The influence of concomitant antidepressant medication on safety, tolerability and clinical...

Editorial

Ethical aspects of publishingHans-Jurgen Moller ............................................................................................................................... 66

Review

Psychiatric symptoms associated with oculogyric crisis: A review of literature for thecharacterization of antipsychotic-induced episodes

Kazuhiko Abe ....................................................................................................................................... 70

Original Investigations

Effect of olanzapine treatment on platelet glutamine synthetase-like protein andglutamate dehydrogenase immunoreactivity in schizophrenia

Gulnur Sh. Burbaeva, Irina S. Boksha, Elena B. Tereshkina, Olga K. Savushkina,Marina S. Turishcheva, Lubov I. Starodubtseva, Oleg S. Brusov, Margarita A. Morozova .............. 75

The influence of concomitant antidepressant medication on safety, tolerability and clinicaleffectiveness of electroconvulsive therapy

Thomas C. Baghai, Alain Marcuse, Melanie Brosch, Cornelius Schule, Daniela Eser,Caroline Nothdurfter, Yvonne Steng, Ines Noack, Katrin Pietschmann, Hans-Jurgen Moller,Rainer Rupprecht .............................................................................................................................. 82

P300 differences exist between Tourette’s syndrome with and without attention deficiencyand hyperactivity disorder in children

Zhu Yan, Liu Po-Zi, Leung Kai-Man, Su Lin-Yan, Wu Da-Xing, Zhou Ming ...................................... 91

Summary of Original Research

Three-dimensional models of neurotransmitter transporters and their interactions withcocaine and S -citalopram

Aina Westrheim Ravna ......................................................................................................................... 99

Viewpoint

The problem of delusional ugliness: Is it really body dysmorphic disorder?Leonardo F. Fontenelle, Mauro V. Mendlowicz, Juliana Kalaf, Marcio Versiani .................................. 110

Case Reports/Case Series

Abdominal cutaneous nerve entrapment syndrome (ACNES) in a patient with apain syndrome previously assumed to be of psychiatric origin

Johannes Thome, Christian Egeler ........................................................................................................ 116

The treatment of recurring auditory hallucinations in schizophrenia with rTMSPaul B. Fitzgerald, Jessica Benitez, Jeff Z. Daskalakis, Anthony De Castella, Jayashri Kulkarni ......... 119

Aripiprazole in patients with Tourette syndromeEmanuel Bubl, Evgeniy Perlov, Ludger Tebartz Van Elst ..................................................................... 123

Announcement

‘‘2nd International Congress of Biological Psychiatry’’ ........................................................................ 125

Letter to the Editor

Addressing the limitations of the CATIE studySiegfried Kasper, Dietmar Winkler ....................................................................................................... 126

Instructions to Authors ....................................................................................................... 128

The World Journal of Biological PsychiatryVolume 7, No 2, 2006

Contents

EDITORIAL

Ethical aspects of publishing

Ethical aspects of publishing have become a matter

of greater interest over the past decade. Considera-

tion of the associated problems led to the formation

of respective societies and relevant congresses, for

example the International Committee of Medical

Journal Editors, The Vancouver Group (Walter and

Bloch 2001) and the Committee of Publication

Ethics in Great Britain (Smith 1997, 2003). Inter-

national congresses about publishing in biomedicine

with a focus on ethical problems took place as early

as 1989, 1993 and 1997 (Rennie 1990; Rennie and

Flanagin 1994, 1998).

Ethical problems affect various aspects of publish-

ing. Some of the most important ones will be

described briefly below, whereby only aspects related

to publishing itself will be discussed and not the

original basis for the publication, i.e. not the results

of scientific studies and the related problems con-

cerning study methods and execution.

The fact that the quality of a young scientist’s

research is nowadays measured by the number or

impact factor of his publications has resulted in a

strong pressure to publish for the individual and his

research group. But there are also other sources of

pressure to publish, e.g. the interest of the pharma-

ceutical companies to present the results of their

studies as widely and diversely as possible. As a

consequence, the results of a scientific investigation

or clinical pharmacological study are not published

in one paper, as would actually be meaningful and

necessary, but as many papers as possible are

published, for example by publication in various

languages. These publications are either real

duplicate publications, or some of them overlap

considerably with respect to the presented results.

Alternatively, new individual subsections are picked

out time and again that are often rather irrelevant

but are used to present repeatedly also the main

results of the corresponding scientific investigation.

Overall, duplication to a greater or lesser extent, or

fragmentation (‘salami tactic’), results in the pub-

lication of more papers than is actually necessary

and meaningful to present the results of a scientific

investigation. One of the results of this publication

technique is an undesirable increase in the flood of

publications, so that even the scientist active in the

respective area has trouble keeping an overview of

the available data. Furthermore, the joint origin of

the various publications, i.e. the actual data source,

is frequently not made apparent enough (often on

purpose!), so that the reader gains the impression

that results of several different studies are being

reported. This inflation of publications is often made

use of for studies with positive results. Besides the

purposeful or accepted deception of the readership,

this publication technique also causes difficulties for

meta-analyses, since it is often not clear to the meta-

analyst how many studies are being reported, thus

leading to a distortion of the data in the sense of a

positive bias. In the case of negative results, there is a

distortion in the other direction in the sense that

they are published only very briefly or not at all. The

technique of fragmented publication is often so

intransparent that it is sometimes not even noticed

by journal editors. For example, Walter and Bloch

(2001) pointed out that in the case of an antide-

pressant almost identical manuscripts were pub-

lished without the editors noticing.

A particularly serious case of ethical problems is

the publication of purposefully falsified data or of

data that are completely made up and do not have a

basis in the sense of an empirical study. Such cases

are almost certainly uncommon, but they are prob-

ably also rarely discovered and one must assume that

a certain number of cases go unnoticed. Several

years ago such a case was discovered in German

genetic research that caused a great stir, all the more

so because the research group had been given

generous support by the DFG (‘‘Deutsche For-

schungs Gesellschaft’’, German Research Associa-

tion) for years and because it had published in very

prestigious international journals. This case shows

that despite both the DFG’s complicated application

process and the careful and extensive review proce-

dures during the publication process at respected

journals, it can be difficult to recognise cleverly

performed falsifications. Editors, who do not usually

have access to the original data, hardly stand a

chance of recognising such falsifications, especially

when the published data appear to be plausible

enough.

Conflicts of interest can also represent a severe

dilemma, in particular the conflict between the

sponsor of a study, mostly the pharmaceutical

The World Journal of Biological Psychiatry, 2006; 7(2): 66�/69

ISSN 1562-2975 print/ISSN 1814-1412 online # 2006 Taylor & Francis

DOI: 10.1080/15622970600700108

industry, and the authors (Helmchen 2003; Miller

et al. 1999). The relationship between the author

and sponsor and the related financial interests

involved on both a personal and research-related

level can lead to a biased presentation, which is not a

falsification of data in the sense described above, but

perhaps a particularly positive depiction of the

results to the sponsor’s benefit, for example. This

can happen in such a way that is not at all evident to

the author, in face of the often very good personal

relationship to the sponsor, but which is almost

subconscious, normally at least unintentional. In

order to reveal this ‘‘conflict’’, most journals these

days require the author to describe any relevant

conflict of interest through a ‘‘disclosure’’ (Hender-

son et al. 2003), i.e. the author discloses the

source(s) of financial support and assistance with

the study, or by whom he was or is supported. He is

required to disclose everything that is potentially

related to the topic of the paper. This requirement

does not infer that the author has a conflict of

interest but serves the purpose to reveal to the reader

the author’s relationships in the matter at hand so

that the reader is specially sensitised for a possibly

biased presentation.

However, the focus on the sponsoring pharma-

ceutical industry, which mostly forms the basis of the

demand for disclosures, is possibly too narrow.

There are definitely other influencing factors which

are probably just as important, for example focussing

on a certain orientation of the overall subject area

(e.g. biological psychiatry versus psychotherapy),

rivalries between people, etc. (Horton 1997). How-

ever, such factors are much more elusive than the

rather ‘‘material relationships’’ with the sponsor of a

study or the sponsoring of a scientist’s research by

the pharmaceutical industry. Since for these reasons

a disclosure that is solely aimed at the sponsoring

by the pharmaceutical industry cannot fulfil the

idealistic demands placed on it, some colleagues

completely disapprove of the disclosure in the way

it is currently practised and brand it as a ‘‘new

McCarthyism’’ (Rothman 1993).

Insufficiently justified authorship is a further

problem in this respect. Under the pressure of the

need to publish and achieve as high an impact factor

as possible, it has increasingly become a habit that

many authors are mentioned on a publication who

may not be associated with, or who may have only a

limited association with the scientific investigation

or the publication. In this respect, unjustified

senior-authorships as a ‘‘favour’’ as well as unjusti-

fied reciprocal co-authorships of members of the

same research group or different research groups

from the same institution should be mentioned, all

of which serve to increase the personal impact factor

or the number of an individual’s publications.

Although the consideration of several publications

offers a chance to obtain clues as to which author has

perhaps just been named as a favour, it requires a lot

of work and the attributes of a detective. Admittedly,

it is sometimes difficult to decide who is entitled to

be named as a co-author of a publication (Helmchen

2001). Proposals of the Vancouver Group (Interna-

tional Committee of Medical Journal Editors 1997)

attempt to describe on different levels the respective

contribution that resulted in co-authorship, e.g.

contribution to study conception and design, con-

tribution to analysis or interpretation of data and

contribution to critical review of the work, etc.

However, on the other side these criteria are still

seen by some to be too soft. It has thus been

demanded that at the end of a paper the respective

contribution of each individual author/co-author is

described in detail.

Besides the naming of co-authors who have not

made a sufficient contribution to the scientific work

or the manuscript, there is the other problem that

scientists who have worked on a project are not

named in the publication for various personal or

institutional reasons. A further problem is the order

of the authors. One normally presumes that the

person who wrote the manuscript is also the first

author and therefore takes responsibility for the

content. Others also give the senior authors a special

role, as he is often head of the research group. The

fact that the order of names is not unimportant

becomes apparent when problems occur, e.g. in the

research falsification mentioned above: the senior

author claimed that he could not take any respon-

sibility for the details of the manuscript because he

had not been involved in the details of data collec-

tion.

Finally, a further bias in the publication process

should be mentioned that is not on the level of the

authors but on that of the editors: an editor and the

reviewers he chooses may follow a certain school of

thought of the subject area and promote this

direction preferentially by accordingly positive pub-

lications.

The editors of scientific journals thus have

an important and increasingly complex task,

which can hardly be accomplished ‘‘on the side’’.

Great demands are placed on the editor with

respect to fair ‘‘handling’’ of the manuscript

through to careful execution of the review process

under consideration of the special problems

mentioned above (Young 2003; Young and Joffe

2004).

An ethical problem of a completely different

dimension is the fact that only colleagues from the

rich industrial nations of the so-called western world

Editorial 67

have adequate access to scientific publications in

highly respected international journals. Colleagues

in economically poorer countries, the so-called

developing countries, often have no access to such

journals since they do not have the financial means

to buy their own copies and often also the university

libraries do not have enough money to buy these

journals. This problem is being increasingly dis-

cussed (Delucchi 2005). As far as I am aware, The

World Journal of Biological Psychiatry was the first

psychiatric journal to take this matter sufficiently

into account. With the help of an unrestricted grant

from the pharmaceutical industry (at that time from

Janssen Cilag and Organon), this journal was sent

free of charge to all members of the WFSBP, so that

also colleagues from the economically poor countries

could profit from the information it contained.

However, this procedure was also criticised at it

was feared that the sponsoring companies may find

an opportunity to influence the content to their

advantage. As Chief Editor of this journal I remain

fully convinced that this was not the case, although I

must admit that theoretically this could have been

the consequence. It is therefore definitely better if

sponsoring by one or two companies is replaced by a

‘‘pool sponsoring’’ by several companies as this

makes it much easier to avoid the possible develop-

ment of any bias.

The World Journal of Biological Psychiatry also

attempted to deal with another problem, although

perhaps in too ideological a way. For several

reasons it is often very difficult for scientists

from economically poor countries to publish the

results of their research. Often, the research is not

on an internationally competitive level, due among

other things to the poor financial setting or an

insufficient tradition or method of research. An-

other important reason is the fact that scientists in

economically poor countries do not have an

adequate command of English scientific language

and the English publication style. A publication is

therefore often rejected by the editor of a re-

spected international journal for reasons of lan-

guage and style, without it even being sent to

reviewers. One of the primary objectives of The

World Journal of Biological Psychiatry was to work

against this publication bias, which was to the

disadvantage of the colleagues from economically

poorer parts of the world. One such approach was

to increase the likelihood that manuscripts by

colleagues from such countries were accepted for

publication by assigning them to a member of the

Editorial Board or a specially chosen reviewer who

helped the author to improve their paper under

these aspects. Admittedly, this idealistic approach

could only be realised to a very limited extent. It

requires so much time and effort that voluntary

editors, members of the Editorial Board or re-

viewers can only be asked to perform such an

additional task in exceptional cases. Principally, it

would be desirable that a journal provides addi-

tional means for this task.

In the context of considerations about how to

make up-to-date knowledge available to all

interested parties in a fair way, the demand was

also expressed that a scientific journal should

realise ‘‘open access’’ in the internet right from

the start (Smith 2004; Suber 2002). However,

this contradicts the economical conditions in

which a journal is published and means must

thus be sought to achieve a balance of all interests

(Moller 2005).

Hans-Jurgen Moller

Chief Editor

The World Journal of Biological Psychiatry

Correspondence:

Professor Hans-Jurgen Moller

Department of Psychiatry

Ludwig-Maximilians-University

Nussbaumstr. 7, 80336 Munich

Germany

Tel: 49 89 5160 5501

Fax: 49 89 5160 5522

E-mail: [email protected]

References

Delucchi G. 2005. Regarding open access to scientific journals.

World J Biol Psychiatry 6:60.

Helmchen H. 2001. [Clinical research methods]. Fortschr Neurol

Psychiatrie 69:291�/299.

Helmchen H. 2003. [Psychiatrists and the pharmaceutical in-

dustry]. Nervenarzt 74:953�/964.

Henderson C, Howard L, Wilkinson G. 2003. Acknowledgement

of psychiatric research funding. Br J Psychiatry 183:273�/

275.

Horton R. 1997. Conflict of interest in clinical research: Oppro-

brium or obsession? Lancet 349:1112�/1113.

International Committee of Medical Journal Editors. 1997. Uni-

form requirements for manuscripts submitted to biomedical

journals. Ann Int Med 126:36�/47.

Miller F, Pickar D, Rosenstein D. 1999. Addressing ethical issues

in the Psychiatric Research Literature. Arch Gen Psychiatry

56:763�/764.

Moller HJ. 2005. Access to The World Journal of Biological

Psychiatry. World J Biol Psychiatry 5:118.

Rennie D. 1990. Editorial peer review in biomedical

publication: The first international congress. J Am Med Assoc

263:1317.

Rennie D, Flanagin A. 1994. The second international congress

on peer review in biomedical publication. J Am Med Assoc

272:91.

Rennie D, Flanagin A. 1998. Congress on biomedical peer review.

J Am Med Assoc 280:213.

68 Editorial

Rothman K. 1993. Conflict of interest: The new McCarthysim in

science. J Am Med Assoc 269:2782�/2784.

Smith R. 1997. Misconduct in research: Editors respond �/ The

Committee on Publication Ethics is formed. Br Med J

315:201�/202.

Smith R. 2003. Draft code of conduct for medical editors. Br Med

J 327:1010.

Smith R. 2004. Travelling but never arriving: reflections of a

retiring editor. Br Med J 329:242�/244.

Suber P. 2002. Open access to the scientific journal literature. J

Biol 1:1�/3.

Walter G, Bloch S. 2001. Publishing ethics in psychiatry. Aust NZ

J Psychiatry 35:28�/35.

Young S. 2003. Peer review of manuscripts: Theory and practice. J

Psychiatry Neurosci 28:327�/330.

Young S, Joffe R. 2004. Ethical conduct of journal editors. Rev

Psychiatr Neurosci 29:334�/336.

Editorial 69

REVIEW

Psychiatric symptoms associated with oculogyric crisis: A review ofliterature for the characterization of antipsychotic-induced episodes

KAZUHIKO ABE

Faculty of Health and Welfare, Seinan Jogakuin University, Kitakyushu, Japan

AbstractAntipsychotics have been found to induce recurrent psychotic episodes lasting minutes to hours, mostly accompanied byoculogyric crisis (OGC). To characterize this side effect, antipsychotic-induced and postencephalitic OGCs that werereported in the literature were compared to find out common characteristics of OGCs and their associated symptoms. Bothpostencephalitic and antipsychotic-induced OGCs were found to occur late in the day and at regular intervals, and wereassociated with autonomic symptoms such as profuse sweating, facial flushing, transitory hypertension and difficulty inmicturition. They were often associated also with transient psychiatric episodes: visual hallucinations and illusions, auditoryhallucinations, delusions, catatonic phenomena, obsessive thoughts and panic attacks. These (OGC) characteristics will beuseful in recognizing antipsychotic-induced psychiatric episodes. The associated psychiatric episodes were noted to recuroccasionally also without OGC in a few postencephalic cases, and during gradual dose reduction or after a switch to a novelor low-potency antipsychotic in drug-induced cases. These findings suggest that episodes with the OGC characteristics butwithout OGC per se, may be less severe reactions to antipsychotic medication than those with OGC, and may representmanifestations of subclinical OGC.

Key words: Oculogyric crisis, antipsychotics, epidemic encephalitis, psychiatric symptoms, autonomic symptoms

Introduction

Antipsychotics, especially high-potency conventional

antipsychotics, have been found to induce recurrent

psychotic episodes lasting minutes to hours (as

described below in detail), mostly accompanied by

oculogyric crisis (OGC). However, since the OGCs

in such cases can be brief or subtle (Rogers 1989;

Thornton and McKenna 1994) and easily missed,

the psychotic episodes could be mistaken for exacer-

bation of the psychosis (Benjamin 1999) and the

antipsychotic medication may be increased rather

than reduced, resulting in further aggravation of the

condition.

To prevent this outcome, antipsychotic-induced

episodes should be characterized, so that they are

easily recognized as such. Although there are not

many case reports where these episodes were de-

scribed in detail, some authors noted similarities

between the episodes in their cases and those which

had been described in association with postencepha-

litic OGC (Sachdev and Tang 1992; Thornton and

McKenna 1994; Bemjamin 1999). However, such

similarities have not been systematically investigated.

Most of the postencephalitic cases were published

in the 1920s and 1930s, and in many of them OGC-

associated psychiatric episodes were described in

detail. In this paper, such episodes are compared to

those associated with antipsychotic-induced OGC,

to find out characteristics common to both, which

will be useful in recognizing antipsychotic-related

transient psychiatric episodes.

Method

For symptoms associated with postencephalitic

OGC, literature was searched by Index Medicus

1925�/1939 with key words, epidemic encephalitis,

sequelae, oculogyric crisis (or Schauanfall, Blickk-

rampf or ocular manifestations), and 30 articles

published in psychiatric, neurological or medical

journals in English, German or French were found.

Of these, 18 described OGC-associated psychiatric

symptoms and are reviewed in this paper. Papers

Correspondence: Professor Kazuhiko Abe, MD, Seinan Jogakuin University, 1-3-5 Ibori, Kokura-Kitaku, Kitakyushu, 803-0835 Japan.

Tel./Fax: +81 940 35 2982. E-mail: [email protected]


(Received 21 March 2005; accepted 16 June 2005)


DOI: 10.1080/15622970500222443

cited by Jelliffe (1929) and Onuaguluchi (1961) on

the subject are also reviewed for this paper.

For symptoms associated with antipsychotic-in-

duced OGC, a computer search was performed

using the key words, oculogyric crisis, neuroleptic-

induced and psychiatric symptoms. Nine articles

were found. These and papers cited by Benjamin

(1999) and Owens (1999) on drug-induced OGC

and associated psychiatric episodes are reviewed for

this paper.

Results

Postencephalitic OGC

Encephalitis lethargica (epidemic encephalitis)

chiefly occurred in the period 1917�/1928, but its

causative agent was never determined, though pre-

sumably it was viral in nature. One of its common

sequelae was parkinsonism, often accompanied by

OGC (Yahr 1978).

The time of the day of occurrence and associated

autonomic symptoms. Postencephalitic OGC tended

to occur late in the day and at more or less regular

intervals (McCowan and Cook 1928; Jelliffe 1929;

Hall 1931; Odegard 1932), and were usually accom-

panied by autonomic symptoms such as profuse

sweating, facial flushing, salivation, transitory hy-

pertension and difficulty in micturition (Euziere et

al. 1933; Onuaguluchi 1961) and often preceded by

forward staring (Onuaguluchi 1961).

The associated psychiatric symptoms. The OGCs were

also often accompanied by a variety of psychiatric

symptoms (Jelliffe 1929). Visual hallucinations

(Pascheff 1926; Marinesco and Nicolesco 1932;

van Bogaert 1933) and illusions (Flach and Palisa

1936), tactile (Georgi 1926; Petit et al. 1926;

Schwab et al. 1951) and auditory hallucinations

(Brody and Freed 1941; Rosner 1942) and distor-

tion in body schema (van Bogaert 1933) were

reported.

Delusions (Brody and Freed 1941; Rosner 1942;

Gillespie 1944; Schwab et al. 1951), unresponsive-

ness bordering on catatonic stupor (Ewald 1925;

Jelliffe 1929; Leigh et al. 1987), hypomania (Pardee

1928), depression (Jelliffe 1929; Urechia 1949;

Schwab et al. 1951), ‘‘sham rage’’ (Oller 1946;

Urechia 1949), obsessive thoughts (Ewald 1925;

Odegard 1932; Euziere et al. 1933; Rosner 1942)

and severe anxiety (Jelliffe 1929; Schwab et al. 1951)

were also reported. These associated psychiatric

symptoms varied from patient to patient but varied

little among OGCs in the same patient, and were

usually absent between the OGCs (Rosner 1942).

On the other hand, the same transient episodes

which were associated with OGC, such as depressive

stupor (Ewald 1925), paroxysmal depression (Ur-

echia 1949; Schwab et al. 1951) or visual hallucina-

tions (Marinesco and Nicolesco 1932) were noted to

occur sometimes without OGC.

The temporal relationship between the OGC and

the psychiatric episode was described in a few cases:

the episode appeared first, became intense and

culminated in OGC or the latter appeared in the

middle of the former (van Bogaert 1933; Brody and

Freed 1941; Gillespie 1944; Urechia 1949; Leigh et

al. 1987).

The influence of treatment. As to the treatment and

prophylaxy of OGC, the administration of scopola-

mine decreased the frequency of OGC (Marinesco

and Nicolesco 1932; van Bogaert 1933). It was also

noted that scopolamine administered during OGC

abolished it, but the associated visual hallucinations

persisted (Marinesco and Nicolesco 1932). Other

anticholinergic drugs, such as hyosciamine (Brody

and Freed 1941; Schwab et al. 1951) and carami-

phen (Schwab et al. 1951), antihistamine, such as

diphenhydramine and pheniramine (Schwab et al.

1951), and amphetamine (Brody and Freed 1941;

Oller 1946), were used.

Anticholinergic combined with amphetamine was

found effective for OGC and its associated delu-

sional episodes (Brody and Freed 1941). In Oller’s

case (1946), recurrent episodes of sham rage asso-

ciated with postencephalitic dystonia lasting 6�/8

hours decreased in frequency from 10 to 5 times per

2 months while on scopolamine 0.8 mg t.i.d. After a

superaddition of amphetamine 10 mg b.i.d., the

dystonia decreased further in duration and fre-

quency and was no longer accompanied by sham

rage. This is the only case where psychiatric episodes

disappeared before OGC due to treatment.

Antipsychotic-induced OGC

The associated psychiatric symptoms. Many decades

later, antipsychotics, especially high-potency con-

ventional antipsychotics, were found to induce

recurrent OGC accompanied by transient episodes

of psychiatric symptoms. Simpson et al. (1976)

described two cases of transient psychotic episodes

in association with antipsychotic-induced dystonia:

one patient became catatonic and hallucinated

hearing threatening demands to kill himself, and

another, a mentally retarded boy, had episodes of

stereotyped activity in association with OGC, pro-

fuse sweating and drooling. The authors stated that

anticholinergic agent terminated such episodes in 10

cases including the afore-mentioned, and considered

Psychiatric symptoms associated with oculogyric crisis 71

that these episodes might be one manifestation of

dystonic reactions.

Psychiatric symptoms that have been reported to

accompany the antipsychotic-induced OGC in pa-

tients with schizophrenia are as follows: visual

hallucinations (Thornton and McKenna 1994; Ben-

jamin 1999; Abe 2004) and illusions (Higuchi et al.

1997; Benjamin 1999), auditory hallucinations

(Simpson et al. 1976; Chiu 1989; Rogers 1989;

Sachdev and Tang 1992; Thornton and McKenna

1994; Benjamin 1999), delusions (Benjamin 1999)

and catatonic phenomena (Simpson et al. 1976;

Thornton and McKenna 1994).

Similar episodes associated with OGC, have also

been reported in non-schizophrenic patients who

were on antipsychotic: visual and auditory halluci-

nations in a patient with epilepsy, and severe anxiety

in a patient with primary hyperparathyroidism

(Leigh et al. 1987), lilliputian micropsia in a patient

with bipolar disorder (Shiratsuchi et al. 1994) and

exacerbation of psychotic features in a patient with

depression (Benjamin 1999).

These psychiatric episodes disappeared after the

medication was changed to low-potency (Chiu 1989;

Thornton and McKenna 1994) or novel (Thornton

and McKenna 1994) antipsychotic or after the

addition of anticholinergic (Simpson et al. 1976;

Chiu 1989; Benjamin 1999). As in postencephalitic

cases, various psychiatric symptoms have been

reported as associated with OGC and they varied

from patient to patient and with no particular

symptom appearing predominant, but the same

symptom tended to reappear stereotypically in the

same patient (Benjamin 1999).

However, some authors maintain that a particular

feature of the episode (‘‘paroxysmal perceptual

alteration’’), a transient increase in the intensity of

visual (and often also auditory) perception that

recurs in the afternoon (most likely in the late

afternoon), is pathognomonic of antipsychotic-in-

duced episodes (Higuchi et al. 1997; Uchida et al.

2003a,b). However, its specificity for antipsychotic-

induced episodes has not yet been established.

Although this feature has been noted in some

antipsychotic-induced cases (Watanabe 1991; Abe

2004, Case 2) and in one postencephalitic case

(Flach and Palisa 1936), it has not been noted in

many other cases, so its prevalence may not be high.

The temporal relationship of OGC and the

psychiatric symptoms was described in detail in a

few cases: the OGC occurred in the middle of the

psychiatric episodes (Rogers 1989; Thornton and

McKenna 1994; Abe 2004) or the psychiatric

symptoms preceded the OGC (Leigh et al. 1987;

Sachdev and Tang 1992).

The time of day of occurrence of OGC. As to the time of

day for the occurrence, most were found to occur

between 14:00 and 20:00 h, suggesting a diurnal

variation (Tan et al. 1994). Over 80% of the episodes

of acute neuroleptic-induced dystonia were seen to

occur in the afternoon (Mazurek and Rosebush

1996). The associated psychiatric episodes had also

been noted to occur in the afternoon (Sachdev 1991;

Watanabe 1991).

The associated autonomic symptoms. The OGC-asso-

ciated episodes were accompanied by autonomic

symptoms such as profuse sweating, salivation, facial

flushing or pallor (Simpson et al. 1976; Watanabe

1991; Thornton and McKenna 1994) and transitory

hypertension (Abe 2004).

Psychiatric episodes unaccompanied by OGC. As in

postencephalitic cases, the transient psychotic symp-

toms which used to appear with OGC can some-

times occur alone. Rogers (1989) reported a case

with transient psychotic episodes most but not all of

which were accompanied by OGC. In response to

treatment, the OGC was usually the first to dis-

appear: having disappeared after the switch to

chlorpromazine (Rogers 1989), or it was barely

noticeable after switching to clozapine (Thornton

and McKenna 1994) while psychiatric episodes

recurred. Transient recurrent visual hallucinations

(Abe 2004; Case 1) were accompanied by OGC

before antipsychotic dose reduction, but afterwards

they continued to recur without OGC. These

recurrent hallucinations also disappeared after a

further dose reduction. The author suggested that

the episodes with OGC might represent more severe

reactions to antipsychotic than those without.

There are also reports of cases with a series of

periodic episodes without OGC, which were con-

sidered antipsychotic-induced: episodes of panic

attacks (Bachman and Modestin 1987; Argyle

1990; Mandalos and Szarek 1999; Higuchi et al.

1999), visual illusions (Higuchi et al. 1997; Uchida

2003), visual and auditory illusions (Higuchi et al.

1997; Abe 2004, Case 2) and catatonia-like unre-

sponsiveness accompanied by OGC-related auto-

nomic symptoms (Abe 2004, Case 3), respectively.

Discussion

Characteristics of OGC

Both postencephalitic and antipsychotic-induced

OGC tended to occur at regular intervals and late

in the day, and were accompanied by autonomic

symptoms such as profuse sweating, facial flushing,

salivation, transient hypertension and difficulty in

72 K. Abe

micturition. Both may be associated with similar

psychiatric symptoms: visual hallucinations or illu-

sions, auditory hallucinations, catatonic phenomena,

transitory delusions or obsessive ideas. The asso-

ciated symptoms varied from patient to patient, but

the same symptoms tended to appear repeatedly in

the same patient.

In postencephalitic cases the psychiatric symptom

grew in intensity and appeared to culminate in

OGC. Similarly, in antipsychotic-induced cases,

the OGCs were noted to occur in the middle of

the psychiatric episodes and to last for a shorter time

than the episodes. In some postencephalitic and

drug-induced cases, OGC-associated psychiatric

symptoms were noted to occur sometimes also as

single episodes unaccompanied by OGC, and in

some other cases the treatment abolished OGC

while the psychiatric episodes continued to recur

periodically as before.

Even in cases unaccompanied by OGC, antipsy-

chotic-induced episodes tended to show the afore-

mentioned OGC characteristics: periodic transient

recurrence of the same psychiatric symptom in the

afternoon accompanied by the autonomic symp-

toms. Taken together, these findings suggest that

the OGC characteristics are useful in recognizing

antipsychotic-induced psychiatric episodes, and that

the episodes without OGC may be less severe

reactions to antipsychotic medication than those

with OGC, and represent manifestations of subcli-

nical OGC.

If its specificity for antipsychotic-induced episodes

is established, ‘‘paroxysmal perceptual alteration’’,

which some authors consider pathognomonic, could

be useful in recognizing such episodes.

Clinical implications for antipsychotic-induced

psychiatric episodes

If episodes with the OGC characteristics are ob-

served in a patient on antipsychotic, an adverse

reaction to the drug is a possibility. Such a possibility

is more likely if one or more of the past episodes had

been accompanied by OGC. Another feature sup-

portive of the diagnosis is a significant decrease in

the frequency or duration of the episodes on anti-

psychotic dose reduction or switch to one of the

novel antipsychotics.

The treatment may be directed to the responsible

antipsychotic and its gradual reduction may be tried

in cases where this is practicable. The OGC may

disappear first, followed by the psychiatric episodes.

Alternative effective measures taken in previous

cases are a switch to a low-potency or novel

antipsychotic, or a superaddition of an anticholiner-

gic. Benzodiazepines have been found useful in the

treatment of OGC (Benjamin 1999; Owens 1999)

and may also be effective in OGC-associated epi-

sodes. However, they could obscure etiology and

cause dependence.

OGC and dopaminergia

The pathophysiology of dystonia is unknown at

present, but it is widely accepted that striatal

cholinergic hyperactivity underlies dystonia. As to

striatal dopaminergic activity, both its hypoactivity

and hyperactivity have been postulated. According

to Marsden and Jenner (1980), antipsychotic-in-

duced dystonias are due to a transient compensatory

dopamine excess. The psychotic episodes accompa-

nied by OGC have also been explained as transient

hyperdopaminergic states (Chiu 1989; Thornton

and McKenna 1994).

It is interesting to note that the side effects of

levodopa resemble the symptoms associated with

OGC (Abe 2002). Its psychiatric side effects include

illusions and hallucinations, which are predomi-

nantly visual but may also be auditory, olfactory or

tactile (Goodwin 1972; Moskovitz et al. 1978);

delusions, hypomania, confusion and panic attacks

(Goodwin 1972; Rondot et al. 1984). Its autonomic

effects are; palpitation and flushing, hypertension,

excessive sweating, urinary frequency and retention

(Parfitt 1999). Furthermore, levodopa can induce

OGC and peak-dose dystonia confined to the face

and neck (as in antipsychotic-induced dystonia) in

patients with Parkinson’s disease (Poewe et al.

1988).

This symptomatic resemblance between the levo-

dopa-induced and OGC-associated symptoms is

compatible with the hyperdopaminergic hypothesis

of OGC, but further studies are required to draw a

conclusion regarding the pathogenesis of OGC and

its associated symptoms.

Statement of interest

The author has no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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74 K. Abe

ORIGINAL INVESTIGATION

Effect of olanzapine treatment on platelet glutamine synthetase-likeprotein and glutamate dehydrogenase immunoreactivity inschizophrenia

GULNUR Sh. BURBAEVA, IRINA S. BOKSHA, ELENA B. TERESHKINA,

OLGA K. SAVUSHKINA, MARINA S. TURISHCHEVA, LUBOV I. STARODUBTSEVA,

OLEG S. BRUSOV & MARGARITA A. MOROZOVA

Mental Health Research Centre of Russian Academy of Medical Sciences, Moscow, Russia

AbstractAccording to contemporary views, the glutamatergic system is implicated in the pathogenesis of schizophrenia, and atypicalneuroleptics exert their effects (at least partially) through the glutamatergic system. Immunoreactive glutamate-metabolising enzymes, such as glutamine synthetase-like protein (GSLP) and two glutamate dehydrogenase isoenzymes(GDH), have been discovered in human platelets. The amount of GSLP in the platelets of 40 chronic patients withschizophrenia was found to be significantly higher than in 33 controls (consistent with our previous finding of increasedamounts of GSLP in the prefrontal cortex of chronic schizophrenia patients). Moreover, survival analysis of the group ofpatients treated with olanzapine for 28 weeks showed that the larger amount of GSLP measured in platelets beforetreatment, the shorter the treatment time needed to achieve a positive clinical response (defined a priori as ]/20% reductionin PANSS total score from the initial level before the treatment). Hence, GSLP level may serve as a predictor of thetreatment duration to achieve a positive outcome with olanzapine. Both GSLP and GDH were found significantly changedin the course of treatment; hence, treatment with olanzapine influences the amounts of glutamate-metabolising enzymes inthe platelets of chronic schizophrenia patients.

Key words: Schizophrenia, olanzapine, glutamate metabolising enzymes, platelets

Introduction

There are numerous lines of evidence implicating

impaired neurotransmitter systems in schizophrenia,

particularly failure of glutamatergic transmission was

proposed to be an important factor in schizophrenia

(Duncan et al. 1999; Krystal et al. 1999; Carlsson et

al. 2000; Tamminga and Frost 2001). The ‘gluta-

matergic hypothesis’ proposes that schizophrenia

may be caused by diminished activity of glutamater-

gic pathways, the major excitatory system in the

brain (Bartha et al. 1997; Krystal et al. 1999;

Tamminga and Frost 2001). Based primarily on

the fact of altered levels of glutamate neurotrans-

mitter, its receptors and transporters, the ‘glutama-

tergic hypothesis’ has been broadened into the field

of brain glutamate metabolism. In fact, significantly

changed levels of glutamate decarboxylase, glutami-

nase, glutamine synthetase (GS), glutamine synthe-

tase-like protein (GSLP, Boksha et al. 2000), and

glutamate dehydrogenase isoenzymes (GDH) have

been found in brains of patients with schizophrenia

compared to controls (Dracheva et al. 2002; Gluck

et al. 2002; McCullumsmith et al. 2002; Burbaeva et

al. 2003).

The search for a reliable peripheral marker linked

to alterations found in the central nervous system is

important for the prediction of development of

schizophrenia, which is essential for psychiatrists in

order to adopt a good strategy and for the optimisa-

tion of subsequent therapy in patients.

Platelets are known to be a rather satisfactory

model reflecting some processes that occur in

nervous tissue. Some components of the glutama-

tergic system have been found in platelets, such as

glutamate receptors and transporters (Berk et al.

Correspondence: Gulnur Sh. Burbaeva, MD, PhD, Mental Health Research Centre, Russian Academy of Medical Sciences, Laboratory of

Neurochemistry, Zagorodnoje Shosse 2-2, Moscow 117152, Russia. Tel: +7 95 952 9129. Fax: +7 95 952 8940. E-mail: burbaeva

@yahoo.com


(Received 4 November 2004; accepted 18 April 2005)


DOI: 10.1080/15622970510029957

2000; Ferrarese et al. 2001; Zoia et al. 2004), and

enzymatic activities of GDH and glutaminase have

been detected (Gluck et al. 2000). Moreover, defects

in glutamatergic systems, such as super sensitivity of

platelet glutamate receptors to glutamate, have been

revealed in platelets in schizophrenia patients (Berk

et al. 1999, 2000).

Recent evidence suggests that effects on glutama-

tergic transmission may contribute to the therapeutic

action of atypical antipsychotics (Goff et al. 2002).

In the present study, we tested a hypothesis that the

level of glutamate metabolising enzymes may be

altered in platelets of patients with schizophrenia

compared with controls, and that this level may be

influenced by treatment with the atypical neurolep-

tic, olanzapine, which is known to act as a modulator

of brain and serum glutamate concentrations (Goff

et al. 2002). Two enzymes involved in glutamate

metabolism, GSLP and GDH isoenzymes, have

been detected in extracts from human platelets.

The amounts of these proteins were determined in

platelets of patients before and during the course of

treatment with olanzapine.

Subjects

The control group consisted of 33 volunteers (11

men and 22 women, 19�/63 years old, healthy

persons with no history of mental or neurological

disorders), blood samples were taken once from each

person, and platelets were accumulated for the

control group during 2 years. Statistics for age are

summarised in Table I.

After receiving approval for the study from the

Ethics Committee, 40 patients (26 men and 14

women) with schizophrenia, paranoid type (DSM-

IV 295.30), were assigned to treatment with olanza-

pine. The main statistics for age, duration of illness,

and PANSS distributions are given in Table II.

Patients were included into the study if they met

the following inclusion criteria: (1) in-patients at

entry who satisfied Research Diagnostic Criteria

(RDC) (Spitzer et al. 1977) for chronic schizophre-

nia, paranoid, episodic type with no inter-episode

residual symptoms; (2) no less than two episodes of

schizophrenia in the previous 2 years; (3) men and

women 18�/60 years old; (4) a level of understanding

sufficient to communicate intelligently with the

investigator and nurse; (5) reliable and agreed to

cooperate with all tests and examinations required

by the protocol; (6) each patient (or a patient’s

authorised legal representative) understood the nat-

ure of the study and signed an informed consent

document; (7) an initial score (before treatment with

olanzapine) on the BPRS, extracted from the

PANNS, of at least 36; (8) an initial score (before

the treatment) on the CGI Severity of at least 3; (9)

concomitant medication (other permitted drug ther-

apy: benzodiazepines (diazepam, phenozepam) and

anticholinergics (trihexyphenidyl)).

Exclusion criteria were the following: (1) women

who were either pregnant or lactating; (2) uncor-

rected hypothyroidism or hyperthyroidism; (3)

myasthenia gravis; (4) narrow-angle glaucoma; (5)

chronic urinary retention and/or clinically significant

prostate hypertrophy; (6) one or more seizures

without clear and resolved etiology; (7) leucopenia;

(8) history of severe allergies or multiple adverse

drug reactions; (9) DSM-IV substance (alcohol or

other drugs) abuse or dependence within the pre-

vious 3 months; (10) judged clinically to be at

serious suicidal risk; (11) participation in clinical

trial of another investigation within 1 month prior to

study entry; (12) any other concomitant medication

with psychotropic activity, other than specified

above; (13) positive hepatitis surface antigen

(HbsAg) or positive IgM fraction of hepatitis core

antibody (anti-HBc(IgM)).

Medication

The study included an initial period, intended for

screening of patients and included the time require-

ment specified for washout from previous therapy

(9 days).

The treatment course consisted of an acute phase

(first 8 weeks) and a maintenance phase (following

20 weeks). The mean modal olanzapine dosage for

the total group of patients was 12.79/3.6 mg/day

(initiated at 5 mg/day, up to 20 mg/day during the

acute phase of the treatment, and finishing at 10

mg/day during the maintenance phase of the treat-

ment). About 15% of patients received benzodiaze-

pine drugs.

Methods

Isolation of platelets and method of extraction of proteins

from platelets

The method was elaborated for preparation of

platelets with optimum extraction of the target

Table I. Statistics for age and glutamine synthetase-like protein

(GSLP) and glutamate dehydrogenase (GDH) immunoreactivity

in control group.

Age

(years)

GSLP GDH

Median 26 75 82

Minimum 19 22 23

Maximum 63 176 214

GSLP and GDH immunoreactivity is expressed in relative units

(in percentages of the pooled control value).

76 G. Sh. Burbaeva et al.

proteins. Blood plasma prepared from 50 ml of

blood taken with citrate buffer, pH 5.7 (1:5, v/v),

was collected for centrifugation (10 000 rpm, 20

min, 58C). The pellet was washed with the citrate

buffer, re-suspended in 62.5 mM Tris�/HCl buffer,

pH 6.8, then frozen in liquid nitrogen and stored at

�/708C prior the analysis of proteins.

Platelet ‘lysate’ was obtained by the addition of

SDS to the platelets (after their thawing) to a final

concentration of 2%, then the samples were heated

(5 min, 958C), the protein concentration was

determined by the method of Lowry et al. (1951),

and 2-mercaptoethanol (to 5% final concentration)

was added to the samples before the electrophoresis.

The aliquots loaded on each lane of polyacrylamide

gel were matched in protein concentration. The

proteins were separated by electrophoresis (Laemmli

1970), with subsequent enzyme-coupled Western

immunoblotting, with chemiluminescent amplifica-

tion of the signal (ECL immunoblotting) for the

immunoreactivity determination.

Enzyme chemiluminescent amplified (ECLTM)

immunoblotting

Enzyme chemiluminescent amplified immunoblot-

ting was performed according to Towbin et al.

(1979) and the Amersham protocol using Hyper-

filmTM ECLTM nitrocellulose membranes, ECL re-

agents which were purchased from Amersham�/

Pharmacia Biotech (UK), and goat anti-rabbit IgG

antibody conjugate was purchased from Sigma

(USA).

GSLP immunoreactivity

GSLP immunoreactivity was evaluated using poly-

clonal antibodies described earlier and raised against

GSLP isolated from human brain (Boksha et al.

2000). Rabbit antiserum (at 1:9000 working dilu-

tion) stained the major protein band corresponding

to GSLP.

GDH immunoreactivity

GDH immunoreactivity was measured using poly-

clonal antibodies raised against two readily soluble

GDH isoenzymes isolated from human brain (Bur-

baeva et al. 2002). The rabbit antiserum (at 1:12 000

working dilution) stained two protein bands corre-

sponding to readily soluble GDH forms. Total

immunoreactivity for both GDH isoenzymes was

evaluated in the experiments as a measure of GDH

amount.

Quantitative analysis of films after ECL immuno-

blotting was performed using a Zeineh laser densit-

ometer and corresponding software (Biomed

Instruments, USA).

Immunoreactivity of GSLP and GDH is given in

relative units in Tables I and III. ‘Relative units’

mean percentages from a pooled control sample.

Statistical analysis

Complete statistical analysis was performed with

Statistica, Version 6.0 (nonparametric module,

Mann�/Whitney U-test, Wilcoxon matched pairs

test, and Spearman correlations were calculated for

comparisons of clinical and demography data with

biochemical measures).

The prognostic relevance of the biochemical tests

was analysed with the Survival Analysis (the Regres-

sion Model, Statistica Version 6). The ‘survival’ time

for each patient was specified as the time from the

start of the treatment right up to the clinical

response (in weeks). The ‘survival’ time distribution

was found to be exponential and proportional to the

values of a separate variable, or of a set of indepen-

Table II. Statistics for age, disease duration, and PANSS for schizophrenia group before and during the treatment with olanzapine.

Age

(years)

Disease duration

(years)

PANSS

(before treatment)

PANSS

(acute phase)

PANSS

(maintenance phase)

Median 31 0.5 76.5 51 49

Minimum 19 0.2 54 30 30

Maximum 56 43 127 102 97

Table III. Statistics for glutamine synthetase-like protein (GSLP) and glutamate dehydrogenase (GDH) immunoreactivity in schizophrenia

group before and during the treatment with olanzapine.

GSLP

(before treatment)

GSLP

(acute phase)

GSLP

(maintenance phase)

GDH

(before treatment)

GDH

(acute phase)

GDH

(maintenance phase)

Mediana 122 112 121.5 86.5 69 64.5

Minimum 12 7 19 7 7 7

Maximum 685 327 370 748 186 289

GSLP and GDH immunoreactivity are expressed in relative units (in percentages of the pooled control value).

Olanzapine treatment in schizophrenia 77

dent variables, before the treatment. The rate

parameter of the exponential distribution can then

be expressed as follows:

S(v)�exp(c�b1�v1�b2v2 � . . .�bmvm)

S(v) denotes the ‘survival’ times, c is a constant, bi

values are the regression parameters (b), and vi is an

independent variable.

Goodness-of-fit. Chi-squared goodness-of-fit was

computed as a function of the log-likelihood of the

model with all parameter estimated, and the log-

likelihood of the model in which all covariates were

forced to zero. If this chi-squared value was sig-

nificant, the null hypothesis was rejected and it was

assumed that the independent variables were sig-

nificantly related to ‘survival’ times.

The reliability of estimation of b coefficients was

determined from t values. The t value is the ratio of

the parameter estimates divided by their standard

errors. Note, the standard errors (and t values) are

computed from the second-order partial derivatives

of the log-likelihood function, resulting in asympto-

tic standard errors (and t values) for the parameters.

Note, if the regression parameter (b) is positive

for the independent variable, it means that the

higher the variable value, the longer the ‘survival’

time for the patient. Inverse relation will be obtained

if the regression parameter (b) is negative.

Results

Glutamine synthetase-like protein and glutamate

dehydrogenase isoenzymes in platelets of controls

Immunoreactive enzymes such as GSLP and two

isoenzymes of GDH were discovered in human

platelet extracts. Figure 1 shows the most typical

pattern for control cases. GSLP, left, and GDH

isoenzymes, right, display virtually the same mole-

cular masses (�/55 kDa, and �/58 and 56 kDa,

respectively) as described for the brain extracts

(Boksha et al. 2000; Burbaeva et al. 2003).

GSLP and GDH were detected in measurable

amounts in all subjects from the control group (33

persons). Relative amounts of the immunoreactive

proteins (GSLP, GDH) in each person from the

control group were evaluated using a calibration plot

drawn using a pooled control (reference) sample.

The immunoreactivity was expressed in relative

units (percentages from the sample pooled from

the five first controls accumulated).

GS and membrane-associated GDH immunor-

eactivities in platelets were below the detection

threshold by the same technique of immunostaining,

using either monoclonal antibody (Biogenesis, UK)

or polyclonal antibodies (Burbaeva et al. 2003),

respectively.

Distribution of GSLP and GDH immunoreactiv-

ity levels in subjects from the control group is

summarised in Table I (non-normal distribution

for both protein values was obtained).

A link between GSLP and GDH levels was found

in the control group (Spearman rank order correla-

tion R�/0.414; t�/2.404; P�/0.02), whereas no links

were found between any of these parameters and age

or gender in this group (P �/0.1).

Platelet GSLP and GDH in patients with schizophrenia

before treatment compared with control group

The staining patterns for subjects from control and

patient groups proved to be mainly similar for GSLP

as for GDH. GSLP and GDH were detected in

measurable amounts in all subjects from the patient

group. Relative amounts of the immunoreactive

GSLP and GDH in each subject from the patient

group were evaluated and expressed in the same way

as for controls. Table III summarises respective

distributions of GSLP and GDH amounts measured

before and during treatment (for the acute and

maintenance phases). A link between GSLP and

GDH levels was found before the treatment (Spear-

men R�/0.616; t�/4.823; P�/0.00002), whereas no

links between any of these parameters and age or

gender were found in the patient group (P �/0.1).

The absence of links between GSLP or GDH

levels and age or gender in both groups (controls and

patients) enabled a comparison of these groups with

respect to amounts of GSLP and GDH. Amount of

GSLP (immunoreactivity level) measured in patients

before treatment was found to be significantly higher

than in the control group (P�/0.003, Mann�/Whit-

ney U-test). A tendency to increased GDH in

Figure 1. Staining pattern of glutamine synthetase-like protein

(GSLP) and glutamate dehydrogenase (GDH) in control; 30 mg of

total protein (platelet extract) were applied on the gel followed by

ECL immunoblotting. GSLP (�/55 kDa band) was revealed by

rabbit antiserum (1:9000). Two isoenzymes of GDH (�/58 and

56 kDa bands) were stained by rabbit antiserum (1:12 000).


patients compared with controls was not significant

(P �/0.1).

Gamma correlation analysis of the patient group

before treatment (a search for a link between clinical

and biochemical �/ GSLP and GDH �/ parameters

from a correlation matrix) resulted in evaluation of

some links: GSLP was linked to unusual thought

content (g�/�/0.33, Z�/�/2.24, P�/0.025), and

GDH was linked to excitement level (g�/0.496,

Z�/ 3.41, P�/0.0006) and conceptual disorganisa-

tion (g�/0.283, Z�/2.21, P�/0.0269).

Platelet GSLP and GDH in patients during olanzapine

treatment

As a result of the treatment, the patients showed

significant improvement in the PANSS total, PANSS

positive and PANSS negative score changes through-

out the 8-week acute treatment phase, as well as

through the following 20-week treatment mainte-

nance period (P�/0.000001, Wilcoxon matched

pairs test). Dynamics of amounts of GSLP and

GDH as a result of the treatment was evaluated by

the same test: both parameters were found to be

significantly changed after the acute phase of treat-

ment (P�/0.038 and 0.012, respectively; Wilcoxon

matched pairs test). The link between amounts of

GSLP and GDH (found before the treatment)

remained rather tight in the acute and maintenance

phases of treatment (Spearman R�/0.553, t�/3.926,

P�/0.0004 and R�/0.405, t�/2.505, P�/0.02, re-

spectively).

As demonstrated in Table III, the data for

amounts of GSLP and GDH measured before

treatment seemed rather scattered, hence the data

were subjected to detailed analysis. The patient

subgroup with high initial GSLP level (higher than

the median value) was considered separately (20

persons). In this subgroup, the levels of GSLP were

found to be significantly changed after the acute and

maintenance phases of treatment (P�/0.007 and

0.004, respectively, Wilcoxon matched pairs test).

In this subgroup, the resulting decrease of GSLP

levels after the acute and maintenance phases of

treatment was significant (Mann-Whitney U-test:

P�/0.009 and 0.003, respectively), but still distin-

guished from the control group levels (Mann�/

Whitney U-test: P�/0.0001). The amount of GDH

in this subgroup was found to be significantly

changed as a result of treatment (P�/0.002 and

0.025 after acute and maintenance phases, respec-

tively, Wilcoxon matched pairs test), and indistin-

guishable from the control group (Mann�/Whitney

U-test: P �/0.1).

Search for predictor of positive clinical outcome of

olanzapine treatment

The data have been ordered by the results of clinical

tests. Clinical response was defined a priori as 20%

or greater reduction in PANSS total score from the

initial level before treatment. The positive clinical

response has been used as a categorised index of the

outcome in the subsequent search for the predictors

of outcome.

Evaluation of predictors of positive clinical out-

come was performed using the regression model of

survival analysis (see Methods).

The regression parameter (b) calculated for

GSLP in the range of maintenance treatment phase

is �/0.00276 (t�/�/2.453, constant c�/2.854, x2

(goodness-of-fit)�/4.795, P�/ 0.0285. The regres-

sion parameter (b) is negative. This means that

GSLP amounts have an inverse relation to ‘survival’

times of patients: the larger the amount of GSLP

measured in platelets before treatment, the less

treatment time needed to achieve a positive clinical

response. Thus, the time (weeks) to a positive

clinical response may be calculated according to

the following equation:

S�exp(2:854�0:00276�GSLP);

where S is number of weeks, and GSLP is amount of

GSLP measured before treatment.

So, amount of GSLP in platelets measured before

treatment has been found to be a possible predictor

of positive outcome in the olanzapine treatment.

Conclusion and discussion

In the present work, immunoreactivity of GSLP and

two readily soluble GDH isoenzymes have been

detected in human platelet lysates, and subunits of

these proteins possess virtually the same mobility on

electrophoresis as their brain forms (Figure 1),

whereas immunoreactivity of GS and membrane-

associated GDH isoenzyme are apparently below the

threshold of the detection technique (using antibo-

dies against brain forms of these proteins). Thus,

human platelets contain components of the gluta-

mate metabolising system, such as GSLP and two

GDH isoenzymes, along with previously found

glutaminase (Gluck et al. 2000), in addition to

glutamate transporters and receptors (Ferrarese et

al. 2001; Zoia et al. 2004).

Amount of GSLP in platelets of patients with

schizophrenia is significantly higher than in controls.

This is consistent with our findings of elevated

amounts of GSLP in the prefrontal cortex in brains

of patients with chronic schizophrenia (Burbaeva et

al. 2003).


Our data indicate that amounts of GDH and

GSLP do not depend on age or gender in either

control persons or schizophrenic patients.

A rather tight link (high correlation coefficient)

has been observed between amounts of GSLP and

GDH measured in platelets of controls and patients

(before and after each phase of treatment). However,

the biochemical parameters were linked to different

clinical parameters (in the patient group before

treatment, amount of GSLP was linked to unusual

thought content, whereas amount of GDH reflected

excitement level and conceptual disorganisation).

The diversity of GSLP and GDH levels measured

in the patient group before treatment is obviously

larger than in the control group (such a high

variability is not limited to glutamatergic system

parameters, but can be found in nearly every

biological variable in schizophrenia). Maximum

amounts of GSLP and GDH are higher in the

patient group than in controls (4 and 3.5 times,

respectively), whereas minimum amounts of GSLP

and GDH are lower (2 and 3 times, respectively,

Tables I and III). This fact is explainable based on

the hypothesis of Krystal et al. (1999), suggesting a

higher variability of glutamatergic system activity in

the schizophrenic brain and/or disability of the

glutamatergic system tuning in patients with schizo-

phrenia.

In general, distributions of GSLP and GDH in the

patient group after the acute and maintenance

phases of treatment were not so widely scattered as

before treatment, wherein amplitude of GSLP tend

to diminish, still differing from the control group.

Hence, treatment with olanzapine affects the

amounts of both enzymes involved in glutamate

metabolism, and the observed phenomenon may

be described as: ‘the treatment makes the GSLP and

GDH levels smooth’ rather than ‘the treatment

normalises the amounts of GSLP and GDH’.

When patients with amount of GSLP higher than

the median value (before treatment) were considered

separately, a significant decrease was found in

amounts of both GSLP and GDH after treatment.

A remarkable positive link has been found be-

tween disease duration and amount of GDH mea-

sured either at the end of the acute or maintenance

phases of treatment (R�/0.412, t�/2.519, P�/0.02,

and R�/0.5295, t�/3.519, P�/0.001, respectively).

This link means that the longer the duration of

illness preceding the treatment course, the higher

level of GDH measured after treatment. Further

investigations are needed to understand whether this

phenomenon reflects the influence of the disease

itself, or neuroleptic treatment preceding the shift to

olanzapine.

To search for a reliable biochemical predictor of

treatment outcome, survival analysis was carried

out. This has enabled us to conclude that level of

GSLP for each individual patient with schizophrenia

may serve as a probable predictor of the treatment

duration needed to achieve a positive outcome of

treatment with olanzapine. The finding is worth

verifying in the future in other treatment trials.

To conclude, the immunoreactivity levels of glu-

tamate metabolising enzymes GSLP and GDH

found in human platelets are influenced by treat-

ment with olanzapine, wherein GSLP enables pre-

diction of the minimum duration of treatment

necessary to achieve a positive outcome. The change

of immunoreactivity levels of GSLP and GDH is

evidence for the effect of olanzapine treatment on

glutamate metabolism, which is consistent with the

finding mentioned above of modulation of serum

glutamate concentration by olanzapine (Goff et al.

2002).

Acknowledgements/Statement of interest

The study is supported by the Stanley Medical

Research Institute, US.

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The influence of concomitant antidepressant medication on safety,tolerability and clinical effectiveness of electroconvulsive therapy

THOMAS C. BAGHAI, ALAIN MARCUSE, MELANIE BROSCH, CORNELIUS SCHULE,

DANIELA ESER, CAROLINE NOTHDURFTER, YVONNE STENG, INES NOACK,

KATRIN PIETSCHMANN, HANS-JURGEN MOLLER & RAINER RUPPRECHT

Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany

AbstractBackground: A major problem in the treatment of severe depression is the onset latency until clinical improvement. So far,electroconvulsive therapy (ECT) is the most effective somatic treatment of depression. This holds especially true fortreatment-refractory disturbances. However, not all patients respond to conventional unilateral ECT. In certain cases,subsequent clinical response can be achieved using bilateral or high-dose unilateral ECT. Also, a concomitantpharmacotherapy can be utilized to augment therapeutic effectiveness. Surprisingly, data in this field are widely lackingand only few studies showed advantages of an ECT/tricyclic antidepressant combination. Method: We retrospectivelyevaluated 5482 treatments in 455 patients to investigate possible therapeutic advantages in combination therapies versusECT monotherapy. Main outcome criteria were clinical effectiveness and tolerability. Moreover, treatment modalities andictal neurophysiological parameters that might influence treatment outcome were analysed. Results: A total of 18.2% of ourtreatments were ECT monotherapy, 8.87% were done with one antidepressant. Seizure duration was unaffected by the mostantidepressants. SSRI caused a lengthened seizure activity. Postictal suppression was lower in mirtazapine and higher inSSRI and SNRI treated patients. A significant enhancement of therapeutic effectiveness could be seen in the patient groupreceiving tricyclics, SSRI or mirtazapine. Serious adverse events were not recorded. Conclusion: Our study supports thehypothesis that mirtazapine can be used to enhance the therapeutic effectiveness of ECT. Controlled studies are necessaryto further investigate the possible advantages of ECT and pharmacotherapy combinations, especially the use of moderndually acting antidepressants which have proven their good effectiveness in treatment-resistant depression.

Key words: Electroconvulsive therapy, major depression, concomitant medication, antidepressant therapy

Introduction

ECT is still the most efficacious treatment option in

pharmacotherapy resistant depression

During recent years there has been considerable

progress in pharmacotherapeutic treatment options

for depressive disorders. Moreover, new treatment

principles are in progress to be established (Baghai

et al. 2006). Nevertheless, electroconvulsive ther-

apy is still one of the best tolerated and most

effective biological treatments of depressive disor-

ders. This holds especially true for severe treat-

ment-resistant major depressive disorder (ECT

Review Group 2003). Since the first publication

of a placebo-controlled double-blind study indicat-

ing the efficacy of ECT in the treatment of

depression (Greenblatt et al. 1964), a variety of

reports, which are summarized in a recent

review (ECT Review Group 2003), described the

excellent therapeutic effectiveness of this method.

Overall, a 20% better improvement in comparison

to tricyclic antidepressants (TCA) and a 45%

better improvement in comparison to monoami-

nooxidase inhibitors have been published in a

metaanalysis (Janicak et al. 1985). A better im-

provement in comparison to the selective serotonin

reuptake inhibitor (SSRI) paroxetine has been

described in a controlled study investigating the

HAMD-score reduction in a responder analysis

(Folkerts et al. 1997). In addition, a more rapid

improvement in comparison to pharmacotherapeu-

tic approaches has been published (Sackeim et al.

1993; Prudic et al. 1996; ECT Review Group

2003).

Correspondence: Thomas C. Baghai, MD, Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University,

Nussbaumstrasse 7, D-80336 Munich, Germany. Tel: +49 89 5160 5812. Fax: +49 89 5160 5391. E-mail: [email protected]


(Received 3 March 2005; accepted 9 June 2005)


DOI: 10.1080/15622970500213871

ECT response is influenced by treatment history

In patient populations not fulfilling the criteria of

therapy resistance, response rates of 80�/90% which

are superior to pharmacotherapy response rates (up

to 70%), have been reported (Prudic et al. 1990,

1996). However, not all patients respond to conven-

tional unilateral ECT. In pharmacotherapy-resistant

depression, typically lower response rates of about

50�/60% can be achieved by ECT (Sackeim et al.

2000). In former publications using lower stimula-

tion energy bilateral ECT has been shown to be

more effective than unilateral ECT (Sackeim et al.

1987, 1993). Additionally, in a recent study uni-

lateral ECT has proven to be as effective as bilateral

ECT if the dose regime allows to use a higher

stimulation energy (Sackeim et al. 2000). Therefore,

in certain cases subsequent clinical response can be

achieved using bitemporal or bifrontal ECTor by the

administration of high-dose ECT.

Augmentation strategies during electroconvulsive

treatment

A further option to augment an ECT treatment

course may be the prescription of concomitant

antidepressants. However study results on a putative

benefit combining ECT with TCA (Nelson et al.

1989; Lauritzen et al. 1996) and the lack of

advantages of other concomitant medication like

SSRI are still controversial (Lauritzen et al. 1996;

Mayur et al. 2000). Especially the efficacy of modern

antidepressants in combination with ECT, e.g., the

dually acting substances mirtazapine and venlafax-

ine, has never been investigated in controlled stu-

dies. Only safety data are available: in a recent study

venlafaxine at dosages lower than 300 mg/day has

been shown to be safe in combination with ECT. In

high dose treatments above 300 mg/day, side effects

of cardiovascular nature such as transient asystolia or

bradycardia were more frequent if ECT was com-

bined with propofol anaesthesia (Gonzalez-Pinto et

al. 2002).

Study plan

Because naturalistic data of retrospective studies

would probably be helpful for the design of con-

trolled studies, we addressed the following questions

in the present investigation: Is the combination of

ECT with antidepressants of benefit for the treated

Table I. Demographic data and major diagnostic groups according ICD�/10. Patients diagnosed as schizophrenic or schizoaffective

revealed statistically significant differences in comparison to patients suffering from major depression: they were significantly younger, the

duration of the treatment series was longer and they received significantly more often bilateral ECT.

Diagnoses (ICD-10) x2-test, ANOVA

F2 F3 Others F, x2; P

n* (%) 134 358 26

(25.9%) (69.1%) (5.1%)

Sex (M/F) 40.2%/59.8% 34.7%/65.3% 10.0%/90.0% 0.57 0.32

Age (mean9/SD) 42.89/12.9 54.09/14.5 44.79/16.2 22.1 B/0.0001

range 18�/80 18�/84 22�/79

ECT treatment modalities

no. of treatments (mean9/SD, n )*

11.29/5.2 11.79/4.6 9.49/3.7 1.50 0.23

Duration (mean9/SD, days)* 49.59/62.6 45.29/79.1 31.29/14.4 4.00 0.008

Treatments per week (mean9/SD, n )* 2.79/1.0 2.89/0.8 2.69/1.2 0.66 0.52

Unilateral (%)**/Bilateral (%)** 50.6%/49.4% 65.0%/35.0% 71.2%/28.8% 211 B/0.0001

Charge (mean9/SD, mC)** 2909/169 2689/111 2239/92 12.5 B/0.0001

*n (treatment series); **n (treatment sessions); F2, schizophrenia (ICD-10); F3, unipolar and bipolar major depression (ICD-10).

Table II. Concomitant psychotropic medication and diagnostic groups.

Diagnoses (ICD-10)

F2 F3 Others Mean

Concomitant psychotropic medication*

None (%)** 13.9% 19.6% 17.8% 18.2%

Antidepressants 42.1% 52.7% 63.2% 50.3%

Neuroleptics 74.4% 58.4% 55.7% 62.2%

Benzodiazepines 16.4% 10.8% 9.8% 12.2%

Lithium 8.5% 8.0% 15.5% 8.3%

*Treatment sessions; **Exception: non-benzodiazepine hypnotics and caffeine; F2, schizophrenia (ICD-10); F3, unipolar and bipolar

major depression (ICD-10).

Electroconvulsive therapy and antidepressants 83

patients regarding ictal electrophysiological para-

meters of potential prospective significance or the

actual clinical effectiveness? Is the combination

therapy of ECT and a concomitant antidepressant

pharmacotherapy as safe as an ECT monotherapy?

Is the incidence of cognitive or cardiovascular side

effects influenced by the concomitant medication?

Are there differences concerning the mentioned

variables between different classes of antidepres-

sants?

Materials and methods

Patients

We analysed data about 5482 ECT treatments in

455 psychiatric in-patients between the years 1995

and 2003 in a retrospective study. A total of

518 treatment series were recorded, because in 63

cases one patient receives more than one treatment

series during the observational time period. Patient

characteristics including major diagnostic groups

(ICD-10) (World Health Organization 1992),

demographic data and ECT treatment modalities

are given in Table I. We analysed data of patients

with treatment resistant paranoid hallucinatory schi-

zophrenia or schizoaffective disorder (F2), with

unipolar or bipolar major depression (F3) and rare

other diagnoses such as organic psychosis, person-

ality disorders and Gilles-de-la-tourette syndrome.

Before starting the treatment patients gave their

written informed consent for ECT procedures and

anaesthesia separately.

ECT treatments (Weiner et al. 1988)

ECT was performed using the Thymatron DGxTM

device during the years 1995 up to June 2000,

afterwards a Thymatron System-IVTM was used

from July 2000 up to 2003. The devices provide

stimulus delivery in form of constant current (900

mA) bi-directional pulse wave stimulation. The

voltage was up to 450 V, impulse width was 0.5�/1

ms (mean9/standard deviation (SD): 0.549/1.3 ms),

the frequency was 20�/70 Hz (51.99/17.7 Hz). The

length of a stimulus train was 0.14�/8 s (5.29/1.9 s).

Stimulus intensity was determined using the

modified age method in case of unilateral stimula-

tion and half-age method in case of bilateral stimula-

tion (Abrams 2002). Lower and upper charge limits

during the first stimulation were 30 and 60% device

adjustment representing a charge of 151 and 302

mC, respectively. Only in a few cases (B/5%) was

dose titration used before the initial treatment

session. In the case of dose titration, unilateral

treated patients received a first stimulus 2.5�/5-fold

over threshold, bilateral treated patients a stimulus

5% over threshold. Restimulation and dosage

elevation in 10% steps during the subsequent treat-

ments was recommended in case of too short EEG

(B/ 30 s) and EMG (B/ 25 s) seizure activity and a

too low postictal suppression index (B/80%). The

maximal charge was 504 mC during the years 1995�/

2001 and 1008 mC since January 2002. The mean

postictal suppression index was 88.09/11.9%, the

mean stimulation energy was 54.19/25.5% (272.79/

128.5 mC).

Electrode placement was primarily unilateral

according the d’Elia method (d’Elia G 1970; d’Elia

G et al. 1975). In the case of therapy resistance or

the knowledge of former inefficient unilateral ECT

bitemporal electrode placement was recommended.

Since electrode placement was not recorded during

clinical routine treatments, these data are lacking in

45.2% of treatments during the years 1995�/1999.

From 2000 on this information is available. 33.5% of

the investigated treatments were unilateral and

21.3% were bitemporal.

Seizure monitoring included one-lead EEG and

EMG monitoring up to June 2002 and two-lead

EEG, EMG and ECG monitoring from July 2002.

The one-lead EEG electrodes were placed left

frontopolar and over the ipsilateral mastoid (FP1�/

A1 according the international 10�/20 system). The

two-lead EEG electrodes were left and right fronto-

polar (FP1�/A1 and FP2�/A2) and over the ipsilateral

mastoid. EMG was conducted in 5�/10 cm over the

flexor carpi ulnaris muscle. The mean seizure

duration was 31.79/16.0 s (EEG) and 19.39/11.4 s

(EMG), respectively.

Anaesthesia

The administered anaesthetic agents were thiopental

(in 71.9% of treatments, mean dosage9/SD: 3649/

93 mg), propofol (20.0%, 1709/51 mg), methohex-

ital (5.5%, 1309/33 mg) and etomidate (2.6%, 329/

32 mg). Due to the clinical objective to achieve

adequate seizures, patients with higher seizure

threshold received more frequent methohexital

than other anaesthetics. During these treatments

most patients received no concomitant antidepres-

sant pharmacotherapy. For muscle relaxation, suc-

cinylcholine or pyridostigmine, together with

atracurium for premedication, were used.

Psychotropic medication

Information about the main treatment groups and

indication of concomitant medication is given in

Table I. A total of 813 treatments were done without

any psychiatric medication, 184 treatments were

done with concomitant non-benzodiazepine hypno-

84 T. C. Baghai et al.

tics. The analysis of all electrophysiological and

clinical parameters revealed no clinically relevant or

statistically significant differences between these two

groups. Due to this result and because no significant

psychotropic effects besides the sedating and sleep-

inducing properties were expected, we merged these

997 treatments in the group of patients without

psychotropic medication (noPT).

In the case of treatment with antidepressants,

42.1% of treatments were performed with concomi-

tant administration of tricyclic antidepressants

(TCA), 21.1% with tetracyclic antidepressants

(TTCA: 92.4% mirtazapine, 7.6% mianserine),

16.1% with selective serotonin reuptake inhibitors

(SSRI), 14.2% with venlafaxine (SNRI), 2.9% with

reboxetine, 2.7% with other antidepressants and

0.9% with monoaminooxidase inhibitors (predomi-

nantly moclobemide). In the case of treatment with

neuroleptics, 45.7% of the treatments were done

with concomitant administration of atypical sub-

stances, 34.3% with high potent classical neurolep-

tics, 12.3% with medium potency and 38.2% with

low potent neuroleptics (also combinations were

given).

Clinical assessments

We included clinical data and ECT treatment data

from the patient records, ECT treatment documen-

tation and ECT-device printouts in a relational

database. Both the diagnoses according ICD-10

(Sartorius 1983; ICD-10 Task Force 1987) and the

severity of disease according the clinical global

impression scale (CGI, Item 1) (National Institute

of Mental Health 1976) were assessed. CGI scores

were recorded in weekly intervals and after each

electroconvulsive treatment. Additional information

about therapeutic response and adverse effects such

as cognitive impairment were registered system-

atically (CGI, Items 3.1 and 3.2) after each ECT

according the clinicians judgments. Serious adverse

events, if applicable, should be recorded in free

form. Clinical, technical and electrophysiological

ECT data such as stimulation parameters, EEG

and EMG derivations including the length of con-

vulsions, postictal suppression, seizure energy and

seizure concordance were registered. Information

about all prescribed medication including psychia-

tric medication, medication prescribed for medical

conditions and substances used for anesthesia were

recorded in detail.

Electrophysiological measures

The minimal duration of generalized convulsions

measured using EEG and EMG techniques is a

necessary but not sufficient criterion for a probable

successful ECT treatment. A duration of at least 25 s

measured in the EEG and 20 s in the EMG is

recommended (Coffey et al. 1995). In most cases

computer-automated electroencephalographic and

electromyographic estimation of the seizure duration

is of sufficient quality (Swartz et al. 1994). But it is

also known that there is no significant correlation

between the therapeutic effectiveness of ECT and

the duration of convulsions (Abrams 1972, 2002;

Nobler et al. 1993). Especially during unilateral

ECT, a higher stimulation energy together with a

higher clinical efficacy (Sackeim et al. 2000) may

lead to shorter convulsions (Frey et al. 2001).

Therefore, other measures are of use to decide

whether a restimulation may be of use during an

individual treatment session. The postictal suppres-

sion index (PSI) shows how fast and complete the

EEG amplitude flattens directly after the convul-

sions. The index is calculated from the quotient of

the mean EEG amplitude during a 3-s derivation 0.5

s after the end of convulsions and the mean

amplitude of a 3-s passage during the convulsions.

Its unit ‘‘% suppression’’ is highly correlated to the

probability of clinical improvement (Suppes et al.

1996). Restimulation is recommended if the PSI is

under 80% (Weiner et al. 1991; Nobler et al. 1993).

The convulsion energy index (CEI) is the product of

the mean EEG amplitude and the duration of

convulsions as a measure of the intensity of the ictal

response after electrical stimulation (mV s) (Weiner

et al. 1991). The convulsion concordance index

(CCI) is a measure for the intracerebral general-

ization of the convulsions (Swartz et al. 1986). It is

calculated as follows: 100�EEG � EMG

EEG � EMG(EEG and

EMG represent the duration of the convulsions).

According to the Thymatron manufacturer So-

matics, restimulation should be considered if the

index is below 51%. Regular monitoring of EEG and

EMG quality and all treatment procedures was

provided by senior psychiatrists.

Statistical analyses

Statistical analyses were performed using SPSS for

Windows (Release 11.0.1, SPSS Inc., Chicago, IL

60606, USA). Mean differences in demographic and

clinical variables between the treatment groups were

compared using independent samples Student’s t-

tests and x2-tests. A one-way analysis of variance

(ANOVA procedure) was performed to detect sig-

nificant differences in electrophysiological variables

and clinical mean scores between the divergent

treatment groups. Bonferroni correction was used


in case of multiple testing. The level of significance

was set at 0.05.

Results

A total of 18.2% of the treatments was done without

any psychotropic medication. In 23.4% a psycho-

tropic monotherapy was prescribed. Comparing

these two groups, the influence of confounding

variables like pharmacokinetic and dynamic effects

combining several substances can be excluded.

Within the group of mono-pharmacotherapeutic

treatments with tetracyclic antidepressants (TTCA)

only 1.9% received mianserine and 98.1% mirtaza-

pine. During 30.4% of the treatments the patients

received two concomitant medications, in 18.3%

three medications and in 9.6% more than three and

up to six psychotropic acting agents were prescribed.

Due to the lack of randomization we could detect

differential applied stimulation energies and charges

in the different treatment groups (ANOVA

F(4,1154)�/13.2, P B/0.0001). Bonferroni cor-

rected post-hoc tests showed a significantly higher

applied charge in the group of treatments without

pharmacotherapy (mean9/SD: 2889/135 mC) in

comparison to treatments with concomitant TCA

(mean9/SD: 2199/103 mC, P B/0.0001), SSRI

(2289/95 mC, P�/0.001) or SNRI (2389/96 mC,

P�/0.039). The stimulation charge in the TTCA-

treated group showed a trend to higher values

(2529/76 mC, P�/0.26, n.s.) which was not statis-

tically significant.

As expected the ANOVA revealed a significant

differences in the duration of generalized convul-

sions (Figure 1; EEG: F(4,1076)�/6.27, P B/

0.0001; EMG: F(4,805)�/4.23, P�/0.002). Bonfer-

roni corrected post-hoc tests showed a significant

longer duration of convulsions in ECT/SSRI com-

bination therapies in comparison to treatments with

TCA (P�/0.012) or serotonin and noradrenalin

reuptake inhibitors (SNRI, venlafaxine) treatment

(P�/0.002) and in comparison to ECT monother-

apy (P�/0.001). TTCA (predominantly mirtaza-

pine) treatments resulted in significantly longer

convulsions in comparison to venlafaxine treatments

(P�/0.019).

The postictal suppression index showed signifi-

cant differences between the five treatment groups

(Figure 2; ANOVA F(4,837)�/5.59, P B/0.0001).

Bonferroni corrected post-hoc tests showed a sig-

nificantly lower PSI after ECT treatments under

TTCA in comparison to SSRI- (P�/0.023) or

SNRI-treated patients (P�/0.014). After treatments

without psychopharmacotherapy significantly lower

PSI than under SSRI (P�/0.015) or SNRI (P�/

0.015) were seen.

Both effectiveness and the rate of side effects were

affected by the concomitant medication. After the

first ECT treatment, the different treatment groups

showed no significant differences concerning the

severity of disease (CGI, Item 1: ANOVA

F(4,218)�/1.02, P�/0.39, n.s.), whereas it was

significantly influenced by the concomitant treat-

ment during the ECT treatment series (Figure 3;

Figure 1. Mean duration of generalized convulsions in EEG- and EMG-derivations. EEG: Significantly longer convulsions in ECT/SSRI

combination therapy in comparison to treatments with TCA, SNRI and treatments without concomitant medication. Significantly longer

convulsions during TTCA in comparison to venlafaxine treatment. EMG: Significant longer convulsions in SSRI- and TTCA-treated

patients in comparison to ECT treatments without psychotropic co-medication. no PT�/no psychotropic medication; exception: non-

benzodiazepine hypnotics in case of insomnia (n�/146 patients); TCA�/tricyclic antidepressants (n�/34 patients); TTCA�/tetracyclic

antidepressants (n�/14 patients); SSRI�/selective serotonin reuptake inhibitors (n�/10 patients); SNRI�/selective serotonin and

noradrenalin reuptake inhibitors (n�/14 patients).


ANOVA F(4,586)�/13.7, P B/0.0001). Bonferroni

corrected post-hoc tests showed a significantly

higher severity of disease during ECT treatments

without pharmacotherapy in comparison to treat-

ments combined with SSRI (P�/0.012) or TTCA

(P B/0.0001). TTCA-treated patients showed also

significant lower CGI Item 1 values in comparison to

TCA- (P B/0.0001) and SNRI (P�/0.002)-treated

patients. Similar results yielded CGI Item 3.1 (over-

all amelioration of symptoms): both treatments

without concomitant medication and SNRI-treated

patients showed higher mean scores and therefore

less improvement in comparison to TCA, TTCA

and SSRI treatments (Figure 3). The possibility to

apply a higher maximal charge since 2002 did not

influence the overall treatment results because high

dose treatments with charges between 504 and 1005

mC were applied infrequently.

The rate of cognitive and cardiovascular side

effects was significantly higher in SNRI-treated

patients in comparison to patients without psycho-

tropic medication. Considering transient cardiovas-

Figure 2. Postical suppression index: significantly higher indices in SSRI or SNRI combined ECT treatments in comparison to treatments

without psychopharmacological medication. Significantly higher convulsion energy index in treatments with TTCA in comparison to the

other treatment groups. No influence of concomitant treatment on convulsion concordance index. PSI�/postictal suppression index;

CCI�/convulsion concordance index; CEI�/convulsion energy index.

Figure 3. Clinical treatment efficacy (judged after each ECT treatment or in weekly intervals): significantly more benefit for the patients in

ECT treatments combined with tricyclics, SSRIs or TTCA. Significantly more cardiovascular or cognitive side effects in patients receiving

SNRI in comparison to patients without concomitant psychotropic medication. CGI Item 1: severity of disease (lower score indicates better

efficacy); CGI Item 3.1: efficacy (lower score indicates better efficacy); CGI Item 3.2: adverse effects (lower score indicates better

tolerability of the treatment).


cular side effects separately, the x2-test showed

two-fold higher rates than expected in the treatment

group receiving TTCA and less than half than

expected during the treatments with concomitant

application of TCA. These effects were statistically

significant (x2 (4,1151)�/20.9, P B/0.0001). There

were no reports about serious adverse events during

the observational time period. In addition there were

no reports about higher frequencies of therapeutic

interventions in case of side effects, e.g., high blood

pressure after ECT in one of the mentioned ther-

apeutic groups.

Discussion

Monotherapeutic antidepressant treatments using

TCA, SSRI or SNRI had significant impact on ictal

electrophysiological indices, the amelioration of

depressive symptoms and the incidence of side

effects.

As known from the literature, concomitant SSRI

treatment can lead to prolonged generalized seizures

(Gutierrez-Esteinou et al. 1989; Curran 1995)

independently from clinical outcome. The presented

investigation confirms this result and shows that also

TTCA, like mirtazapine, are able to lengthen seizure

duration. Patients receiving venlafaxine showed sig-

nificantly shorter seizures in comparison to SSRI

and TTCA treatments. The influence of confound-

ing variables, like concomitant benzodiazepine use,

was excluded, because only monotherapies with one

antidepressant were analysed. Because higher stimu-

lation energy can lead to shorter convulsions (Frey et

al. 2001), the lower applied energy in the SSRI-

treated group may contribute to these results.

Nevertheless, in neither SSRI- nor TTCA-treated

patients had seizures to be terminated using anaes-

thetics or benzodiazepines more often than in other

treatment groups. Also, a more frequent use of

caffeine in the indication to prolong seizures in one

of the treatment groups was not detected.

To evaluate the ECT treatment quality, other

electrophysiological parameters and indices of pro-

spective clinical significance were also used (Swartz

et al. 1986; Weiner et al. 1991; Nobler et al. 1993;

Suppes et al. 1996). In our study the PSI, which

indicates a positive correlation with clinical effec-

tiveness (Suppes et al. 1996), was significantly

enhanced in comparison to treatments without

psychotropic pharmacotherapy if SSRI or SNRI

treatment were prescribed at the same time. In

treatments with a concomitant TTCA the index

was significantly lower than in both mentioned

groups. On the contrary, these predominantly mir-

tazapine-treated patients showed a significantly

higher CEI in comparison to both the unmedicated

and all other medicated patients, which also indi-

cates a positive impact on therapeutic outcome

(Swartz et al. 1986; Weiner et al. 1991). Our

retrospective data show therefore that the CEI may

allow a better prediction of the treatment quality in

patients with concomitant antidepressant treatment

in comparison to both the PSI and the CCI, but due

to the retrospective characteristic of our analysis this

question cannot be answered finally. Postictal sup-

pression seems to be of limited usefulness to predict

the clinical effectiveness in our study, similar to

other prospective studies (Perera et al. 2004). In

addition, no data about the influence of venlafaxine

and mirtazapine on ictal electrophysiological mea-

sures during ECT have yet been published.

Therefore, we tried to investigate the interrelation

between the medication, the described findings and

clinical effectiveness. According the CGI Item 1

(severity of disease), patients receiving ECT and

TTCA had a significant lower score than patients

receiving ECT alone, patients receiving ECT and

tricyclics and patients receiving ECT and venlafax-

ine. SSRI-treated patients had also higher mean

scores than TTCA-treated patients, but this differ-

ence was not statistically significant after Bonferroni

correction. The difference between SSRI-treated

patients and the patients receiving ECT alone

achieved statistical significance. The mean ameliora-

tion of symptoms indicated by the mean CGI Item

3.1 score was also significantly more pronounced

during ECT treatments in combination with a TCA,

TTCA or SSRI therapy in comparison to ECT

alone. During treatments using ECTand venlafaxine

in combination a significantly weaker effect on CGI

Item 3.1 could be seen in comparison to TCA,

TTCA and SSRI combinations with ECT.

These results indicate that the PSI may not be the

best parameter to estimate the clinical effectiveness

of a single ECT treatment if ECT is not adminis-

tered as a monotherapy. This seems to be especially

true in ECT/mirtazapine combination therapy,

where the CEI may be better suitable to predict

clinical effectiveness. Another explanation of these

findings may be the lack of randomization in our

retrospective study of clinical routine treatments.

The patients were not randomized by chance to the

treatment groups and especially both dual acting

antidepressants are used very often in the case of

prior treatment-resistance. This is especially true in

patients receiving this medication in combination

with ECT. Some authors describe a similar effec-

tiveness in severe depression of tricyclics and SSRI

(Hirschfeld 1999), others report a better ameliora-

tion of depressive symptoms during TCA treatment

(Parker et al. 1999). Even if there are contradicting

publications, a favourable therapeutic outcome in


severe and treatment-resistant depression (Hirsch-

feld 1999; Thase et al. 2000) leads to an intensified

use of venlafaxine and mirtazapine. Of course a

higher degree of treatment-resistance, not only

during a pharmacotherapeutic approach but also

during an ECT treatment, leads to lower response

rates and higher estimations of the severity of

disease.

The rate of side effects was higher during ECT

treatments in combination with venlafaxine in com-

parison to unmedicated patients. It is known that a

higher rate of cognitive disturbances can be expected

in case of the use of higher stimulation charges

(Abrams et al. 1991; McCall et al. 2000). This effect

can be excluded to a large extend in our study,

because the treatments without concomitant phar-

macotherapy were done using the highest stimula-

tion charge. Otherwise, in spite of the published safe

use of this combination (Bernardo et al. 2000) in

daily dosages up to 150 mg (Gonzalez-Pinto et al.

2002), several reports about cardiovascular risks

(Agelink et al. 1998; Jha et al. 2002), especially

during high-dose venlafaxine therapy together with

the use of propofol anaesthesia (Gonzalez-Pinto et

al. 2002) and also prolonged seizures (Conway et al.

2001), are published for this combination therapy.

In our sample a total of 284 ECT treatments were

done with concomitant venlafaxine prescription. A

total of 195 (68.7%) of these prescriptions were in

high-dose range above 150 mg, 91 (32.0%) in the

highest doses above 300 mg. The mean dosage was

2559/120 mg/day. Comparably high dosages were

prescribed because of the high degree of treatment-

resistance in this patient group and may be the

explanation for the relatively lower clinical response

together with a higher incidence of side effects.

Nevertheless all observed side effects were only

transient and in most cases no specific treatment

was required.

It has to be mentioned that our analyses were

treatment session oriented and not patient oriented.

This includes the disadvantage that single treatment

series in singular patients who are treatment-resis-

tant in a special way and received more treatments

than other patients may influence the analysis more

than others. On the other hand, as an advantage,

changes in ECT and pharmacotherapy treatment

modalities within the ECT series do not influence

the results and have therefore not to be taken into

consideration.

Overall, our study shows an excellent tolerability

of ECT and ECT in combination with antidepres-

sant pharmacotherapy. The presented data give first

hints that it is not only tricyclic antidepressants that

lead to a therapeutic benefit in treatment-resistant

disorders. Also, other concomitant antidepressant

pharmacotherapies, during an ECT treatment

course like SSRI or the modern dually acting

antidepressant mirtazapine, may be able to enhance

treatment efficacy. Of course, this cannot be proven

in our study due to the naturalistic and retrospective

design. Our study provides data which justify and

demand further controlled evaluations using double-

blind and placebo-controlled conditions in a next

step to answer the question, if and which modern

antidepressants should be used in combination with

ECT to enhance responder rates, shorten the time

until clinical response and cause as fewer side effects

as possible, especially in the treatment of therapy-

resistant psychiatric disorders.


The authors have no conflict of interest with any


the submitted article. The authors would like to

thank Mrs M. Ertl, Mrs S. Rauch and Mr K. Neuner

for patient nursing, ECT organization and database

management.

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P300 differences exist between Tourette’s syndrome with and withoutattention deficiency and hyperactivity disorder in children

ZHU YAN, LIU PO-ZI, LEUNG KAI-MAN, SU LIN-YAN, WU DA-XING & ZHOU MING

Mental Health Department, The Second Affiliated Hospital (Yu Quan Hospital) of Medical School, Tsinghua University,

Beijing, China

AbstractObjective: To study the characteristics of P300 in Tourette’s syndrome (TS) with and without attention deficiency andhyperactivity disorder (ADHD). Method: Auditory evoked P300 were recorded in 19 TS only (TS�/ADHD) children, 15TS with ADHD (TS�/ADHD) children and 20 unaffected control subjects, and their waveforms, amplitudes, latencies andtopographies were compared at Fz, Cz, C3, C4 and Pz. Results: The TS�/ADHD group showed shorter latencies thancontrol subjects at all electrode sites (P B/0.05 or 0.01), and the TS�/ADHD group at CZ and PZ (P B/0.05); however, therewas no significant difference between control subjects and the TS�/ADHD group. The TS�/ADHD group showed smalleramplitudes than the control group at all electrode sites (P B/0.05), and the TS�/ADHD group at Cz (P B/0.05); however,there were no significant differences between control subjects and the TS�/ADHD group. There was no significantdifference in the prevalence of abnormal waveforms between the control, TS, TS�/ADHD and TS�/ADHD groups, butthere were significant differences in the variability of localization of P300 between the control and the TS group (P�/0.003),control and TS�/ADHD groups (P�/0.000), and the TS�/ADHD and TS�/ADHD groups (P�/0.039). P300 in the TS�/

ADHD group tended to spread out to the left and that of the TS�/ADHD group tended to spread out to the right.Conclusions: P300 differences exist between TS�/ADHD and TS�/ADHD in children. These suggested that establishmentdifferent development defects or delay of communications between different structures rather than a delay in maturation ofthe structures themselves may be involved in TS�/ADHD and TS�/ADHD children and ADHD symptoms in TS patientsare likely a trait rather than adventitious or acquired within the TS syndrome.

Key words: Tourette’s syndrome, attention deficiency and hyperactivity disorder, auditory evoked potentials, children

Introduction

Tourette’s syndrome (TS) is a chronic neuropsy-

chiatric disorder characterized by motor and phonic

tics and related somatosensory urges. Prevalence of

TS is higher than previously thought, and may be

present in up to 2% of the population (e.g., Faridi

and Suchowersky 2003). It is a heterogeneous group

of chronic neuropsychiatric diseases, and its aetiol-

ogy is likely multifactorial, including a variety of

biological and psychological factors. The complexity

and variability of these aetiological factors resulted in

various TS subtypes with differences in symptoma-

tology, chronicity and gender distribution, but more

importantly, different degrees of association with

other psychological disorders such as conduct pro-

blems, learning difficulties, emotional disorders and

especially attention deficit/hyperactivity disorder

(ADHD; e.g., Comings 1995; Walkup et al. 1995;

Leckman et al. 1997; Leckman 2002; Faridi and

Suchowersky 2003). Studies found that at least 40�/

50% of TS children had comorbid ADHD (TS�/

ADHD). This group of children was often impul-

sive, overly active and inattentive before develop-

ment of tics, with adverse effects on peer and family

relationships as well as the child’s ability to succeed

in school (e.g., Leckman et al. 1997; Faridi and

Suchowersky 2003). Moreover, treatment of TS�/

ADHD children is often complicated and contro-

versial. Psychostimulants, such as methylphenidate,

dexamphetamine, and related drugs are the most

effective agents for uncomplicated hyperkinetic dis-

order. But these drugs could be used with impunity

in some individuals with tics. Occasionally, they can

precipitate de novo tics or exacerbate pre-existing

Correspondence: Zhu Yan, MD, Mental Health Department, The Second Affiliated Hospital (Yu Quan Hospital) of Medical School of

Tsinghua University, 5 Shijinsan Road, Beijing 100049, China. Tel: +8610 010 86471980. Fax: +8610 010 88258319. E-mail:

[email protected]


(Received 28 June 2005; accepted 25 November 2005)


DOI: 10.1080/15622970500492723

tics in individuals with Tourette’s syndrome (e.g.,

Sandor 1995; Leckman et al. 1997; Scahill et al.

2000). The combination of TS�/ADHD is thus

highly important in child psychiatry. Better under-

standing of these disease subtypes may lead to better

understanding of their aetiology, better treatment

options and more accurate prognostication (e.g.,

Sandor 1995; Leckman et al. 1997; Scahill et al.

2000).

Differences between TS children with and without

ADHD were noted in recent clinical studies. ADHD

was found to cause greater impairment than the tics,

and the severity of ADHD was more predictive of

impaired social adjustment irrespective of the sever-

ity of the tic symptoms (e.g., Harris et al. 1995;

Sherman et al. 1998; Stephens and Sandor 1999;

Carter et al. 2000; Mostofsky et al. 2001; Brand

et al. 2002; Mahone et al. 2002; Sukhodolsky et al.

2003). Comorbid ADHD was found to be predictive

of increased morbidity and poor outcome (e.g.,

Leckman 2003).

Many clinical studies had observed these, but few

have investigated the neurobiological basis of this

difference. Drake et al. (1992) found that TS

patients with and without attention deficit disorder

(ADD) did not differ in brainstem auditory evoked

potential (BAEP) latencies, both groups were not

different from normal controls, and that AEP

latencies did not differ between TS patients and

controls. TS patients with ADD had longer N100

and N200 latencies than TS patients without ADD

(e.g., Drake et al. 1992). Oades et al. (1996) found

that both ADHD and TS groups showed very large

P2 components where the maxima were shifted

anteriorly. The differences in the later potentials

were of a topographical nature. Later indices of

stimulus processing (N2�/P3) showed a frontal

impairment in TS and a right hemispheric impair-

ment in ADHD patients (e.g., Oades et al. 1996).

Straube et al. (1997) found that GTS patients

showed a significant increased latency of antisac-

cades, highly impaired performance of sequences of

memory-guided saccades, and an isolated reduction

in the peak velocity of the antisaccades (e.g., Straube

et al. 1997).

There were also few studies on P300 wave in TS

patients. The P300 wave is a positive component of

the event-related potential (ERP) occurring approxi-

mately 300 ms after an infrequently presented target

stimulus (so-called ‘oddball’ paradigm). It is thought

to reflect underlying fundamental cognitive opera-

tions (e.g., Polich and Kok 1995). Some previous

studies of P300 in TS children showed prolonged

latencies and decreased amplitudes (e.g., Huang and

Liu 1999), while others showed no difference

between normal subjects and TS patients (e.g.,

Fowler and Mitchell 1997). The discordances may

be related to different methods in the recruitment of

subjects (TS is often associated with complications

that are both complex and variable), different

techniques in the recording of P300 and different

analytical methods being used.

We carefully selected 19 TS�/ADHD, 15 TS�/

ADHD and 20 control subjects and tried to show

that TS with and without ADHD are neurophysio-

logically heterogeneous by using P300 as an indi-

cator.

Method

Subjects

Thirty-four, 10�/14-year-old TS patients were

recruited through the Child and Adolescent Psy-

chiatric Health specialist clinic, Mental Health

Institute, Central South University between July

2000 and August 2004. The study was approved

by the Ethics Committee, South Central University

and Department of Health, China. Informed con-

sents for participation were obtained from parents of

all children. The diagnostic procedures started with

child and parent clinical interview. Board-certified

psychiatrists (Liu Po-zi and Su Lin-yan), each with

25 years of research and clinical experience treating

TS children, diagnosed each case on the basis of a

clinical interview with the parent, and completed the

Yale Global Tic Severity Scale (YGTSS). Diagnosis

of TS was based on DSM-IV diagnostic criteria, and

children with organic or somatic disorders, or had

taken haloperidol, tiapride and other medication in

the past month were excluded. Children who

evidenced transient tics or chronic motor or vocal

tics and comorbidities such as obsessive-compulsive

disorder, anxiety disorders, conduct problems,

learning difficulties, as well as bipolar and nonbipo-

lar mood disorders, were also excluded. All selected

TS children suffered severe tic symptoms by YGTSS

assessment. The 34 TS patients were further divided

into two groups, with or without ADHD, diagnosed

by the same board-certified psychiatrists, based on

DSM-IV criteria. The TS only (TS�/ADHD) group

included 19 children (17 boys and two girls)

between the ages of 10 and 14 years (mean�/

11.16, SD�/1.214), with average Ravens IQ score

of 105.46 (SD�/13.04). The average time since

diagnosis was 2.019/0.59 years. The TS with

ADHD (TS�/ADHD) group included 15 children

(11 boys and four girls) between the ages of 10 and

13 years (mean�/11.13, SD�/1.060, IQ�/99.25,

SD�/15.68), and average time of diagnosis being

2.089/1.03 years. Finally, a control group of 20

unaffected children (16 boys and four girls) between

92 Zhu Yan et al.

the ages of 10 and 13 years (mean�/11.45, SD�/

1.146, IQ�/119.25, SD�/12.64) were randomly

selected from local elementary and high schools.

They all received course credits or pecuniary

remuneration for participation. The three groups

were matched in age, sex ratio and IQ (F�/0.440,

x2�/1.493, F�/0.547, P �/0.05). The two study

groups were matched in average time from diagnosis

(Table I).

Measurement

A standard oddball paradigm (Stim-1 systems from

Neuroscan, USA) was used for P300 recording. The

experiments were carried out in a sound-proof room

with temperature controlled at about 258C. Audi-

tory stimuli were delivered through earphones.

Testing subjects, with eyes covered, were asked to

press a response key for target stimuli (20%) and to

ignore standard stimuli (80%). A total of 200 stimuli

were given, with interstimulus interval of 2.0 s.

Before formal recording, subjects were allowed to

get familiar with the procedure and to learn to use

the response key by left figure. Standard 32-elec-

trode cap electroencephalogram (EEG) was used

(ElectroCap International). The reference electrodes

were placed over the mastoid processes, and the

ground electrode on the forehead. The impedance

values were kept below 5 kV. Trials with overt eye or

muscular movements were rejected if the EOG

exceeded 65 mV above the eyes. Peak amplitude

and latency were recorded after the standard

(0.8 kHz), the high (2.0 kHz) and the low deviants

(1.4 kHz). The P300/P300-like peak was the largest

positive component at 240�/540 ms post stimuli

(Oades et al. 1995a,b). P300 amplitude (mv) was

defined as the voltage difference between a presti-

mulus baseline and the largest positive-going peak of

the ERP waveform within a latency window. Latency

(ms) was defined as the time from stimulus onset to

the point of maximum positive amplitude within the

latency window. EEG was amplified 500 times with

a band-pass filter set at 0.10�/40 Hz, sampled at

500 Hz and stored on a hard disk for off-line

analysis. P300 were averaged for each condition

separately. The averaging epoch was 1,000 ms, with

the first 200 ms before stimulus being the baseline.

Trials containing incorrect responses, EOG artifacts

or amplifier saturation were excluded from the

averages. Data were digitally filtered between 0 and

30 Hz. Grand averaged P300 by group average were

calculated using Neuroscan software. Graphs were

plotted after averaging mean amplitude values, and

colour topographic maps generated by superimpos-

ing the records using Neuroscan software. The

waveforms, amplitudes and latencies at FZ, PZ, CZ,

C3 and C4 were chosen and analysed by SPSS/PC�/

program. The mean latency and amplitude were

analysed in each different group by independent-

samples t-test. Waveform variables and topographic

distributions were analysed by 2�/2 table Pearson

Chi-squared test.

Results

P300 latency and amplitude

There was no significant difference in P300

latency between the TS group and control group

except at C4, where control group showed longer

latencies than TS group (P B/0.05). Similarly,

there was no significant difference in P300 latency

between the control group and the TS�/ADHD

group. When compared with the control group,

however, the TS�/ADHD group showed shorter

latencies at all electrode sites (P B/0.05 or 0.01).

Lastly, the TS�/ADHD group showed significantly

longer latencies at CZ and PZ (P B/0.05)

when compared with the TS�/ADHD group

(Tables II�/V).

There was significant difference in P300 ampli-

tude between the TS group and the control group.

TS group showed smaller amplitudes than the

control group at all electrode sites (P B/0.05 or

0.01). Similarly, there was significant difference in

P300 amplitude between the control group and the

TS�/ADHD groups at all electrode sites (P B/0.05 or

0.01). When compared with the control group and

the TS�/ADHD groups, however, the TS�/ADHD

group showed smaller amplitude only at PZ (P B/

0.05 or 0.01). Lastly, when compared with the

TS�/ADHD group, TS�/ADHD showed significant

smaller P300 amplitude only at CZ (P B/0.05)

(Tables II�/V).

Table I. Demographic and clinical characteristics by diagnostic group.

TS-only

(n�/19)

TS�/ADHD

(n�/15)

Controls

(n�/20) Statistical test P value

Mean age9/SD 11.169/1.214 11.139/1.060 11.459/1.146 F�/0.440 0.646

Gender (% male) 89.5 73.3 80.0 x2�/1.493 0.474

Mean IQ score9/SD 105.469/13.04 99.259/15.68 119.259/12.64 F�/0.547 0.594

Average time since diagnosis (years)9/SD 2.019/0.59 2.089/1.03 T�/0.267 0.792

P300 differences between TS�ADHD and TS+ADHD 93

Waveforms

Most of the control subjects showed regular, smooth

and distinct P300. Only seven control subjects

(35%) showed slightly irregular and indistinct waves.

A total of 12 subjects from the two disease groups

(35.29%, four from the TS�/ADHD group and eight

from the TS�/ADHD group) showed irregular

waves, wide waves, bifurcated peaks or indistinct

waves (irregular waves in seven, wide wave in one,

bifurcated peaks in one and indistinct waves in three

cases). There was no significant difference in the

prevalence of abnormal waveforms between the

control, TS, TS�/ADHD and TS�/ADHD groups

(Table VI). By 2�/2 table Pearson Chi-Square test,

the TS�/ADHD and TS�/ADHD groups showed

difference in prevalence of abnormal waveforms

(x2�/3.825, P�/0.051). The differences between

the grand mean difference P300 waveforms for the

three groups are shown in Table VII and Figure 1.

Topography

A symmetrical pattern of scalp distribution and

concentration of P300 maxima along the midline

at the parietal-occipital region were observed in most

controls. Only three control subjects (15%) showed

different localization of P300 maxima, including one

at CZ, one at C3 and one at somewhere between PZ,

P3 and P4. Four subjects in the control group (20%)

showed laterality of P300 electric potential diffusion,

including three with smaller diffusions on the right

and one with smaller diffusion on the left.

In the two disease groups, the localization of P300

maxima was variable. A total of 26 cases (76.47%,

including all 14 subjects from the TS�/ADHD

group and 12 subjects from the TS�/ADHD group)

did not show localization of P300 maxima along the

midline at the parietal-occipital region. These in-

cluded two at the frontal zone, four at the left frontal

zone, two at C3, one at the central parietal, one at

the right parietal-occipital, two at the left parietal-

occipital, 11 at PZ, one at the left occipital, two at the

right occipital and one at the central occipital zone.

A further 13 cases from the two disease groups

(38.24%, five from the TS�/ADHD group and eight

from the TS�/ADHD group) showed laterality of

P300 electric potential diffusion, including four

showing smaller diffusions on the right and nine

showing smaller diffusions on the left (Table VII).

In summary, there were significant differences in

the variability of localization of P300 between the

control and TS groups (x2�/9.113, P�/0.003),

control and TS�/ADHD groups (x2�/12.153, P�/

0.000), and TS�/ADHD and TS�/ADHD groups

(x2�/4.242, P�/0.039). The probability of variation

was highest in the TS�/ADHD group.

Table II. Comparison of P300 latencies and amplitudes between TS and control groups.

Characteristic Electrode site Control (N�/20) TS (N�/34) t P

P300 latency (ms) FZ 390.579/53.65 373.539/71.51 0.922 0.361

CZ 389.899/52.56 376.549/68.83 0.748 0.458

C3 393.769/52.99 371.099/66.56 1.299 0.200

C4 394.779/53.34 379.419/72.78 0.822 0.010*

PZ 390.559/52.74 376.749/70.72 0.757 0.415

P300 amplitude (mv) FZ 7.889/4.08 5.689/3.72 2.029 0.048*

CZ 8.889/4.06 6.429/3.54 2.326 0.024*

C3 8.559/4.13 5.699/3.89 2.546 0.014*

C4 7.559/4.02 4.749/3.52 2.687 0.010*

PZ 10.769/4.21 7.919/2.91 2.933 0.005*

*Statistically significant (P 5/0.05).

Table III. Comparison of P300 latencies and amplitudes between TS-ADHD and control groups.

Characteristic Electrode site Control (N�/20) TS�/ADHD (N�/19) t P

P300 latency (ms) FZ 390.579/53.65 392.729/80.88 0.098 0.922

CZ 389.899/52.56 398.089/74.08 0.400 0.692

C3 393.769/52.99 393.769/71.67 0.199 0.843

C4 394.779/53.34 394.949/76.32 0.008 0.994

PZ 390.559/52.74 400.979/74.77 0.505 0.617

P300 amplitude (mv) FZ 7.889/4.08 5.379/3.16 2.145 0.039*

CZ 8.889/4.06 5.259/3.70 2.905 0.006*

C3 8.559/4.13 5.039/3.56 2.843 0.007*

C4 7.559/4.02 3.849/3.45 3.085 0.004*

PZ 10.769/4.21 7.859/3.11 2.440 0.020*


94 Zhu Yan et al.

The topographic maps from individuals of each

group were superimposed to create a grand mean

group map by group average (Neuroscan). In the

control group, the P300 electric potential diffusion

contour lines formed concentric and symmetric

circles centred around the midline, and the P300

maxima were located along the midline at the

parietal-occipital region. In theTS�/ADHD and

TS�/ADHD groups, P300 spread out in a more

irregular fashion. In general, P300 in the TS�/

ADHD group tended to spread out to the left and

that of the TS�/ADHD group tended to spread out

to the right (Figures 2�/6).

Discussion

P300 evoked potential is a positive component that

appears approximately at 300 ms post-event. Also

known as cognitive potential, P300 is one of the

means to study the reception and cognitive proces-

sing of information by the human brain, an integral

part related to higher brain functions such as

attention, memory, judgment and abstract thinking.

The usual interpretation of P300 latency is that it is a

measure of stimulus classification speed. In this

context, it is important to note that P300 latency is

correlated negatively with mental function in normal

subjects, such that shorter latencies are related to

superior cognitive performance, a view that is con-

sistent with the observation that P300 latency

increases systematically as cognitive capability

decreases because of dementing illness. It is reason-

able to conclude that individual differences in P300

values obtained from a simple stimulus discrimina-

tion task provide a reliable indication of individual

variability in neuroelectric processing capability and

speed (Polich and Kok 1995; Oades et al. 1996).

Simply put, prolonged latency and decreased ampli-

tude in P300 reflect slowdown in information

processing and decreased energetic resources. Stu-

dies showed TS children had developmental delay

(e.g., Pennington and Ozonoff 1996; Palumbo et al.

1997; Bradshaw and Sheppard 2000). This refers to

a delay in the establishment of communications

between different structures rather than a delay in

maturation of the structures themselves (e.g., Polich

and Herbst 2000).

Our study showed that the TS�/ADHD children

had significantly shorted P300 latencies than the

control group, but the TS�/ADHD group did not

show this difference. The TS�/ADHD children also

had shorted P300 latencies than the TS�/ADHD at

CZ and PZ. The TS�/ADHD children showed

significantly decreased amplitudes than the control

group, but this was not seen in the TS�/ADHD

group. The TS�/ADHD children had smaller P300

Table IV. Comparison of P300 latencies and amplitudes between TS�/ADHD and control groups.

Characteristic Electrode site Control (N�/20) TS�/ADHD (N�/15) t P

P300 latency (ms) FZ 390.579/53.65 349.239/50.10 2.319 0.027*

CZ 389.899/52.56 349.259/51.80 2.227 0.029*

C3 393.769/52.99 347.449/52.60 2.567 0.015*

C4 394.779/53.34 359.749/65.23 1.748 0.090*

PZ 390.559/52.74 346.069/52.86 2.467 0.019*

P300 amplitude (mv) FZ 7.889/4.08 6.089/1.14 1.253 0.219

CZ 8.889/4.06 7.909/0.72 0.795 0.433

C3 8.559/4.13 6.549/1.10 1.411 0.168

C4 7.559/4.02 5.889/0.87 1.300 0.203

PZ 10.769/4.21 7.999/0.71 2.217 0.034*


Table V. Comparison of P300 latencies and amplitudes between TS�/ADHD and TS-ADHD groups.

Characteristic Electrode site TS�/ADHD (N�/19) TS�/ADHD (N�/15) t P

P300 latency (ms) FZ 392.729/80.88 349.239/50.10 1.821 0.078

CZ 398.089/74.08 349.259/51.80 2.166 0.038*

C3 393.769/71.67 347.449/52.60 1.913 0.065

C4 394.949/76.32 359.749/65.23 1.422 0.165

PZ 400.979/74.77 346.069/52.86 2.406 0.022*

P300 amplitude (mv) FZ 5.379/3.16 6.089/1.14 0.546 0.589

CZ 5.259/3.70 7.909/0.72 2.305 0.028*

C3 5.039/3.56 6.549/1.10 1.125 0.269

C4 3.849/3.45 5.889/0.87 1.727 0.094

PZ 7.859/3.11 7.999/0.71 0.129 0.090



amplitudes than the TS�/ADHD at Cz, These

results suggested that TS�/ADHD children had

faster information processing, and TS�/ADHD chil-

dren had decreased energetic resources according to

previous studies (e.g., Polich and Kok 1995). This

suggested that there may be functional differences

between the subgroups of these TS children.

Decreased P300 amplitude is often observed in

attention deficits (e.g., Posner and Petersen 1990;

Hansenne 2000). It was interesting that our study

found that TS�/ADHD children showed significantly

decreased P300 amplitude at CZ, C3, C4, PZ when

compared with controls. This results indicated there

maybe still have another unclear biology cause of

decreased amplitude, or suggested that attention

deficit was not the only cause of decreased amplitude

at least in TS children.

Cortical generators of P300 may include the

hippocampus, parahippocampal gyrus and the

amygdala, and different neurotransmitter substances

such as the cholinergic and the serotoninergic

systems and their radiations may also be involved.

Functional impairment in any of these structures

may affect P300 waveform (e.g., Posner and Peter-

sen 1990). Our study found no significant difference

in P300 waveforms between the TS and control

groups, TS�/ADHD and control groups, TS�/

ADHD and control groups and TS�/ADHD and

TS�/ADHD groups. This suggested that the TS

(including both TS�/ADHD and TS�/ADHD) only

suffer mild developmental defects or delays in

different brain structures. It is worth noting that

the TS�/ADHD group showed a tendency for more

alterations in P300 waveforms than the TS only

group, although this has not reached a statistically

significant level.

Developmental defects or functional impairment

in communications between different structures of

the brain may cause alteration in topographic

distribution of P300 potentials (e.g., Polich and

Herbst 2000). In this study, the control, TS�/

ADHD and TS�/ADHD groups showed differences

in P300 distribution in multiple regions. The P300

electric potential diffusion contour lines formed

concentric and symmetric circles centred around

the midline in the control group. However, the TS�/

ADHD and TS�/ADHD groups showed laterality of

Table VI. The probabilities of irregular P300 waveforms in control and TS groups.

Waveform Control (N�/20) TS (N�/34) TS�/ADHD (N�/19) TS�/ADHD (N�/15)

Irregular 7 12 4 8

Regular 13 22 15 7

% Irregular 35.0 35.3 21.1 53.3

Table VII. The probabilities of topography alterations of P300 in control and TS groups.

Topography Control (N�/20) TS (N�/34) TS�/ADHD (N�/19) TS�/ADHD (N�/15)

Irregular 7 26 12 14

Regular 13 8 7 1

% Irregular 35.0 76.5 63.5 100.0

Figure 1. The P300 waveforms from individuals of each group

were superimposed by group average at Fz.


were superimposed by group average at Pz.

96 Zhu Yan et al.

P300 electric potential diffusion. The mean peak

waves tended to show left lateralization in the TS�/

ADHD group and right lateralization in the TS�/

ADHD group. Posner and Petersen (1990) sug-

gested that the right hemisphere is important for

maintenance of a state of alertness and for sustained

attention. Important contributions to information

processing from the right hemisphere may be miss-

ing if right hemisphere function is impaired. As a

consequence, the remaining representation of these

components is recorded from the midline or the left

hemisphere (e.g., Posner and Petersen 1990). Our

study provided evidence to support this hypothesis.

In addition, we found that the origin of P300 was

much more variable in the TS�/ADHD group,

suggesting that there may be more widespread delay

in neural maturation and a more fundamental and

long-lasting functional impairment of communica-

tions between different structures in the TS�/

ADHD group (e.g., Polich and Herbst 2000). It is

interesting that this seemed to be consistent with the

clinical observation that TS�/ADHD patients are

associated with increased prevalence of psychiatric

problems and ADHD is predictive of increased

morbidity and poor outcome (e.g., Harris et al.

1995; Sherman et al. 1998; Stephens and Sandor

1999; Carter et al. 2000; Mostofsky et al. 2001;

Brand et al. 2002; Mahone et al. 2002; Sukhodolsky

et al. 2003). It is also interesting that this seemed to

be consistent with genetic study findings that

ADHD is a polygenic disorder due to the additive

effect of genes affecting dopamine, norepinephrine,

serotonin, GABA, and other neurotransmitters,

while TS is mainly a dopaminergic disorder (e.g.,

Comings 2001; Riederer et al. 2002).

In summary, despite the lack of clinical specificity,

this study has found that there are differences in

P300 between TS children and normal subjects, and

suggested that there may be mild neurological

developmental defects or delay in TS children. We

also found differences in P300 between TS children

with and without ADHD. This suggested that

establishment different development defects or delay

Figure 6. The topographic maps from individuals of each group

were superimposed.


were superimposed by group average at C4.Figure 3. The P300 waveforms from individuals of each group

were superimposed by group average at Cz.


were superimposed by group average at C3.


of communications between different structures,

rather than a delay in maturation of the structures

themselves, may be involved in TS�/ADHD and

TS�/ADHD children, and that ADHD symptoms in

TS patients are likely a trait rather than adventitious

or acquired within the TS syndrome. While altera-

tion of P300 amplitude or latency is indicative of

impaired cognitive efficiency in general, the changes

are non-specific and can be associated with a wide

range of brain disorders affect the fundamental

cognitive operations. More detailed studies of P300

neuropsychological origins are needed in future

studies.


This study was supported by the National Natural

Science and Technology Fund of China (30300118).

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98 Zhu Yan et al.

SUMMARY OF ORIGINAL RESEARCH

Three-dimensional models of neurotransmitter transporters and theirinteractions with cocaine and S-citalopram

AINA WESTRHEIM RAVNA

Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway

AbstractDrugs that act on the human serotonin transporter (hSERT), human dopamine transporter (hDAT) and humannoradrenaline transporter (hNET) are important in antidepressant treatment and well known in drug abuse. Theinvestigation of their molecular mechanisms of action is very useful for designing new ligands with a therapeutic potential.The detailed three-dimensional molecular structure of any monoamine transporter is not known, but the three-dimensionalelectron density projection map of Escherichia coli Na�/H� antiporter (NhaA) has provided structural basis forconstructing models of such transporters using molecular modelling techniques. Three-dimensional models of thesedrug targets give insight into their structure, mechanisms and drug interactions. In these molecular modelling studies, anEscherichia coli NhaA model was first constructed based on its three-dimensional electron density projection map andexperimental studies on NhaA and the Escherichia coli lactose permease symporter (Lac permease). Then three-dimensionalmodels of the neurotransmitter transporters hDAT, hSERT and hNET were constructed based on the NhaA model andstudies of ligand binding to mutated dopamine transporter (DAT) and serotonin transporter (SERT). The structuralproperties of these neurotransmitter transporter models have been examined, and their interactions with cocaine and S -citalopram have been investigated.

Key words: Three-dimensional structure, molecular modelling, S-citalopram, cocaine, secondary transporter

Introduction

The science of pharmacology seeks to identify

interactions of drugs with various drug targets, and

to understand the biochemical and physiological

effects of drugs. The molecular interactions between

drugs and their targets in the human body can be

investigated using molecular modelling techniques.

The interactions seen in drug�/target complexes can

lead to understanding of the intermolecular forces

determining the specificity and the potency of the

drug. Such knowledge is important for structure-

aided drug design, where novel drugs are designed

based on information from three-dimensional mod-

els of drug target proteins.

Advances in crystallography, providing experi-

mental three-dimensional structures, have increased

relevant structural information for making molecular

models of drug targets. A model of a drug target with

an unknown three-dimensional structure may also

be constructed based on the X-ray structure of a

homologous protein by homology modelling.

Homology between two proteins indicates the pre-

sence of similar features because of a common

ancestor. Sequence similarity of the functional parts

of two proteins indicates that these two proteins have

homologous fold, but since their amino acid com-

position in the binding site area may differ from each

other, two homologous proteins may bind different

drugs. However, if no detailed structural informa-

tion about the drug target protein or homologous

proteins is available, information from ligand bind-

ing studies and indirect structural knowledge from

experimental studies may be used as a guideline for

making a molecular model of the drug target.

Most drug targets are membrane proteins. In

general, X-ray crystallography and nuclear magnetic

resonance (NMR) techniques are used for structural

determination of proteins at an atomic resolution,

but making crystals of membrane proteins is techni-

cally difficult, and molecular modelling may be used

as a step forward towards structural knowledge of

drug targets when no experimental structure is

available. However, very few three-dimensional

Correspondence: Dr Aina Westrheim Ravna, Department of Pharmacology, IMB, University of Tromsø, NO-9037 Tromsø, Norway.

Tel: +47 7764 4706. Fax: +47 7764 5310. E-mail: [email protected]


(Received 21 March 2005; accepted 6 October 2005)


DOI: 10.1080/15622970500402144

structures of membrane proteins have been experi-

mentally determined with a quality good enough for

traditional homology modelling.

When the transporter modelling studies described

in this paper (Ravna et al. 2001, 2003a,b) were

performed, only four high-resolution three-dimen-

sional structures of transporters had been reported

from X-ray crystallographic studies, namely the

Escherichia coli multidrug efflux transporter Acri-

flavine resistance protein B (AcrB) (Murakami et al.

2002), the Escherichia coli lipid flippase Lipid A

export ATP-binding/permease protein (MsbA)

(Chang and Roth 2001), the Escherichia coli vitamin

B12 transporter BtuCD (Locher et al. 2002), and

the calcium ATPase SERCA1a, which is localised in

skeletal muscle sarcoplasmatic reticulum

(Toyoshima et al. 2000). However, none of these

transporters were regarded as suitable templates for

modelling neurotransmitter transporters. When our

papers describing the neurotransmitter transporter

modelling were in press (Ravna et al. 2003a,b), a

breakthrough happened regarding secondary trans-

porter structures. X-ray structures of two different

secondary transporters were published; the Escher-

ichia coli lactose permease symporter (Lac per-

mease) (Abramson et al. 2003) and the Escherichia

coli glycerol-3-phosphate transporter (GlpT)

(Huang et al. 2003). When the molecular modelling

studies (Ravna et al. 2001, 2003a,b) described in

this article were performed, the most detailed

structure information about secondary transporter

protein structure was the three-dimensional electron

density projection map of the Escherichia coli

NhaA, determined by electron cryo-microscopy

(Williams 2000).

Secondary transporters

Secondary transporters are ion-coupled membrane

transport proteins that include a diverse group of

proteins, like the sodium:neurotransmitter sympor-

ter family (SNF) transporters for dopamine, nora-

drenaline and serotonin, glucose transporters, the

Na�/H� antiporter (NhaA) and the Lac permease.

Secondary transporter proteins carry small mole-

cules across cell membranes against a concentration

gradient using ion gradients as energy source, thus

facilitating solute accumulation and toxin removal.

Most secondary transporters are predicted to

have 12 transmembrane alpha-helices (TMHs)

with amino and carboxy terminals localised intra-

cellularly (Figure 1) (Reizer et al. 1994; Rothman

et al. 1996; Kaback and Wu 1997; Williams 2000).

In August 2003, the X-ray structures of the

major facilitator superfamily (MFS) transporters

Lac permease (Abramson et al. 2003) and GlpT

(Huang et al. 2003) were reported, giving a more

detailed insight into the three-dimensional structure

of secondary transporters. This has provided an

experimental basis for molecular modelling of sec-

ondary transporters, including the serotonin trans-

porter (SERT), the noradrenaline transporter

(NET), and the dopamine transporter (DAT), based

on the hypothesis that the 12TMH secondary

transporters might belong to a common folding

class.

NhaA

The NhaAs have a central role in maintaining the

circulation of H� and Na� of prokaryotic and

eukaryotic cells. The transporters contribute to the

pH and Na� homeostasis of cells, and in Escherichia

coli it regulates the internal pH at the alkaline pH

range (Padan et al. 1993; Padan and Schuldiner

1994; Padan and Schuldiner 1999).

The sub-cellular location of the Escherichia coli

NhaA is in the bacterial inner membrane. The

antiporter uses the inwardly directed H� electro-

chemical gradient to expel Na� from the cytoplasm

(Taglicht et al. 1991; Padan et al. 1999), with a

stoichiometry of two H� ions per Na� ion.

The activity (Vmax) of NhaA may vary by three

orders of magnitude in the pH range between 7 and

8.5 (Taglicht et al. 1991; Padan et al. 1999). A pH

shift from 7 to 8.5 induces a conformational change

in the protein structure increasing its activity (Pinner

et al. 1995; Padan et al. 1999). High pH sensitivity is

characteristic of transporters involved in pH regula-

tion (Padan et al. 1999).

NhaA crystallises as a dimer (Williams 2000), and

biochemical studies has shown that it also may exist

as an oligomer in the membrane, although it is

unclear whether dimerisation is required for NhaA

monomer function (Gerchman et al. 2001).

SNF and neurotransmitter modulation

The sequence identity within the SNF family is 40�/

90% (Reizer et al. 1994), and the family includes the

transporter molecules for the monoamines seroto-

nin, dopamine and noradrenaline. Monoamine

transporter function and expression is regulated by

Figure 1. Proposed topology of ion-coupled transporters: 12

TMHs.

100 A. Westrheim Ravna

several kinase and phosphatase pathways including

Protein kinase C (PKC) cascades (Jess et al. 2002;

Lin et al. 2003). Experimental studies have indicated

that SERT (Chang et al. 1998; Kilic and Rudnick

2000) and DAT (Hastrup et al. 2001; Torres et al.

2003) may exist as oligomers, but it is unclear

whether oligomerisation has a functional role.

The SNF proteins act as co-transporters of

sodium and chloride ions, and of transmitter mole-

cules (Barker and Blakely 1995) (Figure 2). The

energy for the inward movement of the transmitter

molecules is provided by the sodium gradient across

the cell membrane. Thus the action of the neuro-

transmitter is regulated.

SERT and antidepressant therapy

In the central nervous system (CNS) serotonergic

neurons occur in the pons and medulla (raphe

nuclei), projecting to the cortex, limbic system,

hypothalamus and spinal cord. The serotonergic

pathways in the brain are associated with mood

and emotion, sleep and wakefulness, sensory path-

ways (including nociception), hallucinations, body

temperature, feeding behaviour and vomiting

(Barnes and Sharp 1999).

According to the monoamine theory of depres-

sion, proposed in 1965, depression results from

functionally deficient transmission of serotonin and

noradrenaline in the CNS (Schildkraut 1965). This

theory was based on the observation that antide-

pressant drugs such as tricyclic antidepressants

(TCA) and monoamine oxidase inhibitors (MAOI)

facilitate monoaminergic transmission, but other

pharmacological evidence fails to support this the-

ory. Newer and more complex theories are currently

replacing this theory, and it has been suggested that

mood disorders are associated with impairments of

structural plasticity in the CNS (Manji and Duman

2001). However, the monoamine theory of depres-

sion currently remains a good basis for understand-

ing the action of antidepressants.

SERT is a membrane protein with 630 amino

acids (Ramamoorthy et al. 1993). The class of

antidepressant drugs termed selective serotonin

reuptake inhibitors (SSRIs) elevates the concentra-

tion of serotonin at the synapse by binding to SERT

thus inhibiting presynaptic reuptake of serotonin. In

addition to their antidepressant action, SSRIs are

also prescribed for treatment of obsessive-compul-

sive disorder, panic disorder, bulimia (Stahl 1998)

and pre-menstrual dysphoric disorder (Lin and

Thompson 2001). Inhibition of serotonin reuptake

is achieved rapidly in vitro , but improvement of

mood occurs after 2�/3 weeks of antidepressant

therapy. Long-term exposure of SERT to citalopram

results in down-regulation of the SERT protein at

the expression level (Horschitz et al. 2001).

Both therapeutic drugs, such as TCA, and drugs

of abuse, such as cocaine, bind to SERT and inhibit

serotonin reuptake. Ligand binding studies have

indicated more than one binding site at SERT, and

that cocaine and citalopram bind to the same site

and inhibit serotonin reuptake competitively. Parox-

etine seems to inhibit reuptake by allosteric modula-

tion (Akunne et al. 1992; Boja et al. 1994; Hyttel

1994; Sur et al. 1998; Barker et al. 1999).

DAT- and cocaine-induced reward

There are three main dopaminergic pathways in the

brain, the nigrostriatal pathway involved in motor

control, the mesolimbic/mesocortical pathway in-

volved in emotion- and drug-induced reward sys-

tems, and the tuberohypophyseal neurons involved

in regulation of secretions from pituitary gland. The

reward system, which is linked to drug abuse, starts

at the ventral tegmental area, follows the neuron to

the nucleus accumbens, and then on to the pre-

frontal cortex. The reward system gets activated

when a person receives positive reinforcement for

certain behaviours, which can be both natural

rewards and artificial rewards such as addictive

drugs (Bardo 1998).

DAT is an integral membrane protein with 620

amino acids (Giros et al. 1992). It terminates the

action of dopamine by reuptake of the neurotrans-

mitter into presynaptic neurons, and plays a key role

in neuronal dopamine recycling (Uhl et al. 1998).

When cocaine binds to DAT, the dopamine con-

centration is elevated, resulting in a ‘‘reward’’. The

rewarding properties of cocaine are largely due to its

inhibition of DAT on terminals of mesolimbic-

mesocortical dopaminergic neurons (Uhl et al.

1998), but SERT and NET inhibition also contri-

bute to cocaine reward and cocaine aversion (Hall

et al. 2002; Uhl et al. 2002).

NET and noradrenaline

The cell bodies of noradrenergic neurons are loca-

lised in the pons and medulla. Their axons project toFigure 2. Molecular mechanism of SERT. Transport of serotonin

mediated by inward directed sodium gradient.

Neurotransmitter transporters and cocaine and S-citalopram 101

the cerebral cortex, limbic system, hypothalamus,

cerebellum and the spinal cord. The noradrenergic

neurons are believed to participate in the reward

system, mood, arousal, blood pressure and neuroen-

docrine regulation. A functional deficiency in nora-

drenergic transmission may result in depression.

Drugs that act on the noradrenergic transmission

in the CNS include cocaine, amphetamines, anti-

depressants and some antihypertensive drugs (clo-

nidine, methyldopa).

Therapeutic drugs versus drugs of abuse

Although cocaine and SSRIs share similar molecular

mechanisms of action, cocaine is a highly addictive

drug and SSRIs are therapeutic drugs prescribed for

the treatment of depression. While the purpose of

investigating the molecular interactions of SSRIs

may be to design novel antidepressants with fewer

side effects than the existing ones, the investigation

of cocaine’s molecular interactions may aid to

develop blockers of the binding of cocaine to DAT

without inhibiting the reuptake of dopamine. Such

blockers might be effective in the treatment of

cocaine addiction.

SERT, DAT and NET binding sites

The ligand binding sites of SERT, DAT and NET

probably have a core area for cocaine binding in

common, since cocaine has similar affinities for all

three transporters. Binding studies of SSRIs show

that they are from 300 to 3500 times more selective

towards SERT over NET, and generally have low

affinity for DAT (Tatsumi et al. 1997). This in-

dicates differences in their binding areas that can be

investigated by comparing putative binding modes of

cocaine and S-citalopram in molecular modelling

studies. Both ligands block transmitter reuptake

competitively, and while cocaine is non-selective,

S-citalopram is a selective SERT inhibitor (Barker

and Blakely 1995).

Molecular modelling

Physical and chemical properties of molecules and

interactions between molecules are easier to under-

stand when the molecular structures are constructed

and visualised in three-dimensional models. A tool

for investigating psychotropic drug interactions with

their targets in the CNS is molecular modelling.

Molecular modelling is the generation, manipula-

tion and representation of three-dimensional mole-

cular structures and associated physical, chemical,

biological and pharmacological properties. Molecu-

lar models may be constructed in order to examine

three-dimensional structure and function of CNS

drug targets.

General tools for molecular modelling of mem-

brane proteins are amino acid sequence alignments

and predictions of start- and endpoints of TMHs,

interactive computer graphics and calculations. Ex-

perimental data are implemented in order to gen-

erate realistic molecular models. The modelling

approach may be based on a protein homologue

with a known three-dimensional structure, or, as in

the molecular modelling studies reviewed in this

paper (Ravna et al. 2001, 2003a,b), based on

structural analysis of low-resolution structural data

and site-directed mutagenesis studies.

Molecular modelling comprises both molecular

mechanics and quantum mechanics. Molecular

mechanics is used for calculations concerning

atomic nuclei, while quantum mechanics is used

for calculations concerning electronic system. In

molecular mechanics the atomic structure of a

molecule is considered to be a collection of atomic

masses that interact with each other via harmonic

forces. Molecular mechanics calculations are per-

formed by equations based on Newton’s Classical

Mechanics. The Born�/Oppenheimer approxima-

tion, which states that atomic nuclei move much

slower than electrons, so the vibrational and rota-

tional motions of a molecule can be separated from

the electronic motion, forms the basis of using

classical mechanics for these calculations.

Molecular mechanics calculations include energy

minimisation and molecular dynamics (MD) calcu-

lations. Energy minimisation is the calculation of the

lowest energy conformation of a molecule. The

reason for calculating the low-energy molecular

conformation is based on The Laws of Thermo-

dynamics, which state that molecules seek the lowest

potential energy spontaneously. MD is the simula-

tion of molecular motion during a short period of

time.

In the design of hypotheses regarding the patho-

physiology of affective disorders, molecular

mechanics calculations may be used in the construc-

tion of putative neurotransmitter transporter mod-

els. Such models may be helpful for understanding

the mechanism of molecular interactions between

psychotropic drugs and their CNS targets. In addi-

tion, genetic variants of neurotransmitter transpor-

ters can be modelled, and their possible structural

differences from wild type transporters can be

investigated.

Quantum mechanics enable the calculation of the

energy of an electronic system. Thus geometries

and structures of small molecules can be predicted,

but protein molecules are too big to be solved by

the Schrodinger equation (HC�/EC). Quantum


mechanics is useful for calculation of electrostatic

potentials (ESP) of small molecules.

Molecular modelling and structure-aided drug

design

When information about the three-dimensional

structure of a drug and drug target, and the drug�/

target complexation, is investigated using molecular

modelling techniques, it might be possible to under-

stand the intermolecular forces determining

the specificity and potency of their interaction.

The investigation of the drug�/target interaction at

the molecular level may also give insight into the

structural changes of both the drug and the drug

target for adopting an energetically favourable com-

plex. The obtained information may be used to

predict how a designed drug will fit into the target.

Eventually, new chemical compounds with fewer

side effects may be designed to act as drugs.

Transporter modelling as a working tool for

further studies

The models presented in this paper are mainly

considered as working tools for generating hypoth-

eses and designing further experimental studies

related to secondary transporter structure and func-

tion and their ligand interactions. Site-directed

mutagenesis studies and transporter modelling are

complementary to each other in an iterating process

towards a better understanding of the structure and

function of these proteins. As illustrated in Figure 3,

the construction of these transporter models, dock-

ing of ligand molecules into their putative binding

site and identifying amino acids in the model

interacting with the ligand will aid the selection of

amino acids for further site-directed mutagenesis

studies. If the observations of ligand binding affi-

nities made in the experimental observations are in

accordance with the effects proposed by the model-

ling study, the transporter model may be partly

correct. If not, an adjustment of the model must be

performed. Thus, experimental studies based on

assumptions made from the models may be useful

for further model refinements.

Molecular modelling and falsificationism

Falsificationism, a philosophy of science introduced

by Karl Popper, has the key idea that scientific

theories are falsifiable (Chalmers 2002). Theories

are construed as speculative and tentative conjec-

tures, and the science progresses by trial and

error. According to Popper, science starts with

problems, and, as solution to the problem, falsifiable

hypotheses are proposed by scientists. The hypoth-

eses are then criticised and tested. If the result does

not support the hypothesis, the hypothesis must be

adjusted or eliminated, and if the hypothesis is

validated, it must be subject to even more stringent

criticism and testing. Figure 4 shows the transporter

modelling process viewed from a falsificationistic

point of view. The scientific problem is the three-

dimensional structure of the transporters. A mole-

cular model of the transporter is constructed as a

hypothesis. Ligands are docked into the putative

binding site of the model, and logical predictions are

deducted from the hypothesis by suggesting amino

acids that may be involved ligand binding. Then the

hypothesis is tested experimentally by making single

point mutations in the transporters and testing

ligand binding affinities.

Construction of models

NhaA

A three-dimensional molecular model of the NhaA

was constructed (Figure 5a), using interactive mo-

lecular graphics and energy calculations (Ravna et al.

2001). The model was based on a three-dimensional

Figure 3. Transporter modelling procedure.


electron density projection map of the ion-coupled

membrane protein Escherichia coli NhaA (Williams

2000). Information from biophysical studies deter-

mining the assignment of the 12 TMHs and site-

directed mutagenesis studies of NhaA and Lac

permease were also important for model building

(Gerchman et al. 1993; Inoue et al. 1995; Kaback

and Wu 1997; Kuroda et al. 1997; Noumi et al.

1997; Olami et al. 1997; Gerchman et al. 1999;

Rimon et al. 1998). As indicated by the model

(Figure 5b), a pore was constituted by TMHs 1, 2,

3, 4, 5, 7, 8, 11 and 12. The pore may be the ion

translocation area, and it may be possible for ligands

to inhibit transport by binding to this pore area. The

loop between TMH4 and TMH5, located in the

cytoplasm, divided the pore area into two possible

translocation areas.

The modelling study suggested that the pH-

dependent activity of NhaA might be explained by

charge changes in the intracellular loop between

TMH8 and TMH9. When pH is increased, the

positively charged amino acids within the loop may

be neutralised thus leading to conformational

changes in the transporter protein. In the model,

conformational changes in this loop were seen after

180 ps of MD simulation. Such conformational

changes may alter the positions of TMHs 4, 5 and

11 relative to each other, such that a pore area of the

transporter protein is opened (Ravna et al. 2001).

DAT, SERT and NET

Three-dimensional models of DAT (Ravna et al.

2003b), SERT and NET (Ravna et al. 2003a) were

constructed based on the three-dimensional NhaA

model (Ravna et al. 2001) and site-directed muta-

genesis data on DAT and SERT (Kitayama et al.

1992; Kitayama et al. 1996; Chen et al. 1997; Barker

et al. 1998, 1999; Mitsuhata et al. 1998; Lee et al.

1999; Lin et al. 2000). The SERT model is shown in

Figure 6.

The S-citalopram and cocaine molecules were

docked into the putative ligand binding areas of the

SERT, NET and DAT models. The docking indi-

cated that the four most important residues for

ligand interaction were the conserved amino acids

Asp-98 (TMH1), Tyr-267 (TMH4) and Tyr-289

(TMH5) in SERT (Figure 7), which correspond to

Figure 4. Transporter modelling procedure and falsificationism.

Figure 5. Energy refined NhaA model. (A) Ca traces of the entire

structure, viewed in the membrane plane. The upper side is the

periplasmic side. (B) Ca traces of the TMHs, viewed from the

periplasmic side.


Asp-79, Tyr-252 and Tyr-274 in DAT, and Asp-75,

Tyr-249 and Tyr-271 in NET.

The nitrile group of S-citalopram interacted with

Tyr-95 in SERT. The docking of S-citalopram into

the binding areas of NET and DAT indicated that

the nitrile group of S-citalopram interacted with a

phenylalanine instead of a tyrosine. The amino acids

corresponding to Tyr-95 in SERT are Phe-76 in

DAT and Phe-72 in NET. Thus, it was hypothesised

that Tyr-95 may play a role in S-citalopram’s

selectivity to SERT (Ravna et al. 2003a). This may

explain why S-citalopram has a 3500 times higher

affinity to SERT than to NET (Tatsumi et al. 1997).

The role of Tyr-95 in the selective binding of

S-citalopram to SERT has also been demonstrated

by mutating this residue to a phenylalanine (Barker

et al. 1998).

Validity of three-dimensional secondary

transporter models

In the modelling of three-dimensional secondary

transporters reviewed in the present paper (Ravna et

al. 2001, 2003a,b), no suitable X-ray structure was

available as a template. Therefore, there are more

uncertainties than in traditional homology modelling

with available structural templates, and the results

must also be considered with that in mind.

The helical arrangement of the NhaA model was

based on the electron density projection map of the

Escherichia coli NhaA (Williams 2000). However,

the helical arrangement (Figure 5b) could not be

determined from the projection map, and was based

on site-directed mutagenesis studies on NhaA and

site-directed biophysical studies on Lac permease

(Ravna et al. 2001). The packing arrangement of

TMHs 7, 8, 9, 10 and 11 relative to each other was

derived from Lac permease studies (Kaback and Wu

1997). Furthermore, studies of Lac permease sug-

gest that TMH5 should be adjacent to TMH8

(Kaback and Wu 1997), while studies of NhaA

indicated that TMH4 should be adjacent to TMH11

(Rimon et al. 1998). TMH12 was placed adjacent to

TMH11 due to the short loop between these TMHs,

and the localisation chosen for TMH6 accounts for

the short loop between TMH6 and TMH7 on the

cytoplasmic side where these two TMHs are tilted

towards each other. TMHs 1, 2 and 3 were placed

based on site-directed mutagenesis studies on DAT

and SERT, assuming these TMHs may be a part of a

ligand binding site. In the model, TMH1 has limited

contact with the membrane in accordance with the

hydrophilic character of this segment. TMHs 1, 2, 3,

4, 5, 7, 8, 11 and 12 form a pore area (Figure 5b)

that may be separated into two translocation path-

ways by loop 4�/5 on the cytoplasmic side.

The DAT (Ravna et al. 2003b), SERT and NET

models (Ravna et al. 2003a) were based on the

TMH arrangement of the NhaA model. In these

models the positions of TMH2 and TMH3 were

interchanged compared with the NhaA model in

order to obtain the interactions of TMH3 with

cocaine and (�/)-2b-carbomethoxy-3b-(4-fluoro-

phenyl)tropane (CFT), as suggested by site-directed

mutagenesis data (Chen et al. 1997; Lee et al. 2000).

The positions of TMH2 and TMH3 were the most

uncertain parts of the helix arrangement of the

NhaA model.

There are several uncertainties in the TMH arra-

ngement suggested the models in these modelling

Figure 6. Energy refined SERT model (Ca traces) viewed in the

membrane plane. The upper side is the extracellular side.

Figure 7. S -Citalopram docked into SERT. Amino acids impor-

tant for ligand binding are displayed in the figure (Asp-98

(TMH1), Tyr-267 (TMH4) and Tyr-289 (TMH5)).


studies (Ravna et al. 2001, 2003a,b). It remains to

be firmly proven that the proteins within the group

of secondary transporters share a common folding

motif. Even though their functional mechanism

using an ion gradient as energy source for transloca-

tion of molecules across membranes is common

within the group, some of the transporters, like

NhaA, are antiporters, while others, like Lac per-

mease, DAT and SERT, are symporters. The type of

ions and substrates also differs among these trans-

porters. The low sequence identity within the

transmembrane regions between NhaA and the

SNF proteins SERT, DAT and NET, which is 8�/

11%, may argue against using NhaA as a template

for reliable comparative modelling. However, the use

of bacteriorhodopsin as a template in early molecular

models of G protein-coupled receptors (GPCRs)

(Dahl et al. 1991; Hibert et al. 1991), where the

sequence identity within the transmembrane regions

is 6�/11% (Hibert et al. 1991), was later confirmed

by the X-ray structure of the GPCR rhodopsin

(Palczewski et al. 2000) to be a reasonable approach

for the initial models of GPCRs. Despite the low

sequence identity, bacteriorhodopsin and GPCRs

share a similar overall three-dimensional folding

pattern with seven TMHs.

Several X-ray structures of 12 TMH transporters

were not regarded as suitable templates for DAT,

mainly due to differing functional mechanisms. The

X-ray structure of the Escherichia coli MsbA, which

belongs to the multidrug resistance ATP-binding

cassette (ABC) transporters (Chang and Roth

2001), was not considered as a suitable template

for the present modelling due to relative large

differences in functional mechanisms between the

SNF transporters and the MsbA. The crystal

structure of the bacterial multidrug efflux transpor-

ter AcrB (Murakami et al. 2002) was also considered

as not suitable as a template since the TMH

arrangement of AcrB does not fit with site-directed

mutagenesis data on DAT and SERT (Ravna et al.

2003b). These data suggest that TMH1 and TMH7

are involved in ligand binding, and this does not

seem possible with the AcrB helical arrangement.

AcrB is organised as a homotrimer, an organisation

that has not been suggested by experimental studies

for DAT and SERT. Furthermore, the AcrB protein

is part of an efflux system where it interacts with

other proteins as part of its mechanism, and has a

broad substrate specificity. The Escherichia coli

vitamin B12 transporter BtuCD (Locher et al.

2002) and the calcium ATPase SERCA1a

(Toyoshima et al. 2000) X-ray structures were not

considered as suitable templates due to the fact that

these transporters have 10 TMHs per domain.

Apparently, the NhaA electron density projection

map (Williams 2000) may have provided the best

available structural basis for molecular modelling of

SNF transporter proteins.

The TMH arrangements of the models (Ravna

et al. 2001, 2003a,b) were guided by site-directed

mutagenesis studies. The interpretation of site-

directed mutagenesis studies is, in general, not

unambiguous. The observed effects of mutations

on binding may be due to direct disruption of side

chain�/ligand interactions, or it may be due to other

structural changes in the protein affecting the bind-

ing site and the ligand binding indirectly. The

present models are based on indirect structural

information, and there are always possibilities of

incorrect interpretation of the data, both by mod-

ellers and those carrying out the experimental

studies. Description of experimental conditions

should be accurate in order to avoid misinterpreta-

tion of data. Clearly, the interpretation of literature

data may induce considerable levels of uncertainty of

the models.

Even though there is accordance between site-

directed mutagenesis data on cocaine binding to

mutated SERT and DAT and residues involved in

the binding site of the models, the overall architec-

tures of the models are uncertain. Focus was kept on

qualitative information derived from the models

rather than quantitative information such as ligand

binding energy. Lipid bilayer molecules and water

molecules were not included in the models due to

their relatively low level of accuracy.

Comparison with Lac permease X-ray

structures

In August 2003, the X-ray structures of the MFS

transporters Lac permease (Abramson et al. 2003)

and GlpT (Huang et al. 2003) were published. This

was a major contribution to knowledge of the

structure of secondary transporters, and it provided

a possibility to validate the hypothesis in these

modelling studies (Ravna et al. 2001, 2003a,b)

regarding transporter structure and function. As

shown in Figure 8, there is a striking resemblance

between the membrane spanning domains of the Lac

permease X-ray structure (Abramson et al. 2003)

and the NhaA model (Ravna et al. 2001; Dahl et al.

2004). This demonstrates that molecular modelling

studies such as those presented in this review may

give a reasonably good model of a membrane

protein, provided sufficient biochemical data are

available in addition to a low-resolution structure.

The main common features between the Lac

permease X-ray structure (Abramson et al. 2003)

and the NhaA model (Ravna et al. 2001) are the

architecture of TMHs 1�/6, and the putative binding


site consisting of TMHs 1, 2, 3, 4, 5, 7, 8 and 11.

The main discrepancies are the localisations of

TMH10 and TMH12. According to the Lac per-

mease X-ray structure, it seems that TMH10 is

probably involved in ligand binding, and that

TMH12 is not lining the translocation pathway.

Some differences between the two transporter struc-

tures should also be expected due to amino acid

sequence differences.

In spite of lacking a detailed template structure in

the molecular modelling studies presented here

(Ravna et al. 2001, 2003a,b), the similarities be-

tween the theoretical models and the X-ray struc-

tures indicate that these models can give a prediction

of ligand binding mechanisms. As a test for the

validity of our previous transporter models, the Lac

permease X-ray structure has been used as a

template to construct updated models of the human

serotonin transporter (hSERT), the human dopa-

mine transporter (hDAT) and the human noradre-

naline transporter (hNET) (Ravna et al., 2006).

However, it still remains to be proven whether

secondary transporters share a common architecture

Conclusions

Three-dimensional models of the neurotransmitter

transporters hDAT, hSERT and hNET (Ravna et al.

2003a,b) have been constructed based on the NhaA

model (Ravna et al. 2001) and studies of ligand

binding to mutated DAT and SERT. In lack of any

suitable X-ray structures when these molecular

modelling studies were performed, the NhaA elec-

tron density projection map (Williams 2000) was

used as a structural basis. The recent X-ray structure

of lac permease (Abramson et al. 2003) confirms the

hypothesis regarding secondary transporter ligand

binding and substrate translocation, supporting the

modelling approach used and the electron density

projection map as a basis for the modelling. This

indicates that molecular models based on low

resolution structural information may predict ligand

binding mechanisms and give new insight into the

structure and function of transporter proteins. The

neurotransmitter transporters hDAT, hSERT and

hNET models may represent useful tools in the

discovery more efficient new drugs with fewer side

effects for use in antidepressant therapy and in

treatment of cocaine addiction.

Acknowledgements

The author would like to thank Professor Svein

G. Dahl and Professor Ingebrigt Sylte for their

excellent guidance, encouragement and constructive

criticism.


The author has no conflict of interest with any



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VIEWPOINT

The problem of delusional ugliness: Is it really body dysmorphicdisorder?

LEONARDO F. FONTENELLE1, MAURO V. MENDLOWICZ2,3, JULIANA KALAF1 &

MARCIO VERSIANI1

1Anxiety and Depression Research Program, Institute of Psychiatry, Federal University of Rio de Janeiro (IPUB/UFRJ),

Rio de Janeiro, Brazil, 2Ethics Research Program, Institute of Psychiatry of the Federal University of Rio de Janeiro

(IPUB/UFRJ), Rio de Janeiro, Brazil, and 3Department of Psychiatry and Mental Health (MSM), Fluminense Federal

University, Brazil

Articles published in the Viewpoint section of this Journal may not meet the strict editorial and scientific standards that are

applied to major articles in The World Journal of Biological Psychiatry. In addition, the viewpoints expressed in these articles

do not necessarily represent those of the Editors or the Editorial Board.

AbstractCurrently, the DSM-IV allows individuals with dysmorphic delusions to be diagnosed with either delusional bodydysmorphic disorder (BDD) and delusional disorder, somatic type (DDST). However, given the growing acceptance of adimensional perspective in psychopathology, it is conceivable that future editions of the DSM may recommend theexclusion of the diagnosis of DDST whenever isolated dysmorphic delusions are present, arguing that the latter should beconsidered no more than a symptom of BDD. But is the concept of DDST condemned to extinction in favor of that ofdelusional BDD? While some studies suggest that non-delusional and delusional BDD/DDST may be indistinguishablefrom the clinical, neuroanatomical, and therapeutic perspectives, several facts support the utility of the DDST concept.Firstly, DDST is a wider construct than delusional BDD. Secondly, it is unclear whether DDST in general (as opposed todelusional BDD) belongs to the obsessive-compulsive spectrum. Thirdly, differential pharmacological response may not bean adequate criteria for blending non-delusional and delusional BDD/DDST. Fourthly, ‘‘delusional’’ BDD may not bedelusional at all. Finally, there is more about delusion than just an ‘‘extreme’’ conviction. Future studies are urgently neededin order to substantiate our judgement regarding the existence of diagnostic limits between delusional BDD and DDST withdysmorphic delusions.

Key words: Delusional disorder, body dysmorphic disorder, psychopathology

Introduction

It is beyond question that body dismorphic disorder

(BDD) is a severe mental disorder that can manifest

itself in the form of seriously life-threatening cases

that are associated with high levels of suicidality

(Phillips et al. 1993) and with severe (O’Sullivan

et al. 1999), sometimes bizarre (Fontenelle et al.

2002), self-injurious behaviors (Phillips et al. 1995).

Currently, the DSM-IV-TR (APA, 2000) allows

delusional BDD to be double-coded, i.e. individuals

with dysmorphic delusions may be diagnosed with

both BDD and delusional disorder, somatic type

(DDST). While double-coding is awkward, and has

the drawback of diagnosing the same syndrome as

two different disorders, it also reflects the possibility

that BDD’s delusional and non-delusional variants

may actually constitute the same disorder rather

than being distinct (Phillips 2004).

Given the increasing acceptance of a dimensional

perspective in psychopathology in general, it is

conceivable that future editions of the DSM may

recommend the exclusion of the diagnosis of DDST

whenever dysmorphic delusions are present, arguing

that the latter should be considered no more than a

symptom of BDD. But is there enough empirical

evidence to support such a bold diagnostic shift?

Correspondence: Dr Leonardo F. Fontenelle, Rua Lopes Trovao # 88, Apartment 1501, Bloco A, Icaraı, Niteroi, RJ, CEP: 24220-071,

Brazil. Tel: +55 21 2710 7857. Fax: +55 21 2710 5161. E-mail: [email protected]


(Received 22 April 2005; accepted 18 July 2005)


DOI: 10.1080/15622970500287420

Is the concept of DDST condemned to extinction

in favor of that of delusional BDD? We will

now briefly discuss arguments for and against this

suggestion:

For

1. Non-delusional and delusional BDD/DDST are

indistinguishable from the clinical, neuroanatomical, and

prognostic standpoints

In one of the most often quoted and provocative

articles on this subject, Phillips et al. (1994)

compared 48 patients with non-delusional BDD

with 52 patients with delusional BDD [or, according

to some authors, DDST]. The two groups did not

differ significantly in terms of most variables exam-

ined, including demographics, phenomenology,

course, associated features, comorbidities pattern,

and treatment response. However, delusional sub-

jects had higher total scores in the modified

Y-BOCS, suggesting that the delusional variant of

BDD (or DDST) may be a more severe form of the

non-delusional BDD. In the same vein, recent

neuroimaging studies have identified dysfunctions

in the parietal cortices in both BDD in general

(Carey et al. 2004) and DDST (Wada et al. 1999;

Ota et al. 2003; Hayashi et al. 2004), thus suggesting

that these disorders may share a common neuroa-

natomical basis.

2. Non-delusional and delusional BDD/DDST may

respond preferentially to serotonergic antidepressants

Case series reports suggest that both non-delusional

and delusional BDD/DDST in adults (Phillips 1993,

1994; Torres et al. 1996; Wada et al. 1999; Phillips

et al. 2001; Hayashi et al. 2004) and in children

and adolescents (Sondheimer 1988; Albertini and

Phillips 1999) respond favorably to monotherapy

with serotonin reuptake inhibitors (SRI).

This impression was further reinforced by the

findings of two double blind, placebo-controlled

treatment studies using SRI in BDD. Hollander

et al. (1999) randomized 29 patients with BDD in a

16-week, double-blind, crossover design study com-

paring clomipramine and desipramine. Clomipra-

mine was superior to desipramine in the acute

treatment of BDD and, most strikingly, was equally

effective regardless of whether the patients had

insight or held their dysmorphic misperception

with delusional intensity. Likewise, Phillips and co-

workers (2002) randomized 64 patients with the

DSM-IV diagnosis of BDD or its delusional variant

(DDST) in a 12-week study in which fluoxetine was

found to be significantly more effective than placebo.

Once again, BDD symptoms of delusional patients

were found to be as likely as those of non-delusional

patients to respond to an SRI, namely the fluoxetine.

3. Non-delusional and delusional BDD/DDST do not

respond favorably to treatment with antipsychotics

While some early studies suggested that low-dose

pimozide might be a quite effective approach in the

treatment of DDST (Munro and Mok 1995), a

number of recent reports [including case series

(Phillips 1991, 1994), and a controlled trial (Phillips

2005)] point toward the opposite direction, i.e. that

antipsychotics in general (including pimozide) may

be of no help in the treatment of non-delusional or

delusional BDD/DDST (Phillips 2004). For exam-

ple, in a retrospective study by Phillips (1994), only

one out of 45 trials with antipsychotics was effective

for delusional BDD/DDST. Similarly, in a recent

8-week, placebo-controlled, double-blind, parallel-

group study of pimozide augmentation of fluoxetine

in the treatment of BDD, the antipsychotic was

found to be no more effective than placebo even in

the more highly delusional patients (Phillips 2005).

In fact, early studies employing pimozide may have

had some significant bias that need to be highlighted.

DDST is a heterogeneous construct with several

putative subtypes (Riding and Munro 1975). For

example, Modell et al. (1996) speculated that

affective changes may be more frequent among

patients with dysmorphic delusions while organic

brain diseases may be more common among indivi-

duals with delusions of infestation. This is of para-

mount importance, since the two controlled studies

that have posited the effectiveness of pimozide in the

treatment of DDST have included solely patients

with delusions of infestation (Hamann and Avnstorp

1982; Ungvari and Vladar 1986). Therefore, we

believe that the issue of the efficacy of antipsychotics

as a monotherapy to treat dysmorphic delusions

(delusional BDD/DDST) is, as of yet, far from clear.

Against

We have discussed some preliminary evidence sug-

gesting that delusional ugliness may be just another

facet of BDD. Nevertheless, we feel that it is still

unclear whether this syndrome might be best de-

scribed as BDD or as DDST. In other words, and as

previously stated, is there enough evidence to sup-

port the removal of the concept of DDST in favor of

that of delusional BDD? This is an important

question to be made since in the last few years the

literature on delusional BDD has been rising sig-

nificantly in comparison to that on DDST. We will

now list a number of reasons that we believe support

the utility of the construct of DDST:

Delusional ugliness 111

1. DDST is a wider construct than delusional BDD

The concept of DDST encompasses not only in-

dividuals with dysmorphic delusions but also some

patients suffering from delire des negations [Cotard

syndrome (Berrios and Luque 1995)] and those with

delusions of infestation [Ekbom syndrome (Baker

et al. 1995)], of body odour or halitosis [olfactory

reference syndrome (Pryse-Phillips 1971)], of ab-

normal dental conditions [phantom bite syndrome

(Marbach 1978)] and of infectious diseases (Wurtz,

1998). The recurrent reporting of such cases high-

lights the descriptive utility of the concept of DDST.

2. It is unclear whether DDST belongs to the obsessive-

compulsive spectrum

It has already been suggested that the diagnosis of

BDD (and of its delusional form) should be moved

from the somatoform disorders section of the DSM-

IV to a new section of the future DSM-V that would

be entitled ‘‘obsessive-compulsive spectrum disor-

der’’ (Phillips et al. 2003). Although there have been

previous attempts to incorporate some of these

delusional entities into the so-called obsessive-com-

pulsive spectrum [for example, the olfactory refer-

ence syndrome (Stein et al. 1998)], many of these

categories seem to fit rather forcibly into this

putative spectrum (Swerdlow 2000).

3. Differential profile of pharmacological response may

not be an adequate criteria for blending non-delusional

and delusional BDD/DDST

As noted above, one of the main arguments for the

blending of the delusional BDD/DDSTand the non-

delusional BDD concepts is that both disorders

respond to SRI but not to antipsychotics (Phillips

2004). Nevertheless, it seems counterintuitive to

suggest that delusional BDD/DDST does not re-

spond to the latter class of drugs if BDD is said to

belong to the OCD spectrum (Phillips et al. 1995)

and OCD itself responds to augmentation with

typical (McDougle et al. 1994) as well as atypical

antipsychotics (McDougle et al. 2000; Bystritsky et

al. 2004; Denys et al. 2004). Denys et al. (2004), for

instance, reported a trend towards a significant

reduction in delusionality (according to the BABS

scores) after an 8-week treatment with quetiapine of

patients with OCD. In an interesting report, Grant

(2001) described the efficacy of olanzapine in the

treatment of a patient with non-delusional BDD. We

believe, therefore, that future studies should further

investigate the potential utility of antipsychotics in

the treatment of non-delusional and of delusional

BDD/DDST.

4. Delusional BDD may not be delusional at all

Although several research groups (McElroy et al.

1993; Hollander et al. 1999; Phillips et al. 1994,

2002) could not find any significant clinical and

therapeutic difference between delusional and non-

delusional forms of BDD and concluded that the

concept of BDD might therefore incorporate that of

some forms of DDST, their studies could be

criticized on the basis that they have employed

controversial concepts of ‘‘delusion’’. In the studies

by McElroy et al. (1993) and Phillips et al. (1994),

for instance, subjects were considered delusional if

they were or had ever been completely (or ‘‘100%’’)

convinced for a significant period of time that their

views of their supposed defect were accurate and

undistorted. In their fluoxetine study, Phillips et al.

(2002) employed the Brown Assessment of Beliefs

Scale (BABS), which assesses both dimensionally

and categorically the appealing construct of delusion-

ality but is nevertheless restricted to the ‘‘past

week’’. However, as pointed out by Munro (1999),

delusional disorders are fundamentally longstanding

illnesses, not episodic ones.

The definition adopted by Phillips et al. (1994)

may have inadvertently led to the inclusion in their

study not only of patients with genuine DDST

[i.e. chronically or persistently delusional patients

(Opjordsmoen 1993)] but also of individuals with

BDD with an episodic or fluctuating ‘‘delusional’’

course. These inclusion criteria might have concei-

vably attenuated putative differences between BDD

and DDST.

We acknowledge that some authors have sug-

gested that delusions in general may be more fluid

over relatively short periods of time than it has been

admitted in many classical descriptions and con-

temporary formulations. For example, based on a

1-year follow-up study with 1,136 acutely hospita-

lized psychiatric patients, Appelbaum et al. (2004)

found that only 15.1% of patients were persistently

delusional at each follow-up appointment (every

10 weeks). This study, however, included mostly

patients with schizophrenia, mood, and schizoaffec-

tive disorders. Only 3.5% of the sample comprised

‘‘other psychotic disorders’’, a subgroup that may

have included individuals with delusional disorders

(such as delusional BDD/DDST).

Using obsessive-compulsive disorder (OCD) as a

reference point, Insel and Akiskal (1986) have

suggested that a shift from an obsession to a

‘‘delusion’’ may occur when a disturbed affective

process leads to the abandonment of resistance (the

internal struggle against an obsessional urge or idea)

and loss of insight. We believe that a similar under-

standing can be applied to BDD. For instance, it is

112 L. F. Fontenelle et al.

conceivable that somatic obsessions with dys-

morphic content may evolve into ‘‘understandable’’

secondary delusions or delusion-like ideas [in

Jaspers’ terms (1963)] in patients with non-delu-

sional BDD who develop either a major depressive

episode or a brief psychotic disorder whenever they

are submitted to a significant amount of stressful life

events (Munro, 1999).

In other words, some patients with ‘‘delusional’’

BDD may be in fact suffering from ‘‘delusional-like’’

BDD. The role of disturbed affective processes in

these ‘‘delusional’’ transformations might certainly

explain why the ‘‘delusional’’ patients with BDD

described by Phillips and co-workers (2004) re-

sponded preferentially to SRI rather than to anti-

psychotics. It could also account for the fact that, as

reported by McElroy et al. (1993), patients with

delusional BDD were more likely to be female, to

have experienced suicidal ideation, and to have

received the diagnosis of major depression as com-

pared to those with non-delusional BDD.

5. There is more about delusion than just conviction

Mullen (2003) have argued the identification of

delusions should not be based only on the presence

of extreme or absolute conviction. As seen above,

reports of non-psychotic beliefs (such as those found

in BDD) eventually evolving into a full-blown

delusional system and leading to the establishment

of a diagnosis of a delusional disorder (or any other

psychotic disorder) frequently rely on changes in the

levels of conviction expressed by the subject. This

emphasis on the level of conviction has been

considered naıve by some (Cutting, 1997), since it

ignores the other elements that comprise the delu-

sion construct and which are referred to in various

commonly accepted (modern or classical) defini-

tions of delusion, including that adopted by the

DSM-IV (Mullen, 2003).

Several different features of delusions were de-

scribed in a handful of factor-analytic studies, mostly

with patients with schizophrenia, schizoaffective,

and mood disorder (Kendler et al. 1983; Garety

and Hemsley, 1987; Appelbaum et al. 1999; Oulis et

al. 2000). Conviction seems to be just one of the

basic dimensions, which also include constructs such

as extension or pervasiveness (Kendler et al. 1983;

Appelbaum et al. 1999), bizarreness (Kendler et al.

1983; Oulis et al. 2000), pressure or preoccupation

(Kendler et al. 1983; Appelbaum et al. 1999),

delusional actions (Kendler et al. 1983; Garety and

Hemsley, 1987; Appelbaum et al. 1999; Oulis et al.

2000), negative affect or emotional impact (Kendler

et al. 1983; Garety and Hemsley, 1987; Appelbaum

et al. 1999; Oulis et al. 2000) and delusional

‘‘kinematics’’ [duration and stability of the delusion]

(Oulis et al. 2000). These multiple dimensions,

though, have loaded on a quite variable number of

factors, ranging from two (Kendler et al. 1983) to six

(Oulis et al. 2000).

The developed of the BABS, which also assesses

the multidimensional construct of delusionality and

may be more suitable to be employed in patients

with BDD and OCD, is a significant advance in the

field, although its results seem to load on a single

factor closely related to the level of conviction (Eisen

et al. 1998). In a recent study using the BABS, for

example, Eisen et al. (2004) found that patients with

BDD not only had significantly poorer global insight

than patients with OCD but also displayed signifi-

cantly stronger conviction that their central (dys-

morphic) beliefs were essentially correct, were more

certain that other people’s views were less accurate

than theirs, were more confident that other people

considered that the subjects’ beliefs were true, were

more reluctant to consider the possibility that their

belief could be false, and had less insight regarding

the psychiatric cause of their belief.

Conclusions

We must admit that in many cases it may not be

possible to fully disentangle ‘‘delusional’’ BDD from

DDST from a phenomenological and cross-sectional

point of view (de Leon et al. 1989). In fact, we

believe that the available evidence is not yet suffi-

cient to draw any definitive conclusion regarding the

nosological status of ‘‘delusional’’ BDD/DDST. We

agree with Phillips (2004) in that double-coding

dysmorphic delusions with both BDD and DDST is

awkward, and has the drawback of diagnosing the

same syndrome as two different disorders. However,

this coding also reflects the possibility that delusional

BDD and DDST may actually do not constitute the

same disorder.

Two types of studies are urgently needed in order

to substantiate our judgement regarding the limits

between delusional BDD and DDST with dys-

morphic delusions. Firstly, prospective, long-term

studies of BDD may help unveil how the level of

insight of patients with BDD fluctuates along the

days, weeks and years, and which factors lead to

such variations. Secondly, additional comparisons

between the demographic, clinical, biological, and

therapeutic characteristics of patients with BDD,

with their ‘‘episodic’’ lack of insight, and those of

patients with DDST, with their chronic dysmorphic

delusions, need to be performed in order to deline-

ate precise diagnostic boundaries between these two

disorders.






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CASE REPORT

Abdominal cutaneous nerve entrapment syndrome (ACNES) in apatient with a pain syndrome previously assumed to be of psychiatricorigin

JOHANNES THOME1 & CHRISTIAN EGELER2

1Department of Psychiatry, School of Medicine, University of Wales Swansea, Swansea, UK, and 2Department of

Anaesthesia, Morriston Hospital, Swansea, UK

AbstractA 21-year-old female patient with chronic abdominal pain was referred to a psychiatric outpatient clinic aftergastroenterological and gynaecological pathogeneses had been excluded and a treatment with an antidepressant had hadno beneficial effects. The mental state examination, however, revealed no psychopathology whatsoever. The patient wasinjected with a local anaesthetic loco dolenti which resulted in immediate pain relief. She was diagnosed with abdominalcutaneous nerve entrapment syndrome (ACNES); no psychiatric diagnosis was given.

Key words: Depression, functional, liaison psychiatry, pain, psychosomatic

Introduction

Patients with pain syndromes represent an important

group in psychiatry (Merskey 1989; Pridmore et al.

2001). Often they are referred to mental health units

when no somatic explanation of the symptomatology

can be found. In these cases, it is important to

differentiate between ‘‘real’’ pain syndromes with

somatic background and functional or psychogenic

pain syndromes, even if extensive diagnostic steps

have already been taken (Steinmuller 1979).

Case report

The 21-year-old female patient suffered from

chronic pain for over 2 years. She had presented

herself in gastroenterology and gynaecology, but

no explanation for the pain syndrome could

be found despite extensive diagnostic measures

(X-ray, ultrasound, laparoscopy, barium enema).

A treatment with an antidepressant was suggested

(SSRI); however, the patient stopped taking this

medication after a continuous treatment over a

period of 3 weeks with 20 mg fluoxetine did not

affect her condition at all. She did not exhibit any

side effects either.

When referred to our psychiatric outpatient clinic,

the patient reported to feel frustrated that all

measures so far had failed to produce a diagnosis

and an effective treatment strategy. However, there

were no depressive or any other psychiatric symp-

toms present. Also, there was no sign of any form of

neurotic, stress-related or somatoform disorder,

personality disorder and none of the criteria for

somatoform pain disorders were met. There was

no history of organic mental disorder or use of

psychoactive substances.

The patient was actually able to cope with the

demands of daily life and handled stressful life events

quite well (separation from partner, life-threatening

disease of mother). There was no relation whatso-

ever between the course of these events and the

development and progression of the pain syndrome.

As a student in health sciences, she successfully

attended all teaching sessions and enjoyed social

contacts with her peers. There was no family history

of neuropsychiatric disorders.

Interestingly, the patient mentioned that she had

perused the internet with respect to her pain

syndrome and asked whether it could be associated

with a trapped nerve.

Correspondence: Johannes Thome, MD, PhD, Professor of Psychiatry, School of Medicine, University of Wales, Swansea, Singleton Park,

Swansea SA2 8PP, UK. Tel: +44 1792 602205. Fax: +44 1792 513430. E-mail: [email protected]


(Received 23 January 2005; accepted 20 June 2005)


DOI: 10.1080/15622970500222377

She reported that she had been troubled with

right iliac fossa pain for over 2 years, at times even

necessitating acute admission to hospital with

exacerbation of the pain. The pain was not

associated to her menstrual cycle or to her bowel

motions but could give her quite sharp spasmodic

pain, with a dull background ache. She could

pinpoint the source of the pain deep in the right

inguinal area. On deep palpation there was a

nodule of relatively hard tissue palpable. About

3 months after she had stopped taking the

antidepressant, she agreed to have this injected

with 10 ml 0.25% marcain and 20 mg depome-

drone. She had excellent immediate relief, lasting

well over 2 months. She was diagnosed with

ACNES. About 5 months after this excellent relief

from the trigger-point injection, she found the

pain recurring, but was still considerably better

than previously. An injection with 5 ml 0.25%

marcain and 20 mg depomedrone was repeated

which, again, gave her immediate relief. Since this

course is not untypical for ACNES, this diagnosis

was maintained.

Discussion

ACNES represents a common cause of abdo-

minal pain without other clinically significant

symptoms, often misdiagnosed as irritable bowel,

spastic colon, gastritis, psychoneurosis, depression,

anxiety, hysteria and malingering (Applegate

1973; Hershfield 1992; Suleiman and Johnston

2001).

Its pathophysiology is characterised by a fibrous

ring in the rectus muscle, through which a neuro-

vascular bundle travels. This bundle can move

freely, however compression against the ring

causes nerve ischemia and the acute or chronic

symptoms of ACNES (Applegate and Buck-

walter 1997).

Clinical presentation of ACNES symptoms can

vary, but usually acute or chronic abdominal pain

is described which may depend on physical activity

or certain movements. ACNES pain usually affects

only one side and is typically well localised. On

physical examination, it is normally possible to

palpate a tender spot and underneath a muscular

foramen at the very localisation indicated by the

patient (Applegate 2002).

The injection of a local anaesthetic will immedi-

ately relieve the ACNES-related pain and also

confirm the diagnosis (Applegate 2002; Doouss

and Boas 1975). Addition of steroids to the injec-

tate prolongs pain relief considerably and reduces

tissue tension within the nerve entrapment area.

Whilst repeat injections are often required, these

tend to produce longer pain relief until the pain

virtually disappears.

With respect to the therapy success, it is

important to discuss the possibility of a so-called

placebo effect. However, given the fact that

the patient fulfilled the classical criteria for

ACNES, including a palpable nodule of hard

tissue loco typico, and since psychosocial circum-

stances were clearly unrelated to the pain symp-

toms, it can be concluded that this patient was not

suffering from a psychogenic pain syndrome,

which then was ‘‘cured’’ by the placebo effect of

an injection.

There have been several reports in the literature

about cases in which it took a considerable amount

of time until the correct diagnosis of ACNES

was made, thereby unnecessarily prolonging the

patients’ suffering (Hershfield 1992; Peleg 1999;

Suleiman and Johnston 2001). When comprehensive

diagnostic batteries remain inconclusive, patients

suffering from pain syndromes are often referred to

psychiatrists and psychotherapists, suggesting a

psychogenic or functional disorder. However, it is

important to note that allegedly psychogenic pain

syndromes may well represent somatic conditions

such as ACNES.

Psychiatrists should, thus, be aware of this

syndrome in order to avoid an unnecessary prolon-

gation of their patients’ pain syndrome and to

direct them towards the proper therapy which

will result in immediate relief and is likely to

provide a cure.



commercial or other associations in connection

with the submitted article.

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118 J. Thome & C. Egeler

CASE SERIES

The treatment of recurring auditory hallucinations in schizophreniawith rTMS

PAUL B. FITZGERALD1, JESSICA BENITEZ1, JEFF Z. DASKALAKIS2, ANTHONY DE

CASTELLA1 & JAYASHRI KULKARNI1

1Alfred Psychiatry Research Centre, The Alfred and Monash University Department of Psychological Medicine, Victoria,

Australia, and 2Centre for Addiction and Mental Health, Clarke Division, Toronto, Ontario, Canada

AbstractBackground: Auditory hallucinations are a common and disabling problem for many patients with schizophrenia and oftenfail to respond to optimal antipsychotic therapy. Repetitive transcranial magnetic stimulation (rTMS) has recently beentrialled as an alternative treatment option for these patients. These studies have generally been positive, but treatment hasonly been provided for short periods of time and little is known about the longer-term impact of TMS on the course ofhallucinations. Method: We describe two cases in which rTMS was provided to patients upon relapse of hallucinationsfollowing initial successful rTMS treatment in a clinical trial. Results: A repeat course of rTMS resulted in a markedimprovement in the symptoms experienced by these two patients. Conclusions: rTMS appears to have potential as a long-term treatment for patients with auditory hallucinations, but requires ongoing systematic investigation.

Key words: Hallucinations, schizophrenia, repetitive transcranial magnetic stimulation

Introduction

Persistent auditory hallucinations (AHs) are a

common problem in patients with schizophrenia

and contribute to ongoing disability and morbidity.

Repetitive transcranial magnetic stimulation (rTMS)

has recently been developed and trialled as a

potential new treatment for patients with treatment

resistant AHs. To date rTMS has been subjected to

several small randomised controlled trials. Initially

Hoffman and co-workers applied 1 Hz rTMS over

the left temporoparietal region in two pilot studies,

followed by a randomised sham controlled double-

blind trial (Hoffman et al. 2003), all with positive

results. The double-blind trial involved 24 patients

receiving stimulation over nine treatment sessions

(Hoffman et al. 2003). The active treatment group

experienced a significant improvement in hallucina-

tion severity compared to the sham group, and there

were no significant adverse events reported. There

was a persistence of therapeutic benefit in the

months following the study in a significant propor-

tion of the patients, although none received ongoing

rTMS treatment. Although one study failed to

replicate the findings of Hoffman’s pilot study design

(McIntosh et al. 2004), there have been several

positive replications of the clinical trial work. First,

Poulet and colleagues found a beneficial effect of

stimulation with therapeutic results obtained after

only 5 days of treatment (Poulet et al. 2005).

Second, a therapeutic benefit of 1 Hz rTMS over

both the left and right auditory region was found

with 20 minutes stimulation per day in a 10-day

treatment trial (Lee et al. 2005).

Despite these replications, little is known about

the long-term impact of rTMS on the clinical

outcome of patients with persistent auditory hallu-

cinations. In particular, it is unknown whether

rTMS will have beneficial clinical effects if halluci-

nations return after a successful period of treatment.

In this paper we describe the repeated treatment

with rTMS in two patients with persistent auditory

hallucinations. These cases suggest that TMS may

have an ongoing role to play in the treatment of

patients with hallucinations over time. Both patients

gave written informed consent and this study was

Correspondence: Associate Professor Paul B. Fitzgerald, Alfred Psychiatry Research Centre, First Floor, Old Baker Building, The Alfred,

Commercial Rd Melbourne, Victoria, 3004 Australia. Tel: +61 3 9276 6552. Fax: +61 3 9276 6556. E-mail: paul.fitzgerald

@med.monash.edu.au


(Received 11 August 2005; accepted 2 November 2005)


DOI: 10.1080/15622970500474705

approved by the human research committee of the

Alfred Hospital. Assessments of symptom severity in

both cases were made by a single trained rater using

the Hallucination Change Scale (HCS): this was

initially described by Hoffman et al. (2003) and

consists of a single rating from 0 (non-voices) to 20

(greatest severity) of hallucination severity. At base-

line, the rating is set at 10 with each patient

providing an individual description of the severity

of his/her voices. We also used the hallucinations

item of the Positive and Negative Syndrome Scale

(PANSS) (Kay et al. 1987).

Case report

Patient 1

The first patient, GC, was a 47-year-old male with a

7-year history of schizophrenia characterised by the

persistence of severe auditory hallucinations. He had

been treated over this time with multiple typical and

atypical antipsychotic medications at full therapeutic

doses. These had resulted in an improvement in his

general clinical state but had little impact on the

presence or severity of his hallucinations. At the time

of initial rTMS he had been receiving treatment with

a combination of risperidone (4 mg/day) and aripi-

prazole (30 mg/day) for over 6 months. He described

hearing voices that were negative, derogatory and

often commanding in nature including commands to

commit suicide. The voices were experienced every

day, for many hours at a time and inside his head.

GC was initially randomised to receive placebo

rTMS and this was provided for 10 days as part of

a double-blind sham controlled trial (Fitzgerald et

al. 2005). At the end of this time there was no

change in the severity of his AHs. Immediately after

this he was enrolled in an open active phase of

treatment and received 10 days of rTMS. This was

provided for 15 minutes per day, at 1 Hz, to the TP3

EEG site in the left temporoparietal cortex at 90% of

the resting motor threshold (Fitzgerald et al. 2005).

This resulted in a dramatic reduction of his AHs

from 10 to 0 on the HCS and from 5 to 1 on the

PANSS AH item. His total PANSS score decreased

from 87 at baseline to 52 at study end.

Seven months after rTMS treatment he was re-

referred by his treating psychiatrist due to a gradual

recurrence of his AHs over the previous month.

There had been no change in medication type or

dose since the end of the original rTMS treatment

course; he continued to receive 4 mg of risperidone

and 30 mg of aripiprazole per day. He was believed

by his treating psychiatrist to have remained com-

pliant with medication throughout this period

although this had not been confirmed with plasma

levels. The symptoms had returned to a similar level

of severity to that preceding his original treatment.

GC was provided repeat treatment with rTMS

under identical treatment conditions (same site,

intensity, frequency, number of pulses and dura-

tion). There was a very similar good clinical response

with the second period of treatment. At the end of

the 10 days he reported that he had not experienced

auditory hallucinations for the duration of the

second week of treatment and there was a significant

improvement in his overall level of functioning and

mental well-being. His score on the PANSS AH item

had reduced from 5 to 1 and his score on the HCS

from 10 to 0.

Patient 2

The second patient was an 18-year-old female with

childhood onset schizophrenia beginning at the age

of 9. Over the 9 years of her illness, LM, became

increasingly treatment resistant to the point where

she continued to experience persistent symptoms,

despite treatment with multiple antipsychotic med-

ication. Twelve months prior to referral for rTMS

she commenced treatment with clozapine, which

was progressively increased to 400 mg/day. This

resulted in a significant improvement in her general

positive symptoms and level of disorganisation, but

had little impact on her AHs. LM described multiple

persistent AHs which she experienced almost con-

tinuously. She described hearing several extremely

loud voices that made constant, derogatory and

abusive comments in the second and third person.

LM was also given active rTMS as part of a double-

blind randomised trial (10 sessions given on con-

secutive weekdays, 15 minutes of 1 Hz stimulation at

90% of the resting motor threshold, to the TP3 EEG

site in the left temporoparietal cortex) (Fitzgerald et

al. 2005). This resulted in a reduction in the severity

of the AHs from a rating of 10 to a rating of 3 (HCS)

(6 to 2 on the PANSS AH item). She remained on

400 mg of clozapine throughout treatment and the

follow-up period with medication supervised both

during and after TMS by family members. One

month after the end of treatment, she rated the

severity of the voices as 1 on the HCS. The

improvement in the AHs experienced by LM lasted

approximately 5 months during which time she

remained on an unchanged dose of clozapine. After

this time they gradually returned and increased in

intensity and frequency. Six months after initial

treatment with rTMS she received a further 10

sessions applied in an identical way. She again

experienced a significant improvement in her audi-

tory hallucinations. LM described a reduction in

AHs from being continuously present to occurring

120 P. B. Fitzgerald et al.

fleetingly once every 3�/4 days (HCS 10 to 3,

PANSS AH item 6 to 2). Following this second

trial, LM’s AHs were barely present for a period of 3

months, after which they increased to the previous

level. As a third treatment trial, rTMS was provided

in an identical way, but this time over 15 treatment

sessions (3 weeks). This resulted in a further

response with an almost complete remission of the

AHs which were only experienced approximately

once per day (HCS 10 to 2, PANSS AH item 6 to 2).

Four months after this period of treatment the

patient reported that her AHs remained at the

same minimally present level.

Discussion

Persistent auditory hallucinations are a serious

clinical problem that continue to cause significant

problems for patients with schizophrenia. Repetitive

TMS shows promise in the treatment of this difficult

clinical symptom of schizophrenia. Randomised

trials to date have suggested that rTMS has acute

efficacy in the relief of persistent auditory hallucina-

tions ( Hoffman et al. 2003; Lee et al. 2005; Poulet

et al. 2005). However, little is known with regard to

the long-term impact of rTMS on the clinical course

of patients with hallucinations. Importantly, halluci-

nations are likely to be a recurring and incapacitating

clinical symptom for some patients with schizophre-

nia and it is not clear that continual treatment with

antipsychotic medication results in a continued relief

of AHs after the end of a course of rTMS treatment.

Data on the use of rTMS treatment in the acute

treatment is gradually accumulating. Over the last

year, several positive replication studies (Chibbaro et

al. 2005; Hoffman et al. 2005; Lee et al. 2005;

Poulet et al. 2005) have supported the initial trials by

Hoffman et al. (2003, 2000). However, not all of the

published reports are strongly positive. In fact, the

trial in which the two patients in this report

participated failed to show a strong positive effect

of rTMS treatment (Fitzgerald et al. 2005). In that

study there was significantly greater reduction in the

loudness of AHs reported in patients with active as

compared to sham treatment, but no overall differ-

ence in HCS severity. It is possible that minor

differences in stimulation technique could have

explained the difference in response in this trial.

Perhaps more likely, however, is that even with a

successful treatment the conduct of multiple small

treatment studies in highly treatment non-responsive

populations is likely to produce some negative trial

results. It seems quite timely for the conduct of a

substantial multi-site trial of the efficacy of acute

rTMS treatment, very much as studies of this sort

are currently underway for rTMS treatment in

depression.

The two cases that we have described provide

early evidence that rTMS may have a role in the

treatment of persistent and recurring AHs. Although

the non-blinded treatment of the patients in these

cases introduces the possibility of the influence of

confounding factors, the dramatic nature of the

improvement in symptoms from previously severe

impairment suggest that a placebo effect alone is

unlikely. In addition, there did not seem to be any

other significant factors, such as changes in medica-

tion or site of treatment to account for these effects.

Further systematic evaluation of the effects of rTMS

treatment of AHs over time is clearly warranted.

This should include not just the evaluation of the

effects of rTMS in the treatment of acute episodes

Figure 1. Hallucination change scores (HCS) and Positive and Negative Symptom Scale (PANSS) Auditory Hallucination (AH) item

scores for each subject across the treatment phases.

rTMS and hallucinations 121

but also potentially its role in the maintenance

treatment of these disabling symptoms.


The study was supported by a grant from The

Stanley Medical Research Institute and by Con-

stance and Stephen Lieber through a NARSAD

Young Investigator award (PF).

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122 P. B. Fitzgerald et al.

CASE SERIES

Aripiprazole in patients with Tourette syndrome

EMANUEL BUBL, EVGENIY PERLOV & LUDGER TEBARTZ VAN ELST

Department of Psychiatry, Albert-Ludwigs-University, Freiburg, Germany

AbstractThe treatment of the Gilles de la Tourette syndrome (GTS) is often challenging. One reason for this is the highneuropsychiatric cormorbidity in terms of ADHD or obsessive-compulsive symptoms. Dopaminergic modulation e.g. withantidopaminergic medication is an important part of the medical therapy aimed at motor and vocal tics. We report recentexperiences with treatment with aripiprazole, a novel antipsychotic agent, which not only improved motor and vocal tics butalso ameliorated some behavioural symptoms of the GTS cluster. Furthermore, we discuss possible pharmacologicalmechanisms for the observed effects.

Key words: Gilles de la Tourette syndrome (GTS), aripiprazole, ADD, dopamine

Introduction

The Gilles de la Tourette syndrome (GTS) is a

complex neuropsychiatric disorder, which is char-

acterized by the occurrence of several vocal and

motor tics at the same time (Leckman 2002). Many

patients suffer from co-morbid obsessive-compulsive

disorder (OCD) or attention-deficit hyperactivity

disorder (ADHD) (Leckman 2002). Dopaminergic

modulation, e.g., with classic neuroleptics such as

haloperidol have been an important part of therapy

(Lucas 1967; Devinsky 1983). The treatment of

GTS is particularly difficult when it is associated

with co-morbid psychiatric symptoms. Treatment of

ADHD or OCD symptoms with psychostimulants or

SSRIs can deteriorate tics, whereas treatment of

motor and vocal tics with antidopaminergic medica-

tion sometimes worsens ADHD or OCD. In recent

years atypical neuroleptics such as risperidone have

been widely discussed (Bruun and Budman 1996).

We present a report of a women and a man with

Tourette syndrome successfully treated with aripi-

prazole.

Case reports

Mrs H, a 19-year-old caucasian female with GTS

complained to her psychiatrist about classic motor

and vocal tics of the facial and upper limb muscles

and echopraxia. Furthermore, the patient herself as

well as her partner and family described a marked

impulsivity and verbal aggression which led to

serious interpersonal problems. Apart from that

Mrs H did not suffer from any other medical or

neuropsychiatric disorder, e.g., obsessive-compul-

sive disorder. There was no history of birth compli-

cations, delayed development or streptococcal

infections and no family history of any neuro-

psychiatric disorder. Treatment with haloperidol

1.5 mg did improve the tics to a small extent.

However, there were still major interpersonal pro-

blems due to her impulsive and verbally aggressive

behaviour. Because of this sertraline was started up

to 100 mg with only minor positive effects. While

haloperidol, at the mentioned dosage, was well

tolerated, a therapeutic trial with aripiprazole

15 mg was started in order to minimise the risk of

tardive dyskinesia. Haloperidol was tapered at the

same time. This intervention led to a dramatic

improvement, not only of the motor and verbal tics

but also of the impulsiveness. Due to a decrease of

effectiveness after 4 weeks, the patient herself tried

to increase the dosage up to 40 mg a day. This

dosage proved to be effective and well tolerated, with

a sustained improvement of tics as well as impulsivity

for the follow-up period of over 1 year. Therefore,

the patient was left on this high dosage following

informed consent with respect to off-label treatment.

Correspondence: Ludger Tebartz Van Elst, MD, Department of Psychiatry, Albert-Ludwigs-University, Hauptstr. 5, D-79104 Freiburg,

Germany. Tel: +49 761 270 6501. Fax: +49 761 270 6619. E-mail: [email protected]


(Received 28 July 2005; accepted 9 November 2005)


DOI: 10.1080/15622970500474770

Mr H, a 21-year-old caucasian male, presented in

our clinic with classical vocal and motor tics

beginning in early childhood. Following normal

blood tests, EEG, and neuroimaging, GTS was

diagnosed. Birth history and early development

were normal. There was no family history of any

neuropsychiatric disorder. Psychiatric and neurolo-

gical examinations were essentially normal apart

from the tics. The patient did not show a history

of obsessive-compulsive symptoms. Given our

earlier experience and the good tolerability of

aripiprazole, we started with this substance at

15 mg in the morning. Again, there was a sustained

good response of vocal and motor tics without

significant side effects for the present follow-up

period of about 4 months.

Discussion

These results support similar findings in a number

of case series where aripiprazole was used with a

good efficacy and tolerability in patients with GTS

(Hounie et al. 2004; Dehning et al. 2005; Kastrup

et al. 2005; Murphy et al. 2005). In addition, in

our first case, not only the tics but also the

impulsivity, a common problem in GTS, improved

significantly. Atypical as well as typical neuroleptics

have been widely used in the treatment of GTS

and often show a good response, which is probably

due to modification of dopaminergic neurotrans-

mission. Dopaminergic alterations in the pathophy-

siology of GTS have been discussed earlier

(Devinsky 1983). Pharmacological as well as ima-

ging studies support this assumption (Shapiro et al.

1989; Sallee et al. 1997). Tics often worsen after

discontinuation of antidopaminergic drugs or ad-

ministration of psychostimulants (Mesulam 1986;

Albin et al. 2003).

One major problem in treating tics with typical

or present atypical neuroleptics is the side effect

profile of the different drugs. Whereas classical

neuroleptics are associated with an increased risk

for extrapyramidal symptoms, akathisia or tardive

dyskinesia, many second-generation drugs do have

specific side effects such as weight gain, sedation,

akathisia etc. (Weiden and Bruun 1987). Moreover,

the treatment of psychiatric comorbid conditions

often poses a problem in the medical treatment of

GTS. For example, treating ADHD symptoms is

often challenging, since psychostimulants might

deteriorate tics, as mentioned above. But even SSRIs

are associated with a worsening of tics in some cases

(Ruth et al. 2000).

Aripiprazole is a partial D2 antagonist as well as a

partial 5-HT1A agonist and a 5-HT2A antagonist.

Being a partial D2-agonist, aripiprazole exhibits

functional agonistic properties under hypodopami-

nergic conditions and functional antagonistic prop-

erties under hyperdopaminergic conditions. The

main anti-tic property of aripiprazole is probably

due to the resulting stabilizing effects on dopami-

nergic neurotransmission. However, the serotonergic

action might be of additional benefit in indirectly

attenuating mesolimbic and/or mesocortical dopa-

minergic pathways (Ichikawa et al. 2001). Possible

serotonergic effects on prefrontal serotonergic pro-

jection sites could be responsible for the positive

effects on OCD symptoms or impulsivity.

Given this background and our first positive

experiences, aripiprazole might well turn out to be

an efficacious and well-tolerated drug in the treat-

ment of GTS. It might not only improve tics but also

the common co-morbid (ADHD spectrum) symp-

toms like impulsivity and emotional instability.





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505.

Aripiprazole in patients with Tourette syndrome 125

LETTER TO THE EDITOR

Addressing the limitations of the CATIE study

SIEGFRIED KASPER & DIETMAR WINKLER

Department of General Psychiatry, Medical University of Vienna, Austria

Letters published in this Journal do not necessarily reflect the opinions of the Editors or the Editorial Board.

The Clinical Antipsychotic Trials of Intervention

Effectiveness (CATIE) study by Lieberman et al.

(2005) is important because it represents one of the

largest comparative trials on the differential effec-

tiveness of atypical antipsychotics that has not been

sponsored directly by the pharmaceutical industry.

However, the study shows several severe methodo-

logical limitations, which we would like to discuss

point by point:

1. The treatment groups cannot be compared

easily because the equivalent dosage of anti-

psychotics was not equal: olanzapine, for ex-

ample, was dosed higher compared to the other

compounds. The maximum daily dosage al-

lowed for olanzapine during this study (30 mg/

day) also exceeded the maximum daily dosage

recommended by the company (20 mg/day).

2. The design of the study is biased since the

inclusion/exclusion criteria for the treatment

groups differed: patients with tardive dyskinesia

could enrol, but the randomization scheme

prevented the assignment to the perphenazine

group. This leaves the study with non-compar-

able groups since we know that patients with

tardive dyskinesia might be different in regard

to duration of illness, chronicity and even the

rate of response to treatment (Kasper et al.

2006). Given that the rate of patients with

tardive dyskinesia was as high as 19% in the

group of atypical antipsychotics (15% of all

subjects), this is a severe bias and limits

generalization of the results. Unfortunately

this point is not discussed in the article.

3. The study is not powered adequately to show

differences between the different groups. The

trial only had a statistical power of 76% for

comparisons involving perphenazine and of

58% for comparisons involving ziprasidone.

Therefore a type II error is not unlikely.

4. The study was carried out in different centres,

university hospitals, state hospitals and private

sites, as well as mixed sites, all with different

kinds of patient groups, which makes up for a

large heterogeneity of the study population.

5. It is not clear why the patients were included in

the study. It is only mentioned that they had to

suffer from schizophrenia and that only 28%

had an exacerbation of clinical symptomatology

within the previous 3 months.

6. It is not described if patients with known

treatment resistance to one of the drugs were

randomized to this very substance or excluded

by the protocol.

7. The dosing schedule is quite disconcerting: To

protect blinding, half the patients randomly

assigned to perphenazine, olanzapine, and ris-

peridone were assigned to twice-daily dosing and

half to once-daily dosing. A much more adequate

procedure would have been to assign all patients

to twice-daily dosing, because patients with once-

daily dosing were a priori known to be neither on

quetiapine nor on ziprasidone. Furthermore

differences in dosing are known to influence

compliance (Greenberg 1984) which might

have influenced the rate of discontinuation.

8. The rate of discontinuation of treatment for any

cause is the only primary outcome measure,

which makes this trial different from all the

other studies, but also impedes comparisons

with other studies.

9. The reader is left puzzled: why was quetiapine

associated with a higher rate of anticholinergic

Correspondence: Prof. Siegfried Kasper, Department of General Psychiatry, Medical University of Vienna, Wahringer Gurtel 18�/20,

A-1090 Vienna, Austria. Tel: �/43 1 40400 3568. Fax: �/43 1 40400 3099. E-mail: [email protected]



DOI: 10.1080/15622970600685424

effects than the other antipsychotics, given that

quetiapine patients used less anticholinergic

medication? This point is not mentioned in

the discussion.

10. It is brought up in the introduction that atypical

antipsychotics in general have weight gain and

alterations of glucose and lipid metabolism as

side effects. This is an uncritical statement. The

authors should note that the risk of metabolic

side effects is different between the substances.

For example, ziprasidone and aripiprazole do

not influence weight, lipids or glucose metabo-

lism (Lublin et al. 2005; Newcomer 2005).

Interestingly, their own study also documented

differences, e.g. olanzapine was associated with

greater weight gain and increases in measures of

glucose and lipid metabolism.

Altogether, it is our opinion that this study compares

non-comparable groups and leaves the reader

with results that could lead to wrong conclusions.

Not everybody is an expert with methodological

considerations of randomized controlled trials

and therefore might get the impression that in the

light of higher direct costs prescribing atypical

antipsychotics has no advantage over typical neuro-

leptics.


Siegfried Kasper has received research grants, con-

sultancy fees and lecture fees from a number of

pharmaceutical companies in the area of CNS

development. Dr Dietmar Winkler has no conflict

of interest with any commercial or other associations

in connection with the submitted article..

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The limitations of the CATIE study 127

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