glucocorticoid receptor functioningthat was normalized by antipsychotic medication. Inaddition, pituitary volume was negatively correlated withtreatment efficacy (i.e. increased volume decreasedtreatment efficacy). These data therefore provide furtherevidence for an altered HPA axis functioning inschizophrenia.

Taken as a whole this session provided significantevidence for elevated hippocampal activity as apathophysiological basis for schizophrenia psychosisand moreover, provided a unique target for thedevelopment of novel pharmacotherapies that can actupstream of the dopamine system. Such treatmentsshould be more effective at targeting this disorder at itssource, and potentially circumvent the numerous side-effects associated with prolonged dopamine receptorblockade.

VII. OTHER ETIOLOGICAL CONSIDERATIONS

Experimental analysis of the maternal immune riskfactor for schizophreniaReported by Dr. Thomas H. J. Burne

How far have we come in linking prenatal infectionto increased risk of schizophrenia? The epidemiologicalevidence has been hindered by a lack of biomarkers tolink prenatal exposures to neuropsychiatric outcomes,although there is general consensus that the populationattributable risk for schizophrenia is 14–21% forimmune infections. The chair of this session (JohnMcGrath, Brisbane, Australia) indicated that animalmodels have taken on an important role in schizophreniaresearch and there is now a convergence of clues fromecological and analytic epidemiology as well as animalmodels that have left a fertile discovery trail.

The first talk by Alan Brown (New York, NY)introduced the epidemiological evidence to support thelink between prenatal infection and the increased risk ofschizophrenia. The prenatal determinants of schizo-phrenia study (PDS) aimed to ascertain the exposurefrom archived prenatal serum specimens from earlypregnancy to delivery. In this study people were enrolled


from 1959–1966, with a comprehensive database,serum samples and follow up. There were 64 diagnosedwith schizophrenia that also had maternal sera samples,and were matched 2:1 with controls. There was a 7 foldincrease in the risk of schizophrenia for those exposed toinfluenza during the first half of pregnancy. Toxoplas-mosis is a known CNS teratogen and prenatal exposureleads to cognitive impairment. However, there was noincreased risk of schizophrenia reported. Cytokinesmediate the response to infections. It is possible thatreactivation of infection is transmitted to the fetus viathe placenta or, alternatively, a dormant infectionassociated with increased immunoglobulin G (IgG)levels could cross the placenta. We were told thatelevated maternal and neonate cytokine levels led to avulnerability to brain damage. Maternal levels ofinterleukin-8 (IL-8), but not tumor necrosis factor-alpha (TNFα), IL-1B or IL-6 resulted in a significantlyincreased rate ratio of schizophrenia preconception, butnot during pregnancy. Data from the DevelopmentalInsults and Brain Anomalies in Schizophrenia (DIBS)study looked at in utero infection and schizophrenia.Data were presented from a neurocognitive battery in anexposed group (early to mid gestation to influenza, ortoxoplasmosis) versus those not exposed. Data werereported on 8 exposed and 16 unexposed cases andconfirmed the primary hypothesis. Dr. Brown continuedby saying that the cavum septum pellucidum (CSP)normally closes by 6 months of age and the size of theCSP is increased in schizophrenia. Those exposed to inutero infection had a CSP measuring 5 mm CSP (n=5)using magnetic resonance imaging (MRI), and thoseunexposed had a CSP of 1 mm (n=12). Thus, CSPlength was associated with increased risk. Prenatalinfection was also associated with executive function,and it is the only study to look at specific exposures andCSP.

This presentation stimulated an interesting discussionabout the perceived lack of impact of the flu epidemicsand rates of schizophrenia seen in the community. Forexample, the meta-analysis on the flu epidemic of 1957and the risk for schizophrenia did not increasedramatically, which would suggest that there was noeffect of the pandemic on the incidence of schizo-phrenia. Ecological data is not good because it can'tconfirm an exposure and each exposure may havedifferent effects on the brain depending on the type ofinfection. One would need to look at individualbiomarkers and epidemiology is not comparable togenetic studies.

There was a clear divergence in the remaining fourtalks of the session in which relatively robust behavioral

phenotypes were seen in rodent models of immuneactivation. Of the different animal models of immunechallenge, including intranasal infusion of flu virus andlipopolysaccharide (LPS) challenge, experiments usingthe viral mimic polyriboinosinic–polyribocytidilicacid (PolyI:C) model were shown in most of thepresentations.

In the second talk Paul Patterson (Pasadena,California) reminded us that there are two organs thatcan learn from the environment, the central nervoussystem (CNS) and the immune system, and that there iscross talk between these two systems. Autism andschizophrenia share common risk factors (such asinfluenza, rubella), are associated with autoimmunityand both have immune-related genes dysregulated in theCNS. We were also reminded that a shared fetalenvironment may be important for the incidence ofschizophrenia. For example, two thirds of monozygotictwins share a placenta and one third do not. Of those thatshare a placenta 60% are concordant for schizophreniaand of those that do not share a placenta this falls to11%, whereas dizygotic twins are only twice as high asthat for siblings. A review of data from rodent immunemodels shows that there is a decrease in socialinteraction, decrease in ultrasonic vocalizations,increased eye blink conditioning, decreased prepulseinhibition (a measure of sensorimotor gating), increasedanxiety under mild stress, impaired latent inhibition (ameasure of selective attention) and excessive cognitiveswitching and increased sensitivity to NMDA antago-nists (such as MK-801) and amphetamine. However, noeffects on fear conditioning, avoidance learning orspatial learning were shown. Generally these behavioralabnormalities can be corrected by antipsychotic treat-ment and mostly have a post-pubertal onset. Althoughall of these behaviors are relevant they are not specific toschizophrenia or autism. Maternal immune activation(MIA) offspring display normal long-term potentiation(LTP) but hippocampal neurons in the first sector of thecornu ammonis (CA1) are hyperresponsive to dopa-mine. In fact the changes reported in the excitatorypostsynaptic potential (EPSP) slope may make thembetter at hippocampal dependent tasks. Data werepresented for a mouse model of MIA, in which therewas a spatially discrete deficit in pukinje cells in theadult (33% decrease), primarily due to a delay inmigration of the external granule cell layer at embryonicday (ED) 17. A similar result is seen in PolyI:C model.There were also occasional heterotropic Purkinje cells inlobules VI and VII of the cerebellum of MIA mice andthis neuropathology looks similar to autism. But what isthe mechanism? Antibodies may cross the blood brain


barrier, there may be an elevated corticosteroneresponse, or elevated maternal cytokines (house bet onthis one). There was convergent evidence presented thatIL-6 links maternal immune infection (as well as seasonof birth and urban environment. maternal stress,maternal malnutrition) and behavioral outcomes inmice. For example, IL-6 levels are elevated in thePolyI:C model and the behavioral effect is blocked inanimals treated with anti IL-6 and PolyI:C. In additionPolyI:C animals avoid the center of the open field andthis is reversed with co-injection of IL-6 and blocksgene expression in the brain. Furthermore PolyI:Cinjection into IL-6 knockout mice does not causeabnormal behaviors. What remains for future researchis to address whether IL-6 is the mediator of the riskfactor in humans and may be acting proximal to thefetus. There is a goal to localize the activated IL-6receptor complex and its downstream genes. Forexample, it could be just in the mother, but there ispilot data to show that it is active in the placenta and inthe fetus. Potentially the pathway could involvematernal IL-6 → fetus → self propagating immuneresponse→ elevated cytokine levels → acute effects onbehavior.

Joram Feldon (Zurich, Switzerland) presented con-vincing data in the third talk to show that gestationaltreatment of PolyI:C leads to abnormal dopaminedevelopment and expression in adulthood. Of particularrelevance to the first presentation, critical windowstudies in animal models lead to different symptoms.For example, PolyI:C (5 mg/kg) treatment on gesta-tional day (GD) 9 mimics the positive symptoms ratherthan the negative symptoms of schizophrenia. The shortterm effects in the fetus and long-term effects onbehavior, pharmacology and neuroanatomy are relatedto the dopamine system. The offspring of dams treatedwith PolyI:C have a sensitive mesolimbic dopaminesystem and they demonstrate enhanced sensitivity toamphetamine and have impaired latent inhibition. Thesechanges occur early on in the fetal brain because therewas an increase in the number of mesencephalicdopamine neurons as early as 4 days after immuneactivation at GD 9. With regard to sex differences in theresponses one might predict larger effects in males.However, no sex differences were reported in thepresent studies. We were reminded that in rodents weget severe effects but in terms of epidemiology we arestruggling. We may need a lower dose in the animalmodels.

It was pointed out that while the embryo hasincreased TH staining, the adult has decreased THstaining. There was some speculation that GDNF may

be important in this process, but although we do notknow, longitudinal studies are currently underway.

The first demonstration of schizophrenia like struc-tural abnormalities in a neurodevelopmental animalmodel was presented by Ina Weiner (Tel Aviv, Israel) inthe fourth talk. PolyI:C (4 mg/kg) given to rats on GD 15resulted in delayed onset of impaired latent inhibition,abnormally rapid reversal learning and increasedhyperlocomotion, and progressive neuropathology ofincreased size of the ventricles at postnatal day (PND)90. Data was then presented to evaluate the effect oftreating PolyI:C rats during the prodrome with 7.5 mg/kg/day Clozapine from PND 34–47, providing the firstdemonstration of antipsychotic prevention of the polyI:C phenotype. There was some discussion as to thetiming of the insult because data presented suggestprogressive emergence of enlarged ventricles andhippocampus but the clinical data suggests that in theprodrome the neuroanatomical changes are alreadypresent and this is developmentally mediated. Inresponse Ina Werner indicated that the data suggestprogressive changes, but could appear earlier andcertainly by 7 months the changes in ventricle size aregreater.

Mikhail Pletnikov (Baltimore, Maryland) in the fifthand final presentation of the session reported on adefined genetic mutation, Disrupted-in-Schiziophrenia-1 (DISC1) and a defined environmental candidate(prenatal infection) to model gene by environmentinteraction in the mouse. The transgenic mouse modeluses a Tet-off system to induce mutant human DISC-1(hDISC-1) in forebrain neurons, which results in a64 kDa mutant protein, which is expressed in cortex,dentate gyrus (DG) and CA1 but not in the cerebellum.The Disc-1 protein is involved in neuronal maturationand differentiation and co-segregates with majorpsychiatric illnesses. There were no gross behavioralchanges in the mutant mice but the phenotype includes adoubling in ventricle size and reductions in LIS1,DISC1 and SNAP-25 without effects on PSD-95 orNDEL-1. The behavioral phenotype of the DISC1mutants is mild but includes increased aggression andhyperactivity in the males and impaired memory in thefemales. These data suggest mild behavioral changes.Prenatal immune stimulation with 5 mg/kg PolyI:C onGD9 uncovered behavioral alterations previouslyunseen in mutant DISC-1 mice. For example, PolyI:Cled to reduced time on the open arms of the elevated plusmaze in DISC-1 but not control mice, whereas PolyI:Cincreased ventricle size in controls, but the reverseoccurred in the DISC-1 mutants. The new behavioralphenotype may resemble aspects of mood disorders and


schizoaffective disorders. DISC1 in the Scottish familywas associated with schizophrenia and major depres-sion. Studies relating to inflammatory factors inmicroglia and astrocytes are still to be done.

In summary, the animal models presented in thissession provided overwhelming evidence demonstratingthat prenatal immune activation leads to long lastingstructural and behavioral changes. There still remains alarge gap between the animal models and the epide-miological data. For example each exposure may havedifferent effects on the brain depending on the type ofinfection. The epidemiology can be used to guide theanimal models in a non-correlational manner. Theconcluding remarks of the session indicate that thecurrent recommendation is that one should avoidactivating the immune system during pregnancy.

VIII. SUBSTANCEABUSEANDSCHIZOPHRENIA

The 1st episode of psychosis and substance abuseReported by Marta di Forti

Several substances have been described as able toinduce transient psychotic symptoms. Nevertheless, fewof them have been accepted as causal risk factors for anenduring psychotic illness, although there is debateabout cannabis and its association with the developmentof schizophrenia. In addition, considerable interest hascentered on the role of substance misuse in determiningoutcome of a psychosis.

This session on first-episode psychosis and substanceabuse (chaired and co-chaired by Robin Murray,London, UK and Delbert Robinson, Glen Oaks, USA)was opened by a presentation from Dr. Miriam Schafer(Vienna, Austria) who investigated whether cannabisuse in ultra high-risk (UHR) individuals predictedtransition to psychosis. Previous reports had led tocontradictory findings. For instance, Phillips et al.(2002) showed that cannabis use is not associated withthe development of psychosis in an ultra high-riskgroup, while a later report from Kristensen and Caden-head (2007) indicated that cannabis abuse increased therisk for psychosis in another similar high-risk group. Dr.Schafer presented findings from a randomized controltrial of omega-3 fatty acid (FA) and placebo in a sampleof 81, age 13 to 25 years, ultra-high risk (UHR) for theonset of psychosis according to criteria of Yung et al.,2005. The study was carried out at the Department ofChild- and Adolescent Psychiatry, University of Med-icine, Vienna. At baseline a detailed history of substanceuse was collected using the SCID and the conversion topsychosis at the 12 months follow up was operationally

defined using the PANSS. In the group of 41 subjectsrandomized to omega-3 FA the transition rate wassignificantly lower than in the placebo group (p=0.004).More interestingly, in the omega-3 FA sample 29% ofthose who had a history of past or current drugs use(cannabis being the most prevalent) converted topsychosis compared to only 9% of non-drug users. Inthe placebo group the transition to psychosis was alsopredicted by either current or past drug use (p=0.009).The sample size did not allow differentiation of theeffect of individual classes of drugs used, thus leavingthe cannabis question unanswered. However, the resultsfrom this study suggest a potentially important route forprevention. If UHR individuals, who use illicit drugs,are more likely to progress to psychosis they mayconstitute a particular target group for close monitoringand intervention.

The next presentation was given by Carol Caton(New York, NY) who studied individuals with a first-episode of psychosis and substance abuse who wereevaluated in emergency departments across New YorkCity. Dr. Caton presented data on a two-year follow-upstudy that examined course and outcome of the acuteepisode. The study selected subjects diagnosed atbaseline with a first-episode substance-induced psycho-sis and compared them to those with a diagnosis of first-episode primary psychosis and concurrent substanceuse. This study, extended to several hospitals affiliatedwith Columbia University, and recruited 385 subjectsages 17 to 45 years, with any psychotic symptom(regardless of diagnosis) and with any alcohol and/ordrug use in the last 30 days. Those, with a history ofadmission for psychosis over the previous 6 months,were excluded. The retention rate at two years follow upwas 71% (N=273).

According to the Psychiatric Research Interview forSubstance and Mental Disorders (PRISM/DSM-IV)guidelines, used in the study to differentiate betweenthe two diagnostic groups, individuals whose psychoticsymptoms remitted, following acute intoxication andwithdrawal, were diagnosed with substance-inducedpsychosis. On the contrary, those with persistingpsychotic symptoms following chronic intoxicationduring a period of abstinence or minimal use in excessof 4 weeks were diagnosed with a primary psychosis.The baseline sample, across the two diagnostic groups,was mainly represented by males in their twentiesbelonging to ethnic minorities, mostly unemployed andwith a low level of education. They preferentially usedcannabis, alcohol, and cocaine but poly-drug use wasmore common in the substance-induced psychosisgroup.


Very interestingly at the two years assessment bothgroups experienced a reduction in psychotic symptoms,measured by the PANSS, and number of hospitaladmissions. Patients with substance-induced psychosishad less psychotic symptoms than those with a diagnosisof primary psychosis (pb0.001), but were more likely tobe drug dependent and homeless (pb0.001). Dr. Catonalso showed a significant group by time interaction inexplaining employment, with the proportion of unem-ployed decreasing at a rate of 2% for every 6 months inthe primary psychosis group, and increasing at a rate of1% for every 6 months in the substance-induced group.In the latter group, one-quarter later received adiagnosed of primary psychosis, but at re-analyses thisdid not change outcome findings. In Dr. Catonsuggested that with patients presenting with their first-episode psychosis and co-morbid substance misuse, it isas essential to initiate treatment for the psychoticsymptoms as well as for the substance misuse.

The next presentation was by Dr. Rodolfo Mazzon-cini (Verona, Italy), who described data from thePsychosis Incidence Cohort Outcome (PICOS) study.This is the “first” 1st-episode psychosis study developedin Verona, Italy. One of the general aims of the studywas to provide prevalence data on substance misuse infirst-episode psychosis patients (FEP) and to comparethem with available data from the general populationof the same catchment area (data from IPSAD-Italia®2003 — Italian Population Survey on Alcoholand Drugs). Dr. Mazzoncini presented data on 355subjects, age 15 to 54 yrs, who had presented for the firsttime to psychiatric services.

Nearly a fourth of the FEP had a history of drug use.The prevalence of illicit drugs use over the last12 months was significantly greater for cannabis(p=0.0001), cocaine (p=0.0003) and hallucinogens(p=0.0001) compared with the general population. Dr.Mazzoncini reported that FEP who used illicit drugswere more likely to be males, consistent with datareported on samples from New York, but surprisinglyequally likely to be homeless or still living with thefamily of origin. FEP male users also reported poorschool achievement during adolescence. Otherwise,FEP users did not differ for mode of contact withservices, duration of untreated psychosis (DUP),PANSS score and general level of functioning fromthe FEP with no history of drugs use. 19.4% of the FEPsample had used cannabis over the past year. Thereforedata on cannabis use were analyzed separately. FEP witha history of cannabis use were more often male, andmore likely to be under 36 years, to belong to an ethnicminority and to live in socially disadvantageous

circumstances. There was no difference in terms oftotal mean score for the PANSS positive or negative.However, FEP who had used cannabis scored signifi-cantly higher on excitement and grandiosity than thenon-users.

Next, Dr. Aidan Turkington (Belfast, Ireland) pre-sented clinical and socio-demographics baseline andoutcome data on 256 FEP age 18 to 65 yrs recruited overa two year period. The baseline prevalence for any-substance misused was just over 40%, alcohol was themost widely used followed by cannabis (21%). At oneyear follow-up 73% (N=188) of the baseline sample wasre-assessed and divided into three main groups: thosewho had never used illicit drugs; those who were using atbaseline but had stopped at follow-up and the last groupof those who were using at both time points. The rate ofsubstance misuse showed a significant reduction at oneyear follow up compared to baseline. Consistent with thedata presented from New York and from Verona, in thisstudy FEP with substance misuse at baseline werepredominantly young males. They were also more likelyto have an earlier age of illness onset and to receive adiagnosis of schizophrenia. More severe negative andpositive symptoms at baseline also predicted substancemisuse at one year follow up. Persistent use at follow-upwas associated with significantly worse level offunctioning, more severe depression, more positivesymptoms and overall higher relapse rates. Moreover,there were no differences in outcome between FEP whonever used and those who had stopped. Dr. Turkington' sfindings reiterated once again the importance of targetingaggressively substance misuse in patients with first-episode psychosis, given the significant implications ofpersistent use on outcome.

All the above findings suggest early detection andtreatment of patients suffering from psychosis andmisusing drugs, but do we really know how to best treatthem? But are antipsychotics the right treatment? Dr.Lieuwe De Haan (Amsterdam, The Netherlands)addressed this question presenting some of his pub-lished data showing how at a high striatal D2 occupancycorresponds to a poor rating of the subjective experienceof well being (de Haan et al., 2005). He also showed thatfrequency of cigarette smoking in 36 patients with adiagnosis of schizophrenia who had been treated eitherwith Olanzapine or Risperidone was significantlynegatively related to the availability of striatal D2

receptors, assessed with[123I]IBZM SPECT. The less thestriatal D2 receptor availability, the higher was thenumber of cigarettes smoked (de Haan et al., 2006).

Dr. De Haan also presented some new data from adouble blind randomized control trial investigating


differences in the effect of olanzapine and risperidoneon subjective experience of well being and craving forcannabis. Olanzapine is thought to dissociate faster fromD2 receptors than risperidone, and this was expected toaffect both the experience of well being as the cravingfor cannabis over time. A sample of 131 patientsdiagnosed with schizophrenia was enrolled in the trialand treated over 6 weeks with equivalent doses ofolanzapine or risperidone sufficient to reach baselinestriatal D2 receptor occupancy of 60–70%. Bothsubjective well being and cannabis craving wereassessed at baseline, at one week and 6 weeks. Thefindings showed no evidence for a differential effect ofolanzapine or risperidone on either subjective experi-ence, which increased over time, or craving for cannabiswhich diminished over time.

Dr. Murray started the general discussion by high-lighting the importance of these data in perhapsunderlying the mechanism which leads psychoticpatients to smoke cigarettes all day long. Dr. CyrilD'Souza (New Haven, Connecticut) responded referringto existing findings supporting high prevalence oftobacco smoking in adolescents who later developschizophrenia, before any antipsychotic is prescribed tothem. Nevertheless, smoking tobacco increases themetabolism of some antipsychotics leaving the self-medicating hypothesis still plausible. Psychotic patientsmight smoke so much in the attempt to regain asubjective feeling of well being, by reducing the amountof antipsychotics in their system. Though it remainsuncertain if antipsychotics can play a causal role ininitiating tobacco smoking, they might contribute toestablish a high frequency and enduring pattern of use,through their effect on striatal D2 occupancy. This wasan interesting issue to end a stimulating session.

Cannabinoids and schizophrenia: potentialmechanismsReported by Roohi Abubaker

This session was chaired by Robin M. Murray,professor at the Institute of Psychiatry, Kings College,London UK. The first presentation was by Dr. DeepakCyril D'Souza M.D. who is from Yale UniversitySchool of Medicine. Dr. D'Souza talked about thelaboratory studies of Δ-9-THC in humans and itsrelevance to schizophrenia. He presented a studyperformed on healthy individuals who were exposedto cannabis and on schizophrenic patients who wereusing Delta-9-THC. It was shown that even healthyindividuals using Δ-9-THC, schizophrenia-like positiveand negative symptoms were present. Other symptoms

that were observed included anxiety, perceptual altera-tion attention and memory impairment. In both healthyand schizophrenic individuals, memory impairment wasmarkedly observed, though it was more evident inschizophrenic patients using Δ-9-THC with significantrecall deficits. It was also found that effects ofΔ-9-THCwere influenced by dose and speed of administration.Dr. D'Souza also talked about the difference in lightusers and regular users of cannabis; light user's showedblunted psychotic symptoms. Haloperidol did not blockthe psychotic effects of Δ-9-THC nor it did it block theperceptual effects. Dr. Deepak then talked about the roleof BDNF (Brain derived neurotoxin factor) which playsan important part in neurodevelopment. Inadequatesupport by neurotropic factors during brain develop-ment can result in structural disorganization of brain. Hesaid that prenatal exposure to Delta-9-THC results indecreased BDNF levels.

The second presentation of this session was by Dr.Cecile Henquet from Maastricht University, Nether-lands. Dr. Henquet topic was “genetic moderation of thecannabis induced psychosis”. It was stated that theprevalence rate of cannabis use is higher in people withschizophrenia; one explanation can be that cannabis isused to alleviate psychotic symptoms. One of theobjectives of her presentation was to shed some light onthe dynamics of delta-9-tetrahydrocannabinol and thegenetic liability to psychosis. She mentioned severalfactors affecting the interaction between delta-9-tetra-hydrocannabbinol and psychosis, such as duration andamount used and age at first use. In the study it wasshown that carriers of Val allele of the COMTVal158Met genotype were more sensitive to the effectsof cannabis. In young people vulnerability to early useof cannabis will result in long lasting psychosis. Thestudy ascertained 30 patients with schizophrenia and 30controls. The patients showed social and mood deficitswhile using cannabis and had more hallucinations whileintoxicated then controls.

The next presentation was by Dr. Murray, the chair ofthe session, and the topic of the presentation was“Cannabis Induced psychosis as a model of schizo-phrenia.” Cannabis was mentioned as one of the mostwidely used illicit drug, with a rapid rise in its use worldwide. Dr. Murray mentioned French psychiatrist JacquesJoseph Moreau (1804–1884) who first studied theeffects of cannabis and said that cannabis induced someof the same hallucinations and disordered thoughts thathe saw in his psychiatric patients. He said that over thelast 5 years a number of cohort studies have beenperformed on cannabis use and risk for psychosis. Hispresentation described a large study where 320 people


with no past history of psychosis and no family historyof psychosis were injected intravenous 2.5mg delta-9-tetrahydrocannabinol over 5 months. Dr. Murraycompared Δ-9-THC and CBD (cannabidiol) and saidthat while Δ-9-THC causes hallucinations, attention,memory and learning impairment, CBD has no adversecognitive effects or perceptual disturbances. He alsomentioned the GAP (Genetics and Psychotic Illness)study which is a large study of 1000 individualspresenting to services in South East London with theirfirst-episode of psychosis, as well as 2400 epidemiolo-gically matched healthy controls. One of the aims of thisstudy is to investigate whether there are any genes thateither alone or through interaction with environmentalrisk factors including cannabis use that can increase therisk or affect the outcome of a psychotic illness.

The next presentation was by Philip McGuire,professor at the Institute of Psychiatry, London UK.The topic was “ A functional MRI study of the effects ofdelta-9-THC and cannabidiol effects in humans”. One ofthe objectives was to study how delta-9-THC and CBDaffect the brain. He mentioned that there has been onlyone neuroimaging study done in 2004 on CBD. Thestudy showed the effects of THC and CBD in the brainregions which are critical for memory, responseinhibition and emotional processing in healthy volun-teers. The selection of tasks was verbal paired learning,auditory stimulation and viewing of fearful faces.Activation of brain and vascular response were studied.It was noted that CBD reduced anxiety if there is any. Itwas noted that THC increased the ventral striatalactivation as well as PANSS scores. THC alsoattenuated the right inferior frontal cortex activation.THC also increased anxiety on viewing the fearful faceswhere as CBD attenuated the activation of amygdaleand cingulate gyrus when subjects viewed fearful facesand suppressed anxiety. It was evident that THC andCBD influence different brain areas and differentcognitive processes.

The last presentation was by David A. Lewis, who isthe director of the Translational Neuroscience Depart-ment at The University of Pittsburgh, Pennsylvania,USA. The topic was “Cannabis use and risk ofschizophrenia: potential biological mechanisms” Dr.Lewis explained the neuromechanism by which canna-bis use increases the risk of schizophrenia. He said thatin patients with schizophrenia, there is reduced GABAneurotransmission in the dorsolateral prefrontal cortex(DLP FC) the cannabinoid receptor CB 1 receptor isfound in the axon terminals of DLPFC region. In thisstudy CB1 receptor mRNA in DLPFC from 23 pairs ofschizophrenia and control subjects was measured. It was

seen that use of antipsychotic medication does not alterCB1mRNA as well as other confounding factors such asage, sex and the use of other stimulants. The decreaseseen in CB1mRNA in schizophrenic patients can be acompensatory mechanism to increase the GABAtransmission; he further said that use of exogenousexposure to cannabis counteracts these compensatoryresponses. Dr. Lewis also talked about the role ofGAD67 (glutamate acid decarboxylase) and CCK(cholecystokinin) which mediate the GABA releaseand the differences in CB1mRNA expression correlatewith the levels of GAD67 and CCK in schizophrenicpatients. He further said that use of exogenous exposureto cannabis counteract these compensatory responses.

The discussion at the end of the session mainly dealtwith the use of cannabis in healthy individuals versusthose with schizophrenia. There was mention of thestructural changes seen in cannabis users namely inamygdala, hippocampus and cingulate gyrus. Thequestion was also raised as to why schizophrenicpatients prefer cannabis, but this remains unknown.The hypothesis of self medication of cannabis byschizophrenic patients was also discussed. A questionwas asked if there is any study done to examine changesin the amygdala and hippocampus in cannabis users.There was also mention of the progressive changes seenin schizophrenic patients and whether they could be dueto cannabis use. These issues still remain unresolved.

IX. ANIMAL MODELS

Updates in developmental models forschizophreniaReported by: Pauline Belujon

Development of animal models is a crucial issue inthe study of psychiatric disorders since they allow theuse of more invasive research methods than could beapplied to humans. Thus, scientists have developednumerous approaches to evaluate the validity andreliability of animal models for studying humanbehavior and human disorders. This session examinednew developmental animal models used to studyschizophrenia.

NMDA antagonists such as PCP or MK801 caninduce a transitional and reversible psychotic stateincluding the full range of positive and negativesymptoms of schizophrenia in healthy individuals(Mechri et al., 2001). Dan Rujescu (Munich, Germany)presented an animal model of psychosis based onchronic low-dose application of the NMDA receptorantagonist, MK801 in juvenile rats (Rujescu et al.,


2006), in order to have more information concerning theNMDA hypofunction hypothesis (Mohn et al., 1999) ondifferent levels such as genetic association, endopheno-types, pharmacogenetic responses. First, electrophysio-logical recordings from CA1 pyramidal neurons haveshowed that inhibitory postsynaptic potentials (IPSPs)are reduced in animals treated with MK801, andbehavioral analyses have revealed that these animalshad impaired cognitive performance (declarative andworking memory). Interestingly, immunohistochemicalanalyses revealed that parvalbumin-positive (PV+)interneurons, reduced in schizophrenia in differentbrain regions (Torrey et al., 2005), were reduced in thehippocampus (HPC) after administration of MK801 andthat this is negatively correlated with the amplitude ofthe IPSPs recorded in the HPC (Rujescu et al., 2006;Braun et al., 2007). Moreover, haloperidol was able tonormalize the MK801-induced decrease in PV+ neuronnumber without having a significant effect alone. Thesefindings taken together suggest that there might be adisinhibition of local feedback circuits that is amelio-rated by haloperidol. Some genetic experiments haverevealed that haloperidol differentially regulates theexpression of phospholipase C and many of the genes inthe MK801 and haloperidol groups have all beendiscussed in the context of schizophrenia. Haloperidolis a high potent substance used for the treatment ofpsychosis but treated patients developed lots serious anddebilitating side effects. Moreover, some studies havereported that phospholipase C activity was significantlyincreased in postmortem samples from the brains ofschizophrenic patients and patients with Parkinson'sdisease when compared with controls (Wallace andClaro, 1993). Some pharmacogenetic studies have beendone in patients with acute psychotic disorders that weretreated with haloperidol. Different single-nucleotidepolymorphisms (SNPs) were tested and one haplotypeblock was associated with akathesia whereas anotherone was associated with Parkinson. Another differen-tially expressed gene was methionine sulfoxide reduc-tase and was involved with dyskinesia. Taken together,these data confirmed the importance of genes variant inschizophrenia and that variation in these genes areassociated with haloperidol responses and also withpsychosis.

Another animal model for schizophrenia uses themethylazoxymethanol (MAM) during late gestation, atgestational day (GD) 17 (Grace and Moore, 1998;Moore et al., 2006), and was presented by Gwenaelle LePen (Paris, France). Rats exposed to MAM presenteddifferent symptoms related to those observed inschizophrenia. Thus, MAM-treated rats were tested at

pre- and post-puberty and compared with GD17 saline-injected (sham) rats. To explore the face and constructvalidity of the MAM model, spontaneous locomotion,working memory, social interaction, and prepulseinhibition of the startle were measured (Le Pen et al.,2006). In comparison with sham animals, MAM-exposed rats exhibited a spontaneous locomotor hyper-activity only after puberty, and this hyperactivity isthough to reflect hypersensitivity of subcortical dopa-minergic system. MAM-treated rats also exhibitedhypersensitivity to the locomotor activating effect ofMK801, an NMDA-antagonist. These symptomsobserved in MAM-treated rats are related with thepositive symptoms observed in schizophrenia patients.Moreover, the MAM-treated rats exhibit deficits insocial behavior and working memory (Le Pen et al.,2006), theses results being related to the negativesymptoms in schizophrenia patients. Finally, deficits insensorimotor gating processes were observed in MAM-treated rats at both pre- and post-puberty using theparadigm of the prepulse inhibition of the startleresponse (Le Pen et al., 2006). Some neuroanatomicalperturbations related to those observed in schizophreniaare also observed in the MAMmodel, such as a decreaseof the prefrontal cortex area, hippocampus, dentategyrus, thalamus and entorhinal cortex (Le Pen et al.,2006). To validate the predictive validity of this model,some antipsychotic drugs were tested acutely (haloper-idol, clozapine and risperidone) or chronically (cloza-pine and haloperidol). Thus, preliminary results fromMarie-Odile Krebs laboratory showed that acute treat-ment of haloperidol, risperidone and clozapine reversedthe spontaneous locomotor hyperactivity, as well as theMK801-induced hyperactivity, in MAM-treated rats.However, while chronic treatment of haloperidolinduced a complete reversal of the locomotor hyper-activity, chronic treatment of clozapine had only apartial effect. Taken together, this data strengthen thevalidity of the MAM model of schizophrenia as aneurodevelopmental model for schizophrenia to explorepsychosis onset and to study the interference betweenearly developmental insult and adolescent brainmaturation.

Dopamine in the prefrontal cortex plays a critical rolein cognitive functions such as working memory andattention and thus, disruption in DA-PFC interactionsmay underlie the onset of cognitive deficits in schizo-phrenia in the adolescence or early adulthood (Lipskaand Weinberger, 1998). However, mechanisms under-lying synaptic changes in the PFC by DA betweenadolescence and adulthood are still unknown. One of thehypotheses presented by Kuei-Yuan Tseng is that


changes in the relative dominance of pre- and post-synaptic signaling mechanisms, known as the spike-timing dependent plasticity (STDP), occur in the PFCfrom the adolescence to the adulthood and that thesechanges are regulated by DA. Thus, whole-cell record-ings were performed on coronal slices containing themedial PFC, from adult and young animals. UsingSTPD, long-term depression (LTD) was induced atpyramidal neuron excitatory synapses, and a highermagnitude of the LTD was observed in the adult PFCwhen compared to pre-pubertal animals. Interestingly,blocking NMDA receptors abolished the LTD, suggest-ing that a presynaptic component underlies the expres-sion of this form LTD. To test this hypothesis,endocannabinoids receptors were blocked with anantagonist and a shift from LTD to LTP was observed,but only in adult animals. These findings uncover thatsynaptic plasticity at PFC excitatory synapse is devel-opmentally regulated and dependent on a balancebetween pre- and post-synaptic mechanisms throughendocannabinoid and NMDA receptors mediated sig-naling. In addition, in adult animals, application of theD2 agonist quinpirole blocked LTD in pyramidalneurons as well as the LTP induced by the endocanna-binoid antagonist, whereas activation of D1 receptorsfavor the formation of LTP over LTD. Taken together,these findings provide new insights concerning thecellular mechanisms underlying synaptic changes in thePFC from adolescence to adulthood, mechanisms thatare timing and dopaminergic dependent.

Lots of evidence suggests that pre- and perinatalevents that influence the immune system contribute tothe development of neuropsychiatric disorders. Thus,one animal model of schizophrenia is the exposure ofpregnant rats to the bacterial endotoxin lipopolysacchar-ide (LPS), presented by Jose Borrell. LPS affects theimmune systems by inducing the release of differentcytokines and rats that were exposed to LPS showeddeficit of prepulse inhibition of startle (PPI) (Borrellet al., 2002), deficit that is related to schizophrenia. Inthis model, serum levels of different cytokines wereanalyzed. An increase of levels of interleukin (IL)-2, IL-6, IL-12 and TNFα in 6-month old rats were observed,whereas there was no change in the levels of IL-1β orIL-12 (Romero et al., 2007). Moreover, in the nucleusaccumbens, an increase of DA levels but no change inone of its metabolites DOPAC, were shown in LPS-exposed rats. The expression of DARPP-32, a proteinthat mediates DA effects, was decreased in LPS-exposed animals in the prefrontal cortex, whereas nochange was observed in the amygdala and in thehippocampus (Romero et al., 2007). These results

confirmed that critical changes emerge at adulthoodafter exposure to LPS, and that studying a model notonly in young or preadolescent animals but also in adultand old animals is really important (Romero et al.,2008). One important aspect for studying a model ofschizophrenia is to study the effect of antipsychoticdrugs. Thus, after 14 days of treatment with haloperidol,LPS-exposed rats showed a reversal of serum levels ofIL-2, IL-12, IL-6 and TNFα (Romero et al., 2007).Moreover, injection of LPS to pregnant dam during the3rd week of pregnancy induced a higher deficit in theadult animals, confirming that the symptomatology istiming dependent. Taken together, these data support thecrucial influence of perinatal events on developmentalprocesses and their consequences at adulthood.

Taken as a whole, this session provided criticalinformation concerning developmental models of schi-zophrenia that can help to understand the variousmechanisms underlying the psychosis transition fromadolescence to adulthood.

Further session on relevant animal modelsReported by Pauline Belujon

As seen in the previous session, developmentof animal models is a critical issue to study psy-chiatric disorders. This session examined some of thenew developmental animal models used to studyschizophrenia.

The phenotypic characterization of an animal modelis one of the first steps to establish the validity of thismodel. The most frequent approach presented by BitaMoghaddam has been the use of pharmacologicaltreatment that generates schizophrenia-like symptomsin healthy individuals, such as chronic exposure toamphetamine (for review see Snyder, 1973), use ofNMDA antagonists such as phencyclidine (PCP) orketamine, or acute exposure to LSD or cannabis. Thesemodels may have important constructive validity andprovide information to understand some of the patho-physiological basis of schizophrenia. Postmortem andfunctional brain imaging studies showing abnormalitiesin the PFC in schizophrenia patients support this idea.Thus, damage of the PFC is associated with cognitivedeficits and changes in behavior that are related toschizophrenia. Some non-published preliminary datafrom Bita Moghaddam's laboratory (Pittsburgh, Penn-sylvania) highlight the constructive validity of somepharmacological models that act by disrupting corticalactivity. Electrophysiological recordings were madefrom the prefrontal and orbitofrontal (OFC) cortex.These preliminary data were primarily focused on the

http://dx.doi.org/doi:10.1038/mp.2008.44

http://dx.doi.org/doi:10.1038/mp.2008.44


OFC since the literature shows abnormalities within theOFC that correlates with positive and affective symp-toms as well as cognitive deficits of schizophrenia.Thus, rats that were exposed to MK801, an NMDAreceptor antagonist, or amphetamine both showed anincrease of firing rates in PFC and OFC regions.Moreover, this overactivation seemed to be relevantsince it was blocked by existing antipsychotic drugssuch as haloperidol or clozapine, or new compoundssuch as CDPPB, an mGluR5 agonist. Thus, the key tounderstand the pathophysiology of schizophrenia and todesign better treatments may be to identify thefunctional networks that are associated with schizo-phrenia and the pharmacological models can helpidentified this common network in order to betterunderstand the pathophysiology of schizophrenia.

Multiple risk factors can contribute to the pathophy-siology of schizophrenia, such as influenza or maternalstress and, by introducing this factor during the gestationsome of the deficits observed in schizophrenia can bereplicated (for example see Gelowitz et al., 2002), aspresented by Anthony Grace. Timing of the insult is acritical variable for these models, as shown for examplewith the prenatal polyIC injection into mice model usedby J. Feldon (Meyer et al., 2008). Dr. Grace's laboratoryhas been focused on a particular model, the methyla-zoxymethanol acetate (MAM) rodent model of schizo-phrenia. When MAM is injected to a pregnant dam ongestation day 17, anatomical (cell packing density,decreased cortical thickness), behavioral (decrease ofprepulse inhibition of startle and impairment of reversallearning) and pharmacological (increased response toPCP and amphetamine) changes are noticed in the adultoffspring, and are comparable to those observed inschizophrenia (Flagstad et al., 2004; Moore et al., 2006).Recent clinical studies support the presence of hyper-activity in the hippocampus (HPC) in schizophreniapatients (Malaspina et al., 1999; Heckers, 2001; Medoffet al., 2001), and furthermore suggest that it may berelated to the psychotic states, such as a DA hyperre-sponsivity. Interestingly, with activation of the ventralHPC in normal animals, there is an increase in thenumber of dopaminergic (DA) neurons firing, with nochange in the firing pattern or firing rate. Similarly,MAM-treated rats show HPC hyperactivity and anincrease in the number of DA neurons firing. This effectseems to be a consequence of HPC hyperactivity sinceinactivation of the ventral HPC reversed the increasedDA neuron population activity and normalized theaugmented amphetamine-induced locomotor behavior(Lodge and Grace, 2007). Tonic DA neuron populationactivity is driven specifically by the ventral HPC, and

this population activity provides the “gain” in the DAsystem by modulating the number of DA neurons thatcan respond with phasic burst firing responses driven bythe pedoculopontine tegmentum (Lodge and Grace,2006). Thus, hyperactivity in the hippocampus mayinduce a maximized gain that will disrupt the system. Toconclude, stress from multiple factors such as maternalinsults, fetal stress or genetic predisposition maypredispose an individual to pathophysiological changesof the hippocampus which can potentially lead to theonset of schizophrenia in the adult.

As previously described, the validity of develop-mental models depends on critical factors such as thetiming of the insult but also the circuitry involved. Thishas been confirmed with the neonatal hippocampaldisconnection model, which shows an array of abnorm-alities reminiscent of schizophrenia emerging postpub-erty in animals with early but not late-induced insults inthe hippocampal–prefrontal cortical circuitry (Lipskaand Weinberger, 2002). This model confirms that thereis a critical time in development during which an earlyinsult produces abnormalities that are consistent withmany aspects of the human disorder. Recent evidencesuggests that the “lesion” may be due to geneticabnormalities and interactions between genes andenvironment. Thus, understanding how genes contributewill be critical for understanding pathophysiology of thedisease and designing treatment. Some of the candidategenes for schizophrenia studied in this context havebeen presented by Barbara Lipska. One gene involved isCOMT encoding an enzyme catabolizing DA and thusregulating cortical DA levels. Human postmortemstudies in PFC (Chen et al., 2004) and studies fromBarbara Lipska's laboratory in transgenic mice over-expressing the human COMT-Val allele demonstratedthat, by increasing prefrontal DA catabolism, the COMTVal allele impairs prefrontally-mediated cognition, andthus may increase the risk for schizophrenia (Papaleoet al., J Neurosci, in press). This is however a complexstory as COMT appears to exert its pathological rolethrough the interactions of Val/Met with other single-nucleotide polymorphisms (Shifman et al., 2002), aswell as by interactions with other factors (e.g. environ-ment). DISC1 is another strong candidate geneimplicated in schizophrenia. Its pathological role is notknown yet. It appears that alternative splicing of DISC1is complex and may play a role in schizophrenia as somenovel short transcripts are enriched in the hippocampusof patients with schizophrenia. These short DISC1transcripts identified in human brain are predicted toencode “truncated” proteins. Therefore, animal modelsof DISC1 (mutations and induced truncation) may help


understand how short transcripts exert abnormal functionin brain. Indeed, mutation (Clapcote et al., 2007), deletion(Koike et al., 2006) or overexpression of truncated DISC1(Hikida et al., 2007) in mice result in behavioralphenotype similar to human psychiatric disorders.Cellular models also show that truncated DISC1 variantsexert abnormal functions. Moreover, studies by Lipska etal. (Bethesda, Maryland) showed that short DISC1transcripts are abundant in fetal frontal cortex and thatthe expression profile of short transcripts in fetal PFC isassociated with a risk DISC1 genotype. Thus, a newgeneration of models will help understand pathologicalrole of genes, protein–protein interactions, distributionand function of abnormal transcripts/proteins.

It should be noted that mutants are not models ofschizophrenia per se. They are models of the functionalroles of genes associated with risk for schizophrenia orwith putative endophenotypes. John L. Waddington firstpresented two mutants related to the pathophysiology ofschizophrenia, linked to the dopamine hypothesis andthe NMDA hypothesis. The conditional striatal D2receptor over-expression model (Kellendonk et al.,2006) showed impairment in PFC-mediated workingmemory and behavioral flexibility. Moreover, a putativeglutamatergic NMDA hypofunction (Mohn et al., 1999)induced hyperactivity, which was reversed with cloza-pine, and disruption of social behavior related to thatobserved in schizophrenia. Many genes are candidatesand contribute to the risk for schizophrenia, such asDISC1 or NRG1. For example, NRG1 mutants showeddisruption in social novelty preference that is related toschizophrenia but no impairment of spatial learning andworking memory, whereas COMT mutants have normalsocial behavior and enhancement of spatial learning/working memory (O'Tuathaigh et al., 2007). Increasingour understanding of pathogenic processes underlyingthe development of schizophrenia means that new genesinvolved in these processes may be good candidates forgenetic studies in humans. In particular, such processesinclude neuronal migration, axon guidance and synap-togenesis, together with control of synaptic activity and/or plasticity. Functional investigation of such genes inpreclinical paradigms can also indicate new hypothesis-driven avenues for clinical research.

To conclude, Carol Tamminga (Dallas, Texas),highlighted the idea that having powerful models forschizophrenia provoke a better understanding of thedisease, and more pharmacological targets can be found.In schizophrenia, there are component symptomscomplexes that run together, and focusing on themwill help in developing more selective drugs. The mostpowerful model might be based on both genetic and

environmental variables and a genetically humanizedanimal model is important to relate to the humanpresentation. As confirmed by Pierre Sokoloff (Paris,France), it is easier to model an aspect of schizophreniathan schizophrenia itself in animals. Moreover, facevalidity is a difficult question concerning animal modelssince the psychosis symptoms cannot be assessed inanimals. Thus, behavioral tests, used in animal models,should be used also in patients.

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