Review Article

From bench to bedside: translating new researchfrom genetics and neuroimaging into treatment

development for early-onset schizophreniaeip_142 243..258

Sanjiv Kumra, Robert Asarnow, Anthony Grace, Matcheri Keshavan, Jon McClellan, Linmarie Sikichand Ann Wagner

Division of Child and AdolescentPsychiatry, University of MinnesotaMedical School, Minneapolis, Minnesota,USA

Corresponding author: Dr Sanjiv Kumra,Division of Child and AdolescentPsychiatry, University of MinnesotaMedical School, F256/2B West, 2450Riverside Avenue, Minneapolis, MN55454, USA. Email: kumra002@umn.edu

Disclosure: The authors report noconflicts of interest.Any necessary credits: The opinions andassertions contained in this manuscriptare the private views of the authors andare not to be construed as official or asreflecting the views of the Department ofHealth and Human Services, the NationalInstitutes of Health, or the NationalInstitute of Mental Health.Description of financial support relevantto the paper: None.

Received 26 May 2009; accepted 28August 2009

Abstract

Objective: Children and adolescentswith schizophrenia share a similarpattern of phenomenological, geneticand cognitive abnormalities to adultswith schizophrenia. However, anearly-onset of schizophrenia (EOS)(prior to 18 years of age) is associatedwith a higher frequency of risk indica-tors associated with schizophrenia(e.g. developmental delays and famil-ial spectrum disorders) and a worselong-term outcome. This overviewexamines recent research on theneurobiological alterations, possiblecauses, developmental trajectory andtreatment of EOS and attempts toidentify gaps in the field.

Method: The authors provide a selec-tive review of major findings fromgenetics, neuroimaging and treat-ment studies of pediatric schizophre-nia that were presented at a workshopsponsored by the National Institute ofMental Health. These data are synthe-sized in conjunction with preclinicalstudies into a model of the patho-physiology of EOS.

Results: EOS is associated with a highfrequency of cytogenetic abnormali-ties (e.g. velocardiofacial syndrome,sex chromosome anomalies) andother rare denovo chromosomalaberrations. Brain imaging researchin adolescents with EOS has revealeda progressive loss of cortical greymatter post-onset of psychosisand subtle abnormalities in whitematter microstructure. Although EOSpatients are more likely to betreatment-refractory than their adultcounterparts, there are substantialdata that this subgroup is particularlyresponsive to clozapine.

Conclusions: Genetic or environmen-tal factors operating during adoles-cence that reduce frontal capacitymight contribute to an EOS in suscep-tible individuals. Additional longitu-dinal studies of adolescents withschizophrenia are needed to betterunderstand the relationship betweenstructural changes in fronto-limbicregions, stress responsivity, andcognitive and neurochemicaldevelopment.

Key words: adolescents, early-onset schizophrenia, intervention,pathophysiology.

Although schizophrenia is generally considered tobe a disorder of late adolescence and early adult-hood, it is becoming increasingly evident that theroots of this pathology lie in early development.1,2

Over the past decade, there has been an upsurge instudies focusing on early-onset schizophrenia (EOS)(onset of psychotic symptoms by age 18 years) andin particular childhood-onset schizophrenia (COS)

(onset of psychotic symptoms by age 13 years).However, a basic neurobiological model of EOS thatcould be translated into novel treatment interven-tions is lacking. To begin to address this problem,the National Institute of Mental Health (NIMH) andthe National Institute of Health Office of Rare Dis-eases convened a meeting of basic, translationaland clinical investigators to review the current

Early Intervention in Psychiatry 2009; 3: 243–258 doi:10.1111/j.1751-7893.2009.00142.x

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knowledge on the phenomenology, treatment,causes and developmental trajectory of COS andadolescent-onset schizophrenia in June, 2007. Theworkshop provided an opportunity for brainstorm-ing and discussion among scientists. The overarch-ing goal of this cross-disciplinary discussion was toidentify avenues of research that could lead to thedevelopment of improved or novel interventions forEOS, and for the earliest possible intervention inadult-onset schizophrenia (AOS).

The primary focus of this paper is to demonstratehow early-onset psychosis may represent a moresevere variant of schizophrenia and could thereforeultimately provide a more understandable model ofschizophrenia. We provide a brief overview ofthe neurobiological similarities and differencesbetween EOS and AOS and the current state of treat-ment of EOS. Together, the similar pattern of neuro-biological abnormalities and treatment responsesuggest that EOS and AOS share the same etiopatho-physiology, but that EOS may have a larger compo-nent of neurodevelopmental risk factors. Secondly,the paper comprehensively reviews major findingsfrom genetics and neuroimaging studies in EOSfrom over the past 5 years and identifies severalgaps in the current established pathophysiologicalmodel of schizophrenia (i.e. the neurodevelopmen-tal model). The genetics and neuroimaging data aresynthesized in conjunction with preclinical andadult studies to present a relatively novel hypothesisabout the pathogenesis of EOS. We then examine

how recent genetic and neurobiological dataprovide a rationale for the use of glutamatergic-based therapies in EOS. Lastly, we identify critical‘next steps’ and areas of research needed to elabo-rate our understanding of the neurodevelopmentalmodel of EOS.

HOW DOES EOS COMPARE WITH AOS?

Several comprehensive reviews have documentedthe neurobiological characteristics of EOS and havecompared it with AOS.3–7 Rather than attempting tosummarize all of these data, which would not befeasible in the context of this review, we highlightkey similarities between EOS and AOS that suggestcontinuity (Table 1).

Structural magnetic resonance imaging (MRI)and Diffusion Tensor Imaging (DTI) studies

By contrast with the literature on AOS, relatively fewbrain imaging studies of EOS have been conducted(for reviews see Reference 7 and 14). The NIMH EOSstudy pioneered structural brain imaging studiesin this population. Initial cross-sectional anatomicMRI studies of comparing EOS with healthycontrols have consistently shown lower regionalGM volumes (e.g. prefrontal cortex, thalamus,

TABLE 1. Comparison of early and adult onset schizophrenia: neurobiological features

Neurobiological measure Abnormality Effect in adult-onset schizophrenia

Diffusion tensor imaging Reduced fractional anisotropy observed in white matter inearly-onset schizophrenia patients relative to healthyvolunteers in the frontal regions, anterior cingulateregion, parietal regions, hippocampal region and inferiorlongitudinal fasciculus8–13

Present

Structural brain magneticresonance imaging

Whole brain and grey matter volume is reduced andventricular volume is increased in early-onsetschizophrenia patients relative to healthy volunteers.Volumetric differences have also been reported inthe basal ganglia, temporal lobe structures (e.g.hippocampus and superior temporal gyri), thalamusmidsagittal area, cerebellum, corpus callosum andprefrontal cortex7,14,15

Present

Magnetic resonancespectroscopy

Reduced N-acetylaspartate concentrations reported inearly-onset schizophrenia patients relative to healthyvolunteers in the prefrontal region and hippocampus16–19

Effect size difference may belarger in EOS patients comparedwith AOS19

Eye movementabnormalities

Abnormalities in smooth pursuit eye movements havebeen observed in EOS patients relative to healthyvolunteers with abnormal anticipatory and catch-upsaccades. Similar abnormalities have also beenreported in first-degree relatives of EOS patients20,21

Effect size difference in relatives maybe larger in unaffected relatives ofEOS patients compared with AOSpatients21

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cerebellum, anterior cingulate, corpus callosum)and larger ventricle volumes as well as larger basalganglia volumes with similar effect size differencesto those reported in studies of AOS.7 Volumetricalterations in the hippocampus in EOS populationshave been less consistent. In contrast to adult mor-phometric studies, initial cross-sectional studiesreported no hippocampal volume differences inadolescents with EOS that may reflect the smallsample sizes used and lack of power.22,23 However, amore recent study from the NIMH EOS cohort thatbenefited from improved methodology andincreased sample size revealed bilateral reduction intotal hippocampus volume, particularly in the ante-rior and posterior portions.24 Furthermore, involve-ment of the hippocampus early in the diseaseprocess has been suggested by separate reportsdocumenting abnormalities in verbal learning andmemory,25 similarities in formal thought disorderbetween children with schizophrenia and childrenwith complex partial epilepsy,26 proton magneticresonance spectroscopic imaging16 and DTI27 in EOSpatients.

As we will discuss later, longitudinal studies ofdevelopmental trajectories, as opposed to staticmeasures, have shown more striking progressivelosses of cortical grey matter volumes and increasesin ventricular volumes in adolescents with schizo-phrenia post-onset of psychosis as compared withadult populations.6 However, it is theoretically pos-sible that AOS patients might also experience asimilar pattern of exaggerated cortical grey mattertissue loss during mid-adolescence, but this wouldbe a difficult hypothesis to test as it would requirea large, prospective longitudinal study of at-riskyouth.

A recent study by Pagsberg et al.28 suggests thatwhite matter abnormalities may also be prominentin EOS. It is possible that abnormalities in myelina-tion and oligodendrocytes could influence certainaspects of disease expression, particularly age atonset of psychotic symptoms in schizophrenia.8

White matter integrity in EOS has been investigatedusing DTI. Cross-sectional DTI studies comparingfractional anisotropy (a measure of white matterintegrity) between patients and controls haveconsistently found reduced fractional anisotropy inpatients, but there has been less consistency regard-ing which brain regions are affected by the diseaseprocess. To date, findings of decreased fractionalanisotropy have been observed in diverse brainregions using both region of interest and voxelwiseapproaches, but as shown in Table 1, abnormalitiesin frontal and temporal white matter seem to be themost well replicated findings.9–13,27,29 Brain white

matter abnormalities may be one of the key etio-pathological findings in EOS. This aspect of thepathophysiology of EOS may account for the profileof generalized cognitive deficits observed in EOSand is potentially consistent with the glutamatergicmodel of the illness given the prominent role of glialcells in glutamate-glutamine homeostasis.30

Magnetic Resonance Spectroscopy (MRS)studies

Proton MRS studies of children and adolescentswith schizophrenia show reduced N-acetyl aspar-tate (NAA) (expressed as a ratio to the creatininesignal, often used as an internal standard) in the leftprefrontal white matter,17 medial prefrontal cortex,31

and in the prefrontal cortex bilaterally.16 A morerecent study18 reported prefrontal NAA abnormali-ties in male, but not female children and adoles-cents with schizophrenia. Bertolino et al.16 observedbilateral reduction of NAA/creatine ratios in the pre-frontal cortex in COS patients, as well as in schizo-phreniform and chronic schizophrenia patients.N-acetylaspartate is synthesized in neuronal mito-chondria and it has been shown to a marker sensi-tive to a number of pathological processes affectingneuronal integrity. A reduction in NAA is oftenconsidered to represent decreased density and/ordysfunction of neurons and axons.

Electrophysiological studies

Event-related potential (ERP) studies are valuable indetermining the precise nature of information pro-cessing deficits in schizophrenia. The University ofCalifornia, Los Angeles COS studies have reportedERP abnormalities in EOS.32,33 The amplitude of thelate positive response (P300), a well-known index ofstimulus recognition and processing in relationto cognitive tasks, is reduced in EOS as well as inother disorders such as attention deficit disorders(attention-deficit/hyperactivity disorder). Severalbrain regions have been implicated in the genera-tion of the P300 including the superior temporalgyrus, inferior parietal lobe, frontal lobe as well asthe hippocampus and thalamus.34 The negative ERPresponse at 400 ms (Np) is also reduced in EOSas well as in AOS but not in attention deficit dis-orders, suggesting some measure of diagnosticspecificity.33

A large body of literature exists for eye-trackingabnormalities in AOS. Abnormal smooth pursuit isalso found in unaffected relatives, suggesting thatthese may represent heritable endophenotypes forthe disorder. Only a few studies have examined this

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measure in EOS, and have found abnormalities inboth the smooth pursuit system and in inhibition ofthe saccade system similar to AOS patients.20,21

Pursuit deficits have been observed to be related toreduced function in the extraretinal motion process-ing pathways.35 Ross et al.21 found that the parents ofEOS patients performed more poorly than theparents of adult-onset patients on the anticipatorysaccade measure in the pursuit task. These datafurther support the possibility that EOS may beassociated with higher genetic loading and suggestthat the study of endophenotypes in unaffectedrelatives might be a valuable strategy to under-stand which endophenotypes associated with schi-zophrenia might contribute to an early onset of thedisease.

In comparison with other childhood psychiatricdisorders, there has been relatively considerableneurobiological research conducted in EOS.However, the examination of the possible relevantcandidate endophenotypes for schizophrenia inchildren and adolescents still remains incompletein comparison with the work conducted in adultswith schizophrenia (Table 1).36 It should be notedthat there have been few neurobiological studiesdirectly comparing EOS and AOS and that thesample sizes of the existing studies have been small.This increases the likelihood of possible sample biasand could account for some of the observed effectsize differences for certain neurobiological mea-sures (e.g. MRS). Overall, the pattern of the observedneurobiological alterations would support ahypothesis that EOS is on a continuum with AOS.These data would suggest that insights into thepathophysiological mechanisms operating in early-onset cases may have relevance for understandinganomalies in neurodevelopmental processes thatcontribute to the more typical forms of schizophre-nia that have their onset in late adolescence andearly adulthood.

WHY MIGHT THE INDIVIDUAL DEVELOP THEOBSERVED PATHOPHYSIOLOGICAL ALTERATIONS?

As shown in Table 2, EOS appears to be associatedwith a higher frequency of premorbid impairments,higher genetic loading and a more adverse andunremitting outcome compared with AOS. Similarto AOS, there is also wide agreement that the cogni-tive deficits observed in EOS reflect dysfunction indistributed neural networks, many of which involvecircuits with heavy involvement of the frontal lobesthat support a number of higher cognitive pro-cesses. Similar to AOS, the challenge in cognitive

studies of EOS has been in identifying the underly-ing cognitive processes that could produce such awide range of performance deficits. As with AOS,there does not appear to be a progressive general-ized loss of cognitive functioning after an initialdecline around the onset of psychotic symptoms.57

This stability of general cognitive functioning dem-onstrated in longitudinal analyses, for periods up to13 years in COS patients, is noteworthy givenchronic illness and related long-term exposure toanti-psychotic medications and the concomitant,progressive loss of cortical grey matter.57

While multiple theories have been advancedto provide a pathophysiological mechanism tointegrate these key clinical observations of EOS,the results of various genetics and neuroimagingstudies conducted across patients with schizophre-nia provide broad support for the neurodevelop-mental model.2 More recent iterations of themodel5,61,62 propose that in addition to multipleforms of neuropathological insults occurring ‘early’(pre- and peri-natal) in development61 that there aredisruptions of typical maturational processes thatoccur later in childhood and adolescence. Together,these perturbations are thought to contribute tosymptom expression in EOS.5,62 (see Fig. 1) In EOS,neuroimaging studies have been largely instructivein revealing atypical trajectories of adolescent braindevelopment post-onset of psychosis, which arethought to reflect exaggerations of normal synapticpruning/elimination processes and abnormalitiesof myelination. Herein, we critically review datafrom genetics and neuroimaging to identify criticalgaps in the neurodevelopmental model in generalfor EOS patients and data which provide support forour specific hypothesis. Based on our review of theliterature, we hypothesize that EOS represents anextreme variant with an enrichment of schizophre-nia susceptibility factors and that these risk factorsinteract to compromise the development of fronto-limbic circuitry and render the brain vulnerable todopamine dysregulation.

Genetics studies

At present, there is no consensus on what is thebest methodology to identify genes for complexinherited disorders such as schizophrenia. It is pos-sible that multiple forms of neuropathologicalinsult and therefore multiple etiologies may con-tribute to the development of symptom expressionin schizophrenia. For the majority of EOS patients,specific causal mechanisms remain unknownand it is unclear to what extent genetic hetero-geneity is inhibiting our capacity to understand

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schizophrenia at a neurobiological level. Twin,family and molecular genetic studies support astrong genetic basis for schizophrenia,63,64 includingearly-onset cases.21,40,41 Early-onset cases may beparticularly informative for genetic research inschizophrenia because they potentially represent aform of the disorder associated with a higher fre-quency of neurodevelopmental risk factors, and it ispossible that they are more likely to harbor particu-larly large deleterious mutations that couldadversely affect neurodevelopment and that areeasier to detect with current technologies.

Most current genetic research in schizophreniahypothesizes that the illness is the sum result of dif-ferent susceptibility genes, with each genetic riskvariant only contributing a small degree of risk. Thisis the common-disease common-variant model,which presumes that individuals share susceptibil-

ity genes that confer cumulative vulnerability tovarious traits of complex psychiatric illnesses,including putative endophenotypes. The combina-tion of risk variants and/or exposures to environ-mental risk factors ultimately leads to the illness.

Large collaborative linkage studies with affectedadults have identified multiple candidate chromo-somal regions, which in total encompass a signifi-cant portion of the genome. For COS, positiveassociations have been replicated for putativeschizophrenia susceptibility genes identified in AOSthat affect glutamatergic and neuregulin pathways(e.g. G7265, GAD166, neuregulin67 and dysbindin68).Although our knowledge of when these genes areexpressed in development and how these geneticvariations could impact brain development duringchildhood and adolescent remains incomplete,there is some evidence that certain genes that affect

TABLE 2. Comparison of early and adult onset schizophrenia: key clinical and neurocognitive features

Clinical characteristic Abnormality Effect in adult-onset schizophrenia

Premorbid impairments Abnormalities/delays in social, language and motordevelopment have been frequently reportedin EOS patients prior to onset of psychosis37–39

Patients with an onset of schizophrenia before age13 years have been observed to have significantlymore premorbid social, language and motordelays and difficulties compared with patientswith onset later in adolescence or adulthood37

Familial aggregation ofschizophreniaspectrum disorders

Schizophrenia and spectrum disorders(schizoaffective disorder, schizotypal and paranoidpersonality disorder) are increased in relatives ofEOS patients in comparison with ADHD probandsand healthy volunteers40,41

Parents of COS probands had a significantly highermorbid risk of schizophrenia spectrum disorders(24.7%) than parents of AOS (11.4%) andcommunity comparison probands (1.5%)41

Functional outcomes The rates of remission of psychotic symptomsreported in COS patients are low (starting from3%)42 to 33%43 at follow-up intervals of 5 and7 years respectively and the majority of patientswere diagnosed with schizophrenia orschizophrenia-spectrum disorders at baselineretain their diagnoses at follow-up42,44–46

Long-term functional outcomes (e.g. work history,educational achievement, ability to liveindependently) in COS are generally worsecompared with AOS46–48

Neurocognitiveimpairments

EOS patients perform poorly on a wide variety ofcognitive tasks including tests of attention49–51;serial visual search52,53; visual and spatialworking memory54; verbal learning and memory49;and executive functioning49,50,55

The finding that expressive language skills areamong the least impaired functions in EOSsuggest that early language deficits representdelays in the acquisition of skills that are at thecusp of development in schizophrenia56 ratherthan a language disorder per se.

There is wide agreement that the cognitive deficitsobserved in COS reflect dysfunction in distributedneural networks many of which involve circuitswith heavy involvement of the frontal lobes thatsupport a number of higher cognitive processes.

There does not appear to be a progressivegeneralized loss of cognitive functioning after aninitial decline around the onset of psychoticsymptoms49,51,53,54,57–60

The profile of cognitive deficits in EOS is similarto what has been observed in adults with afirst-episode of schizophrenia,59 but may bepossibly more severe in magnitude with respectto motor performance60

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glutamatergic function (e.g. G72) may adverselyeffect cortical grey matter loss in the frontal lobes.67

However, although many promising results arenoted, the schizophrenia genetics literature is char-acterized by small effect sizes, lack of replicationand variable results. Causal relationships betweenthe illness and candidate genes are difficult to estab-lish. Genome-wide association studies have notreplicated putative candidate genes or genomicregions previously thought to play a role in adultswith schizophrenia.69,70

An alternative model suggests that a proportion ofcases of schizophrenia may arise from individuallyrare, large effect mutations.71 Recent research hasdemonstrated that individuals with schizophreniaharbor significantly more rare deletions and dupli-cations that impact genes than healthy controls.72,73

Patients with onset of illness before 19 years are athigher risk to harbor a rare structural mutation incomparison with patients with a later onset ofschizophrenia.72 Genes disrupted by mutations in

affected individuals are more likely to be involvedwith neuronal signaling, including glutamate andneuregulin pathways.72 In these studies, most indi-viduals with schizophrenia had a different mutationthat impacted different genes.

Individuals in the NIMH EOS cohort (who repre-sent an especially severe and rare, treatment-refractory group of EOS patients) have a higher rateof cytogenetic abnormalities than reported in adultswith unspecified onset including an inherited bal-anced 1:7 translocation, one case of mosaic TrisomyX (50% XXX), two cases of atypical Turner’s syn-drome (XO) and four cases of 22q11 deletion syn-drome.74 Furthermore, this cohort is also enrichedfor rare microduplications and microdeletions.72

Many of these rare smaller structural mutationswere inherited from unaffected parents. This doesnot rule out an association with the illness, butrather suggests variable penetrance and/or the roleof other genetic, epigenetic and environmentalfactors in phenotypic expression.

FIGURE 1. Stages of illness and possible pathophysiology.

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Collectively, these recent findings suggest thatschizophrenia may be characterized by enormousgenetic heterogeneity, and that many, perhaps mostcases, have a unique genetic cause. This does notimply that the illness stems from a different gene ineach case. Rare large effect mutations are likely tooccur in genes that harbor other disease-associatedalleles, some of which may be common. However,the common allele and rare allele models imply sub-stantially different strategies for gene-finding. Mostcurrent gene-finding strategies for schizophreniaresearch – sib-pair linkage analyses, case-parenttriad studies, candidate gene studies and haplotypeassociation studies – are intended to identify single-nucleotide polymorphisms or haplotypes shared bylarge numbers of cases compared with appropriatecontrols. However, if a large number of differentindividually rare mutant alleles are responsiblefor the illness, these approaches will predictablystruggle with variable findings and lack of replica-tion. The ‘rare allele’ model points to the potentialvalue of intensive studies of individual cases orsingle families. The search for shared causalityshould focus on common neurobiological pathwaysdisrupted in affected individuals, rather thanindividual genes or variants.

Neuroimaging studies

There have been a number of recent brain imagingstudies in EOS and we attempt to synthesize thesedata in the context of the neurodevelopmentalmodel of the disorder.5,61

Evidence supporting disruption of early stages ofneurodevelopment

Although early descriptions of schizophreniafocused on delays in the acquisition of motor,speech and language and social skills as early asinfancy75 the nature and timing of insults thatadversely affect neurodevelopment and lead to thedevelopment of symptom expression in patientswith EOS remains elusive.76 Neuroimaging studieshave revealed a number of brain structural anoma-lies in EOS, which are indicative of an early neu-rodevelopmental insult such as anomalies in gyralpatterning77, absence or reversal of normal ana-tomical brain asymmetries in the planum tempo-rale78 and a higher prevalence of cavum septumpellucidum79 compared with age-matched healthycontrols similar to what has been observed in adultswith schizophrenia. It is possible that an inter-ruption of early brain development in individualsat genetic-risk for schizophrenia may push the

trajectory of brain development out of the normalgroove80 and in the absence of normalizing events,into a persisting trajectory of abnormality.

Evolution of psychotic symptoms and braindysmaturation during childhood and adolescence

The emergence of schizophrenia is thought to berelated to ‘anomalies or exaggerations of typicaladolescent maturation processes acting in concertwith psychosocial factors (e.g. school relationships)and/or biological environmental factors (e.g. puber-tal hormonal changes, drugs of abuse)’.81 As wewill discuss, although longitudinal neuroimagingstudies have revealed abnormal trajectories of braindevelopment in patients with EOS and their healthysiblings, the neurobiological mechanism(s) under-lying the transition to psychosis in EOS remainunknown. Clinical studies of EOS indicate that theonset of psychotic symptoms is insidious and thatnonspecific emotional/behavioral disturbancesfrequently precede first onset of psychotic symp-toms.82 Around the onset of psychosis, a progressivefunctional decline from already impaired premorbidlevels appears to occur in a subgroup of patientswith EOS. Investigators have used a correlationalapproach to understand the relationship betweenpremorbid developmental deviations and structuralbrain abnormalities in EOS. Of interest, premorbidfunction, as assessed with the Premorbid Assess-ment Scale, has been associated with reduced greymatter volume in the ventral prefrontal cortex, infe-rior parietal cortex, cerebellum, anterior cingulateand in the medial temporal cortices bilaterally inadolescents with schizophrenia.7 These same brainregions were found to show progressive grey mattervolume reduction in a longitudinal comparisonof adults scanned before and after the onset ofpsychosis.83,84 Together, these data support thenotion that pathophysiological mechanisms under-lying the early developmental derailment asso-ciated with EOS85 may be related to the mechanismsunderlying the transition to psychosis in the prodro-mal phase in young adults with schizophrenia.

Although there have been several recent reviewsthat have summarized neuroimaging data in EOSelsewhere,5,6 there has been relatively little focuson the possibility that abnormalities in the deve-lopment of fronto-limbic connectivity duringadolescence could represent an alternate patho-physiological mechanism involved in the transitionto psychosis. We hypothesize that a developmentaldisruption in prefrontal cortical development couldinitiate a cascade of events that possibly leads todysregulated limbic system function who are at risk

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for developing schizophrenia.86,87 Several lines ofevidence from neuropsychology,1,49 structural brainimaging,15,88 proton MRS,16–18,89 DTI,11 positronemission tomography78 and genetics90 suggest thatgenetic or environmental factors operating duringchildhood and adolescence that reduce frontalcapacity could represent a risk indicator for EOS. Ofinterest, the superiority of clozapine for treatment-refractory EOS patients may reflect the fact thatclozapine has the capacity to fine-tune the sponta-neous and disrupted activity of prefrontal cortexneurons.91 In the NIMH cohort, the typical decreaseobserved in frontal grey-matter volume that wasobserved in healthy subjects during adolescencewas exaggerated fourfold.92 Lower volumes of theprefrontal cortex were also observed in the healthysiblings of probands with COS at age 14 years, butthese anomalies normalized by age 20 years.88

Better social and cognitive ‘competence’ was asso-ciated with normalization or inhibition of theregional GM loss. These data suggest that greymatter morphological abnormalities in the frontalregions are most likely to be familial/trait markersinfluenced by shared genetic markers.

An emerging theory of adolescent developmentsuggests that brain maturation involves a changingbalance of function whereby many of the cognitiveprocesses initially performed by more primitivelimbic/subcortical structures come under thecontrol of the prefrontal cortex.93 It has been sug-gested that the ability of the prefrontal cortex tomodulate amygdala activity is likely to play animportant role in the ability to cope with stres-sors.87,94,95 According to the neurodevelopmentalmodel of schizophrenia, insults occurring early inbrain development may be masked until these cir-cuits are taxed by later developmental demands.2

Childhood and adolescence represent criticalperiods in social development. Stress is known toactivate structures such as the amygdala, with theprefrontal cortex playing a major role in modulatingits impact on forebrain structures. Indeed, studiesshow that activation of the amygdala96 can lead tointerneuron loss in temporal lobe structure and hip-pocampal hyperactivity, as has been observed inboth developmental animal models97 and in clinicalimaging studies of schizophrenia patients.98,99

Animal studies have shown that the adolescentand early adult period is a time when both dopam-ine and amygdalar fibres are actively growing intoneocortical regions and form interconnections withprojection cells and GABAergic interneurons.100 TheGABAergic neuron appears to be critical to normaldevelopment and functioning of these networks.The establishment of this corticolimbic circuitry,

largely during adolescence, may contribute to theintegration of emotional responses with attentionaland other cognitive processes. Normal ingrowth ofprojections from the amygdala could ‘trigger’ theonset of schizophrenia and indeed other forms ofpsychopathology by influencing the expressionof unique sets of susceptibility genes that definespecific cellular endophenotypes within vulnerablepopulations of GABA cells. Alternatively, exposure tostressful events or illicit substances may affect thedevelopmental plasticity of amygdalar fibres result-ing in the excessive sprouting of basolateralamygdalar projections to the anterior cingulateregion. Thus, exposure to stress may theoretically beassociated with increased dopaminergic andglutamatergic inputs to frontal cortical neurons. Aplausible mechanism for GABA cell dysfunction inschizophrenia within amygdalar terminal fields isthat abnormally increased amygdalar activity mayproduce an environment of increased glutamatergictransmission and possibly even oxidative stress.95,96

Animal data suggest that the brain responds toincreased demands imposed by behavioral experi-ence by myelinating previously unmyelinated axonsor by extending new, myelinated axons.101 However,as previously discussed adaptive processes suchas myelination may be more impaired in EOS ascompared with AOS.9

Post-illness onset progression of brain pathology

To date, neuroanatomical studies suggest that thereis a dynamic evolution of brain abnormalitiesevident post-onset of psychosis in EOS,88,102–104 withsome exceptions.105 Longitudinal data from EOSsubjects, mostly available from the NIMH cohort,suggest that the disease process in schizophreniacontinues post-onset of psychosis throughout ado-lescence and that the pattern of trajectory of brainchanges in schizophrenia appears to represent anexaggeration of normal brain development. Datafrom the NIMH cohort support a more exaggeratedback-to-front wave of cortical GM volume reductionpost-onset of psychosis which starts in the parietallobe and progresses anteriorally into the temporallobes, sensorimotor and dorsolateral prefrontal cor-tices, and frontal eye field,103 together with dorsal-to-ventral frontal GM reductions across the medialhemispheric surfaces of the frontal lobe which wereclearly separated from cingulate-limbic areas.104 Theprogressive loss of cortical GM developmental inadolescents with EOS normalized in parietal regionsand became more circumscribed to the prefrontaland superior temporal cortices as EOS subjectsmoved into adulthood.106

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The neuroanatomical changes observed in EOSpatients could be related to a dysregulated develop-mental myelination trajectory resulting in brainvolume loss without neuronal loss.107 This possibil-ity is supported by reduced expression of myelingenes,108,109 oligodendrocyte numbers,110 myelinstaining,111 and declines in MRI measures of whitematter volumes107,112 and anomalies in white matterstructural integrity.113,114 Similar data are nowemerging that developmental trajectories of EOSmay be affected by genetic variation occurring inmyelination signaling genes.67,115,116 Alternatively,these imaging findings may reflect exaggerationsof normal synaptic pruning/elimination pro-cesses.117,118 These developmental processes arecritically mediated by an intact glutamatergicsystem acting via NMDA receptors, whose hypo-function has been implicated in schizophrenia.119 Ithas also been suggested that there might be alimited deteriorative phase in at least some patientswith EOS that contributes to functional disabilitysecondary to glutamate mediated excitotoxicity,apoptosis and/or oxidative stress.120 It is alsopossible that these changes could be attributed tomedication treatment given that there are someemerging animal studies which have found brainanatomic changes after chronic exposure to anti-psychotic medication.121

REVIEW OF THE STATE OF SCIENCEON TREATMENT

Treatment in EOS has been based almost exclusivelyon pharmacologic treatment strategies in adults.The evidence base for most pharmacologic agentshas been quite limited until recently with mostacute phase trials involving very few participantswho were treated for short periods of time rangingfrom 6 to 12 weeks (see Table 3). Dosing may beslightly less than seen in adult studies, but is gener-ally comparable. Four main points have emergedfrom these trials. As shown in Table 3, all anti-psychotic treatments tested have typically resultedin statistically significant reductions in psychoticsymptoms, but true remission is rare and despitetreatment the course of EOS appears to be quitechronic and debilitating. Secondly, children andadolescents seem to experience frequent, but notunique, adverse effects. Thirdly, comparative trialswith agents other than clozapine have failed todetect differences in efficacy between various drugs,but have highlighted the differences in the adverseeffect profiles.122–124,126,133,134 Finally, clozapine

appears to have significantly greater benefits foryouth with treatment resistance than haloperidol orolanzapine.125,127,128

The dopaminergic system represents theprimary target for all of the antipsychotic medica-tions tested for EOS. Overall, the pattern of treat-ment response for both ‘first-line’ antipsychoticsand clozapine in patients with EOS is similar towhat has been reported in adults with schizophre-nia which provides further support of continuitybetween EOS and AOS. Although several recentcontrolled treatment trials have demonstrated theeffectiveness of second-generation antipsychoticmedications for EOS, across studies less than halfof youth with EOS achieve adequate clinicalresponse from currently available ‘first-line’ treat-ments. These data suggest that treatment strategiesneed to move beyond the oft-beaten paths, andtowards proof of concept trials of novel,hypothesis-driven interventions. As we will show,genetic studies of patients with EOS have thepotential for discovering new biological pathwaysand new targets for treatment.

POTENTIAL NOVEL INTERVENTIONS FOR EOS

One utility that can be garnered from a betterunderstanding of potential pathophysiologies ofschizophrenia as derived from animal modelsrelates to the development of new therapeuticapproaches. Both clinical98,99 and developmentalanimal model97 studies have illuminated a potentialrole for hyperactivity within the hippocampus as apotential factor in psychosis. Indeed, longitudinalimaging studies have targeted the hippocampus as asite where alterations may occur in parallel with thefirst break135 and as reviewed earlier, abnormalitiesin the hippocampal formation and the limbic cortexcircuit have been repeatedly observed in EOSpatients. The hippocampus itself has a potent regu-latory role over dopaminergic neuron firing,136,137

and the dopaminergic hyper-responsivity in themethylazoxymethanol acetate model of schizophre-nia can be effectively remediated by removing thisinfluence from the dopamine neurons.97 These datasuggest that a more effective approach to treatingschizophrenia psychosis would not be to directlyblock dopamine receptors, but instead to treat thealterations in the glutamatergic state in the hippoc-ampus that is responsible for this pathology.

Adult studies showing that selective glutamater-gic drugs such as ketamine and PCP will mimicor exacerbate the symptoms of schizophrenia138–140

and the association between glutamate and frontal

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cortical function141–143 have suggested a primarypathology within the glutamatergic system.144

However, it should be noted that trials with otherglutamatergic agents such as glycine andD-cycloserine145 and lamotrigine146 that have beenused as adjuncts to existing antipsychotics haveprovided disappointing results in adults. These dis-appointing results along with the side effect profilefor some of these agents (e.g. lamotrigine) haslimited enthusiasm for use of these agents in chil-dren. Animal studies based on the glutamatergicmodel have led to the development of a new class ofcompounds, the mGluR2/3 agonist,147 which is thefirst non-dopaminergic drug shown to have efficacyin treating schizophrenia.148 Indeed, it may be thatthe mGluR2/3 agonist could act at least in part viarestoration of normal glutamatergic function

upstream from the dopamine system. Assumingthat the mGluR2/3 agonists are shown to have asuitable risk:benefit profile once they come tomarket, this class of drugs represents an obviouschoice for inclusion in future clinical trials in EOSgiven that the available data suggest that suscepti-bility genes that affect glutamatergic and neuregulinpathways are associated with EOS (e.g. G7265;GAD166; neuregulin67; and dysbindin68) and appearto adversely affect trajectories of brain developmentin patients. Because it is also known that NMDAantagonists (e.g. ketamine and phencyclidine) thataffect cortical excitability have different behavioraleffects in children in that they do not produce psy-chosis and/or the same level of cognitive impair-ment, it will be necessary to conduct separate trialsof these agents in children. This may be particularly

TABLE 3. Clinical trials of antipsychotic medications in early onset schizophrenia

Study (Reference) Design Results

122 Parallel group, double-blind comparison of loxitane(n = 25), haloperidol (n = 25), and placebo(n = 25)

Response rate differed between placebo (36%) andactive drugs (88%, 70% respectively) only inseverely ill patients

123 Small open comparison of thiothixene (n = 13) andthioridazine (n = 8)

No difference between drugs in efficacy. Overall36% ↓ in BPRS; 52% response rate

124 Placebo-controlled, double-blind crossover trial ofhaloperidol (n = 16)

Significant benefit for haloperidol with 28% vs. 6%↓ BPRSC; 92% response rate with haloperidol

125 Parallel group, double-blind comparison ofclozapine (n = 11) and haloperidol (n = 10) intreatment-resistant youth

Significant benefit for clozapine for all outcomes,especially negative symptoms. ↓BPRS (37% vs.24%). ↓Negative symptoms (41% vs. 13%)

126 Parallel group, double-blind comparison ofhaloperidol, olanzapine and risperidone inpsychotic youth. 21/50 pts had EOSS; majority(13) of EOSS were on risperidone, four each onhaloperidol and olanzapine)

In all psychoses, no differences in BPRSC orresponse rate. In EOSS only, no differencesbetween drug groups. Side effect profiles ofdrugs differed

127 Parallel group, double-blind comparison ofclozapine (n = 12) vs. olanzapine (n = 13)

Clozapine much better for negative symptoms(48%↓ vs. 27%↓). Numeric advantages forclozapine in ↓BPRS (28% vs. 19%) and response(42% vs. 31%), but these were not statisticallysignificant

128 Parallel group, double-blind comparison ofclozapine (n = 18) vs. olanzapine (n = 21)

No difference in BPRS. Response was twice as likelyin clozapine (66%) vs. olanzapine (33%).Clozapine reduced negative symptoms more(36% ↓ vs. 19%↓)

129 Industry-sponsored, double-blind comparison ofolanzapine (n = 72) vs. placebo (n = 36)

Olanzapine superior for PANSS reduction (22%↓ vs.9%↓). Olanzapine superior for response (38% vs.26%). Olanzapine with significant side effects

130 Industry-sponsored, double-blind comparison ofaripiprazole (n = 201) and placebo (n = 101)

Aripiprazole superior to placebo for PANSSreduction (34%↓ vs. 22% ↓)

131 Industry-sponsored, double-blind comparison ofrisperidone (n = 106) and placebo (n = 52)

Risperidone superior to placebo for PANSS reduction(33%↓ vs. 16%↓). Risperidone superior forresponse (72% vs. 35%). Only low dose (1–3 mg)superior for negative symptoms. Risperidone withsome side effects

132 NIMH-funded, double-blind comparison ofmolindone (n = 40), olanzapine (n = 35), andrisperidone (n = 41)

No difference between drugs for PANSS reduction.No difference between drugs for response(molindone 50%, olanzapine 34%, andrisperidone 46%). Side effect profiles differed

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important because as previously discussed youngerpatients with schizophrenia may have greater cog-nitive disabilities than subjects with AOS.

FUTURE DIRECTIONS AND CONCLUSION

The design of novel treatments for EOS is contin-gent upon an improved understanding of the patho-physiology of the disease. As shown in this review,several aspects of the neurodevelopmental modelremain underspecified. New research developmentsin EOS critically depend on both conceptual andmethodological advances. Future research in EOS islikely to focus on several thematic areas:

1 Further refinement of the EOS phenotype – theinitial wave of neurobiological studies largelyfocused on the similarities and differences inbetween EOS and AOS to establish continuity,but did not rigorously assess the heritability andsuitability of different endophenotypic measuresfor genetic studies in EOS. In addition, neuro-biological studies in EOS, to date, have notsystematically attempted to distinguish COS fromadolescent-onset schizophrenia, which may wellprove to be a very important distinction if hor-monal hypotheses of the onset of schizophreniaprove to be partly correct.149 Also, it should benoted that studies of adolescents with a first-episode of psychosis suggest that some of neuro-biological alterations identified in EOS appear tooverlap with other early-onset psychoses andshow a lack of specificity to schizophrenia (e.g.lower prefrontal grey matter volumes).15 Clarifica-tion of which endophenotypes appear to bespecific to EOS89 will provide greater detail to neu-robiological models of the disorder.

2 Further assessment of how causal risk factorsassociated with EOS influence trajectories ofbrain development – the nature (both genetic andenvironmental) and timing of insults, includingexpression of schizophrenia susceptibility genes,which adversely affect neurodevelopment in EOS,remain unclear. Existing paradigms in etiologicresearch, which have not yielded adequateinsights, need to be revised in light of newer para-digms to more reliably identify susceptibilitygenes for schizophrenia (e.g. common, smalleffect vs. rare, large effect models as discussedearlier). As rare structural mutations appear toaccount for a proportion of EOS cases usingcurrent methodologies, further ascertainmentwill be necessary for uncovering further geneticvariation and to confirm which neurobiological

pathways are disrupted in EOS. Better delineationof endophenotypic markers and susceptibilitygenes are likely to help develop more valid animalmodels for further hypothesis testing. In addition,a broader understanding of the influence ofpotential risk factors associated with schizophre-nia (e.g. gonadal steroids, dysregulation of thehypothalamic–pituitary–adrenal axis function)and how experience (e.g. stress, social isolation,school absence, substance misuse) affect trajec-tories of child- and adolescent brain developmentis also needed to provide greater specification tothe neurodevelopmental model of schizophrenia.

3 More precise characterization of the critical neu-robiological pathways involved in EOS – prelimi-nary genetics data in EOS have implicatedneuregulin and glutamate pathways in the patho-genesis of the disorder. To date, longitudinal neu-roimaging studies of EOS have largely focused oncharacterizing age-related changes in brain struc-ture, but have not examined changes in geneexpression, brain activity and neurochemicaldevelopment. As noted in this review, severalanomalies in neurodevelopment have beeneither identified (e.g. grey and white matter devel-opment) or have been hypothesized to occur inEOS patients (e.g. development of the fronto-limbic circuitry, glutamate function). It is notclear how these processes might be interrelatedand/or represent distinct pathophysiologicalmechanisms leading to symptom expression inEOS. These data suggest that additional neuroim-aging approaches need to be applied to EOS.Proton MRS studies using strong magnetic fieldscould help to quantify neurotransmitter systemsimplicated in the transition to psychosis such asthe GABA and glutamate systems.81

4 Studying healthy siblings of youths with schizo-phrenia, given the family history of the disorder –studies of patients with EOS can only provideindirect information regarding the mechanism(s)of onset of psychosis. As many of the siblings ofEOS have not passed through the period of riskfor developing schizophrenia they provide anideal group to understand mechanism(s) of tran-sition to psychosis.88 Family studies supportthe possibility that EOS may be associated withhigher genetic loading in comparison with AOSand suggest that the study of endophenotypes inunaffected relatives might be a valuable strategyto understand which endophenotypes associatedwith schizophrenia might contribute to an earlyonset of the disease.21,88

5 Establishing novel psychosocial treatmentsvia controlled trials – it is possible that the

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neuroanatomical changes observed in patientswith EOS post-onset of illness represent ongoingmaladaptive changes in an already dysfunctionalcortical processing system. Two studies of cog-nitive remediation in EOS have been pub-lished.150,151 The smaller (n = 25) earlier studyshowed that a 30 h intervention improved func-tioning on early visual information processingonly if IQ was included as a covariate. However,the larger study (n = 40) found that 40 h of cogni-tive remediation significantly improved cognitiveflexibility and improvements in cognitive func-tioning were associated with reduced symptomsand fewer difficulties with social functioning.Because of their young age and the enhancedplasticity of the adolescent brain there is a needfor larger trials of psychosocial interventions forEOS.

In conclusion, the findings presented hereinindicate that EOS represents a severe variant ofthe disorder associated with a higher frequency ofpremorbid impairments, higher genetic loading, amore severe and unremitting outcome and greaterloss of cortical grey matter volumes comparedwith AOS. We anticipate that future genetic andneuroimaging studies of this unique population willprovide an improved understanding of the neurode-velopmental mechanisms underlying the disorder,which should lead to advances in diagnostic andtreatment strategies.

ACKNOWLEDGEMENTS

The authors wish to acknowledge the other partici-pants of the workshop: Manzar Ashtari, PhD,University of Pennsylvania; George Bartzokis, MD,University of California, Los Angeles; FrancineBenes, MD, PhD, Harvard University; William Cook,PhD, Maine Medical Center; R. Douglas Fields, PhD,National Institute of Child Health and HumanDevelopment; Sophia Frangou, PhD, Institute ofPsychiatry; Jean Frazier, MD, Cambridge HealthAlliance; Jay Giedd, MD, National Institute of MentalHealth; Thomas Insel, MD, National Institute ofMental Health; Lars Fredrick Jarskog, MD, Univer-sity of North Carolina, Chapel Hill; Wendy Kates,PhD State University of New York Upstate MedicalUniversity; James McCracken, MD, University ofCalifornia, Los Angeles; James Meador-Woodruff,MD, University of Alabama; Jonathan Mill, PhD,University of Toronto; Bita Moghaddam, PhD, Uni-versity of Pittsburgh; Judith Rapoport, MD, NationalInstitute of Mental Health; Brien Riley, PhD, Virginia

Commonwealth University; Akira Sawa, MD, PhD,Johns Hopkins University; Ezra Susser, MD, Colum-bia University; Carol Tamminga, MD, University ofTexas, Southwestern Medical Center; Sophia Vino-gradov, MD, University of California, San Francisco;Daniel Weinberger, MD, National Institute of MentalHealth.

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