Association study of the glycogen synthase kinase-3β gene polymorphism with prophylactic lithium response in bipolar patients

Editorial

Announcement of the first impact factor for The World Journal of Biological PsychiatryHans-Jurgen Moller, Rainer Rupprecht ................................................................................................. 130

Reviews

Peripheral thyroid dysfunction in depressionKonstantinos N. Fountoulakis, Sotiris Kantartzis, Melina Siamouli, Panagiotis Panagiotidis,

Stergios Kaprinis, Apostolos Iacovides, George Kaprinis .................................................................. 131

Melatonin in mood disordersVenkataramanujan Srinivasan, Marcel Smits, Warren Spence, Alan D. Lowe, Leonid Kayumov,

Seithikurippu R. Pandi-Perumal, Barbara Parry, Daniel P. Cardinali ............................................... 138

Original Investigations

Striatal dopamine transporter availability and DAT-1 gene in adults with ADHD: No higherDAT availability in patients with homozygosity for the 10-repeat allele

Johanna Krause, Stefan H. Dresel, Klaus-Henning Krause, Christian La Fougere,Peter Zill, Manfred Ackenheil ............................................................................................................ 152

Association study of the glycogen synthase kinase-3b gene polymorphism with prophylacticlithium response in bipolar patients

Aleksandra Szczepankiewicz, Janusz K. Rybakowski, Aleksandra Suwalska,Maria Skibinska, Anna Leszczynska-Rodziewicz, Monika Dmitrzak-Weglarz,Piotr M. Czerski, Joanna Hauser ....................................................................................................... 158

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

Caroline Nothdurfter, Daniela Eser, Cornelius Schule, Peter Zwanzger, Alain Marcuse,Ines Noack, Hans-Jurgen Moller, Rainer Rupprecht, Thomas C. Baghai .......................................... 162

Viewpoint

Disasters and mental health: New challenges for the psychiatric professionJuan J. Lopez-Ibor Jr ............................................................................................................................. 171

Case Reports

Sulbutiamine, an ‘innocent’ over the counter drug, interferes with therapeutic outcome ofbipolar disorder

Athanasios Douzenis, Ioannis Michopoulos, Lefteris Lykouras ........................................................... 183

Autism and Williams syndrome: A case reportSabri Herguner, Nahit Motavalli Mukaddes ......................................................................................... 186

Instructions to Authors ....................................................................................................... 191

The World Journal of Biological PsychiatryVolume 7, No 3, 2006

Contents

EDITORIAL

Announcement of the first impact factor for The World Journal of

Biological Psychiatry

Over the last two decades the impact factor has

developed into the ‘gold currency’ in the world of

scientific publications, and every scientist, including

scientifically active psychiatrists, considers himself

rich and happy when he possesses as much of this

‘gold currency’ as possible. Although this is only a

virtual currency that cannot be used to buy any-

thing, it has become increasingly relevant, some-

times even decisive, for both an individual’s

academic career and the rating of institutions. It is

also seen as an indicator of a journal’s quality and,

together with other factors, determines among other

things how attractive a journal is to authors.

Three years after acceptance of The World Journal

of Biological Psychiatry for indexing by Thomson ISI

we are thrilled to announce that our first impact

factor has put us in the upper league of psychiatric

journals. The World Journal of Biological Psychiatry

has achieved an impact factor of 2.800 for 2005, and

is ranked 31st of 94 journals in this field (Source:

2005 JCR Science Edition). To put this into

perspective, Schizophrenia Bulletin is ranked 30th

with an impact factor of 2.871, and Acta Psychiatrica

Scandinavica 28th with an impact factor of 2.968, to

name just two examples.

Our thanks go out to all those who have supported

The World Journal of Biological Psychiatry over the

past 6 years, without whom this great success would

never have been possible. Those to be thanked

include all authors, reviewers, associate editors and

editorial board members, members of WFSBP

Guideline Task Forces who invested time and effort

to prepare global treatment guidelines for various

psychiatric indications, the staff at Taylor & Francis

whose knowledge of and expertise in the world of

scientific publishing have advanced the Journal even

further since commencement of our cooperation at

the beginning of last year, the staff at the WFSBP

Global Headquarters, and last but not least the staff

at the Editorial Office.

Without wanting to dampen the excitement, some

problematic consequences associated with the per-

haps too great importance of the impact factor

should be mentioned here. An impact factor can

be manipulated by various means. For example, it is

known that among colleagues who are particularly

experienced with respect to the ‘impact currency’,

impact circles have already existed for a longer time

which push up the impact factor of all involved

through mutual citations. Anyone who does not join

such an impact circle can optimise his impact factor

by regularly citing his own articles. Also journals that

are worried about their impact factor have developed

regulating systems to improve it, for example by

motivating authors to cite earlier publications from

the journal whenever possible. A particular absurdity

is the fact that papers with bold hypotheses and

perhaps first relevant results achieve an especially

high impact factor, even when shortly afterwards

they are shown to be false. This absurdity even

happens with publications reporting falsified results.

Together with the newly introduced online manu-

script submission and administration system, Manu-

script Central, the impact factor can be expected to

cause an increase in the number and quality of

papers submitted to The World Journal of Biological

Psychiatry. Despite the elation about a relatively

good impact factor, it should not become decisive

for the future manuscript policy of the Journal of the

WFSBP, but the original idea behind the foundation

of the Journal should not be forgotten: a truly global

psychiatric journal that brings the whole world of

biological psychiatry to the whole world.

Hans-Jurgen Moller Rainer Rupprecht

Chief Editor Assistant Chief Editor

The World Journal of Biological Psychiatry, 2006; 7(3): 130

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

DOI: 10.1080/15622970600889521

REVIEW

Peripheral thyroid dysfunction in depression

KONSTANTINOS N. FOUNTOULAKIS, SOTIRIS KANTARTZIS, MELINA SIAMOULI,

PANAGIOTIS PANAGIOTIDIS, STERGIOS KAPRINIS, APOSTOLOS IACOVIDES &

GEORGE KAPRINIS

Laboratory of Psychophysiology, 3rd Department of Psychiatry, Aristotle University of Thessaloniki, University Hospital

AHEPA, Thessaloniki, Greece

AbstractThe involvement of the thyroid gland and thyroid hormones is generally believed to be important in the aetiopathogenesisof major depression. Major support comes from studies in which alterations in components of the hypothalamic�pituitary�thyroid (HPT) axis have been documented in patients with primary depression. However, screening thyroid tests areoften routine and add little to the diagnostic evaluation. Overt thyroid disease is rare among depressed inpatients. Thefinding that depression often co-exists with autoimmune subclinical thyroiditis suggests that depression may causealterations in the immune system, or that in fact it could be an autoimmune disorder itself. The outcome of treatment andthe course of depression may be related to thyroid status as well. Augmentation of antidepressant therapy with the co-administration of thyroid hormones (mainly T3) is a well-documented treatment option for refractory depressed patients.Review of the literature suggests that there are no conclusive data on the role of thyroid function in depression. It is clearthat depression is not characterised by an overt thyroid dysfunction, but it is also clear that a subgroup of depressed patientsmay manifest subtle thyroid abnormalities, or an activation of an autoimmune process. There is a strong possibility that thepresence of a subtle thyroid dysfunction is a negative prognostic factor for depression and may demand specific therapeuticintervention.

Key words: Depression, thyroid function, psychoneuroendocrinology

Introduction

There is a general and widespread belief among

psychiatrists that depression is characterised by

subtle neuroendocrinological disorders. The invol-

vement of the thyroid gland and thyroid hormones is

believed to be important.

The thyroid hormones (Reed and Pangaro 1995),

L�3,5,3?,5?-tetraiodothyronine (T4) and L�3,5,3?-triiofothyronine (T3) are synthesised by the follicu-

lar epithelial cells of the thyroid gland. This synthesis

requires the availability of iodine and is increased by

thyroid-stimulating hormone (TSH) from the ante-

rior pituitary gland. Some T4 is converted to T3

before release. These steps are under the influence of

TSH or other proteins that bind to the TSH

receptor. However, most T3 (80�85%) is derived

from extrathyroidal conversion of T4 in peripheral

tissue, mostly in the liver and kidney. The balance

between production and degradation is mediated by,

among other things, nutrition, non-thyroidal illness,

exercise, pregnancy and medications. Less than 1%

of the total circulating amount of each hormone is

free in the plasma (free T3-FT3, free T4-FT4).

Thyroid hormone regulation is directed through the

hypothalamic �pituitary� thyroid� peripheral tissue

axis. The system extends higher to neuroendocrine

modulation at the hypothalamus and lower to

peripheral thyroid hormone metabolism. This sys-

tem has autocrine (enzyme autoregulation), para-

crine (somatostatin, TRH) and hemocrine

autoregulation that is also influenced by environ-

mental factors (energy balance, circadian variation,

illness).

Depression itself is not a homogeneous disorder.

It is traditionally classified into two opposite poles

(Roth 1959; Van Praag et al. 1965; Overall et al.

1966; Fountoulakis et al. 1999), today named

‘melancholic’ (APA 1994) or ‘somatic’ syndrome

(WHO 1993) versus ‘atypical’ features (that is

Correspondence: K.N. Fountoulakis, MD PhD, 1st Parodos, Ampelonon Street 55535, Pournari Pylaia, Thessaloniki, Greece. Tel: �/30

2310 994622. Fax: �/30 2310 266570. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 131�137

(Received 23 November 2004; accepted 9 November 2005)

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

DOI: 10.1080/15622970500474739

‘reverse neurovegetative symptoms’, increased appe-

tite, weight gain, increased sleep and interpersonal

rejection sensitivity (Sargant 1960; Dally and Rohde

1961; Liebowitz et al. 1988)).

Of the various hypothalamic�pituitary-end organ

axes, the thyroid and adrenal systems are those most

often implicated in affective disorders. Patients

with primary thyroid disease have high rates of

depression, and patients with Addison’s disease or

Cushing’s syndrome have relatively high rates of

affective and anxiety symptoms. However, the major

support for the involvement of endocrine axes in the

pathophysiology of mood disorders comes from

studies in which alterations in components of the

hypothalamic�pituitary�thyroid (HPT) (Legros

et al. 1985; Staner et al. 1992; Rao et al. 1996)

and the hypothalamic�pituitary�adrenal (HPA)

axes (Mendlewicz et al. 1984; Kocsis et al. 1985;

Evans and Golden 1987; Nelson and Davis 1997)

have been documented in patients with primary

depression.

Thyroid dysfunction and depression

It has been argued that depression might be char-

acterised by a ‘low-thyroid function syndrome’

(Legros et al. 1985; Staner et al. 1992; Rao et al.

1996). Hypothyroidism is associated with anxiety

(Iacovides et al. 2000) or refractory depression,

suggesting that this characterises one biological

subtype of refractory depression. However, screen-

ing thyroid tests are often routine for depressed

inpatients, and data suggest that thyroid screening

may add little to the diagnostic evaluation. Overt

thyroid disease is rare among depressed inpatients

(Ordas and Labbate 1995), and the role of thyroid

hormones in the pathophysiology of affective dis-

orders remains to be clarified (Joffe and Sokolov

1994).

According to Musselman and Nemeroff (1996),

concerning the HPT axis, depressed patients have

been reported to have:

a. alterations in thyroid-stimulating hormone re-

sponse to thyrotropin-releasing hormone

(TRH);

b. an abnormally high rate of antithyroid antibo-

dies; and

c. elevated cerebrospinal fluid (CSF) TRH con-

centrations.

Moreover, tri-iodothyronine has been shown to

augment the efficacy of various antidepressants,

although opposite reports exist. All of the HPA axis

alterations in depression studied thus far are state-

dependent, whereas the HPT axis alterations may be

partially trait and partially state markers.

There are several papers suggesting that the

thyroid function of depressed patients is within the

normal range, hypothyroidism and hyperthyroidism

are extremely uncommon and that the presence of

subtle thyroid function abnormalities does not have

an impact on treatment outcome (Joffe 1987; Harris

et al. 1989; Fava et al. 1995; Joffe et al. 1996;

Haggerty et al. 1997; Pop et al. 1998). However, on

the contrary, there are even more papers supporting

the idea of a subclinical thyroid dysfunction, espe-

cially in melancholic or refractory patients, possibly

of an autoimmune origin (Banki et al. 1985;

Kjellman et al. 1985; Nemeroff et al. 1985; Gewirtz

et al. 1988; Marchesi et al. 1988; Nemeroff 1989;

Rao et al. 1989; Rupprecht et al. 1989; Howland

1993; Bunevicius et al. 1994; Maes et al. 1994a; Rao

et al. 1996) suggesting that subclinical hypothyroid-

ism may lower the threshold for the occurrence of

depression (Haggerty et al. 1993), or generally to

any mental disorder (O’Donnell et al. 1988; Stein

and Uhde 1989; Haggerty et al. 1990). Also, it has

been suggested that patients with bipolar disorder

are particularly sensitive to variations in thyroid

function within the normal range (Cole et al. 2002).

So, most patients with depression, although gen-

erally viewed as chemically euthyroid, may have

alterations in their thyroid function (Joffe et al.

1992; Custro et al. 1994; De Mendonca Lima et

al. 1996) including slight elevation of the serum FT4

(especially in melancholic patients) (Maes et al.

1993), blunted TSH response to thyrotropin-releas-

ing hormone (TRH) stimulation (Loosen 1985),

and loss of the nocturnal TSH rise, and this may

reflect brain hypothyroidism in the context of

systemic euthyroidism (Bauer et al. 1990; Jackson

1998; Sullivan et al. 1999).

Thyroid dysfunction, however, may constitute an

expression of a coordinated neuroendocrine-im-

mune response to nonthyroidal illness (Maes et al.

1994b), and this is in accord with the finding that

depressive symptoms are associated with positive

thyroid antibody status in the postpartum period

(Harris et al. 1992). The general idea is that while

patients with symptomless autoimmune thyroiditis

are clinically euthyroid, what might be symptomless

for the endocrinologist might be a syndrome pre-

senting with psychiatric symptoms to the psychiatrist

(Gold et al. 1982).

High (but within the normal range) serum TSH

(beyond the upper 25th percentile) is reported to be

positively associated with recurrent depression the

presence of somatic disease condition and the

number of suicide attempts (Berlin et al. 1999).

132 K. N. Fountoulakis et al.

Some data suggest that the 5-HT reduced activity

is more pronounced in those patients without HPT

axis abnormality. In this frame, HPT dysregulation

may be regarded as a compensatory mechanism for

diminished central 5-HTactivity (Duval et al. 1999),

which is a suggestion similar to another one pro-

posed concerning the hypothalamus�pituitary�adrenal axis (Fountoulakis et al. in press). These

just reflect the fact that the true relationship of

peripheral indices to brain function is always an open

question (Frye et al. 1999).

The availability of thyroid testing led to a bulk of

research on thyroid dysfunction in non-thyroidal

illness. Data suggest that, within a given patient’s

status, change of thyroid function is determined by

the severity and duration of illness as well as the

presence of mitigating influences that are associated

with the specific underlying disorders. These thyroid

disturbances in the frame of non-thyroidal illness

constitute a diagnostic problem which needs focused

attention. Figure 1 represents a graphical solution

suggested by Kaptein (1993), and includes data

from our group (Fountoulakis et al. 2001). In this

figure, it is evident that most depressed patients are

clearly euthyroid, with some of them falling in the

‘non-thyroid illness’ area. The most prevalent and

pronounced anomaly in the parameters of thyroid

function during a non-thyroidal illness is a decrease

in the serum total and free T3 levels. This is present

in 70% or more of hospitalised patients and is

considered to be the conditio sine qua non of the

euthyroid sick syndrome (Bermudez et al. 1975).

The effect of prolonged fasting on the FT3 levels is

important, since they start to descend within the first

24 hours and reach a plateau within 1�2 weeks. FT4

levels are either normal or slightly increased, while

TSH levels return to baseline within 96 hours

(Burch, 1995).

The autoimmune hypothesis

The hypothalamus�pituitary�thyroid axis (HPT) is

not isolated from the rest of the endocrine system,

and it is heavily influenced by autoimmune disorders

and stress. It seems that conditions associated with

significant changes in the stress system activity, such

as acute or chronic stress or even cessation of

chronic stress, severe exercise, pregnancy, the post-

partum period, and anxiety and mood disorders,

may suppress or potentiate autoimmune diseases

activity and/or progression through modulation of

the systemic or local pro/anti-inflammatory cytokine

balance (Elenkov and Chrousos 2002). It has been

also reported that patients affected by coeliac disease

tend to show a high prevalence of personality and

major depressive disorders. Association with sub-

clinical thyroid disease appears to represent a

significant risk factor for these psychiatric disorders

(Carta et al. 2002, 2003).

Depressed patients are reported to have an

abnormally high rate of antithyroid antibodies

(Musselman and Nemeroff 1996).

The finding that depression often co-exists with

autoimmune subclinical thyroiditis suggests that

depression may cause alterations in the immune

system, or that in fact it could be an autoimmune

disorder itself.

Microsomal antibodies are frequently present in

patients with chronic lymphocytic thyroiditis, while

thyroid binding inhibitory immunoglobulins inhibit

the binding of TSH to its receptor, and lead to

hypothyroidism.

Whereas acute stress may initiate a transient

immunologically protective response, prolonged or

poorly controlled psychosocial stressors may result

in depression of different components of the im-

mune system. These responses may be related to, or

independent of, changes in the neuroendocrine

FT4

TSH (mU/lt)

0 10 20 30 40 50 60 70

Primary Hypothyroidism

Primary Hyperthyroidism

Non-Thyroidal Illness

100.00

1.00

0.0

Normal reference range

Figure 1. Bivariate scatterplot between TSH and FT4 levels. There is no difference between the two groups of patients. All depressed

patients are located within the area of non-thyroidal illness

Peripheral thyroid dysfunction in depression 133

system. As the rather prolific literature in this infant

area of psychoneuroimmunology reveals, there are

many complex levels of interaction that require

further investigation (Schindler, 1985), concerning

a close relationship between delayed hypersensitivity

to neural tissue antigens and immunopsychiatric

diseases, and they may imply that cell-mediated

immune mechanisms may be involved in the patho-

genesis of certain mental disorders (Jankovic 1985).

It is also believed (although not well documented)

that depression is accompanied by various direct and

indirect indicators of a moderate activation of the

inflammatory response system. Increased produc-

tion of proinflammatory cytokines, such as inter-

leukin-1, interleukin-6 and interferon (IFN-g), may

play a crucial role in the immune and acute phase

response in depression (van West and Maes 1999).

However, the research in the area of psychoim-

munology is very delicate and one should be very

careful in interpreting results. Apart from problems

arising from the limitations in laboratory techniques

themselves, depressed patients may suffer from

secondary alterations of immune function, while

controls may be ‘super-normal’.

Gestation and the postpartum period

Although some authors report that the presence of

abnormal thyroid function tests is not related to a

distinct clinical picture (Kent et al. 1999), others

suggest that serum T4 levels may be lower in

seasonally affected patients (Sher et al. 1999), and

an elevated level of peroxidase antibodies may be

related to depression in perimenopausal women

(Pop et al. 1998). However, again, the literature is

split and the results are inconclusive (Kuijpens et al.

2001; Lucas et al. 2001; Harris et al. 2002). The

most robust relationship between thyroid dysfunc-

tion and depression concerns gestation and the

postpartum period. Thyroid antibody-positive wo-

men are prone to hypothyroidism, which is often

preceded by transient hyperthyroidism after delivery

(Harris et al. 1992; Harris 1999). Also, lower range

total and free thyroxine concentrations during late

pregnancy may be related to postpartum depressive

symptoms (Pedersen 1999).

Response to treatment and long-term outcome

It was mentioned above that successful therapy

alleviates thyroid dysfunction, if present. There are

not many studies on this issue. One study reported a

significant reduction of 11.2% in thyroxine during

treatment with 20 mg paroxetine in 25 severely

depressed patients (Konig et al. 2000). It has also

been reported that 4 weeks of sertraline treatment

leads to increased plasma cortisol levels, while a 24-

week treatment leads to increased plasma T3 levels

in depressed patients (Sagud et al. 2002). On the

contrary, other authors report no effect on thyroid

function (Schule et al. 2005) Another study

(blinded, placebo-controlled) reported that repeated

transcranial magnetic stimulation over the prefrontal

cortex administered to healthy individuals, produces

acute elevations of mood and serum TSH (Szuba et

al. 2001). The same results are reported concerning

sleep deprivation. However, it is suggested that sleep

deprivation responders compensate by secreting

more TSH with normal bioactivity while, on the

contrary, non-responders compensate by secreting

TSH with increased bioactivity (Orth et al. 2001).

Responders were also reported to have lower T3

uptake levels than non-responders in both prospec-

tive and retrospective studies (David et al. 2000).

The outcome of treatment and the course of

depression seem to relate to thyroid status as well.

Time to recurrence is reported to be inversely

related to T3 levels but not to T4 levels (Joffe and

Marriott 2000). But again, opposite reports exist

(Joffe 1999).

There is an open question concerning the role of

subtle thyroid dysfunction in the long-term outcome

of depression. There are scarce reports that cognitive

deficits caused by hypothyroidism persist after

patients return to euthyroid status, with concentra-

tion, recall and short-term memory appearing to be

most severely affected (Leentjens and Kappers

1995). Several risk factors have been proposed for

Alzheimer’s disease (AD), among them depression

(Broe et al. 1990; Kokmen et al. 1991), and prior

thyroid disease (Heyman et al. 1984).

Augmentation of antidepressant therapy with the

co-administration of thyroid hormones (mainly T3)

is a well-documented treatment option for refractory

depressed patients, and although no clear biochem-

ical or clinical predictors of preferential response to

T3 have been found, its effect may be related to

thyroid function even within the normal range.

Surprisingly, only minimal side-effects have been

reported in the literature (Nemeroff 1996; Joffe

1997, 1998; Post et al. 1997; Cadieux, 1998;

Sussman and Joffe 1998; Thase et al. 1998; Shelton

1999; Dording 2000; Fava 2000; Joffe and Sokolov

2000; Marangell 2000; Bauer 2002; Bauer et al.

2002; Agid and Lerer 2003; Altshuler et al. 2003;

Pridmore and Turnier-Shea 2004).

Recently, a study of our group suggested that

depressed patients who responded well to treatment

might have lower FT4 and TSH as well as TBII,

but higher FT3 levels in comparison to poor

responders. That study suggested that when

the function 20.86�1.52*[FT4]�0.98*[TSH]�/

134 K. N. Fountoulakis et al.

0.74*[FT3]�0.07*[TBII] takes values above zero,

the patient is likely to be a good responder (with

89.47% chance of correct prediction) (Fountoulakis

et al. 2004).

However, this function is yet to be validated, and

has been reported in only one study. It needs further

research and validation, and currently is not recom-

mended for clinical use.

Conclusion

Thus, a review of the literature suggests that there

are no conclusive data on the role of thyroid function

in depression. It is clear that depression is not

characterised by an overt thyroid dysfunction. It is

also clear that a subgroup of depressed patients may

manifest subtle thyroid abnormalities, or an activa-

tion of an autoimmune process; however, the cause

of this phenomenon and its implications are unclear.

There is a strong possibility that the presence of a

subtle thyroid dysfunction is a negative prognostic

factor for depression and may demand specific

therapeutic intervention.

Statement of interest

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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Peripheral thyroid dysfunction in depression 137

REVIEW

Melatonin in mood disorders

VENKATARAMANUJAN SRINIVASAN1, MARCEL SMITS2, WARREN SPENCE3,

ALAN D. LOWE3, LEONID KAYUMOV3, SEITHIKURIPPU R. PANDI-PERUMAL3,4,

BARBARA PARRY5 & DANIEL P. CARDINALI6

1Department of Physiology, School of Medical Sciences, University Sains Malaysia, Kubang Kerian, Kota Bharu, Kelantan,

Malaysia, 2Gelderse Vallei Hospital, Department of Neurology and Sleep Disorders, Ede, The Netherlands, 3Sleep and

Neuropsychiatry Institute (SNI), Scarborough, ON, Canada, 4Comprehensive Center for Sleep Medicine, Division of

Pulmonary, Critical Care, and Sleep Medicine, Mount Sinai School of Medicine, New York, NY, USA, 5Department of

Psychiatry, University of California, San Diego, La Jolla, CA, USA, and 6Departamento de Fisiologıa, Facultad de

Medicina, University of Buenos Aires, Buenos Aires, Argentina

AbstractThe cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep�wake and core body temperature rhythms, all suggest that dysfunction of the circadian time keeping system may underlie thepathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses hasgained attention. Melatonin can be both a ‘state marker’ and a ‘trait marker’ of mood disorders. Measurement of melatonineither in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations inmelatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing ofmelatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phasedelay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion.Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD,winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.

Key words: Melatonin, mood disorders, depression, bipolar affective disorder, seasonal affective disorder

Introduction

Mood disorders comprise a group of psychiatric

disorders in which pathological mood and related

psychomotor disturbances dominate the clinical

picture. The cluster of signs and symptoms is

sustained over a period of weeks to months and

tends to recur often in a period or in a cyclical

fashion (Kahn 1999). The most common mood

disorders are major depressive disorder, bipolar

affective disorder, mania and seasonal affective

disorder (SAD), winter type. Cycles of recurrence

are manifested in these disorders interspersed with

periods of euthymia. Since mood disorders are cyclic

in nature, disturbances in circadian rhythms have

been often implicated as one of the major precipitat-

ing factors for these disorders. However, it is not

clear whether this relationship is causal or is only an

epiphenomenon of the disease.

Periodic episodes of depression and mania are

usually linked to disorders of the time-keeping

system. Epidemiological studies reveal that insomnia

is a prominent comorbidity of depression (Riemann

et al. 2001). Sleep loss is a major risk factor for

occurrence of mania in patients with bipolar disorder

(Wehr 1991). Many studies place emphasis on the

importance of stable sleep�wake rhythms and

proper sleep hygiene for preventing relapses in

bipolar disorders (Frank et al. 1997).

A large number of studies undertaken in recent

years have clearly shown that the pineal hormone

melatonin (N-acetyl-5-methoxytryptamine) is in-

volved not only in the regulation of sleep and

sleep�wake rhythms but of many circadian functions

(Pandi-Perumal et al. 2005). In circadian rhythm

disorders, the disturbances in melatonin rhythm

and amplitude have become prominent features

Correspondence: Dr D.P. Cardinali, Departamento de Fisiologıa, Facultad de Medicina, UBA, Paraguay 2155, 1121 Buenos Aires,

Argentina. Tel/Fax: �/54 11 59509611. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 138�151

(Received 5 October 2005; accepted 3 January 2006)

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

DOI: 10.1080/15622970600571822

(Srinivasan 1997; Srinivasan et al. 2006). Both the

amplitude and rhythm of melatonin secretion are

altered in patients suffering from both major depres-

sive disorder as well as in patients suffering from

bipolar affective disorder (Tuunainen et al. 2002;

Wetterberg 1999). The onset, offset and duration of

melatonin secretion has been found altered in major

depressive disorders and in bipolar affective disorder

patients.

This review discusses the role of melatonin in

mood disorders with emphasis in SAD. The changes

of melatonin secretion in major depressive disorder

and the response of melatonin to treatment with

antidepressants will be also analysed. The hypothesis

as to whether or not internal desynchronization and

changes in melatonin rhythmicity participates in the

genesis of bipolar affective disorder will be discussed.

Lastly, the activity of melatonin as an antidepressant

in delayed sleep phase syndrome (DSPS) with com-

orbid depression will be analysed in some detail.

Generally, the studies discussed were selected based

on their relevance and of the quality of their

scientific evidence.

Melatonin: Biosynthesis and physiological

effects

Melatonin is the major product secreted from the

pineal gland of all animals and in man. Extrapineal

synthesis of melatonin occurs in places like the

retina, the gastrointestinal tract, bone marrow and

lymphocytes; however, circulating melatonin only

derives from the pineal gland (Cardinali and Pevet

1998; Claustrat et al. 2005). Tryptophan serves

as the precursor for melatonin biosynthesis. It is

hydroxylated at C5 position and then decarboxy-

lated to form serotonin. Serotonin is N-acetylated

by the enzyme serotonin N-acetyltransferase, the

rate-limiting hormone to form N-acetylserotonin.

Serotonin N-acetyltransferase activity increases

30�70-fold at night. N-Acetylserotonin is finally

O-methylated by the enzyme hydroxyindole O-

methyltransferase (HIOMT) to form melatonin.

Melatonin production occurs at night in all species

irrespective of whether they are nocturnal or diurnal.

The rhythm of melatonin secretion is endogenous

and is driven by the suprachiasmatic nucleus of the

hypothalamus (SCN), the so-called ‘biological

clock’. The rhythm is synchronized to a 24-h day/

night cycle by light acting through the retinohy-

pothalamic pathway in animals and human beings

(Cardinali and Pevet 1998; Claustrat et al. 2005).

Exposure of animals to light at night rapidly

depresses pineal melatonin synthesis. Based on

denervation or nerve stimulation studies, a simple

model of pineal regulation was envisioned, compris-

ing two premises: (1) the neural route for environ-

mental lighting control of melatonin secretion is the

neuronal circuit ‘retina�retinohypothalamic tract�SCN�periventricular hypothalamus�intermediolat-

eral column of the thoracic chord gray�superior

cervical ganglion (SCG)�internal carotid nerves�pineal gland’, (2) norepinephrine released from

sympathetic terminals at night activates postsynaptic

b-adrenoceptors coupled to the adenylate cyclase�cAMP system, therefore increasing melatonin synth-

esis and release. However, the presence of functional

a-adrenoceptors as well as the characterization of

central peptidergic pinealopetal pathways point to a

complexity of mechanisms regulating melatonin

biosynthesis (Cardinali and Pevet 1998; Claustrat

et al. 2005).

Once formed, melatonin diffuses out into the

capillary blood and the cerebrospinal fluid (CSF)

(Arendt 2000; Tricoire et al. 2002). The delicate

connective tissue capsule of the pineal gland does

not prevent diffusion of melatonin into CSF. Mela-

tonin arrives early in the third ventricle CSF as

compared with the lateral ventricles. As melatonin

passes through all biological membranes with ease,

brain tissue has higher melatonin levels than other

tissues in the body (Reiter and Tan 2002). Indeed,

CSF melatonin levels have been found to be 5 to 10

times higher than those of melatonin in blood

(Tricoire et al. 2002).

Human plasma melatonin rhythm is remarkably

constant within the same individual and occurs with

invariant regularity from day to day and week to

week. However, melatonin production exhibits con-

siderable inter-individual differences (Macchi and

Bruce 2004), with more than 10-fold variability in

nocturnal plasma melatonin concentrations among

individuals (Zeitzer et al. 1999). The finding that,

compared to the general population, the variability

of rhythmicity in melatonin production is reduced in

siblings suggests that it may have a genetic basis

(Griefahn et al. 2003). Melatonin concentrations in

body fluids over a 24-h period have been found to be

useful for investigating the ‘free running rhythm

failure’ encountered in certain subtypes of depres-

sive patients, a fact which has been interpreted by

some (Wetterberg 1999) to support either a phase

advance or phase delay hypotheses of mood dis-

orders.

Melatonin is involved in the control of various

physiological functions like seasonal reproduction

(Reiter 1980), sleep regulation (Monti et al. 1999;

Wurtman and Zhdanova 1995), immune function

(Esquifino et al. 2004; Guerrero and Reiter 2002),

inhibition of tumor growth (Blask et al. 2002), blood

pressure regulation (Doolen et al. 1998; Scheer et al.

2004), retinal physiology (Dubocovich et al. 1999)

Melatonin in mood disorders 139

and control of circadian rhythms (Dawson and

Armstrong 1996; Kunz 2004), control of human

mood and behavior (Srinivasan 1997) and free

radical scavenging (Reiter et al. 2005). Melatonin

participates in many of the respective mechanisms

by acting through G-protein coupled membrane

receptors like MT1 and MT2 (Dubocovich et al.

2000; Reppert et al. 1994, 1995) and nuclear

receptors like RZR/ROR (Wiesenberg et al. 1995).

Within the G-protein coupled receptor family of

proteins, melatonin acts through a number of signal

transduction mechanisms that ultimately result in

specific physiological responses (Witt-Enderby et al.

2003). In addition to receptors in the proper sense,

melatonin acts through another binding site, origin-

ally thought to represent another membrane-bound

receptor (MT3), but later confirmed to be the

enzyme quinone reductase-2 (Nosjean et al. 2000).

Melatonin also binds directly to calmodulin and

cytoskeletal proteins (Benitez-King et al. 1996).

Melatonin in major depressive disorder

For a diagnosis of a major depressive disorder at

least five of the following symptoms must have been

present continuously for more than 2 weeks: (1)

depressed mood, (2) markedly diminished interest in

work, (3) significant weight loss, (4) insomnia or

hypersomnia, (5) psychomotor agitation, (6) fatigue

or loss of energy, (7) feelings of worthlessness,

(8) diminished ability to concentrate, (9) recurrent

thoughts of death (Kahn 1999). The nature and

extent of disruption of melatonin secretion in major

depressive disorder has been under intense investi-

gation during the last few decades, ever since

Wetterberg and co-workers (1979) formulated the

‘low melatonin syndrome’ hypothesis, i.e., the con-

cept that low melatonin secretion can be a biological

marker for susceptibility to depressive disorders.

Numerous studies have substantiated a deficiency

of melatonin secretion in depressives (Brown et al.

1985a,b; Claustrat et al. 1984; Miles and Philbrick

1988; Nair et al. 1984; Paparrigopoulos et al. 2001;

Sack and Lewy 1988; Venkoba rao et al. 1983;

Zeiten et al. 1987). In some studies clinical symp-

toms such as suicidal ideas correlated with the

decrease in melatonin levels (Venkoba Rao et al.

1983). It has been suggested that the low melatonin

levels seen in depressives are due to low norepi-

nephrine and serotonin levels in the brain (Arendt

1989).

Measurement of melatonin in the body fluids such

as plasma or saliva, or of its metabolite 6-sulfatox-

ymelatonin in the urine, is a reliable index of

noradrenergic activity. In a study undertaken in

patients with major depressive disorder, Paparrigo-

poulos et al. (2001) reported that the administration

of clonidine, a partial a2-adrenergic agonist, reduced

melatonin levels in depressives but not in healthy

controls. The authors concluded that depressive

symptoms could be due to a supersensitivity of a2-

adrenoceptors that in turn would result in reduced

norepinephrine release from sympathetic nerve

terminals and reduced melatonin secretion from

the pineal gland.

Additional evidence suggests a more complex

model of melatonin dysfunctionality than that of a

deficiency of melatonin production. For instance,

the number of studies reporting low melatonin levels

in depressives is at least equaled by those document-

ing increases in melatonin production (Crasson et al.

2004; Rubin et al. 1992; Sekula et al. 1997; Shafii

et al. 1997; Stewart and Halbreich 1989; Szymanska

et al. 2001; Thompson et al. 1988).. Rubin et al.

(1992) noted that in both men and women who were

diagnosed as having major depressive disorder,

nocturnal melatonin secretion increased significantly

above the average seen in normal subjects. The

authors could not find any relationship between

melatonin levels and depressive symptomatology nor

any particular type of depression. In addition to high

nocturnal melatonin levels, a late nocturnal peak

time of melatonin secretion was noted in patients

(Rubin et al. 1992). Higher nocturnal serum mela-

tonin levels were found in female depressives (Sekula

et al. 1997). In depressive patients classified into two

categories, those with Hamilton depression scores of

20�29 points and those with scores of 30�40 points,

high diurnal serum melatonin levels were observed

in parallel with higher Hamilton scores (i.e. with a

greater intensity of depressive symptoms) (Szy-

manska et al. 2001). With respect to nocturnal

melatonin levels, both groups of depressive patients

exhibited significantly higher melatonin levels when

compared to healthy controls of the same age group.

Treatment of patients with clorimipramine for a

period of 8 weeks significantly reduced mean mela-

tonin levels, although even after complete remission

those levels continued to be high as compared to

controls (Szymanska et al. 2001). The authors

attributed the elevated melatonin levels encountered

in their depressive patients to some kind of bio-

chemical defect in the retina or to a disrupted

homeostasis between the SCN and the pineal gland.

Crasson et al. (2004) also reported a significant

elevation of daytime urinary 6-sulfatoxymelatonin

secretions among depressives. In a study on 382

postmenopausal women, a positive family history

of depression was associated with longer duration

of 6-sulfatoxymelatonin excretion (Tuunainen et al.

2002). This study suggested a familial vulnerability

140 V. Srinivasan et al.

in endogenous melatonin signal in subjects prone to

depression.

The discordant results on melatonin levels in

depressive patients may well reflect subcategories

of illness. Inasmuch as a drop or rise in melatonin

levels is paralleled by comparable alterations in

serotonin levels, it may be relevant here to allude

briefly to the extensive research on the two bio-

chemical subtypes of endogenous depression: those

with low dopamine levels and those with low

dopamine plus low serotonin; the second group is

the most severe, the ‘impulsive depressives’, and at

the greatest risk for suicide. According to Wetterberg

(1999), patients with low melatonin syndrome are

different clinically and biochemically from patients

with normal or high melatonin secretion. Proper

identification of these subgroups of patients is

essential for designing a specific pharmacotherapy

to correct the underlying abnormality. In any event,

the disturbance of melatonin secretion in patients

with major depression supports the suspicion of

photoperiodic abnormality in depression.

A study performed in 459 postmenopausal women

revealed that those patients experiencing lower

levels of illumination had more depression and more

complaints of sleep disturbance (Kripke et al. 2004).

It was further noted that Hispanic African women

suffered more depression due to low levels of illumi-

nation than Native American women, thus revealing

ethnic differences in depression related to restrictions

in light exposure (Kripke et al. 2004). In a study of

pregnant women with major depressive disorder

according to Diagnostic and Statistical Manual of

Mental Disorders IV (DSM�IV) (American Psychia-

tric Association 1994), bright light treatment advan-

ced the melatonin rhythm and improved symptoma-

tology, thus supporting the applicability of bright light

therapy to treat antepartum depression (Epperson

et al. 2004).

Melatonin phase position in major depressive

disorder

In addition to changes in the amplitude of diurnal or

nocturnal melatonin secretion, a number of studies

have analysed melatonin rhythm in depressives. In

patients with major depressive disorder there is a

phase advance of melatonin rhythm (Beck-Friis et al.

1985a; Branchey et al. 1982; Claustrat et al. 1984;

Nair et al. 1984; Wehr et al. 1985). Beck Friis et al.

(1985a) studied the number of nocturnal melatonin

peaks that occurred in their sample before and after

01:00 h. The depressive patients with an abnormal

dexamethasone suppression test response had a

trend toward significantly earlier melatonin peaks

than those with a normal response to dexamethasone

or controls.

Indeed, a phase shift of melatonin secretion is a

prominent feature of major depressive disorder.

Rubin et al. (1992) noted a trend towards a later

peak (phase delay) in nocturnal melatonin secretion.

In a study on 14 depressive patients, Crasson and

co-workers (2004) found a delay of 77 min in the

serum melatonin peak when compared to normal

controls of the same age and at the same month of

sampling. As far as the onset in nocturnal melatonin

production, Rubin et al. (1992) reported that it

began at 21:00 h, and reached a maximum level at

around 03:00�05:00 h in depressives. This was in

contrast to that seen in normal subjects in which the

nocturnal melatonin onset began at around 23:00 h.

Thus, a trend towards earlier onset of melatonin

secretion was noted in depressed patients as com-

pared to normal healthy controls.

Sekula et al. (1997) found a significant correlation

between a delay in the offset of serum melatonin and

delayed acrophase with lifetime major depressive

disorder. A significant delay in the onset of urinary

6-sulfatoxymelatonin excretion was reported in post-

menopausal women with major depressive sympto-

matology (Tuunainen et al. 2002). The duration of

melatonin secretion was also longer than that

observed in healthy controls. Collectively, the results

suggest that it is the melatonin offset that is delayed

in major depressives. Offset melatonin time is signi-

ficant in determining the duration of melatonin

secretion.

Melatonin response to treatment with

antidepressants

The response of melatonin secretion to antidepres-

sant treatment has been studied. Chronic treatment

with desmethylimipramine for a period of 3 weeks

increased the amplitude of melatonin secretion

(Thompson et al. 1985). In another study, treatment

with imipramine for 2 weeks increased melatonin

excretion (Venkoba Rao et al. 1983). Sack and Lewy

(1986) reported a sustained increase in urinary 6-

sulfatoxymelatonin levels in depressed patients after

treatment with desipramine for a period of 3 weeks.

Golden et al. (1988) reported a significant increase

in 6-sulfatoxymelatonin excretion in depressives

following treatment with either imipramine or the

monoamine oxidase inhibitor bupropion. Experi-

mental studies in rats have also revealed that the

administration of imipramine increased pineal mel-

atonin content significantly (Srinivasan 1989).

A deficiency of norepinephrine at the synaptic

cleft of postganglionic sympathetic nerve fibres origi-

nating in the SCG resulted in a decrease of

Melatonin in mood disorders 141

melatonin production by the pineal gland as demon-

strated by the studies of Paparrigopoulos et al.

(2001). Taking the pineal neuroendocrine junction

as an end point is useful for considering the role of

catecholamines in the regulation of mood, and in

particular, how melatonin can be involved in this

process.

Several studies have supported the hypothesis that

melatonin secretion is an index of norepinephrine

activity in depressed patients. The evidence obtained

is consistent with Schildkraut’s original ‘catechola-

mine hypothesis of depression’ (Schildkraut 1965)

and can be considered an extension or corollary of it.

The clinical evidence indicating that antidepressant

drug treatment changes melatonin secretion in major

depressive disorder patients points to the possibility

that the pineal gland may play a role in the aetiology

of mood disorders. Higher serum melatonin levels

were found in patients suffering from major depres-

sive disorder which decreased after pharmacological

treatment (Varma et al. 2002). In another study in

patients diagnosed of major depressive disorder who

failed to respond to pharmacological therapy, elec-

troconvulsive therapy brought about a significant

decrease in depression symptomatology and urinary

6-sulfatoxymelatonin excretion (Krahn et al. 2000).

A close association between depressive symptoms

and delayed offset of 6-sulfatoxymelatonin excretion

occurred, indicating that the timing of melatonin

secretion may be important in depression (Tuunai-

nen et al. 2002).

Internal desynchronization and bipolar

affective disorder

Bipolar affective disorders are characterized by the

occurrence of mania or hypomania either preceded

or followed by episodes of depression. Bipolar I is

characterized by episodes of mania and depression,

while in bipolar II disorder, hypomania is preceded

or followed by major depression (Kahn 1999).

According to DSM-IV criteria for mania, the follow-

ing symptoms should be present for at least 1 week:

(1) inflated self esteem, (2) decreased need for sleep,

(3) more talkative, (4) flight of ideas, (5) distract-

ibility, (6) excessive involvement (Kahn 1999).

Several clinical features of bipolar disorder suggest

that disturbances in the timing or phase position of

circadian rhythms may play a role in precipitating

the disorders. Patients with bipolar disorder often

exhibit an infradian sleep/wake rhythm, i.e. the

patients forego sleep in a complete night between

two nights of normal sleep (Wehr et al. 1982).

Studies of sleep in recurrent depressive and

bipolar affective disorders have been useful for

theoretical considerations about the aetiology and

pathophysiology of the disease. Bunney and his co-

workers (1970) first noted that bipolar depressive

patients exhibited marked reduction in sleep during

the night before they switched from depression.

These observations were subsequently confirmed

(e.g., Sitaram et al. 1978). Manic-depressive pati-

ents at the beginning of a manic episode exhibited

one or more 48-h rest�activity cycles, i.e. the pati-

ents spent one complete sleepless night in between

two nights of normal sleep (Wehr and Goodwin

1979).

Similar responses have been observed in healthy

human subjects after a few weeks of exposure to

constant environmental conditions. The period of

rest/activity cycle lengthened to 45 h, whereas their

temperature and rapid eye movement (REM) sleep

rhythms remained synchronized to 25 h, resulting in

internal desynchronization (Wever 1986). The simi-

larities between bipolar patients and healthy human

subjects in an internal desynchronization situation

suggest that bipolar disorders imply internal desyn-

chronization. Kripke et al. (1978) hypothesized that

mania and depression are the result of a beat pheno-

menon generated when two rhythms go in and out of

phase. The hypothesis that internal desynchroniza-

tion causes a change in mood has gained support

from sleep deprivation studies also. Not only do

anxious patients exhibit significant sleep distur-

bance, but conversely sleep deprivation produces

elevations in anxiety symptoms (Bourdet and Gold-

enberg 1994). Indeed, depression has a significant

anxiety component, e.g., eight questions on the

Hamilton Anxiety Scale are shared in common

with the Hamilton Depression Scale.

The disturbance of circadian rhythms seen in

bipolar disorders can be due to disturbance in the

function of the SCN�pineal�melatonin link. In-

deed, melatonin has a regulating effect on the SCN

causing entrainment of circadian rhythms to a

natural 24-h cycle via MT2 receptors.

Melatonin amplitude and rhythm in bipolar

affective disorder

As a rhythm-regulating factor and a hormone

involved in the physiological regulation of the

sleep�wake rhythm, melatonin has drawn the atten-

tion of investigators studying bipolar affective dis-

orders. In view of its central role as an internal

synchronizer (Zeitgeber), melatonin fits more appro-

priately with bipolar illness than with any other type

of psychiatric disorder.

In a study on melatonin levels in unipolar and

bipolar depressive patients, Beck-Friis et al. (1985b)

noted significantly lower melatonin levels in euthy-

mic bipolar patients. Souetre et al. (1989) reported

142 V. Srinivasan et al.

reduced amplitude of melatonin secretion in 11

bipolar patients during the depressive phase that

came back to normal on remission. In a longitudinal

study of a single manic-depressive patient, an

increase in melatonin secretion was noted during a

manic phase was noted that was twice that of

melatonin levels during the euthymia and depressed

phases (Kennedy et al. 1989).

Based on melatonin level studies in bipolar

patients, Lewy et al. (1985) concluded that the

amplitude of melatonin secretion is state-dependent

rather than reflecting brain noradrenergic activity.

Kennedy and co-workers (1996) studied nine bipo-

lar patients during manic, depressed and euthymic

states. Serum melatonin levels were lower during

euthymic, depressed and manic phases, when com-

pared with healthy normal controls. The authors

concluded that the decreased melatonin production

is a trait marker and not a state marker of bipolar

disorders (Kennedy et al. 1996).

Numerous studies have demonstrated that the

phase of melatonin secretion varies systematically

with mood changes in bipolar affective disorder.

Lewy et al. (1979) were the first to report changes in

phase position of melatonin levels in bipolar pa-

tients. In a study of four manic patients, they found a

phase advance of melatonin levels when compared to

normal subjects. In a longitudinal study of a single

manic patient, Kennedy et al. (1989) noted a phase

advance of the nocturnal melatonin peak during the

manic phase which preceded that of the euthymic or

depressed phases by at least 1 h (i.e. the melatonin

peaks occurred at 03:00 h in the manic phase, at

04:00 h during the euthymic phase and at 05:00 h in

the depressed phase).

Several studies have demonstrated that bipolar

patients can be treated according to the chronobio-

logical principles, such as exposure to bright light or

administration of melatonin, which are used for

other phase disordered patients who do not have

depressive symptomatology (Leibenluft et al. 1997).

Bright light shifted melatonin levels, with morning

light advancing the melatonin rhythm and evening

light delaying melatonin rhythm (Minors et al.

1991). The use of morning bright light caused

bipolar patients in a hypomaniac phase to cycle

more dramatically. Liebenluft et al. (1997) observed

that the administration of 5�10 mg of melatonin in

the evening (or midday administration of bright

light) stabilized the phase of endogenous melatonin

rhythm. In another study, abnormalities of melato-

nin secretion were reported in bipolar I patients with

delayed peak melatonin time and baseline melatonin

levels lower than 60 pg/ml (Nurnberger et al. 2000).

To what extent the changes in melatonin observed

were related to the pharmacotherapy per se or to the

improvement in the depressive symptoms remains to

be defined.

Light suppression of nocturnal melatonin

secretion in bipolar affective disorder

The natural light�dark cycle plays an important role

in regulating circadian rhythms. Retinal stimulation

by light sends a tonic stimulatory signal to the SCN.

In turn, the SCN inhibits the firing of neurons in the

paraventricular nucleus (PVN) to regulate melatonin

secretion by the pineal gland. During nighttime

hours, when the SCN is not stimulated by light,

the neurons of the PVN are released from SCN

inhibition and pineal melatonin secretion is stimu-

lated. Signals initiating this process are transmitted

through the multisynaptic pathway involving the

median forebrain bundle, the intermediolateral col-

umn of the upper thoracic spinal cord and the SGG

(Moore 1996).

Lewy et al. (1980) were the first to demonstrate

that light of an intensity higher than 500 lux

suppresses melatonin secretion in human beings.

Subsequently, the same authors showed that sup-

pression of melatonin secretion by 500-lux light was

greater in manic-depressive patients (Lewy et al.

1981). In this study they found that exposure to

500 lux caused a 50% suppression of melatonin

levels in manic-depressive patients but had no effect

in controls. Therefore, an increased responsiveness

to light in manic-depressives could explain the

circadian rhythm abnormalities seen (such as phase

advances in temperature or REM sleep rhythms). In

another study of 11 euthymic bipolar patients,

exposure to 500 lux of light at 02:00 and 04:00 h

caused suppression of melatonin by 61.5% as

compared to age- and sex-matched control subjects,

in which exposure to light caused only 28% suppres-

sion of melatonin secretion (Lewy et al. 1985). The

authors concluded that an increased sensitivity to

light might be a trait marker for bipolar affective

disorder. The fact that some normal subjects also

exhibited increased sensitivity to light pointed to the

possibility that those normal individuals could be at

risk for developing a mood disorder.

In a study carried out in 29 euthymic bipolar

patients, 24 patients with unipolar depression and 50

non-psychiatrically ill control subjects, Nurnberger

et al. (2000) found a 29.8, 32.2 and 34.6% of light-

induced melatonin suppression in bipolar, unipolar

and control groups, respectively. Although no evi-

dence could be obtained for increased suppression

of melatonin secretion in bipolar patients, when

bipolar patients were sub-divided, patients with

bipolar I disorder showed a trend towards increased

dark-adjusted melatonin suppression (62.7%) as

Melatonin in mood disorders 143

compared to matched controls (40.0% suppression).

Taken together these findings, they support the

hypothesis that excessive light-induced suppression

of melatonin secretion may be a risk factor for

development of a mood disorder. What remains

to be established is what mechanism or factor(s)

mediates this light-induced suppression response.

Three meta-analyses published by Cochrane data-

bases support the efficacy of light therapy in mood

disorders (Forbes et al. 2004; Montgomery and

Dennis 2002; Tuunainen et al. 2004).

Melatonin in SAD

SAD, winter type, is characterized by recurrent

episodes of depression during winter months and

euthymia or hypomania in spring or summer. First

documented by Rosenthal et al. (1984), the major

symptoms of this disorder were noted to be

hypersomnia, hyperphagia, carbohydrate craving or

weight gain. Since some SAD patients suffer from

reduced appetite, weight loss and insomnia, at least

two clinical types of SAD (corresponding to the

atypical and melancholic feature specifier according

to DSM-IV) can be distinguished.

Patients suffering from SAD also exhibit delayed

circadian rhythms, and according to Lewy and co-

workers (1987, 1988) it is the phase delay of the

circadian pacemaker relative to the timing of the

sleep�wake cycle that underlies the pathogenesis of

the disease. While Lewy’s phase delay hypothesis of

winter depression has been supported by a number

of studies (Avery et al. 1997; Dahl et al. 1993; Lewy

et al. 1998; Sack et al. 1990), other investigations

(Eastman et al. 1993; Thompson et al. 1997; Wirz-

Justice et al. 1996) have failed to confirm it. To

understand the pathophysiology of SAD, Wehr et al.

(2001) studied the duration of melatonin secretion

in 57 patients and 62 healthy controls during

summer and winter seasons and under constant

dim light conditions. The levels of melatonin were

measured in plasma samples obtained every 30 min

for 24 h during each season. The results of the study

revealed that duration of active melatonin secretion

in summer tended to be shorter in patients (8.49/

1.4 h) than in healthy volunteers (8.99/1.2 h). This

difference was statistically different in the case of

men (8.59/1.4 h in SAD patients, 9.39/1.2 h in

healthy controls). There were no significant differ-

ences between patients and healthy controls in the

duration of melatonin secretion during winter (Wehr

et al. 2001).

Seasonal changes in the duration of melatonin

secretion can be manifested by changes in the time

of onset or offset of melatonin secretion. In SAD

patients the most prominent marker of seasonal

variance was the change in the time of melatonin

offset (Wehr et al. 2001). This study was the first to

document that patients with winter depression gen-

erate a biological signal of change in season in a

manner similar to that of photoperiodic mammals

(Wehr et al. 2001). By what mechanism patients

with SAD are able to produce changes in the

duration of melatonin secretion remains to be

defined.

One possibility is that the retina or neural circuits

that mediate responses to seasonal changes in day

length are only slightly affected by artificial light in

patients with SAD but respond well to the higher

luminance of sunlight. Some are of the opinion that

photosensitivity in SAD patients may be secondary

to a pineal dysfunction (Pacchierotti et al. 2001).

Nearly 90% of the SAD patients meet the criteria

of the DSM-IV for bipolar disorder II (American

Psychiatric Association 1994; Faedda et al. 1993;

Wehr et al. 1987). Patients with SAD have delayed

offset of melatonin secretion by 2 h (Terman et al.

1987). The importance of the circadian rhythm in

the causing SAD has gained much support from

bright light treatment studies. Exposure to bright

light in the morning has been shown to correct phase

position and acts as an effective antidepressant

(Lewy et al. 1998). As SAD patients appear to

have abnormally phase-delayed rhythms, application

of bright light for 1 or 2 h immediately upon

awakening is recommended.

By using plasma melatonin onset as the circadian

phase marker, Terman et al. (2001) looked for the

effects of morning and evening bright light on

melatonin phase-shift responses and clinical re-

sponses in SAD patients. Morning and evening

bright light exposure (10 000 lux, 30 min) produced

significant phase shifts in melatonin rhythm. A

significant correlation between the magnitude of

phase advances of melatonin secretion to morning

light and improvement in depression ratings was

detected (Terman et al. 2001). The direction and

magnitude of phase shifts depended upon the inter-

val between the dim light melatonin onset (DLMO)

and the time of light administration. According to

Terman et al. (2001), it is the DLMO to time of light

administration interval that provides a unifying

metric for circadian time. Consequently, they have

recommended that the best treatment for winter

depression was exposure to light having an intensity

of 10 000 lux for 30 min. For maximum effective-

ness, the initiation of the light exposure period must

be scheduled in circadian time, that is, about 8.5 h

after the DLMO. Significant correlations between

the magnitude of the phase advance after morning

light and improvement in depression ratings

144 V. Srinivasan et al.

supported the validity of this therapeutic strategy

(Terman et al. 2001).

The therapeutic effect of bright light treatment has

been demonstrated in several studies. Association of

winter type of SAD with reduced day length and

therapeutic response to bright light suggest that

either photoperiodic time measurement, or a delayed

circadian phase, or both, play a role in the aetiology

of the disease (Putilov et al. 2005). Changes in the

profiles of melatonin secretion in SAD could be

linked to the beneficial effects of bright light and the

remission during spring and summer. The delayed

phase and long duration of melatonin secretion in

SAD patients may be responsible for the symptoms

of hypersomnia and late awakening seen in this

disorder (Putilov et al. 2005). An abnormal melato-

nin secretion during daytime could account for the

SAD symptoms as well.

The association between season and mood

changes has also been studied in normal people.

Murray et al. (2003) tested Lewy’s phase shift

hypothesis of SAD in a normal community sample

of 244 adults in Melbourne. Seasonality of mood

was measured by using self-report analysis for a

3-year period. They also used a morningness�eveningness questionnaire to assess the self-report

estimates of circadian phase. A positive association

was found between lowered mood in winter and

winter phase delay among a random community

sample. This study provided additional support for

Lewy’s hypothesis in a normal population and

supported the role of seasonal influences in mood

disorders (Murray et al. 2003).

The efficacy of melatonin treatment to treat SAD

has been explored by Wirz-Justice et al. (1990).

Melatonin, at the same doses used to treat circadian

rhythm-related sleep disturbances, had no effect on

the depressive symptoms in SAD patients, whether

given early (07:00 h) or late (23:00 h) for a week.

Other placebo-controlled randomized studies on

melatonin/melatonin analog efficacy in the treatment

of mood disorders are listed in Table I.

Melatonin as an antidepressant in delayed

DSPS with comorbid depression

Weitzman et al. (1981) were the first to report the

presence of chronobiological abnormalities in half of

a sample of depressed patients, a finding which was

later supported by other investigators who found a

high prevalence of depression in adolescents with

DSPS (Ferber 1985). Several studies also supported

the view that a close association exists between

disorders of sleep onset and mood (Regestein and

Monk 1995; Regestein and Pavlova 1995; Thorpy et

al. 1988). In depressed states, circadian rhythms are

thought to be abnormally phase advanced with

respect to the sleep�wake cycle (Gwirtsman et al.

1989; Linkowski and Hubain 1995; MacLean et al.

1983; Shiromani et al. 1991). Since REM sleep is

predominantly controlled by circadian processes

(Borbely 1982), the apparent phase advance in

circadian rhythms provides a plausible explanation

for the short REM sleep latency and temporal

redistribution of REM sleep frequently observed in

depression (Coble et al. 1981; Hamilton and Sha-

piro 1990; Kupfer et al. 1984a,b; Reynolds and

Kupler 1988). Advancing sleep in some depressed

patients has been shown to have an antidepressant

effects (Wehr et al. 1979). There is evidence that

sleep deprivation in the second half of the night (but

not the first half) can be transiently helpful for

ameliorating depressive symptoms in many cases

Table I. Placebo-controlled randomised studies on melatonin/melatonin analogue efficacy in the treatment of mood disorders.

Melatonin/

melatonin

analogue

Dose Type of mood

disorder

Effect Reference

Melatonin 150�1150 mg/day Major depressive

disorder

increased dysphoria (Carman et al. 1976)

Melatonin 5 mg/day SAD loss of sleep & weight (Wirz-Justice et al. 1990)

Melatonin 10 mg/day Bipolar affective

disorder

No effect (Leibenluft et al. 1997)

Melatonin 5�10 mg/day,

slow release

Major depressive

disorder

Improved sleep, no effect on symptoms of

depression

(Dolberg et al. 1998)

Melatonin 5�10 mg/day Resistant depression No antidepressant effect but 20% decrease in

Hamilton scores, 36% decrease of insomnia

(Dalton et al. 2000)

Agomelatine 1�25 mg/day Major depressive

disorder

Significant antidepressant effect, even in

severely affected patients with sufficient

severity. Reduced anxiety associated with

depression

(Loo et al. 2002)

Melatonin 5 mg/day DSPS with comorbid

depression

Reduced fatigue, increased alertness, reduced

sleep disorder

Kayumov et al.

unpublished results

Melatonin in mood disorders 145

(Berger et al. 1997; Riemann et al. 1996; Schilgen

and Tolle 1980).

According to the internal coincidence theory of

depression, an internal phase angle disturbance

exists between sleep and other circadian rhythms

(Wehr and Wirz-Justice 1982). Thus, sleep induces

or exacerbates depression when sleep coincides with

the circadian phase that is sensitive to the effects of

sleep. In DSPS patients with comorbid depres-

sion, an internal phase angle disturbance may exist

because sleep is not as delayed as other circadian

rhythms, or conversely, because the circadian rhy-

thms are not as delayed as the sleep�wake cycle.

Late sleeping itself does not exacerbate nor precipi-

tate depression (Globus 1969; Surridge-David et al.

1987; Wehr et al. 1979), probably because sleep is

not as phase shifted as other circadian rhythms.

Theoretically, manipulations correcting the phase

angle disturbance between sleep�wake cycle and

circadian rhythms should result in an amelioration

of both DSPS and comorbid depression (Nagtegaal

et al. 2000).

It has been shown that exogenous melatonin

affects the phase of underlying biological rhythms

as well as the phase of the sleep�wake oscillator

(Arendt and Skene 2005; Cardinali et al. 2006).

Based on this fact, one of us assessed, in a rando-

mized, double-blind placebo-controlled study, the

effects of exogenous melatonin in eight patients

with established diagnosis of DSPS and comorbid

depression (Kayumov et al. unpublished results).

The diagnosis of depression was based on pre-study

clinical interviews and high scores on the CES-D

and Hamilton Depression scales (Radloff and Rae

1979). During melatonin treatment, the depression

scale scores decreased and increased again when the

subjects were placed on placebo. The patients with

depressive features treated with melatonin had sig-

nificantly more total sleep time than on placebo.

REM sleep latencies were within the normal range.

Interestingly, while on melatonin treatment the

patients showed a normal distribution of REM sleep

and an increase in REM sleep duration. The REM

density tended to be greater after melatonin treat-

ment (Kayumov et al., unpublished results).

An altered rhythm of melatonin secretion was

reported in DSPS patients (Shibui et al. 1999). A

relationship may exist between the magnitude of the

DSPS symptoms and the severity of comorbid

depressive features and abnormalities in the circa-

dian pattern of circulating melatonin as judged by

the excretion of major metabolite 6-sulfatoxymela-

tonin (Kayumov et al. unpublished results). The

patients with marked comorbid depression and

extreme symptoms of DSPS showed an abnormal

circadian pattern of melatonin secretion on placebo

treatment, with a peak during the diurnal period

(between 08.00 and 15.00 h). Melatonin adminis-

tration at a dose of 5 mg/day to DSPS patients with

comorbid depression normalized the circadian pat-

tern of 6-sulfatoxymelatonin excretion, with the

usual nocturnal rise and rapid decline of 6-sulfatox-

ymelatonin during daytime hours. This explains why

the patients did not report any hangover effects after

melatonin as judged by the subjective assessment of

the circadian pattern of sleepiness, fatigue, and

alertness. It is reasonable to conclude that a phase

advance in melatonin output and possibly in other

circadian rhythms along with a sleep�wake cycle

produced by exogenous melatonin resulted in ame-

lioration of symptoms of depression. This specula-

tion is supported by the findings of Nagtegaal et al.

(2000) showing that melatonin treatment alleviates

feelings of depression in DSPS patients as assessed

by the SF-36 mental health sub-scale. These find-

ings contradict the surprisingly widespread opinion

that melatonin may cause or exacerbate depression

(Chase and Gidal 1997; Cupp 1997). It must be

stressed that in DSPS patients with comorbid

depression, melatonin administration improved cir-

cadian profile scores of sleepiness, fatigue, and

alertness, thus having antidepressant properties.

Antidepressants with a more rapid response are

highly desirable for treating major depressive dis-

order. Agomelatine, a MT1/MT2 melatonin agonist

and selective antagonist of 5-HT2C receptors, has

been demonstrated to be active in several animal

models of depression. In a double-blind, rando-

mized multicentre multinational placebo-controlled

study, including 711 patients (238 males; 473

females, mean age 42.3 years) suffering from major

depressive disorder agomelatine (25 mg) was sig-

nificantly more effective ( 61.5%) than placebo

(46.3%) in the treatment of major depression (Loo

et al. 2002).

Conclusions

For quite some time, there has been a continuing

search for ‘biological markers’ of affective disorders

such as recurrent depressive and bipolar affective

disorders. A number of neurotransmitter substances

including norepinephrine, serotonin, acetylcholine

and dopamine, as well as hormones such as thyrox-

ine and cortisol, have all been implicated, but none

has provided a single model explaining the basis of

mood disorders. The occurrence of disturbed diur-

nal rhythms, such as delayed sleep onset, early

morning awakening, or body temperature variations

that are seen in depressives, suggest that dysfunction

of the circadian apparatus perhaps underlies the

pathogenesis of depression. An internal desynchro-

146 V. Srinivasan et al.

nization hypothesis has been advocated to explain

the periodic episodes of rapid cycling depression and

mania seen in bipolar disorders.

Indeed, health can be defined as the individual’s

ability to optimize internal rhythms so that they

synchronize with those of external light�dark cycles.

Both the pineal gland and its hormone melatonin are

involved in this adaptation. Measurement of mela-

tonin levels or that of its metabolites in body fluids

has shown that, in major depressive disorder, these

levels are altered during the active phase of illness.

Treatments with antidepressants have been shown

either to increase or to decrease melatonin levels in

depressive patients and after clinical remission,

although some studies could not find evidence to

support that hypothesis. Alteration in the phase

position of melatonin secretion has been documen-

ted in a number of studies of major depressive

disorder patients. Studies of melatonin levels in

bipolar affective disorders has demonstrated de-

creased levels during the depressive phase and

increased secretion during the manic phase.

Melatonin has been suggested as both a ‘state

marker’ as well as ‘trait marker’ in mood disorders,

although convincing evidence for this effect awaits

future studies. Phase advance in melatonin secretion

has also been reported in bipolar patients. Use of

bright light treatment is effective in restoring the

correct phase position of melatonin rhythm in

bipolar patients. Use of light brighter than 500 lux

suppresses nocturnal melatonin secretion in human

beings. This suppression is greater in bipolar

patients as compared to normal individuals. Such

supersensitivity to light has also been documented in

some normal subjects, perhaps indicating a propen-

sity to develop bipolar affective disorder. Like

recurrent depressive and bipolar affective disorders,

SAD, winter type, is also considered a mood

disorder. In SAD patients, a phase delay in circadian

rhythms has been documented and the use of bright

light in the morning has been found effective in

correcting this condition, including the melatonin

production cycle. Patients with winter depression

have been shown to exhibit altered onset duration

and offset of melatonin secretion as compared to

healthy subjects.

A change in the onset, duration and offset of

melatonin secretion was seen in patients during

summer and winter seasons. Patients with SAD

generate a biological signal in accordance with the

change in season. The use of bright light for treating

patients with SAD at the correct circadian time

rather than in clock time has been found beneficial

in correcting the underlying abnormalities seen.

Bright light or the judicious administration of

melatonin has been found beneficial in restoring

the disordered photoperiodic mechanism, involving

retina, SCN and pineal gland, disruptions of which

are all associated with, and may possibly be causally

involved in mood disorders, particularly SAD.

Melatonin regulates the rhythm of many func-

tions, and alterations in its secretory pattern have

been found in a number of psychiatric disorders.

Besides SAD, these include bipolar disorder and

unipolar depression, bulimia, anorexia, schizophre-

nia, panic disorder and obsessive compulsive dis-

order (Pacchierotti et al. 2001). At present, it is not

clear whether these changes are causal to or simply a

marker for other neurochemical alterations. Further,

it is not known if melatonin is equally involved in the

development of the pathophysiology of each of these

disorders.

Acknowledgements/Statement of interest

One of authors (VS) would like to acknowledge

Puan Rosnida Said, Department of Physiology,

School of Medical Sciences, University Sains

Malaysia, Malaysia for her secretarial assistance.

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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Melatonin in mood disorders 151

ORIGINAL INVESTIGATION

Striatal dopamine transporter availability and DAT-1 gene in adultswith ADHD: No higher DAT availability in patients with homozygosityfor the 10-repeat allele

JOHANNA KRAUSE1, STEFAN H. DRESEL2, KLAUS-HENNING KRAUSE3,

CHRISTIAN LA FOUGERE3, PETER ZILL4 & MANFRED ACKENHEIL4

1Outpatient Clinic for Psychiatry and Psychotherapy, Ottobrunn, Germany 2Department of Nuclear Medicine,3Friedrich-Baur-Institute, and 4Department of Neurochemistry, Ludwig-Maximilians-University, Munich, Germany

AbstractIn 29 adults with attention deficit hyperactivity disorder (ADHD) striatal dopamine transporter (DAT) availability wasassessed by [99mTc]TRODAT-1 SPECT and correlated with 3? VNTR polymorphism of the DAT gene on chromosome5p15.3. Seventeen patients showed homozygosity for the 10-repeat allele, two homozygosity of the 9 allele and 10 wereheterozygous (9�10). No statistically significant difference in DAT availability was found between patients with 10�10carriers (DAT 1.289/ 0.34) and with at least one 9 allele (DAT 1.319/0.27); when smokers were excluded, DAT availabilitywas 1.389/0.28 in the 10�10 carriers (n�/12) and 1.429/0.19 in the 9�10 and 9�9 carriers (n�/7). In conclusion, nohigher striatal DAT was found in patients with homozygosity of the 10 allele of the DAT gene in this study. These resultsdiffer from a study in 11 Korean children with ADHD, in which 10�10 carriers showed higher DATavailability in [123I]IPTSPECT. Discrepancies may be explained by differences in patient’s age, ethnical differences, different imaging techniques orthe limited number of patients included in both studies.

Key words: Attention deficit hyperactivity disorder (ADHD), brain imaging techniques, dopamine transporter (DAT),

TRODAT-1 SPECT, DAT gene

Introduction

Neuroimaging studies with MRI, PET and SPECT

suggest involvement of striatal structures in ADHD

(Bush et al. 2005; Castellanos and Tannock 2002;

Krause et al. 2003; Spencer et al. 2005). Most of the

DAT-SPECT imaging studies showed a higher

availability of DAT binding sites in adult patients

with ADHD (Cheon et al. 2003; Dougherty et al.

1999; Dresel et al. 2000, Krause et al. 2000, Madras

et al. 2005). From molecular genetic studies an

involvement of a polymorphism of the DAT1 gene in

ADHD was described (e.g., a higher rate of homo-

zygosity of the 10-repeat allele in the 3? untranslated

region of exon 15 of the DAT gene on chromosome

5p15.3) (Chen et al. 2003; Cook et al. 1995;

Cornish et al. 2005; Faraone et al. 2005; Gill et al.

1997; Waldman et al. 1998). It has been postulated,

that individuals with the 10 repeat allele may have

increased DAT availability (Kirley et al. 2002). In

accordance with this assumption, Cheon et al.

(2005) found higher DAT availability in the seven

of 11 ADHD children with 10�10 genotype. To our

best knowledge this is the first study, which investi-

gated the influence of 3? VNTR polymorphism on

striatal DAT availability in adult patients with

ADHD.

Patients and methods

Striatal DAT binding was measured in 29 adult

patients (19 males, 10 females, age 19�54 years,

mean9/SD 37.69/10.0) with ADHD, using

[99mTc]TRODAT-1 SPECT. The patients were

diagnosed by a board-certified psychiatrist (J.K.).

Diagnosis of ADHD was made according to DSM-

IV criteria (American Psychiatric Association 1994)

by structured interviews. No patient has ever been

treated with stimulants. Exclusion criteria were a

known history of alcohol or drug abuse or past or

Correspondence: Johanna Krause, MD, Schillerstr. 11a, D-85521 Ottobrunn, Germany. Tel: �/49 89 6012471. Fax: �/49 89 60019387.

E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 152�157

(Received 1 September 2005; accepted 8 December 2005)

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

DOI: 10.1080/15622970500518444

current history of psychosis, bipolar disorder, anxi-

ety disorder, major depression or dysthymia. To

avoid type I and type II errors due to population

stratification the patients were of Caucasian origin

from the same geographical region in Southern

Germany. The study was approved by the ethics

committee of the University of Munich and was

performed in accordance with the ethical standards

laid down in the Declaration of Helsinki. All subjects

gave their informed consent prior to inclusion.

SPECT images were acquired using a triple headed

gamma camera (Picker Prism 3000 XP). All subjects

were injected with 740 MBq [99mTc]TRODAT-1

three hours before scanning. Images were acquired

in a 128�/128 matrix with a pixel width of 2.26 mm

in the projection domain. Post processing was

performed treating the data as time-point calculation

(3 h p.i.). After reconstruction and attenuation

correction the final slice thickness was 3.56 mm. In

order to assess specific tracer uptake in the striatum,

we used the region of interest (ROI) approach. In

each patient, data were evaluated in the two con-

secutive transverse slices showing the highest tracer

accumulation in the basal ganglia. Templates were

used for defining the striatal ROI. The size and

shape of the templates was established and opti-

mized using the data of a control group. The

templates were adjusted to fit individuals and

corrected for anatomical differences in angle, size

and distance between the interesting structures. The

observer was blinded to the clinical data. Mean

specific activity in the striatal region was calculated

by subtracting the mean counts per pixel in the

cerebellum as background (BKG) from the mean

counts per pixel in the striatal region (STR) and

dividing the result by the mean counts per pixel in

the background ([STR-BKG]/BKG). This method

has been validated as a suitable semiquantitative

method for evaluating DAT availability in the brain

(Kung et al. 1996).

Genomic DNA was extracted from peripheral

white blood cells by standard methods. Polymerase

chain reaction (PCR) was used to amplify the 40-

base pair VNTR located in the 3?-UTR of the DAT

gene on chromosome 5p15.3 as previously described

(Sano et al. 1993). PCR products were subjected to

electrophoresis in 2.5% agarose gels containing

ethidium bromide, and fragment sizes were deter-

mined by comparison to molecular weight stan-

dards. The numeric designation of each allele

refers to the number of repeats it contains.

Our own previous studies showed that nicotine

may act directly on DAT in a way such as stimulants

(Krause et al. 2002). Therefore, additionally groups

of patients with and without nicotine abuse were

compared. The patients without nicotine abuse had

no history of smoking. Subgroups of ADHD with

pure attention deficit on one side and with symp-

toms of hyperactivity/impulsivity on the other side

were compared with relation to DAT gene and DAT

availability.

For statistical analysis of differences in DAT

availability between the groups of patients with and

without 9 allele of DAT1 gene Student’s t-test was

used. The level of significance was set at 0.05.

Results

Table I displays individual patient’s characteristics

(age, gender, type of ADHD, striatal DAT avail-

ability, alleles of DAT 1 gene and use of nicotine).

Seventeen patients showed homozygosity for the 10-

repeat allele, two were homozygous for the 9-repeat

allele and 10 were heterozygous (9�10). The age

(mean9/SD) of the 17 patients with homozygosity of

the 10 allele was 38.69/11.1 years, that of the 12 pa-

tients with at least one 9 allele was 36.09/8.4 years.

Table I. Age, gender, type of ADHD (C�/combined, A�/

inattentive, HI�/hyperactive-impulsive), striatal DAT availability

in TRODAT1 SPECT [(mean counts per pixel in the striatal

region�mean counts per pixel in cerebellum)/mean counts per

pixel in cerebellum], alleles of DAT1 gene and nicotine abuse in

29 adult patients with ADHD.

Age Sex

Type of

ADHD

DAT

availability

Alleles of

DAT1-gene

Nicotine

use

25 f C 0.95 9�9 �/

45 f C 1.24 9�9 �21 m A 1.75 9�10 �25 m A 1.06 9�10 �/

34 m A 1.03 9�10 �/

36 m A 1.12 9�10 �/

36 m A 1.58 9�10 �/

39 f C 1.58 9�10 �40 m A 1.49 9�10 �41 f A 1.51 9�10 �42 f C 1.12 9�10 �48 m HI 1.27 9�10 �19 m C 1.58 10�10 �/

20 f A 1.9 10�10 �30 f A 1.61 10�10 �30 m A 1.28 10�10 �30 f C 1.28 10�10 �32 m A 1.39 10�10 �32 m C 1.25 10�10 �/

35 f A 1.56 10�10 �40 m A 1.34 10�10 �43 m A 0.92 10�10 �43 m C 0.88 10�10 �/

47 m A 1.01 10�10 �48 m C 0.70 10�10 �/

50 m A 1.08 10�10 �51 m C 0.98 10�10 �/

53 m C 1.50 10�10 �54 f A 1.39 10�10 �

Striatal dopamine transporter and DAT-1 gene in ADHD 153

Patients with homozygosity for the 10 allele pre-

sented with a mean specific binding of 1.289/0.34 in

striatum, patients with 9�9 and 9�10 carriers had a

value of 1.319/0.27 (not significant in t-test, P�/

0.83). After the exclusion of smokers, there was a

tendency to lower DAT binding in 10�10 carriers

(1.389/0.28, n�/ 12) compared to patients with 9�10 and 9�9 (1.429/0.19, n�/ 7) as shown in Figure

1, but no level of significance was reached (P�/

0.71). Subgroup evaluation (ADHD patients with

pure attention deficit and with symptoms of hyper-

activity/impulsivity) showed similar rates in patients

with homozygosity of the 10 allele (10 with pure

attention deficit, seven with additional hyperactive

symptoms in childhood) and the 9�9 and 9�10

carriers (7/5). Both patients with the 9�9 genotype

suffered from combined type of ADHD. In the

inattentive subgroup, five patients were smokers

and 13 non-smokers, in the combined subgroup,

seven were smokers and three non-smokers, and the

one patient with the hyperactive-impulsive subtype

was a non-smoker.

Discussion

Three SPECT studies recently investigated the

influence of the 3? VNTR polymorphism on DAT

availability in patients with different psychiatric

disorders and described various findings. In a group

of 14 abstinent alcoholics and 11 controls 9-repeat

individuals (e.g., 9�10 heterozygotes) DAT binding

was significantly higher (22%) than in 10-repeat

subjects (10�10 homozygotes) (Heinz et al. 2000).

Furthermore, in a study that included 14 recently

detoxified cocaine abusers and 30 healthy controls,

an increased striatal [123I]b-CIT binding (13%) was

found in patients 9-repeat carriers (9�9 homozy-

gotes and 9�10 heterozygotes) when compared to

10�10 homozygotes (Jacobsen et al. 2000). In a

sample of 29 patients with schizophrenia and 31

healthy controls, no significant association was

found between VNTR polymorphism and DAT

availability (Martinez et al. 2001). It is of particular

interest that all three studies used [123I]b-CIT for

labelling the DAT. However, in contrast to studies

using [123I]FP-CIT or [99mTc]TRODAT-1, no ele-

vation of DAT was shown in patients with ADHD,

when [123I]b-CIT was used (van Dyck et al. 2002).

Until now, the reason for these discrepancies is

unsolved, but perhaps may be related to clinical

differences like severity and duration of the disorder.

Otherwise differences may also be caused by the very

slow kinetics of b-CIT or lower specificity of this

radiotracer, which also labels the serotonin trans-

porter.

Recently Cheon et al. (2005) investigated the

correlation between homozygosity for 10-repeat

allele at DAT1 gene, response to methylphenidate

0,90

1,00

1,10

1,20

1,30

1,40

1,50

1,60

1,70

Specific binding([STR-BKG] /BKG)

incl. smokers excl. smokers

n=17 n=12 n=12 n=7

10-10 9-9 / 9-10 10-10 9-9 / 9-10

Figure 1. DAT binding (mean9/SD) in non-medicated adult ADHD patients with homozygosity of the 10 repeat allele of DAT1 gene and

with 9�9 homozygosity and 9�10 heterozygosity, including and excluding smokers.

154 J. Krause et al.

and DAT availability measured with [123I]IPT

SPECT in 11 korean children with ADHD. They

found that the seven children with 10�10 homo-

zygosity had higher DAT binding ratio than the

others. With regard to treatment with methylphe-

nidate, the response was better in the four children

without homozygosity, who all responded well to

methylphenidate, whereas only two of the seven

children with homozygosity were responders. The

finding of better response to methylphenidate in

patients without homozygosity is in accordance with

the results of Winsberg and Comings (1999), who

found in their sample of 30 African�American

children a generally very low response rate of

53%, as well as of Roman et al. (2002), who

investigated 50 Brazilian youths with ADHD. In

accordance we identified three 10�10 carriers with

reduced DAT availability, who all were non-respon-

ders to methylphenidate (unpublished results). In a

sample of 18 non-smoking adults with ADHD we

found that response to methylphenidate generally

seems to be depending on DAT availability: patients

with low DAT availability showed no response

(Krause et al. 2005). In contrast to the finding of

Winsberg and Comings (1999) and Roman et al.

(2002) a study, which investigated Irish children

with ADHD, reported a significant better response

to methylphenidate in the 53 children with 10�10

homozygosity as compared to 42 children with at

least one 9-repeat DAT1 allele (Kirley et al. 2003).

An interesting result concerning the effect of

another stimulant, d-amphetamine, on self-report

measures (euphoria, anxiety, feel drug) found Lott

et al. (2005) in 96 healthy volunteers with a double-

blind crossover design: in this study the effects of

amphetamine were indistinguishable from placebo

in all eight subjects with 9�9 genotype, whereas the

9�10 and 10�10 subjects showed the expected

effects of amphetamine. Accordingly, in a double-

blind, placebo-controlled, crossover study with

forced weekly titrations of three dose conditions of

methylphenidate in 47 children with ADHD Stein

et al. (2005) documented, that the six children with

9�9 homozygosity responded poorly to methylphe-

nidate in comparison to the children with one or

two copies of the 10-repeat allele. Additional

studies with higher number of patients are war-

ranted to confirm these preliminary results, show-

ing an atypical stimulant response in people with

9�9 genotype. In our study only two patients

showed a 9�9 genotype; one had a low DAT

availability, but was a heavy smoker, so that the

low DAT could be caused by nicotine abuse

(Krause et al. 2003), the other presented with

slightly elevated DAT availability. It is of further

interest, that Ujike et al. (2003) found, that 9

repeat allele of the DAT gene seems to be a strong

risk factor for prolonged metamphetamine psy-

choses, confirming earlier results of Gelernter

et al. (1994), who saw links between the 9 allele

and cocaine-induced paranoia.

Concerning the subgroups of ADHD and their

relation to DAT1 gene we could not confirm the

results of Waldman et al. (1998), who found

differences between the purely inattentive subtype

and the hyperactive-impulsive or combined sub-

types, the former showing lower frequency of the

10 allele of the DAT 1 gene than the latter. However,

the number of patients in this study is too small to

allow a final conclusion. Our results are in accor-

dance with the study of Stein et al. (2005), who

found no significant differences between patients

with 9�10 alleles (68% with combined type, 32%

with inattentive type) and 10�10 alleles (63% with

combined type, 37% with inattentive type); but from

six patients with 9�9 genotype 5 (83%) had the

combined and only 1 the inattentive type. In our

study both patients with the 9�9 genotype showed

the combined type.

In conclusion, the impact of the abnormalities of

VNTR polymorphism of DAT1 gene seen in

ADHD on the striatal DAT is far from clear. Our

first results definitely show no higher striatal DAT

availability in the ADHD patients with homozygos-

ity of the 10 allele compared with those having the 9

allele. It should be mentioned that the heteroge-

neous results of our study compared with some

published reports might be due to ethnical differ-

ences in our patient sample or to the limited sample

size. Furthermore, differences possibly could result

from the use of different imaging techniques; our

study was the only one, in which [99mTc]TRODAT-

1 was used as radiopharmaceutical, whereas in the

other studies [123I]IPT or [123I]b-CIT were used for

labelling the DAT. In the three studies with [123I]b-

CIT (Heinz et al. 2000; Jacobsen et al. 2000;

Martinez et al. 2001) no patients with ADHD

were investigated, and the only other study, which

dealed with ADHD patients, using [123I]IPT

(Cheon et al. 2005), included even much fewer

patients than our study. Although our patients were

Caucasians from the same geographical region of

Southern Germany we cannot fully exclude popula-

tion stratification effects. The results of our study

are preliminary and it appears to be important to

investigate relations between the different subtypes

of ADHD, DAT availability and genetics in higher

number of patients. In this context sequence analy-

sis of the tandem repeat region in the 3?-UTR of the

DAT gene in patients with ADHD would be of

interest.

Striatal dopamine transporter and DAT-1 gene in ADHD 155

Statement of interest

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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Striatal dopamine transporter and DAT-1 gene in ADHD 157

ORIGINAL INVESTIGATION

Association study of the glycogen synthase kinase-3b genepolymorphism with prophylactic lithium response in bipolar patients

ALEKSANDRA SZCZEPANKIEWICZ1, JANUSZ K. RYBAKOWSKI2, ALEKSANDRA

SUWALSKA2, MARIA SKIBINSKA1, ANNA LESZCZYNSKA-RODZIEWICZ2,

MONIKA DMITRZAK-WEGLARZ1, PIOTR M. CZERSKI1 & JOANNA HAUSER1,2

1Laboratory of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland, and2Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland

AbstractA relationship between response to lithium prophylaxis and T-50C polymorphism of glycogen synthase kinase-3b (GSK-3b) gene was investigated in 89 bipolar patients (41 male and 48 female) who have been taking lithium for at least 5 years.The patients were delineated as excellent responders, partial responders and non-responders to lithium. The resultsobtained suggest that this polymorphism may not be related to the degree of prophylactic lithium response.

Key words: Association, bipolar disorder, glycogen synthase kinase-3b gene, lithium response

Introduction

The enzyme, glycogen synthase kinase-3b (GSK-

3b), is essential player in a number of intracellular

signaling pathways and regulates several transcrip-

tion factors and cytoskeletal elements. GSK-3b is

pro-apoptotic factor and plays a significant role in

neuroprotection processes. The pathogenic impor-

tance of GSK-3b has been recently implicated in

such illnesses as bipolar mood disorder and Alzhei-

mer’s disease (Gould et al. 2004b).

The gene for GSK-3b was mapped to 3q21.1

region and several polymorphisms of this gene have

been described. The �50 T/C polymorphism is

localized in an untranscribed region of the promoter

that is not putative transcriptional binding site (Russ

et al. 2001). However, it is located in an effective

promoter region (nucleotide �171 to �/29) of the

gene encoding GSK-3b and decreased expression of

the gene was found after deletion of this promoter

region (Lau et al. 1999).

Lithium is one of the most commonly used drugs

in the prophylaxis and treatment of bipolar disorder.

The mechanisms of mood-stabilizing effect of

lithium incorporate its effect on the processes of

intracellular signalling and neuronal plasticity. Many

possible targets of mood-normalizing action of

lithium have been delineated such as phosphatidyli-

nositol system, brain-derived neurotrophic factor

(BDNF) and also GSK-3b (Manji and Zarate

2002). In our recent study, an association was

demonstrated between lithium prophylactic re-

sponse and BDNF gene polymorphisms (Ryba-

kowski et al. 2005).

Lithium exerts inhibitory effect on the GSK-3

activity at concentrations relevant for bipolar dis-

order treatment, thus promoting impaired cellular

resilience and synaptic plasticity in this illness

(Gould et al. 2004a; Li et al. 2002). In addition,

lithium also affects circadian clocks which distur-

bances may play pathogenic role in bipolar disorder

(Padiath et al. 2004). GSK3-b is the mammalian

orthologue of an enzyme which regulates molecular

clock in Drosophila (Martinek et al. 2001) and it was

observed that long-term lithium administration, via

reduction of GSK-3 activity, lengthens the circadian

clock (Iwahana et al. 2004).

Recently, Benedetti et al. (2005) reported that the

efficacy of long-term lithium prophylaxis is influ-

enced by the T-50C polymorphism in GSK-3b gene.

In their sample, a better efficacy of lithium was

observed in the carriers of mutant C allele of this

Correspondence: Aleksandra Szczepankiewicz, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, ul. Szpitalna

27/33, 60-572 Poznan, Poland. Tel: �/48 61 8491311. Fax: �/48 61 8480-392. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 158�161

(Received 20 July 2005; accepted 22 December 2005)

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

DOI: 10.1080/15622970600554711

polymorphism. In the present study we make an

attempt to verify their findings in thoroughly char-

acterized group of bipolar patients receiving long-

term lithium prophylaxis.

Experimental procedures

Patients

The study was performed on 89 patients with

bipolar disorder (n�/82 of bipolar I and n�/7 of

bipolar II) according to DSM-IV and ICD-10

criteria using SCID, recruited from Wielkopolska

region, attending the Outpatient Lithium Clinic at

the Department of Psychiatry, Poznan University of

Medical Sciences. All patients involved in the study

(41 males with a mean age of 49 years, SD�/12; 48

females with a mean age of 47 years, SD�/15) have

been treated with lithium carbonate for at least 5

years (5�27 years, mean 15 years). Serum concen-

tration of lithium has been maintained in the range

between 0.5�0.8 mmol/l.

The course of illness was assessed retrospectively,

based on the analysis of medical outpatient charts,

inpatient records and semi-structured reviews. The

efficacy of lithium treatment was assessed according

to the following criteria: excellent lithium responders

(ER) had no affective episodes on lithium; partial

lithium responders (PR) showed 50% reduction in

the episode index (number of episodes per year to

pre-lithium period); lithium non-responders (NR)

showedB/50% reduction, no change or worsening in

the episode index.

All patients gave written consent to the study.

The study was approved by the Local Bioethics

Committee.

Genotyping

The DNA was extracted from 10 ml of EDTA

anticoagulated whole blood using the salting out

method (Miller et al. 1988). A 344-basepair frag-

ment of the GSK-3b gene was amplified by PCR

reaction with set of primers described by Russ et al.

(2001) using PTC-200 (MJ Research) thermal

cycler. PCR product (4.0 ml) was then digested

with AluI restriction endonuclease (MBI Fermen-

tas). The uncut PCR product size was 344 bp. After

RFLP analysis, the following alleles were observed:

uncut C allele (127 bp), for Tallele the bands of 220

and 124 bp. Restriction analysis for uncut C allele

was repeated to confirm the results.

Statistical analysis

The Pearson’s chi-square (x2)-test and Fisher’s exact

test were applied to test differences in the genotypic

and allelic (respectively) distribution between groups

of lithium responders. Additionally, stepwise logistic

regression analysis was performed including the

GSK-3b polymorphism and lithium response as

covariates. Calculations were performed using the

computer programme SPSS version 11.5. For small

numbers of patients in cells (see Table I, below 5) we

performed Fisher�Freeman�Halton test with Stat-

Xact-4 v 4.0.1 programme.

Results

Genotype distribution of analysed population was in

concordance with Hardy�Weinberg equilibrium

(P�/0.18). Among this group, 23 patients (25.8%)

were classified as excellent responders (ER), 47

(52.8%) as partial responders (PR) and 19

(21.3%) as non-responders (NR) to lithium prophy-

laxis. Clinical data of these patients are presented in

Table I.

No significant differences in genotype distribu-

tions and allele frequencies between GSK-3b T-50C

polymorphism and the degree of lithium response

was found (P�/0.646 and P�/0.675, respectively).

Data are shown in Table II. Analysis by gender did

not reveal any significant differences in genotype and

allele frequencies, either (P�/0.788 for males, P�/

0.649 for females).

Due to very small number in the case of

homozygous patients, we performed the Fisher�Freeman�Halton test considering small amount in

some cells in Table I (below 5). However, no

Table I. Clinical characteristics of the bipolar patients on lithium prophylaxis.

Total (n�/89) ER (n�/23) PR (n�/47) NR (n�/19)

Age, years [mean9/SD] 54.89/12.3 57.89/14.2 53.29/12.2 54.19/8.4

Gender [M:F] 38:51 11:12 16:31 10:9

Family history of psychiatric illness, N (%) 41 (46.6%) 11 (40.7%) 24 (53.3%) 6 (37.5%)

Age at onset, years [mean9/SD] 31.59/10.7 33.09/11.6 31.19/10.9 30.19/8.5

Duration of illness before lithium, years [mean9/SD] 7.49/7.4 9.79/9.6 5.69/5.9 8.79/6.0

Duration of lithium treatment, years [mean9/SD] 14.69/7.3 14.09/7.1 15.39/7.9 13.89/5.8

Affective episodes before lithium, N [mean�/SD] 6.29/4.1 7.09/3.6 6.09/4.5 5.89/3.9

Affective episodes on lithium, N [mean�/SD] 3.39/3.9 0 3.59/2.7 8.29/4.8

Association study of GSK-3b T-50C polymorphism and lithium response 159

statistically significant differences were found be-

tween the analysed groups (P�/0.6977).

Discussion

The main finding of our study is lack of significant

association between T-50C polymorphism in the

GSK-3b gene and the degree of prophylactic re-

sponse to lithium carbonate in carefully character-

ized group of bipolar patients. Thus, the results

obtained in our analysis are not consistent with the

previous study performed by Benedetti et al. (2005).

In our study, in comparison to that of Benedetti’s

group, a nearly identical number of bipolar patients

was involved (89 vs. 88, respectively). On the other

hand, the duration of lithium prophylaxis in our

study was much longer (at least 5�27 years on

lithium) what enabled more precise assessment of

quality of lithium prophylactic effect. Our division of

bipolar patients on lithium into three groups (ex-

cellent, partial and non-responders) makes it possi-

ble to analyse an association between GSK-3b and

prophylactic lithium response in the groups of

bipolar patients with distinct clinical characteristics.

Excellent lithium responders are characterised by

episodic course of disease and low rates of comor-

bidity (MacQueen et al. 2005). On the other hand,

family studies showed that lithium non-responders

had 10 times higher prevalence of schizophrenia in

first-degree relatives compared to lithium responders

(Grof et al. 1994). Therefore, our analysis may be

complementary to that of Benedetti et al. (2005) and

extend it.

A closer inspection of Table II reveals that the

ratio of ER/NR in carriers of C allele (patients with

T/C�/C/C genotypes) was higher than ER/NR ratio

in patients with T/T genotype (1.5 and 0.9, respec-

tively). Therefore, this may be a slight hint to

suppose that ER may be more likely to have C allele

than NR. Although it may resemble a relationship

found by Italian investigators, this is not supported

by any statistical significance for neither genotypes

nor alleles.

In conclusion, the role of GSK-3b in the patho-

genesis of bipolar illness and in the prophylactic

action of lithium remains to be further elucidated.

Some association has been found between GSK-3bgene polymorphism with some features of illness

such as later onset or antidepressant response to

total sleep deprivation (Benedetti et al. 2004a,b). On

the other hand, studies of GSK-3b in postmortem

brains of bipolar patients were negative (Beasley et

al. 2002; Lesort et al. 1999). Although the study of

Benedetti et al. (2005) suggested an association

between GSK-3b gene polymorphism and lithium

prophylactic effect, we were not able to confirm their

results with our population of patients.

Acknowledgements/Statement of interest

This study was supported by the Polish Committee

of Scientific research (KBN), grants no. 2P05B

01 226 and 2P05B 00 226. Dr P.M.C. is the

recipient of a 2004 Annual Stipend for Young

Scientists from the Foundation for Polish Science

(FNP).

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prophylaxis.

Lithium response Genotypes Alleles

T/T T/C C/C T C

ER 8 (34.8%) 14 (60.9%) 1 (4.3%) 30 (65.2%) 16 (34.8%)

PR 16 (34.0%) 25 (53.2%) 6 (12.8%) 57 (60.6%) 37 (39.4%)

NR 9 (47.4%) 8 (42.1%) 2 (10.5%) 26 (68.4%) 12 (31.6%)

Difference, ER vs. PR vs. NR � x2 �/2.475, df�/4, P�/0.649 for genotypes, P�/0.675 for alleles.

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Association study of GSK-3b T-50C polymorphism and lithium response 161

ORIGINAL INVESTIGATION

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

CAROLINE NOTHDURFTER, DANIELA ESER, CORNELIUS SCHULE, PETER

ZWANZGER, ALAIN MARCUSE, INES NOACK, HANS-JURGEN MOLLER,

RAINER RUPPRECHT & THOMAS C. BAGHAI

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

AbstractBackground: Electroconvulsive therapy (ECT) is still considered to be the most efficacious treatment option in majordepressive disorder and treatment-resistant schizophrenia. Unfortunately, in some cases patients do not respond sufficientlyto conventional unilateral ECT, or even to bilateral or high dose ECT. In these cases, concomitant pharmacotherapy can bea useful augmentation strategy to improve clinical effectiveness. Interestingly, there is not much data about ECT andconcomitant neuroleptic medication. Method: We evaluated 5482 treatments in 455 patients in our retrospective study tosee whether there might be differences between combination therapies (ECT and concomitant neuroleptic medication) andECT monotherapy. We focused on clinical effectiveness and tolerability; furthermore we investigated treatment modalitiesand ictal neurophysiological parameters that might influence the treatment. Results: A total of 18.2% of all treatments weredone with no psychotropic medication, 2.8% with a neuroleptic monotherapy. Seizure duration according to EEGderivations turned out to be significantly longer in patients treated with neuroleptics of lower antipsychotic potency, whereasseizure duration in EMG was shorter in treatments done with atypical substances. Postictal suppression was highest intreatments done with atypical neuroleptics, whereas the same group was lowest regarding convulsion energy and convulsionconcordance indices. The best therapeutic effectiveness was seen in treatments done with atypical substances. Adverseeffects were not influenced significantly by concomitant neuroleptic medication. Conclusion: Our study suggests that theremight be a clinical benefit by combining ECT treatment with neuroleptic medication; especially atypical substances seem toenhance improvement. The tolerability of ECT treatment was not influenced by concomitant neuroleptic medication.

Key words: Electroconvulsive therapy, major depression, schizophrenia, neuroleptics, clinical effectiveness

Introduction

ECT is still considered to be a very efficacious and

well-tolerated treatment option in different psychia-

tric diseases, such us major depressive disorder or

schizophrenia, especially in cases of pharmacother-

apy resistance (Tharyan et al. 2002; ECT Review

Group 2003). In major depressive disorder, there is

evidence that ECT is even the most efficacious

therapeutic regimen (ECT Review Group 2003).

As far as schizophrenic disorders are concerned,

clozapine is still considered to be the standard

medication in patients who do not respond to other

neuroleptics (Fink 1990), but with this medication

there still remain 40% of patients who do not show a

significant improvement of their symptoms (Meltzer

et al. 1989). Taken together, one-fifth of all schizo-

phrenic patients do not respond sufficiently to

pharmacotherapeutic treatment. In the case of

therapy resistance, atypical neuroleptics, especially

clozapine, have to be considered as a treatment

option (Schafer et al. 2004). This shows the

necessity of alternative therapeutic strategies. Pub-

lished data support the idea that neuroleptics in

combination with ECT might be more efficacious

than single neuroleptic medication. Kales et al.

(1999) found that combining ECT and clozapine

seems to be a safe and effective alternative treatment

option in some patients who suffer from refractory

schizophrenia. Tang and Ungvari (2002, 2003)

showed that ECT might be a worthful augmentation

strategy in schizophrenic patients who do not

sufficiently respond to a neuroleptic medication,

whereas there are hints that such a positive effect

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

Nussbaumstrasse 7, D-80336 Munich, Germany. Tel: �/49 89 7095 2717. Fax: �/49 89 7095 2715. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 162�170

(Received 4 May 2005; accepted 29 September 2005)

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

DOI: 10.1080/15622970500395280

of this combination might be limited over time.

Suzuki et al. (2004) showed that the relapse rate of

patients suffering from catatonic schizophrenia after

response to acute ECT is high after 6 months,

although neuroleptic pharmacotherapy was contin-

ued. These findings and the fact that ECT still is one

of the best tolerated and most efficacious therapies

raised the question of the influence of concomitant

neuroleptic medication on safety, tolerability and

clinical effectiveness of electroconvulsive therapy.

Clinical effectiveness of ECT and treatment history

The clinical effectiveness of ECT depends on

different treatment parameters, such as stimulation

energy and stimulation modus. In general, unilateral

ECT is a very widespread method of treatment.

Unfortunately, not all patients respond to unilateral

ECT, so that in some cases bilateral stimulation is

necessary. Using this method, lower stimulation

energy is needed, e.g., according to the half-age

method (Abrams 2002). Another possibility of

intensifying the therapy is the use of high-dose

ECT. Using higher stimulation energy in a unilateral

treatment mode can be even as efficacious as

bitemporal or bifrontal ECT (Sackeim et al. 2000).

Augmentation strategies in ECT

Furthermore, additional psychopharmacotherapy

can be used for the augmentation of an ECT

treatment series. Concerning antidepressant conco-

mitant medication, study results indicate that there

is a benefit of combining ECT with tricyclic anti-

depressants (Lauritzen et al. 1996). In the case of

concomitant antipsychotic treatment, published data

are very rare. There is consensus that combining

ECT and clozapine can be a useful augmentation

strategy to improve clinical response in schizophre-

nic patients (Fink 1990; Kupchik et al. 2000), but if

there is a clinical benefit in prescribing neuroleptics

during ECT, this treatment still has to be investi-

gated in more detail.

Study plan

In our retrospective investigation, we addressed the

following questions: Is the combination of ECT and

neuroleptics beneficial for patients with regard to

ictal electrophysiological parameters that might be of

prospective significance for clinical effectiveness?

Are safety or tolerability of ECT treatment altered

if combined with neuroleptic medication in compar-

ison to an ECT monotherapy? Does concomitant

neuroleptic medication influence the incidence of

cognitive or cardiovascular side effects? Are there

differences between different classes of neuroleptics

with regard to ictal electrophysiological parameters

and clinical effectiveness?

Materials and methods

Patients

A total of 5482 ECT treatments in 455 patients,

treated from 1995 to 2003, were analysed in our

retrospective study. We recorded 518 treatment

series; in 63 cases one patient received more than

one treatment series during our period of observa-

tion. A total of 1075 treatments (19.6%) were done

with a concomitant psychopharmacological mono-

therapy (14.4% of treatments were done with no

concomitant medication at all), of which we ana-

lysed 452 treatments (42%) that were done with a

neuroleptic monotherapy. Table I gives patient

characteristics, diagnostic groups according ICD-

10 (World Health Organization 1992), demographic

data and ECT treatment parameters. The patients

were subdivided into two major diagnostic groups:

patients with schizophrenia or schizoaffective

Table I. Demographic data and ECT treatment parameters according to the major diagnostic groups (ICD-10) of ECT treatments. Most

of the treatments were done with patients who suffer from major depressive disorder; as expected, they were older than patients who suffer

from schizophrenia. Depressed patients were more often unilaterally stimulated with lower energy, whereas schizophrenic patients were

mainly bilaterally treated with higher energy.

Diagnoses (ICD-10) x2-Test, ANOVA

F2 F3 F ; x2; P

n (%) 170 (38.5%) 267 (60.5%)

Sex (M/F) 40.9/59.1% 41.5/58.5% 0.492

Age (mean9/SD) 47.49/14.1 54.89/13.8 B/0.0001

ECT treatment modalities

No. of treatments (mean9/SD, n ) 11.59/5.3 10.69/2.8 0.61

Duration (mean9/SD, days) 75.49/95.7 31.79/10.5 B/0.0001

Unilateral (%)/bilateral (%) 24.5/75.5% 85.8/14.2% B/0.0001

Charge (mean9/SD, mC) 3349/193 2629/110 B/0.0001

F2�/schizophrenia (ICD-10); F3�/unipolar and bipolar major depression (ICD-10).

Electroconvulsive therapy and concomitant neuroleptic medication 163

disorder (F2), patients with unipolar or bipolar

major depression (F3). Four treatments were carried

out in patients with rare diagnoses (such as Gilles-

de-la-Tourette syndrome) which were not explicitly

mentioned in the results. The patients gave their

written informed consent for ECT treatment and

anaesthesia separately.

ECT treatments (Weiner et al. 1988)

The Thymatron DGxTM device was used from 1995

to June 2000 for ECT treatments; we then used the

Thymatron System-IVTM from July 2000. Both

devices deliver stimuli in the form of a constant

current (900 mA) bi-directional pulse wave. The

voltage was B/450 V, impulse width was 0.5�1 ms

(mean9/standard deviation (SD): 0.559/0.13 ms),

frequency was 20�70 Hz (52.99/16.8 Hz), length of

stimulus train was 0.14�8 s (5.29/2.0 s).

Stimulus intensity was chosen according to the

modified age method in the case of unilateral

stimulation and the half-age method in the case of

bilateral stimulation (Abrams 2002). The lower

charge limit during the first stimulation was

30% (151 mC), the upper charge limit was 60%

(302 mC). In a very few cases (B/5%) dose titration

was necessary before starting the initial treatment

session. In these cases, unilaterally treated patients

received a first stimulus 2.5�5-fold over threshold,

bilaterally treated patients a stimulus 5% over

threshold. In the case of EEG B/30 s, EMGB/25 s

and postictal suppression index B/80%, we re-

stimulated in 10% dosage elevation steps. The

maximal charge was 504 mC during 1995�2001

and 1008 mC since January 2002. The mean

postictal suppression index was 83.89/21.3%, and

the mean stimulation energy was 57.29/29.9%

(288.39/150.7 mC).

In the case of unilateral stimulation, the treatment

electrodes were placed according to the d’Elia

method as follows (d’Elia 1970; d’Elia and Raotma

1975): one electrode was placed temporally 1 cm

above the centre-point of a line between the outer

eyelid angle and the external acoustic meatus;

the other electrode was placed 12�13 cm distant,

2�3 cm lateral to the vertex. In therapy-resistant

cases, or if former inefficient unilateral ECT treat-

ments were reported, we used bitemporal stimula-

tion. In these cases, electrodes were placed on both

sides according the description above for the tem-

poral electrode. During 1995�1999, electrode pla-

cement was not recorded during clinical routine

treatments, so that these data are lacking in 46.5%

of the analysed treatments. From 2000, 30.3%

unilateral and 23.2% bitemporal treatments were

recorded.

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 position of the one-lead EEG electrodes was left

frontopolar and over the ipsilateral mastoid (FP1�A1

according the international 10�20 system). The

two-lead EEG electrodes were positioned left and

right frontopolar (FP1�A1 and FP2�A2) and over

the ipsilateral mastoid. EMG conduction was placed

5�10 cm over the flexor carpi ulnaris muscle. The

mean seizure duration was 33.49/18.3 s (EEG) and

20.39/12.8 s (EMG).

Anaesthesia

Thiopental was used in 71.9% of treat-

ments (mean dosage9/SD: 3609/88 mg), propofol

was used in 15.0% (1759/64 mg), methoh-

exital was used in 4.4% (1359/31 mg) and

etomidate was used in 2.2% (359/5 mg). The

choice of anaesthetic agent was made according to

the clinical need to achieve adequate seizure

control. Patients with higher seizure threshold

more often received methohexital than other

anaesthetics. For muscle relaxation, succinylcholine

or pyridostigmine, together with atracurium, for

precurarisation were used.

Psychotropic medication

There were 787 treatments done without any

psychiatric medication; 1075 treatments were done

with concomitant non-benzodiazepine hypnotics.

The analysis of all electrophysiological and clinical

parameters revealed no clinically relevant or statis-

tically significant differences between these two

groups.

As far as treatment with neuroleptics as a

monotherapy is concerned, 36.7% of the treat-

ments were done with concomitant medication in

the form of atypical substances, 17.2% with high

potency classical neuroleptics, and 8.2% with

medium and 36.7% with low potency neuroleptics

(Benkert et al. 2003). In the case of atypical

substances, clozapine (41%) and olanzapine

(18%) were given in most cases; antipsychotics

of high neuroleptic potency were predomi-

nantly haloperidol (57%) and benperidol (16%).

Perazine (38%) was the most commonly pre-

scribed medium potency neuroleptic; prothipendyl

(46%) and promethazine (36%) were mainly given

in the case of low potency neuroleptic medication.

The distribution of concomitant neuroleptic med-

ication to the different diagnostic groups is shown

in Table II.

164 C. Nothdurfter et al.

Clinical assessments

We recorded ECT treatments and clinical data from

the ECT treatment documentation and ECT device

printouts in a relational database (Microsoft Access

2000) and from patient records. The severity of

disease, according to the Clinical Global Impression

scale (CGI, Item 1; National Institute of Mental

Health 1976), and diagnosis (ICD-10) were as-

sessed. CGI scores were recorded after each electro-

convulsive treatment, and additionally every week in

the patient records. Furthermore we registered

information about therapeutic response (CGI, Item

3.1) and adverse effects with special regard to

cognitive impairment (CGI, Item 3.2) systematically

after each treatment (serious adverse events were

recorded in free form). We also recorded clinical,

technical and electrophysiological ECT (stimulation

parameters, EEG and EMG including the length of

convulsions, postictal suppression, seizure energy

and seizure concordance). All prescribed medication

(psychiatric medication, substances used for anaes-

thesia, and others, including dosages) were also

recorded.

Electrophysiological measures

To estimate the success of ECT treatment, the

minimal duration of generalised convulsions mea-

sured using EEG and EMG is necessary, but not

sufficient. Measurements of at least 25 s duration in

the EEG and 20 s in the EMG are required (Coffey

et al. 1995). In most cases, computer-recorded EEG

and EMG estimation of the seizure duration is of

sufficient quality (Swartz et al. 1994). On the other

hand, there is evidence that there is no significant

correlation between the clinical therapeutic effec-

tiveness of ECT and the duration of convulsions

(Abrams 1972, 2002; Nobler et al. 1993). In the

case of unilateral ECT, a higher stimulation energy

may result in shorter duration of convulsions (Frey

et al. 2001a), although the clinical effectiveness is

higher (Sackeim et al. 2000). For these reasons,

other measures can be utilised to decide whether

restimulation may be recommended during an

individual treatment session. One of these is the

postictal suppression index (PSI). The PSI shows

how fast and complete the EEG amplitude flattens

directly after the convulsions. It 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. There is a high correlation between its

unit ‘‘% suppression’’ and the probability of ther-

apeutic efficacy (Suppes et al. 1996). If the PSI is

under 80%, restimulation should be taken into

consideration (Weiner et al. 1991: Nobler et al.

1993). As a measure of the intensity of the ictal

response after electrical stimulation (mV �/s), the

convulsion energy index (CEI) is used (Weiner

et al. 1991). It is calculated from the product of

the mean EEG amplitude and the duration of

convulsions. The convulsion concordance index

(CCI) is a measure for the intracerebral general-

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

calculated in the following way:

100�EEG � EMG

EEH � EMG

(the duration of the convulsions is represented by

EEG and EMG). If the index is below 51%, the

patient should be re-stimulated. Senior psychiatrists

provided regular monitoring of EEG and EMG

quality and all treatment procedures.

Statistical analyses

SPSS for Windows (Release 12.0.1, SPSS Inc.,

Chicago, IL 60606, USA) was used for all statistical

analyses. For the comparison of mean differences in

demographic and clinical variables between treat-

ment group independent samples Student’s t-tests

and x2-tests were used. A one-way analysis of

variance (ANOVA procedure) was performed to

detect whether there were significant differences in

electrophysiological variables and clinical mean

scores between the treatment groups. In the case of

multiple testing, Bonferroni correction was used;

0.05 was set as the level of significance.

Results

Psychotropic medication was given in 81.8% of all

treatments, in 23.4% as a psychotropic monother-

apy. A total of 14.6% of the treatments done with

neuroleptics was as a monotherapy. Within the

group of mono-pharmacotherapeutic treatments

with neuroleptics, which was of special interest in

Table II. Description of the major diagnostic groups (ICD-10)

and concomitant neuroleptic medication. Most of the treatments

were done with low potency neuroleptics or atypical substances,

less than half the treatments were done with high potency or

medium potency neuroleptics.

Diagnoses (ICD-10)

Neuroleptic monotherapy (%) F2 F3 Mean

High potency 32.9% 67.1% 17.2%

Medium potency 44.7% 55.3% 8.2%

Low potency 8.2% 89.3% 38.6%

Atypical substances 78.7% 21.3% 38.6%

F2�/schizophrenia (ICD-10); F3�/unipolar and bipolar major

depression (ICD-10).

Electroconvulsive therapy and concomitant neuroleptic medication 165

this study, 17.2% were done with high potency

neuroleptics, 8.2% with medium potency neurolep-

tics, 38.6% with low potency neuroleptics, and

38.6% were with atypical substances (Table II).

Depressed patients predominantly received low

potency neuroleptics to achieve sufficient sedation,

avoiding benzodiazepine medication.

Firstly, we compared the mean duration of gen-

eralised convulsions in EEG and EMG between

treatments done with a neuroleptic monotherapy

(either high, medium or low potency, or atypical

substances) and treatments done without any psy-

chotropic medication. ANOVA revealed statistically

significant differences in the duration of convulsions

in both EEG and EMG (Figure 1; EEG: F�/5.239,

P B/0.0001; EMG: F�/3.129, P�/0.014). Bonfer-

roni-corrected post-hoc tests showed significantly

longer durations of EEG convulsions in treatments

done with low potency neuroleptics than in treat-

ments done with no psychotropic medication. Con-

cerning EMG convulsion durations, treatments

done with atypical substances showed significantly

shorter durations than treatments done with high

potency neuroleptics.

The electrophysiological indices to estimate treat-

ment quality also showed statistically significant

differences between the above-mentioned groups

(Figure 2): ANOVA: PSI: F�/7.615, P B/0.0001;

CEI: F�/4.079, P�/0.003; CCI: F�/4.248, P�/

0.002. Bonferroni-corrected post-hoc tests revealed

that the PSI of treatments done with atypical

substances was significantly higher than the PSI of

treatments done with low potency neuroleptics and

those done without any psychotropic medication.

Regarding the CEI and the CCI, this turned out to

behave in the opposite way; the treatments done

with atypical substances had significantly lower CEIs

and CCIs compared to the treatment group without

any psychotropic medication. Furthermore, the

treatments done with atypical substances also

showed lower CEIs than those done with high

potency neuroleptics, and lower CCIs than the

treatments done with medium potency neuroleptics.

To judge the influence of concomitant neuroleptic

medication during ECT treatment on clinical effec-

tiveness, we compared the documented CGI item

3.1 after an ECT treatment series between the

different treatment groups (Figure 3). ANOVA

revealed significant differences as follows: F�/

8.335, P B/0.0001. Bonferroni-corrected post-hoc

tests showed the best clinical improvements in the

treatments done with atypical substances, which

were statistically significant compared to the treat-

ments done with medium and low potency neuro-

leptics as well as compared to the treatments done

without any psychotropic medication. Regarding

adverse effect such as memory impairment and

cardiovascular adverse effects, we did not find any

statistically significant differences. Nonetheless, con-

cerning memory impairment (ANOVA) judged by

CGI item 3.2, less impairment seemed to appear in

treatments done with medium potency neuroleptics.

Referring to cardiovascular adverse effects (tempor-

ary cardiac arrhythmia, recorded during an ECT

0

10

20

30

40

no PT HP MP LP Atypmea

n du

rati

on o

f co

nvul

sion

s (s

econ

ds)

n=733 n=83 n=37 n=184 n=169

:n=1206 ECT treatmentsANOVA: EEG p<0.0001 EMG p=0.014

EEG

EMG

EEG *p=0.009EMG *p=0.041

Figure 1. Mean duration of generalised convulsions in dependency of neuroleptic medication. The duration of convulsions measured using

EEG derivations was significantly longer in treatments done with low potency neuroleptics than in treatments done with no concomitant

psychotropic medication. As far as convulsions in the EMG are concerned, they lasted significantly shorter in treatments done with atypical

substances than in treatments done with high potency neuroleptics: no PT�/no psychotropic medication; HP�/high potency neuroleptics

(n�/patients); MP�/medium potency neuroleptics (n�/patients); LP�/low potency neuroleptics (n�/patients); Atyp�/atypical substances

(n�/patients).

166 C. Nothdurfter et al.

treatment) (x2-test) which were mainly bigemini

(50%), ventricular extra systoles (15.6%) and short

periods of asystolia (15.6%) (data not shown), there

was a tendency towards the treatments done with

high potency neuroleptics to occurring more often

cardiac arrhythmia.

Discussion

In a retrospective study we analysed ECT treatments

with and without concomitant neuroleptic mono-

therapy to investigate statistically significant differ-

ences in ictal electrophysiological measures and

indices, clinical effectiveness and adverse events.

When comparing generalised convulsions we

found that the electroencephalographic estimated

duration of convulsions was the longest in the group

of treatments done with neuroleptics of lower anti-

psychotic potency. This is a remarkable fact, as the

patients who received these substances were pre-

dominantly elderly depressed patients who were

treated using a rather low stimulation charge in

comparison to younger schizophrenic patients. This

was true in spite of the fact that stimulation energy

was chosen according to the modified age method

(Abrams 2002). On the other hand, a possible

explanation for the long-lasting convulsions in the

treatment group receiving low potency neuroleptics

may be that younger schizophrenic patients were

more often stimulated bitemporally in comparison to

depressed patients, which results in shorter dura-

tions of convulsions while intensifying the treatment

towards a better clinical effectiveness (Abrams

1986).

80

85

90

95

no PT HP MP LP Atyp

0

500

1000

1500

2000

no PT HP MP LP Atyp

50

55

60

65

70

75

80

no PT HP MP LP Atyp

post

icta

l sup

pres

sion

inde

x co

nvul

sion

ene

rgy

inde

x co

nvul

sion

con

cord

ance

inde

x

*p<0.0001

*p=0.006

postictal supression index (%)

ANOVA: p<0.0001

convulsion energy index (µV*seconds)

ANOVA: p=0.003

*p=0.027 *p=0.004

convulsion concordance index (%)

ANOVA: p=0.002

*p=0.009 *p=0.010

Figure 2. Estimation of the quality of convulsions by the postictal suppression index (PSI), convulsion energy index (CEI) and convulsion

concordance index (CCI). Treatments done with atypical substances had significantly higher PSI, whereas the low potency-treatment group

had rather low PSI. Concerning the CEI, the treatments done with atypical substances were much lower than the treatments done with high

potency neuroleptics and the treatments done with no psychotropic medication. The CCI was also rather low in treatments done with

atypical substances compared to the medium potency-treated group and the treatments done with no psychotropic medication. PSI�/

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

Electroconvulsive therapy and concomitant neuroleptic medication 167

Regarding the durations of convulsions measured

using EMG derivations, we recorded times incon-

sistent to the EEG derivations. The duration of

convulsions in EMGs was relatively short in patients

treated with atypical substances. According to the

known independence of clinical benefit from the

duration of convulsions (Sackeim et al. 1991; Frey

et al. 2001b), this seems to have no impact on

clinical improvement, which was best in this group

of patients. In accordance to the literature, in our

patients the duration of convulsions in the EMG

seems also not to be of major importance for the

quality of treatment. It has to be taken into account

that the cuff method was not used to detect

convulsions in clinical routine, since EEG deriva-

tions were by a standard clinical procedure. There-

fore EMG derivations were considered not to be a

reliable indicator for the estimation of the duration

of convulsions because of the dependence of kind

and dosage of muscle relaxants.

Comparing the electrophysiogical indices of the

different treatment groups for estimation of the

treatment quality, ECT treatments combined with

atypical neuroleptics showed the best results regard-

0

0,5

1

1,5

2

2,5

no PT HP MP LP Atyp

0

0,5

1

1,5

2

no PT HP MP LP Atyp

0

5

10

15

20

25

no PT HP MP LP Atyp

clin

ical

eff

icac

y C

GI

item

3.1

CGI item 3.1: 1: very much improved 2: much improved 3: minimally improved 4: no change

ANOVA: p<0.0001

mem

ory

impa

irm

ent

CG

I it

em 3

.2

CGI item 3.2:1: no adverse effects 2: slight impairment3: severe impairment4: predominating desired therapeutical effects

ANOVA: no statisticallysignificant differences

card

iac

arrh

ythm

ia (

% o

f ea

ch g

roup

)

2-test: no statistically significant differences

*p=0.001

*p<0.0001

*p<0.0001

Figure 3. Clinical efficacy after a treatment series and adverse effects. Treatments done with atypical substances showed a significantly

better clinical improvement than treatments done with medium and low potency neuroleptics as well as treatments done with no

psychotropic medication. As far as adverse effects are concerned, there were no statistically significant differences seen in our study. CGI

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

treatment).

168 C. Nothdurfter et al.

ing postictal suppression (PSI), thus supporting the

hypothesis that this index seems to be a very reliable

parameter for judgment of therapy quality (Suppes

et al. 1996). This is further confirmed by the clinical

improvement judged by CGI item 3.1, which was

also best in the patients treated with atypical sub-

stances. On the other hand, the convulsion energy

index (CEI) was highest in patients treated with high

potency neuroleptics, whereas the convulsion con-

cordance index (CCI) was favourable in the group of

medium potency treated patients. The inhomogene-

ity of these electrophysiological indices shows that

they might have to be seen critically during a therapy

combining ECT and neuroleptics (especially CEI

and CCI). So far, there have been no published

studies investigating the influence of neuroleptic

medication on the electophysiological indices sys-

tematically.

As already mentioned, the clinical effectiveness

(according CGI item 3.1) turned out to be best in

patients treated with ECT and concomitant atypical

neuroleptics, which underlines the quality of ECT

treatments judged by the PSI. Treatments done with

concomitant medium and low potency substances

showed less convincing results, which might be

explained by the fact that these patients were more

severely ill and agitated, and thus needed more

sedative medication in form of low and medium

potency substances.

We also compared adverse effects (CGI item 3.2),

especially with regard to memory impairment

between the different groups of patients treated

with an ECT monotherapy or different neuroleptics

additionally to ECT treatment. Here we did not find

any statistically significant differences, which sup-

ports our assumption that the combination of ECT

and neuroleptic medication is not an additional risk

(O’Brien et al. 1993). It has to be mentioned that

there was no incidence of severe adverse effects at

all; mild cardiovascular side effects occurred only

temporarily during the ECT treatment and did not

need further intervention in most cases.

Due to the retrospective character of our investi-

gation and the inhomogeneous pharmacological

treatments using concomitant neuroleptics, our

analyses were oriented at treatment sessions rather

than to treatment courses of individual patients. In

clinical routine, treatment regimes very often change

with regard to ECT and pharmacotherapy treatment

modalities (data not shown). In this way the analysis

of singular treatment series in patients who are

treatment resistant and who have received more

treatments than other patients, may have more

influence on our analysis than patients showing a

better treatment response. An advantage of this kind

of analysis might be the fact that changes in ECT

and concomitant neuroleptic medication treatment

modalities within one ECT series cannot influence

the results significantly.

It is noteworthy that the different groups analysed

in our study differ not only in their treatment

modalities, but also concerning clinical and demo-

graphic data (Table I). We analysed predominantly

treatments of depressed patients (60.5%), who were,

as expected, significantly older (7.4 years) than

schizophrenic patients. Depressed patients very

often received low potency neuroleptics with sedat-

ing properties in order to avoid benzodiazepines

during ECT, whereas most of the treatment-resistant

schizophrenic patients received atypical neurolep-

tics. These differences can of course make the

interpretation of our results more difficult.

In summary, our results show an excellent toler-

ability of ECT treatment as a monotherapy as well as

in combination with neuroleptic medication. The

study gives further hints that especially atypical

substances are beneficial with regard to the clinical

effectiveness of ECT treatments. The retrospective

design of the study is of course of a certain

limitation. Our study provides data that demand

further controlled analyses using double-blind and

placebo-controlled conditions in order to prove

whether concomitant neuroleptic medication should

be recommended in ECT treatment to enhance

responder rates and shorten the time until clinical

improvement, and cause as few adverse effects as

possible. Furthermore it could be of interest to

further analyse the influence of individual neurolep-

tics on ECT treatment parameters, for there are

hints that there are differences, especially in the

group of atypical substances. It has been found that

clozapine and olanzapine are epileptogenic, whereas

quetiapine seems to reduce seizure activity (Amann

et al. 2003; Gazdag et al. 2004). In this way,

recommendations for the choice of concomitant

neuroleptic medication during an ECT treatment

might be made even easier.

Acknowledgements

The authors would like to thank Mrs M. Ertl, Mrs S.

Rauch and Mr K. Neuner for patient nursing, ECT

organisation and database management. Parts of this

study were done in the framework of the doctoral

thesis of Mrs Ines Noack which has been submitted

to the Faculty of Medicine, University of Munich.

Statement of interest

Each author certifies that he or she has no commer-

cial associations that might pose a conflict of interest

in connection with the submitted article.

Electroconvulsive therapy and concomitant neuroleptic medication 169

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VIEWPOINT

Disasters and mental health: New challenges for the psychiatricprofession

JUAN J. LOPEZ-IBOR JR

Department of Psychiatry and Medical Psychology, Complutense University, Institute for Psychiatry and Mental Health,

San Carlos Clinical Hospital, Madrid, Spain

Articles published in the Viewpoint section of this Journal may not meet the strict editorial and scientific standards that are appliedto major articles in The World Journal of Biological Psychiatry. In addition, the viewpoints expressed in these articles do notnecessarily represent those of the Editors or the Editorial Board.

AbstractA disaster is the consequence of an extraordinary event that destroys goods, kills people, produces physical or psychologicalharm but, above all, which overcomes the adaptive possibilities of the social group. Disasters have strong politicalbackground and consequences. They shake the life of a community and raise questions about safety, social organization andthe meaning of life. Disasters confront psychiatrists with challenges far beyond regular clinical activities or researchstrategies. During early interventions after a disaster, psychiatrists often have to work out of their usual clinical premises, incontact with unfamiliar professionals (i.e. rescue personnel) and with individuals who should not be considered as ‘cases’,and therefore without keeping regular clinical records. In the latter stages they have to confront many factors which tend tocause the clinical consequences of those affected and who developed a psychiatric condition to be chronic. Reactions tostress occur in stages, each one characterised by a specific psychological mechanism. Symptoms include flashbacks,difficulties in remembering, avoidance of stimuli, blunting of responses, high arousal level and obsessive ruminations. Thestrong biological and psychosocial factors which are unchained after a disaster should be recognised and chanelled. Theexperience of psychiatry with the bio-psycho-social model can help to understand what disasters are, how some negativeaspects of them could be prevented, and how their consequences, both clinical as well as social, can be reduced.

Key words: Disaster, catastrophe, stress, posttraumatic stress disorder

Introduction

The psychological reactions to and psychopatholo-

gical consequences of disasters have not received,

until recent times, all the attention they deserve.

Only in 1948 were they recognized in the Interna-

tional Classification of Diseases (ICD-6; WHO

1948), and they did not appear until 1980 in the

Diagnostic and Statistical Manual of the American

Psychiatric Association (DSM-III; APA 1980).

Furthermore the descriptions and criteria are very

unsatisfactory in both classification systems which,

on the other hand, are very different from each other

(WHO 1992; APA 1996; Lopez-Ibor Jr 2002).

There are several reasons for this situation. The

first one is to consider that it is up to human nature

to be able to face up to all calamities, independently

from the fact that occasionally some individuals

could yield, due to a lack of personal strength. The

other one is to accept that the personality is stable

and does not change throughout lifetime, even after

experiencing extreme situations. The concentration

camps of Nazi Germany changed these views:

tolerance has limits, there are situations under which

any individual would succumb. Experiences in

communist concentration camps showed how the

combination of physical deprivation, isolation and

psychological humiliation shatter the most solid

defences. The study of concentration camp survivors

led Venzlaff (1958), and later von Baeyer et al.

(1964), to describe for the first time persistent

transformations of the personality.

Correspondence: J. J. Lopez-Ibor Jr, World Psychiatric Association, Nueva Zelanda, 28035 Madrid, Spain. Tel: �/34 91 330 3572.

Fax: �/34 91 316 2749. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 171�182

(Received 23 August 2005; accepted 21 October 2005)

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

DOI: 10.1080/15622970500428735

A third reason for the relative little interest in this

subject, is that it has mainly been studied by military

psychiatrists, who are usually confronted with many

difficulties when trying to publish and share their

experiences with other colleagues, as they may well

be on opposing sides in a war or confrontation. This is

changing, and there is a greater collaboration between

the civil and the military worlds, and this allows the

transference of the great experience accumulated

during military conflicts to civil disasters.

What is a disaster

Research in disasters is very difficult, because it is

hard to integrate it into the rescue tasks which

have priority and because it usually recalls negative

reactions from the perspective of the victims. In-

vestigation is therefore opportunistic and after-the-

event (Kasl et al. 1981). Furthermore, the involve-

ment of psychiatrists in the rescue and care of

victims is usually late and often because of secondary

reasons, for instance, in the case of court litigation.

This also reduces the opportunities for research

(Lopez-Ibor et al. 1985). On the other hand,

reactions to the most different disasters are extra-

ordinarily similar. This allows to accumulate and

share experiences, create groups of experts and

prepare plans and intervention groups.

It is almost impossible to find an acceptable

definition by a majority of what a disaster is. Korver

(1987) collected, many years ago, forty different

definitions of disaster; many more that have ap-

peared since can be added. Some authors (Freud

1969; Winnik 1969; Furst et al. 1971; Crocq 1992,

1993; Benyacar 2002) consider that the notion of

what a traumatic event is, is inherent to the complex-

ity of human existence and therefore inaccessible to

a consensus. However, it is necessary to define what

a disaster is in order to face up to the risks derived

from them and their consequences. Quarantelli

(1998) states that if the experts do not reach an

agreement as to whether a disaster is a physical event

or a social construct, the field will have serious

intellectual problems and that the worries about

what a disaster is should not mean that we become

involved in a futile academic exercise. On the

contrary, agreement consists of delving into what

are the important and significant characteristics of

the phenomenon, of the conditions that lead to it

and to its consequences. But further definition is

needed in order to understand the phenomenon,

because any concrete disaster unchains the question

on its sense. Therefore, the conceptualisation of

what a disaster is, is necessary in order to cope and

to understand it.

Most dictionaries define disasters and cata-

strophes in similar ways, as events in which there is

a lot of harm and destruction. The word catastrophe

has a larger and deeper semantic scope than a

disaster.

Human losses, number of injured persons, mate-

rial and economic losses and the harm produced to

the environment are often considered in order to

define a disaster. For some the number of 25

deceased has to be exceeded (Dombrowsky 1998),

for others this figure has to be larger, more than 100

deceased and more than 100 injured or losses worth

more than $US 1 million (Sheehan and Hewitt

1969), and for others the limit is still higher: an event

leading to 500 deaths or $US 10 million in damages

(Tobin and Montz 1997). According to Wright

(1997), experience shows that when an event affects

more than 120 persons, except for cases of war, non-

routine interventions and the coordination between

different organisations are needed, something which

is already indicating other important characteristics

of a disaster.

To define a disaster based on the magnitude of the

damage caused has many inconveniences. First, it

may be difficult to evaluate the damages in a first

stage, or to assign them later on. Second, they are of

no use for comparative studies in different countries

or social situations and they are affected by inflation

(Dynes 1998). Third, disasters are very different.

Earthquakes of the same intensity are only a fright in

California nowadays but would have been a cata-

strophe before 1989, and would be a catastrophe in

many developing countries at present. There may

even exist disasters with zero harm. The best

example for this was the broadcasting in 1935 by

Orson Welles of The War of the Worlds (Holmsten and

Lubertozzi 2001). More than one million persons

showed intense panic reactions because of what they

believed to be a Martian invasion.

Disasters are often considered as elements of the

physical environment harmful to human beings and

caused by forces foreign to them (Burton and Kates

1964; Burton et al. 1993). It has also been assumed

that disasters are the consequence of not very

frequent and non-routine events. Disasters are

normally unforeseen and catch the population and

administration affected off-guard. However, there

are disasters which repeat themselves, for example in

areas affected by flooding, and others which are

persistent, as in many forms of terrorism. In these

cases, a culture of adaptation and resignation to

disasters develops.

Disasters are normally considered as ‘chance’

events and are therefore unavoidable. In the past

they were ascribed to a divine punishment, and even

nowadays it is not strange to read that an event

172 J. J. Lopez-Ibor Jr

‘reached Biblical proportions’, or that nature’s

powers have been unchained as they were when

God had to punish evilness of human beings with the

Flood. In fact, the etymology of disaster, from Latin

desastrum (des ‘lack, loss’, astrum ‘heavenly body,

star’), indicates bad luck or fortune. The word

started to be used in a generalised way in France,

from where it extended to other countries as a

consequence of the secularisation brought about by

the Enlightenment.

An important characteristic of disasters is their

centrality (Green, 1982). A disaster is peripheral

when the persons affected were in the place by

chance (for example, in a plane crash) and when the

victims come back to their intact social surrounding

where they can rely on the support of relatives.

Catastrophes are disasters of a great magnitude, of a

great centrality. A total breakdown of everyday

functioning takes place in them, with the disappear-

ance of normal social functioning, loss of immediate

leaderships, insufficient health and emergency sys-

tems, in such a way that survivors do not know

where to go to receive help.

Human-made disasters are normally distinguished

from those consequences of natural disasters.

Among the former, some are not intentional, that

is to say they are a consequence of human errors. In

this case, the responsibility is considered to be

institutional, and compensations from insurance

companies are granted. Possible calculated risks

should be guaranteed based on their probability.

There are also disasters which are a consequence

of a clear intention, e.g., as conventional war would

be. In these cases, individuals are able to start up

more or less legitimate or efficient coping or defence

mechanisms to confront the aggression.

In other occurrences, violence is due to terrorist

attacks, assaults by rapists or similar events. This is

an anonymous violence the goal of which is to cause

harm to anybody, something that prevents victims

from developing any kind of defence. This kind of

violence may affect any person, in any place of the

world, at any time.

However, it is not possible to accept that there are

purely natural disasters, since the human hand is

always present. This is Steinberg’s thesis (2000); he

has studied a large series of disasters in the USA. It

has to be taken into account that the degree of

development of a community is a determinant fact.

Between 1960 and 1987, 41 out of the 109 worst

natural disasters took place in developing countries,

in which 758,850 persons died, while the remaining

59% of disasters took place in developed countries,

in which 11,441 persons died (Benz, 1989). In

another series studied between 1990 and 1998,

94% of the 568 greater disasters occurred in poor

countries causing 97% of deaths related to them. It

is curious enough that these proportions are similar

to the ones caused by famine, HIV or by refugees

(Easterly 2001).

Definitions of disasters based on the idea of an

exceptional agent are not fully satisfying. In fact,

when reviewing them other elements already appear

which are related to social conditions. The flooding

of an uninhabitated non-cultivated plain with no

ecological value is not a disaster, human involvement

is needed.

Therefore the impact of a danger on a social group

is related to the mechanisms and adaptive capability

the community has developed to face up to the effects

of potential destructive events. If they are efficient,

we can speak of an emergency, not of a disaster.

Disasters have been defined from this perspective as

external attacks that break social systems (Burton

and Kates 1964), which exert a disruptive effect on

the social structure (Benyacar 2002). The social,

political and economic environment is as determi-

nant as the natural environment, it is what makes

dangers turn into disasters (Blaikie et al. 1994), and

the disruption may create more difficulties than its

physical consequences (Quarantelli 1988).

The United Nations Coordinating Committee for

Disasters (UNDRUCO 1984) stipulates that a

disaster, seen from a sociological point of view, is

an event located in time and space, producing

conditions under which the continuity of the struc-

tures and of the social processes turns problematic,

and The American College of Emergency Medicine

(1976) points out that a disaster is a massive and

speedy disproportion between hostile elements of

any kind and the available survival resources needed

in order to re-balance the situation in the shortest

period of time possible (Dynes et al. 1987). This is

similar to that appearing in a definition by the WHO

(1991).

Crocq et al. (1987) point out the importance of

the loss of social organisation after a disaster. For

them the most constant characteristic is the altera-

tion of social systems that secure the harmonious

functioning of a society (information systems, circu-

lation of persons and goods, energy production and

consumption, food and water distribution, health

care, public order and security keeping, as well as

everything related to corpses and funerary ceremo-

nies in cemeteries).

In summary, disasters are events as a consequence

of a danger that affect a social group and which

produce such material and human losses that the

resources of the community becomes overrun and,

therefore, the usual social mechanisms for coping

with emergencies are insufficient.

Disasters and mental health 173

As a consequence, it has to be pointed out that a

disaster is something exceptional, not only because

of its magnitude: it is not enough to mobilise more

material and staff, these events go beyond the

jurisdiction of organisations and institutions, unfa-

miliar tasks have to be carried out, changes in the

organisations of the institutions in charge of respond-

ing to the disaster are enforced, new organisations

appear and persons and institutions which normally

do not respond to emergencies, are mobilised.

Several things are needed in order to produce a

catastrophe: an extraordinary event able to destroy

material goods, to cause the death of persons or to

produce injuries and suffering (Cohen 1999), or an

event after which a community lacks any adequate

social guidelines to react (Anderson 1968). This

leads to the need for intervention and of external

support, to a personal sensation of helplessness, to

feeling threatened, to tensions between social sys-

tems and individuals (Schulberg 1974), as well as to

a deterioration of the links that unite the population

and of the prevalence of the sense of pertaining to

the community (Erikson et al. 1976).

Disasters not only affect social functioning, they

are also the consequence of a certain social vulner-

ability up to then hardly perceived. They reveal

previous failures. Vulnerability decreases with the

degree of development of civilizations, which in

essence precisely aims to protect human beings

from the negative consequences of their behaviour

and from the forces unchained by nature (Gilbert

1998).

This social vulnerability is present even in the

clinical reactions to disasters. Among the risk factors

for post-traumatic stress disorder, more often iden-

tified in the USA, are the following: female sex, to be

Hispanic (Ruef et al. 2000), personal and familiar

history of psychiatric disorders, experiences with

previous traumas, especially during childhood, social

instability, low intelligence, neurotic traits, low self-

esteem, negative beliefs of oneself and the world and

an external locus of control (van Zelst et al. 2003).

Curiously enough there is a preventing factor, and

that is political activism.

Disasters are political events. Several authors have

dealt with this important aspect of a disaster. If

politics is an allocation of values, the link between

politics and disasters is determined by the allocation

of values on the authorities regarding security in the

period previous to the event, the survival possibilities

during the emergency stage and the opportunities to

survive during recovery and reconstruction (Olson

2000).

A disaster is also a political opportunity to develop

innovative initiatives, essential to diminish the present

and future consequences of the danger. A thorough

statistical study (Drury et al. 1998) on the relation-

ship between the severity of a disaster and political

instability showed that the repercussion is restrained

by the repression exercised by an authoritarian regime

and by a high level of development, but not because

of inequality of income (this last fact against the

hypothesis of the authors).

There is also a political use of disasters analysed

by Edelman (1977). Governments usually behave in

different ways when confronted with a problem and

with a crisis. In the case of a problem, they try to

cause a systematic deflation of the attention on the

inequality of the goods and services offered to the

population. On the contrary, in the case of a crisis,

they try a systematic inflation of threats, allowing

them to legitimate and demand an increase of

authority. When crises repeat themselves, authori-

tarianism increases; this is not restrained by the

presence of problems which are being dampened. In

this way, governments maintain their liturgies on an

increase of authoritarian power.

The political management of a crisis is based on a

political and organisational symbology and opens up

new opportunities for those responsible for new

initiatives and for other players who will achieve

visibility and prominence. In this way, the directive

elite exploits the resource of symbology in order to

influence the collective conceptualisation of the

situation and to enhance the chosen actions. Con-

crete strategies are started like, for example, the

framing of the crisis in a determined context, the

ritualisation maintained by collective action and the

masking of possible alternative conceptualisations

(Edelman 1977). It has to be pointed out that

Edelman’s remarks can be applied to any kind of

crisis, for example, in the management of corpora-

tions.

Disasters are a great opportunity to appoint

scapegoats, efforts to burden the guilt on a person

or a group are constant. But scapegoating is not a

means of finding and assigning responsibility. It is a

means of avoiding finding and assigning true re-

sponsibility. Whenever one finds the scapegoat

mentality at work, responsibility has been abrogated,

not shouldered (Allinson, 1993). Therefore, the

thesis of something accidental or unavoidable cannot

be accepted, because in the long run it turns into a

prophecy that fulfils itself and prevents us from

concentrating on the real causes.

Reactions to disasters

Stages in the reactions to disasters

One aspect of stress has not been considered in

depth in ICD-10 (WHO 1992) or in DSM-IV (APA

174 J. J. Lopez-Ibor Jr

1996), namely that reactions to stress develop in

phases. There are various descriptions of the phases

of a disaster, including a different number of them,

generally between three and seven. However, it has

to be pointed out that all of them are characterised

by a great homogeneity of the factors associated to

each one of them, and that they cannot be con-

sidered as rigid periods in time since their display has

a great diversity in different disasters. That is to say,

the important thing is to know that the mechanisms

and the psychological and psychopathological con-

sequences vary along time and that therefore they

have to be anticipated, although in each moment

various given reactions may appear with different

cadences.

Glass (1959) has described them, adding for the

first time the dominant psychological mechanism in

each one of them. His description is based on the

bombings on the civil population during Second

World War, but it may apply to all disasters.

The first phase, pre-impact period, is previous

to the event itself. Denial mechanisms are dominant

in this stage: the bomb will not fall here , Hitler will not

invade Poland , the mountain of accumulated slag will

not fall , the dam will resist , and so on. This phase is

important since it facilitates the disaster and mainly

because the reactions to it include not only the event

itself, but also the consequences which made it

possible.

The second phase is the one of alarm period. In

it an inefficient hyperactivity takes place. It is a phase

of panic, of heroic and altruistic behaviour, but is not

always efficient.

The third phase described by Glass is the one of

the impact period, this refers to the explosion of

the bomb. During this stage there is no psychological

reaction due to its shortness. This stage is not

present in other types of disasters and may well be

dismissed.

Following comes a phase of recoil period, in

which the mechanism put into action before the start

begins to make its effect. Combat exhaustion,

hypoactivity, apathy and disappointment appear. In

military psychiatry it is known as combat exhaustion

or the ‘syndrome of the old sergeant’.

The fifth and last phase described by Glass is the

post-impact period. In this phase feelings of rage

and hostility may appear directed towards those

possibly responsible, but also against the society in

which the disaster took place and against its leaders.

All disasters leave their print in the political life of a

country.

However, there is another phase to which Glass

did not pay attention, maybe because he wrote about

the phases very soon after the events during the

Second World War. It is a phase of reconciliation

(Lopez-Ibor et al. 1986, 1987) in which the social

group again comes to terms with itself, buries its

dead and its ghosts, gives a new meaning to the lives

of its individuals, the ones who died and the ones

who survived, be they injured or not. This stage is

not always reached, or it is not reached in a radical

enough way. The monuments for those fallen in war,

or to battles, try to be this.

Levels in the reactions to disasters

Reactions to disasters develop in three levels: biolo-

gical, psychological and social. A challenge for

research is to find out insomuch how they develop

in parallel and how each level influences the others.

Biological level . Stress and stressing agent are the

same. Stress is the reaction that appears when the

individual is threatened by an environmental factor

or factors, which are the stressing agents or stressors

(physical, chemical, psychological or social), that

disturb or threaten to disturb a state of internal

balance (homeostasis). They are a group of unspe-

cific responses that are set off before having been

able to identify the specific threat. Their purpose is

to prepare the individual for action: for fight or

flight.

In a first stage, an activation of the hypothalamus�hypophysis�suprarenal axis, with a rapid and brief

CRF-ACTH glucocorticoid secretion increase, takes

place. Later, a sustained response characterises

chronic stress: a more general activation of the

central nervous system takes place, specially of the

neurons of the paraventricular nucleus and an

increase of CRF and VP giving way to a a-adrenergic

and 5-HT1a, 5-HT, nicotinic, cholinergic, interleu-

kin 1, angiotensin II, TRF, neuropeptide Y and

vasopressin stimulation (Dıaz-Marsa et al., 2000).

The consequence of all this is an increase in the

activity of several neurotransmitters, among others

dopamine in the limbic system, in the cortex, in the

hypophysis and in the cerebellum, and hormones

like epinephrine, with an increase of blood pressure,

pulse rate, fat catabolism and the metabolism of

carbohydrates. Also, corticoids and various physio-

logical responses increase, insulin and growth hor-

mone secretions and also immunological responses

decrease, causing among other things, stress ulcers

(Yehuda 1997).

Hormonal secretion has a characteristic temporal

pattern. Immediately after the impact of the stres-

sing factor, in a few minutes GH secretion falls and

secretion of b-endorphins, ACTH and LH show a

significant increase, this is also the case for TSH but

to a lesser degree. This last recedes in minutes, but

LH takes some hours to decrease. LH secretion

Disasters and mental health 175

recovers its basal level after 4�5 hours, although

afterwards it may remain under basal levels for

longer. ACTH levels are maintained over basal levels

for 12 hours or more, with b-endorphins for up to

24 hours.

In recent years, research has been centred on the

biological processes unleashed after exposure to

disruptive situations (Bremner et al. 1995; Yehuda

2000). Bremner et al. have studied in a systematic

way the possible brain injuries as a consequence of

stress and McEwen (1999) studied the dysfunctions

and plasticity of the hippocampus (Bremner 1999;

McEwen 1999; Gould et al. 1999). Research on the

functional specificity of the amygdala and its trophic

mechanisms in disruptive situations that produce a

dysfunction of emotional memory has to be added

(Roozendal et al. 1997; Post et al. 1998; Cahil and

McGaugh 1998).

Neuroimaging studies have provided some impor-

tant data. First, a reduction of the volume of the

hippocampus in persons who have been exposed to

stressful situations, for example US army veterans

(Hedges et al. 2003) or women with a history of

sexual abuse during childhood (Bremner et al.

2003). In a PET the blood flow is generally

increased, but specially in the cerebellum and in

the precentral, superior temporal and right fusiform

circumvolutions. The cerebellosum and extra-stria-

tal flow positively correlate with depression and post-

traumatic scales (Bonne et al. 2003).

Psychological level. Bakan (1968) has underlined the

strong parallelism between Freud’s ideas (Freud

1926) and the concept of reaction to stress described

by Selye. It is curious that Freud’s death instinct

came from the observation of dreams of traumatic

events, which could not be explained by the libido

and the desiderative character of dreams. He came

to the notion of a non-libidinous, autodestructive

principle: death instinct, thanatos. The individual

psychological response of human beings to external

aggressions or threats (real or imagined) is anxiety

that, at the same time, unchains various defence or

coping mechanisms. In some circumstances, defence

mechanisms anticipate themselves in order to face

up to threats still not identified that may result in

harm for the individual’s organism and, in the end,

may even entail a risk for survival. The notion of

autodestructive mechanisms in individuals was men-

tioned by Freud in his description of the death

instinct or thanatos and is present in the concept

of adaptation illnesses.

In this context it’s worth remembering Sartre’s

(1939) concept on emotion: its a substitute beha-

viour in which the affected person, in front of an

irrational unbearable senseless situation, assumes a

metaphoric relationship with the world allowing

him/her to continue living. For example, sadness is

the possibility to survive the loss of a beloved person,

shutting oneself in on oneself, becoming isolated

from a world lacking any sense after the loss of the

beloved person. Moreover, all emotions have their

vegetative correlate. They are the serious face of

emotion.

Emotion ends when the moment and the possibi-

lity is given to elaborate the trauma and to give it a

significance, that is to say, when it is rationalised

(Lopez-Ibor et al. 1999). Rationalisation implies a

verbalisation.

A series of particular behaviours maintains the

validity of the trauma, like the avoidance of those

things that may remind of it, suppression of thoughts

and remembrances, ruminations, a behavioural pat-

tern of avoidance the individual considers as ‘safe’,

dissociation mechanisms and alcohol and drug

abuse (Ehlers and Clark 2000).

Many psychological theories, not incompatible

among them, have been postulated. For Foa

(1986, 1997), there is an association of banal stimuli

with fear. For Charney et al. (1993), there are two

different conditionings of fear, one related to envir-

onmental stimuli that cause discomfort and another

one which is an operating and instrumental deter-

minant that gives way to avoidance. For Brewin et al.

(1999), trauma has a double representation in

memory, one is accessible to verbalisation and the

other one to the situation.

In any case, after a traumatic event, a transforma-

tion of the vision of the world, of oneself and of the

future, takes place. Memory becomes dissociated

from its context (Ehlers and Clark 2000), requiring a

re-adaptation process to reality consisting of a re-

elaboration of the trauma (Horowitz 1993). On the

other hand, new beliefs appear and other false and

old ones are surmounted (Janoff-Bulman 1992) like,

for example, ‘the world is a safe place’ or ‘the worst

always happens to me’ or ‘it never rains but it pours’.

In any case, it occurs as the appearance of a new

emotional conscience which, as any emotional state,

is always accompanied by a vegetative correlate.

Social level . This bio-psychological model has to be

expanded to become bio-psycho-social, including

reactions to collective stresses, like, for example, in

disasters and catastrophes. Here, the overwhelming

external threat has a much lesser role for individual

vulnerability than for neurotic disorders. What

happens in the initial stages has consequences on

the more advanced ones. The impact of an event for

which an individual is not prepared (no protection or

immunity is available, or negation has prevented

preparation for action) unchains an exaggerated

176 J. J. Lopez-Ibor Jr

response, smoothing the way for consecutive re-

sponses: strain and chronic states.

In the aetiopathology of these manifestations,

group factors and the psychopathology of the masses

have to be taken into account. The nature and

characteristics of group membership and factors like

lack of security, isolation, intra-group conflicts, role

distribution during immediate reactions and the

elaboration of sequelae are more important. Also,

imitation and identification mechanisms have an

influence.

Among the factors of macrosocial predisposition

to be pointed out are the low cohesion of the group,

which functions as a mass (a mass is a totally

unstructured group lacking any cohesion), and the

lack of working experience are common. Therefore

those groups recently created or re-created are very

vulnerable to panic. The qualitative�quantitative

failing of the organisational frame is another factor

to be taken into account. There are groups with very

vulnerable precarious levels characterised by ex-

treme nationalistic ideas and collective defence

values, and there are there are intrinsic fragile groups

like children, frustrated individuals, and women, in

general. Benyacar (2002) has also pointed out

personal vulnerability with changes in recent biolo-

gical events such as marriage, divorce, death of

partner, home moving or changes in job conditions.

Integrative model . The reaction stages and levels

subsequent to a disaster are integrated and sum-

marised in Table I (Lopez-Ibor et al., 1985).

Clinical manifestations of reactions to stress

In order to better understand what a disaster is, it is

necessary to briefly think about the characteristics of

the clinical manifestations of the reactions which

may evidence the following:

1. Affective and emotional symptoms, like anxiety,

phobias, depression, irritability, apathy and

withdrawal. All of them unspecific symptoms

appearing in many other disorders. [Indican una

mala respuesta ante el estres .]

ICD-10 follows the model Kretschmer

(1948) proposed for hysteria, in which two

very primitive defence mechanisms are present,

the tempest of movements, for example hyster-

ical movements, which is what chickens do

when they flutter around when feeling threa-

tened in the farmyard. The second defence

mechanism is the dead reflex, present in

hysterical paralysis, which is a mimicry of

threatened animals as when an ostrich buries

its head in the sand. Lopez Ibor Sr. (1950)

extended this description to all neurotic phe-

nomena in general and called them ‘sobresalto ’

and ‘sobrecogimiento ’ (lit. startle and terror

reactions).

2. Physiological disorders, among them to be

pointed out, a constant vegetative hyperactiva-

tion evoked by the memory of the trauma or by

other traumas.

3. Sleep disorders and dreaming, specially insom-

nia and untimely awakening, mainly caused by

daydreaming and nightmares of the traumatic

event.

4. Memory disorders, consisting of two apparently

different things. On the one hand, a voluntary

evocation of the memories of the trauma is not

possible, and when it is possible to do so the

memories are confused, sketchy, unorganised

and scarcely elaborated. On the other hand,

memories burst in at untimely moments during

consciousness, generally like flash-backs, with

very lively and intrusive images, sometimes

unchained by clues that bring the event to the

memory. In other words, the memory is dis-

sociated from its context (Ehlers and Clark

2002).

It has to be taken into account that many

theories on the function of sleep and day-

dreaming coincide in importance of including

Table I. The reaction stages and levels in front of a disaster.

Biological level general

adaptation syndrome

Psychological level post-traumatic

stress disorder Social level disasters

1. Pretrauma Negative or

insufficient defenses

(congenital or acquired)

Lack of immunological

barriers

Non-adaptative defence

mechanisms, pathological life

styles, poor self-identification

Poor planification,

denial, lack of identity

and social stability

2. Acute response HHA Axis Ergotrophic

Trofotrophic

Alert period (anxiety, fright).

Withdrawal period (anguish, fright)

Alert period (hyperactivity)

Withdrawal period (apathy)

3. Chronic maladaptation Adaptative illnesses

(immunological)

Post-impact period (rage,

resentment). Illness as a form

and way of survival)

Institutionalisation

4. Recovery New immunological

mechanisms

To live with the losses Sense

for existence is recovered

Reconciliation

Disasters and mental health 177

the stimuli previous to the sleep. Sleep is an

active process of memory consolidation, a

cognitive process for the re-elaboration of

experiences. The main function of REM sleep

is to forget everything unnecessary, and there-

fore daydreaming becomes the organised con-

science and interprets the information the

individual has available (Crick and Mitchinson

1983). Therefore, a non-elaborated trauma

erupts time and again during daydreaming

and also during wakeful consciousness because

it has not been elaborated, that is to say, it has

added the forgotten heritage from our past.

This interpretation coincides with some psy-

chological theories that refer to a double

representation of the trauma in the memory,

one accessible to verbalisation and another one

to the situation (Brewin 1999). Others impinge

on the two conditionings of fear, one a con-

ditionant of environmental stimuli that un-

chains discomfort, and another an operative

or instrumental one, responsible for avoidance

(Charney 1993).

5. Behaviours that reinforce and maintain the

trauma in the conscience, generally with beha-

viours of avoidance which prevent from over-

coming the object of phobia related to the

trauma. The avoidance to remember, the

suppression of the thought and memories, the

grumbling, ‘safe’ behaviours, dissociation and

alcohol or drug consumption do not help to

overcome the trauma, but give place to an

increase in the frequency of the symptoms since

the suppression creates an increase of intrusive

thoughts and prevents any positive changes in

behaviour.

6. Repercussions on the basic beliefs of oneself

and the world. The idle effort to find a sense to

this experience and the fact of worrying once

and again about the trauma accompanied by

feelings of guilt (because of having survived the

beloved ones) and of shame. This factor leads,

on the one hand, to seek external comfort and,

on the other hand, to reject it due to the shame

produced by the inability to cope with the

consequences, giving way to feelings like rage

and hostility towards the community, consider-

ing them even responsible for the catastrophe

and its consequences.

Do disasters have a meaning?

Up to now, I have been using the words disaster and

catastrophe as synonymous, although pointing out

some differences. One of them is the magnitude of

the impact on society. In fact, in many languages a

catastrophe is a disaster of great proportions.

The word catastrophe comes from the Greek

katastrvf/h (Katastrophe), from kata (kata) ‘under-

neath’ �stofoin (strephein) ‘to turn around’ and

etymologically refers to the movement of the chorus

on stage. Its primitive significance is the outcome,

especially when it is a very dramatic one, of a poem or

a theatre play.

A disaster is not bad luck, it is an empirical

falsification of human action, the proof of the

incorrectness of human beings’ conception of nature

and culture (Dombrowsky 1998). It is also a state of

lack of certainty, of inability to spot real or supposed

dangers, especially when it is something impreg-

nated in mental schemes to be able to understand

the dominant reality in a community (Gilbert 1958).

A disaster not only affects structures and social

functioning, also many mental schemes break down.

All of a sudden death anxiety and the loss of sense of

invulnerability becomes obvious (Lifton 1969).

Frankel (1962), who survived a Nazi concentration

camp, and Brull (1969) and others, have pointed out

that, after such an experience, sense of the context of

existential experience disappears. The vision of the

world, of oneself, of the future, changes. Therefore,

during the phase of overcoming the trauma a process

of re-adaptation to reality, a re-elaboration of the

trauma (Horowitz, 1993), the establishment of new

beliefs, and the overcoming of other old and false

beliefs, like the ‘world is a safe place’ and those

negative ones established after a disaster like ‘all the

worst always happens to me’, ‘it never rains but it

pours’, and so on (Janoff-Bulman 1992), is needed.

Victims or damaged?

The worst thing that can happen is the victimisation

of those affected and here psychiatry can play an

important role (Benyacar 2002).

The victim is a person who remains trapped by

the situation, petrified in that position, and passes

from being an individual to become an object of the

social, losing in this way his/her subjectivity. It is a

biblical concept, inherent to the expiatory needs of

society. Since the moment of the disruptive event,

society’s needs for restoration intermingle with the

needs of the individual. The demand that the outer

world repairs the harm he/she has suffered arises.

The damnified is the person who has suffered a

damage, prone to be repaired or irreparable in its

whole or partly. The concept ‘damnified’ connotes

psychic mobility, as well as the preserving of the

individual’s subjectivity. Therefore, mental health

services have to assist all those affected not as victims

but as damnified.

178 J. J. Lopez-Ibor Jr

Compensations in disasters

Reactions to disasters and their definition have been

always been marked by compensation. Literature on

compensation neurosis is old (Kinzie et al. 1996). In

fact, definitions that emphasise the presence of a

stressing agent of great magnitude which would

affect almost any persons, as DSM-III (APA 1980)

did, turn even witnesses into victims. Since a disaster

destroys social frames and is a consequence of it, it is

natural that any individual turns to society to ask

that the harm suffered be repaired. This is why there

is a tendency for victims to maximise ‘secondary

benefits’, perpetuating the psychic harm in order to

receive compensation, be it economic, affective or of

any other kind. This is reinforced by the fact that

psychic harm affects persons who functioned within

parameters of normality before the disaster and if

afterwards they cannot do so it is because an external

factor, of a social nature, has caused them harm.

According to Cohen (1999), most persons and their

relatives affected by a disaster have functioned in an

adequate way before the tragic event, but their

ability to solve problems becomes limited because

of the threat inherent to the situation.

Compensations in disasters are indispensable and

have to include psychic harms. However, the reper-

cussion on the mental health of the damnified must

also be evaluated, if he/she turns into a victim the

risk exists to make out of the disaster and the

compensation his/her new life style. It is also true

that mental health professionals are there to avoid

iatrogenia and should help the victims to overcome

this situation so as to avoid the situation where the

disability becomes chronic. It is also true that society

can impose its limits subsequent to any possible

victimisation abuses.

Mental health professionals should participate in

the judging of indemnifications and in the decision

to include victims in reintegration programmes to

their everyday activities (Benyacar 2002).

Therapeutic interventions

From all what has been exposed before, it can be

said that an intervention in disorders secondary to

severe stress has to be multifaceted, embracing all

social, psychological and biological aspects.

Strategy

A mental health programme has to start with the

following (Benyakar et al. 1994, 2002; Cohen 1999):

� Evaluation of the needs.

� Definition of intervention objectives.

� Take into consideration other possible options.

� Design of a program.

� To put into practice and carry out a care-giving

project in mental health.

Intervention has to be quick, as immediate as

possible, following the strategy of preventing the

consolidation of hard-to-treat clinical conditions,

which could even lead to an irreversible transforma-

tion of the personality.

Intervention has to be integrated (Collazo 1985;

Lebigot 1998), following the model of liaison

psychiatry (Soria et al. 1983a,b). It has to be carried

out as near as possible to the site where the events

took place (Cohen and Ahearn 1989) and include

individual and collective reactions (Crocq et al.

1987; Andreoli 2000).

One of the characteristics of this kind of situation

is the inability of the victim to ask for help, and

therefore an in-person intervention is needed in

which the mental health professional tries to directly

contact the victims in order to avoid the develop-

ment of psychic disorders that could be unchained

by lack of possibility or ability to cope with the event

in an adequate way.

Benyacar (2002) recommends the three basic

elements proposed during the First World War

(Salmon 1919): immediacy, proximity and expec-

tancy.

Immediacy refers to the fact that the victims

should be assisted immediately after the event.

Proximity refers to the fact that the victim should

be assisted as near as possible to the place where the

event took place. The principle of expectancy main-

tains that the professional and the colleagues of the

victim have to keep expectancy and express the will

that the victim goes back to his/her usual activities

developed before the event, as soon as possible.

Mental health professionals have to be integrated

into the disaster intervention staff in all its different

levels, the immediate ones, as well as subsequent

ones (Collazo 1983, 1985; Lebigot 1999).

Care should be provided to the population as a

whole and not only those who have suffered physical

harm. It should include close relatives directly

involved or those not so close, passers-by and

witnesses, emergency staff, and also mental health

professionals and others, including social leaders. It

has to be taken into account that for each physically

affected victim there will be three persons who will

suffer consequences in their mental health (Benya-

kar 1997), and for each death or severely injured

person there will be up to 400 psychically affected.

Extremely dramatic news, rumours, information

‘wars’ and collective panics have to be avoided, and

it has to be tried to provide adequate information.

Disasters and mental health 179

Panic situations have occurred without the slightest

trace of harm or threat.

Training, preparedness and anticipation are es-

sential factors in order to prevent a disaster and its

consequences.

Psychological interventions

In this kind of intervention, the professional acts as a

mediator so that the victim is able to articulate in his/

her psyche all what has happened using his/her own

idiosyncratic psychic abilities.

Cohern and Ahearn (1989) point out that an

important goal for mental health intervention is the

adequate use of techniques for restoring the ability of

the victims to solve the stressful situation in which

they are in, and to help them to reorganise their world

through social interaction. A second goal is contin-

uous and active collaboration with other groups or

organisations that offer help, support and attention

to victims in particular and to the community in

general.

These authors add that clear therapeutic inter-

vention guidelines have to be taken into account.

Among them:

1. Risk factors:

� the patient’s mature or immature person-

ality;

� stress related to social behavioural func-

tions or expectancies, according to what the

victims themselves judge, and those of

others living with them;

� persisting environmental stress in the phy-

sical as well as in the social surroundings;

� crisis the victims may have experienced

before or after the disaster.

2. Social environment: the social environment in

which the victims are resettled is an important

variable that affects decisions about the type of

psychological intervention. The specific inter-

vention type for each environment has to be

clarified.

3. Medical and clinical resources. The diagnosis

of disorders that put life in a considerable risk,

require the intervention of medical staff and

have to be part of the evaluation process.

Essential intervention aspects are verbalisation, in-

terviewing and social support strategies. Group

therapies are also essential, as well as the incorpora-

tion of the affected persons in rescue activities, as

long as this is feasible.

The formulation of a differential diagnosis is

important, also the identification of severe cases

and those which cannot be treated on site and have

to be evacuated to rearguard positions or even to

psychiatric units.

‘Psychiatrisation’ of cases should be avoided, as

well as the problem of associating the stigma of

mental illnesses to the existing harm.

Individual psychological resources have to be

favoured and mobilised, trying to avoid victimisation

and an indiscriminate and exaggerated compensa-

tion system. An iatrogenic type compensation neu-

rosis should be avoided as much as possible.

Pharmacological treatments

Psychosocial meassures have to be accompanied by

pharmacological interventions (van der Kolk 1987;

Kandel 1999; Friedman 2002; Morgan et al. 2003)

aimed at diminishing non-adaptative phyisological

responses. Taking into account their role in the

treatment of anxiety, selective inhibitors of serotonin

reuptake are a good option.

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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CASE REPORT

Sulbutiamine, an ‘innocent’ over the counter drug, interferes withtherapeutic outcome of bipolar disorder

ATHANASIOS DOUZENIS, IOANNIS MICHOPOULOS & LEFTERIS LYKOURAS

Department of General Hospital Psychiatry, Athens University Medical School, ‘Attikon’ Hospital, Athens, Greece

AbstractA case of a patient with bipolar disorder with a history of hospitalizations and addiction to sulbutiamine is presented.Sulbutiamine is a precursor of thiamine that crosses the blood�brain barrier and is widely available without prescriptionin most countries or over the internet. Because of this patient’s need to consume ever increasing quantities of sulbutiamine,his psychiatric care was severely compromised through him defaulting appointments and frequent changes of psychiatrists.This paper reviews the current scientific knowledge about sulbutiamine, and some of the information and claims availableon the web about its use and potential. It is argued that doctors need to be aware of the potential misuse of medicationavailable over the counter or on the internet and its potential harmful influence.

Key words: Sulbutiamine, bipolar disorder, addiction

Introduction

Healthy adult men and healthy adult non-pregnant,

non-lactating women consuming a usual, varied

diet do not need vitamin supplements. Vitamins in

therapeutic amounts may be indicated for the

treatment of deficiency states, for pathological con-

ditions in which absorption and utilization of vita-

mins are reduced or requirements increased, and for

certain non-nutritional disease processes. The deci-

sion to employ vitamin preparations in therapeutic

amounts clearly rests with the physician (Council on

Scientific Affairs 1987).

ICD-10 has a special category for abuse of non-

dependence-producing substances, such as vitamins.

Although the medication may have been medically

prescribed or recommended in the first instance,

prolonged, unnecessary, and often excessive dosage

develops, which is facilitated by the availability of the

substances without medical prescription. Attempts

to discourage or forbid the use of the substance are

often met with resistance. Although it is usually clear

that the patient has a strong motivation to take the

substance, no dependence or withdrawal symptoms

develop as in the case of the psychoactive substances

specified in mental and behavioural disorders due

to psychoactive substance use (World Health Orga-

nization 1993).

Patients with psychiatric disorders are more likely

to use over the counter drugs than those with other

diseases (Mamtani and Cimino 2002). Substance

abuse is a major comorbidity in bipolar patients

(Strakowski and DelBello 2000; Cassidy et al.

2001). In fact, as many as 50% of individuals with

bipolar disorder have been found to have a lifetime

history of substance abuse or dependence (Sonne

and Brady 1999). Although rates decrease in older

age groups, substance abuse is still present at

clinically important rates in the elderly. Bipolar

patients with comorbid substance abuse may have

a more severe course (Cassidy et al. 2001).

The case report, presented below, shows the

relationship between the abuse of sulbutiamine, an

over the counter ‘psychoactive’ substance, and the

outcome of bipolar disorder.

Case report

Mr Z is a 42-year-old single man who works in

the local municipal services and lives with his

parents. At the age of 18 he suffered a manic episode

with agitation, aggressive behaviour and paranoid

Correspondence: Lefteris Lykouras, MD, PhD, FICPM, Professor in Psychiatry, Department of General Hospital Psychiatry, Athens

University Medical School, ‘Attikon’ Hospital, 1 Rimini St. 124 62, Athens, Greece. Tel: �/30 210 5832426. Fax: �/30 210 5326453.

E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 183�185

(Received 14 July 2005; accepted 24 November 2005)

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

DOI: 10.1080/15622970500492616

ideation that required admission to a psychiatric

hospital. He subsequently suffered a depressive

episode that led to a serious suicide attempt.

Following this he had three further manic episodes

that required involuntary hospitalization. Apart from

the depressive and manic episodes his life was

organized, he had a steady job and managed to

have additional income from playing the stock

market. His latest admission was due to a manic

episode and he was discharged in January 2004

normothymic on two mood stabilizers (lithium and

carbamazepine), as well as a combination of two

different antipsychotics in high doses (haloperidol

20 mg and olanzapine 20 mg OD), benzodiazepines

(diazepam 40 mg and temazepam 10 mg OD) and

antiparkinsonics (biperiden 4 mg OD). Following

this discharge he has been followed-up by the

outpatient psychiatric department of our hospital.

Mr Z was first seen in March 2004 and has kept

regular contacts since. On assessment he presented

as a physically healthy man with mild pressure of

speech and flight of ideas, expressing grandiose ideas

that he did not act upon. During this session he also

mentioned that he had started receiving sulbutia-

mine (Arcalion) by a private prescription 4 months

before his latest admission. He was given this

medication when he complained of ‘lack of energy’

and ‘slowing down’. He found the medication help-

ful and on his own increased the dose. Before his last

admission he was taking ‘much more’ than he was

prescribed when assessed. Mr Z was adamant that

this prescription should be continued, although

sulbutiamine was not included in the Greek national

formulary. He was advised that according to medical

opinion there was no reason for him to receive

sulbutiamine and was also informed that the dose

would be gradually reduced and finally stopped.

Subsequent appointments revealed that the main

reason for attending his outpatient appointments

was to have prescriptions of sulbutiamine that he

consumed in vast quantities (more than 2 g/day). It

also emerged that one of the reasons he decided to

approach our services was the fact that his previous

psychiatric carers were unwilling to prescribe sulbu-

tiamine. It transpired that he requested similar

prescriptions from other clinics as well. When

confronted about his behaviour he became evasive

and agitated. He claimed that he used ‘Arcalion’

because it gave him ‘a high’, it raised his body

temperature and gave him a ‘warm feeling’. He also

felt stronger and consumed the medication before

swimming in the sea as it increased his stamina but

also made him withstand the cold water for a long

period that he could not tolerate otherwise (he is a

winter swimmer). It is worth noting that Mr Z never

overused the benzodiazepines prescribed and was

also willing to reduce the dose of diazepam he

was receiving so that he could continue the same

amount of sulbutiamine ‘while taking fewer pills

on the whole’.

Attempts to reduce the dose of sulbutiamine failed

and the patient managed to acquire prescriptions

from other doctors. This confrontation was the

main reason for repeated missing appointments,

unwillingness to perform regular blood tests and

non-compliance with the medication. On March

2005, after having missed several appointments, he

was urgently referred to our department. His clinical

picture was characterized by grandiose ideas, irrit-

ability, restlessness, pressure of speech, offensiveness

and inappropriate familiarity (he was hypomanic).

He was not taking his psychotropic medication

regularly, and insisted that medication was not

helpful. He kept saying: ‘the only drug that makes

me feel good is ‘‘Arcalion’’’. Reinstitution of his

previous medication and regular follow up led to

normothymia within 1 month.

Whenever sulbutiamine was reduced, he denied

experiencing somatic withdrawal symptoms, but

maintained that without sulbutiamine he felt less

energy, drowsiness and ‘unlike his normal self ’.

Eventually, he agreed to a gradual reduction and

now he receives 600 mg of sulbutiamine (initial dose

2 g) and 10 mg of diazepam (initial dose 40 mg)

without a change in his mental state and activities,

although he is complaining of feeling ‘less energetic’.

Discussion

Sulbutiamine is a hydrophobic molecule that easily

crosses the blood�brain barrier and gives rise to

thiamine and thiamine phosphate esters in the

brain (Van Reeth 1999). It does not have psycho-

stimulant properties or antidepressive effect, but it

can hasten the resorption of psycho-behavioural

inhibition occurring during major depressive epi-

sodes and thereby facilitate the rehabilitation of

patients in their social, professional and family life

functioning (Loo et al. 2000). Sulbutiamine may be

a useful adjunct to specific anti-infective treatment

(Shah 2003).

Information on the effects of sulbutiamine in

human brain is lacking. There is only one study

in which it was shown that acute sulbutia-

mine injection led to a significant decrease of the

dopamine levels in the prefrontal cortex and

3,4-dihydroxyphenylacetic acid levels (DOPAC) in

both the prefrontal and the cingular cortex in

rats, although homovallinic acid (HVA) concentra-

tion did not differ from the controls in these two

areas. Regarding glutaminergic transmission, acute

administration of sulbutiamine induced no change

184 A. Douzenis et al.

of density of N-methyl-D-aspartate (NMDA) and a-

amino-3-hydro-5-methyl-4-isoxazole propionic acid

(AMPA) receptors in cingular cortex, but signifi-

cantly decreased in the kainaite binding sites

(Trovero et al. 2000). The authors postulate that

sulbutiamine might exert a modulatory effect on

glutaminergic and dopaminergic transmission within

the prefrontal cortex. This could play a role in the

psychoactive effect of sulbutiamine. In this context,

it can be argued that it might also affect the

mechanism of action of the antipsychotic medi-

cation. It is also noted that searching in the litera-

ture did not reveal any report of pharmacokinetic

interaction between sulbutiamine and psychotropic

medication.

Thiamine deficiency in both man and animals is

known to produce memory dysfunction and cogni-

tive disorders which have been related to an impair-

ment of cholinergic activity. Sulbutiamine is

considered to improve memory formation in mice

and this behavioural effect could be mediated by

an increase in hippocampal cholinergic activity

(Micheau et al. 1985). In rhesus monkeys, sulbutia-

mine showed effect upon the mechanisms regulating

waking and light sleep, facilitating a state of wakeful-

ness (Balzamo and Vuillon-Cacciuttolo 1982).

There are no reports of any impairment caused by

overuse of sulbutiamine or other vitamins of the B

complex group except pyridoxine. It is reported that

one patient developed a severe sensory and a mild

motor neuropathy due to massive and prolonged

ingestion of pyridoxine (B6) (10 g daily for 5 years)

(Morra 1993).

A Google search on the internet showed almost

14,000 sites in which sulbutiamine (Arcalion) is

discussed. Some of them say that ‘(Arcalion) speeds

up the reflexes and reaction times in clinical tests,

promotes wakefulness and alertness’. In other sites

sulbutiamine is being sold among sexual merchan-

dise. Though sulbutiamine has no specific therapeu-

tic indication or clinical use, and it does not appear

to have an addictive profile, it seems to be used a

great deal by individuals. The same happens with

most vitamin preparations (Council on Scientific

Affairs 1987). It is well known that bipolar disorder

is associated with substance abuse and addiction

(Sonne and Brady 1999; Strakowski and DelBello

2000; Cassidy et al. 2001). Our patient fulfilled the

DSM-IV criteria for abuse and addiction of this

substance. His addiction to sulbutiamine interfered

with his treatment for bipolar disorder and the

therapeutic relationship with his doctors. Further-

more, it should be noted that the patient increased,

on his own, the sulbutiamine dosage by more than

2 g/day. This was temporally associated with the

emergence of the manic episode. In this regard the

large dose of sulbutiamine may have contributed to

the manic relapse. The widespread use of sulbutia-

mine can lead to the assumption that individuals

with mental illness can use it as well without their

doctors’ knowing. Bearing in mind the case pre-

sented, it might be clinically relevant to enquire of

psychiatric patients of young age about the use of

sulbutiamine.

Statement of interest

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

References

Balzamo E, Vuillon-Cacciuttolo G. 1982. Facilitation of a state of

wakefulness by semi-chronic treatment with sulbutiamine

(Arcalion) in Macaca mulatta . Rev Electroencephalogr Neuro-

physiol Clin 12:373�378.

Cassidy F, Ahearn EP, Carroll BJ. 2001. Substance abuse in

bipolar disorder. Bipolar Disord 3:181�188.

Council on Scientific Affairs. 1987. Vitamin preparations as

dietary supplements and as therapeutic agents. J Am Med

Assoc ;257 10(14):1929�1936.

Loo H, Poirier MF, Ollat H, Elatki S. 2000. Effects of

sulbutiamine (Arcalion 200) on psycho-behavioral inhibition

in major depressive episodes. Encephale 26:70�75.

Mamtani R, Cimino A. 2002. A primer of complementary and

alternative medicine and its relevance in the treatment of

mental health problems. Psychiatr Q 73:367�381.

Micheau J, Durkin TP, Destrade C, Rolland Y, Jaffard R. 1985.

Chronic administration of sulbutiamine improves long term

memory formation in mice: Possible cholinergic mediation.

Pharmacol Biochem Behav 23:195�198.

Morra M, Philipszoon HD, D’Andrea G, Cananzi AR, L’Erario

R, Milone FF. 1993. Sensory and motor neuropathy caused by

excessive ingestion of vitamin B6: a case report. Funct Neurol

8:429�432.

Shah SN; Sulbutiamine Study Group. 2003. Adjuvant role of

vitamin B analogue (sulbutiamine) with anti-infective treat-

ment in infection associated asthenia. J Assoc Phys India

51:891�895.

Sonne SC, Brady KT. 1999. Substance abuse and bipolar

comorbidity. Psychiatr Clin North Am 22:609�627, ix.

Strakowski SM, DelBello MP. 2000. The co-occurrence of bipolar

and substance use disorders. Clin Psychol Rev 20:191�206.

Trovero F, Gobbi M, Weil-Fuggaza J, Besson MJ, Brochet D,

Pirot S. 2000. Evidence for a modulatory effect of sulbutiamine

on glutamatergic and dopaminergic cortical transmissions in

the rat brain. Neurosci Lett ;292 29(1):49�53.

Van Reeth O. 1999. Pharmacologic and therapeutic features of

sulbutiamine. Drugs Today (Barc) 35:187�192.

World Health Organization. 1993. The ICD-10. In: Classification

of Mental and Behavioural Disorders: Diagnostic Criteria for

Research. Geneva: World Health Organization.

Sulbutiamine interferes with therapeutic outcome of bipolar disorder 185

CASE REPORT

Autism and Williams syndrome: A case report

SABRI HERGUNER & NAHIT MOTAVALLI MUKADDES

Department of Child and Adolescent Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

AbstractWilliams syndrome (WS) is a neurodevelopmental disorder caused by a deletion in the 7q11.23 region which includes atleast 17 genes. The presence of autistic features in WS is a controversial issue. While some authors describe WS as theopposite phenotype of autism, recent studies indicate that both share many common characteristics. We report a 12-year-old boy diagnosed as autistic disorder and WS with hemizygosity at the elastin locus and a karyotype of46,XY,del(7)(q11.21q11.23). Molecular genetic studies have shown that deletion at the elastin gene may account for thecardiovascular abnormalities seen in WS, but autistic features are likely caused by other genes flanking elastin.

Key words: Autistic disorder, Williams Syndrome, 7q11.23

Introduction

Autism is a severe neuropsychiatric disorder char-

acterized by impairments in reciprocal social inter-

action and communication, restricted and stereo-

typed patterns of interests and behaviours. Although

there are many studies on autistic disorder (AD) in

genetic syndromes, concurrence of AD and Williams

syndrome (WS) is reported to be very rare (Gillberg

and Coleman 2000).

WS is a rare neurodevelopmental disorder caused

by the hemizygous deletion of 7q11.23 and asso-

ciated with an ‘elfin face’ appearance, cardiovascular

abnormalities (particularly supravalvular aortic ste-

nosis), transient infantile hypercalcaemia, and

growth and developmental retardation (Pober and

Dykens 1996). Individuals with WS generally have

a unique neurological and behavioural profile.

They have poor spatial cognition, but have notably

intact language and musical abilities, and relatively

strong face-processing ability. Affected individuals

are highly sensitive to certain classes of sounds

and have mild mental retardation, with an average

IQ of 60. In addition, approximately 70% of WS

individuals suffer from attention deficit and hyper-

activity disorder (ADHD) and there is a high

incidence of anxiety and simple phobias (Bellugi

et al. 1999).

The presence of autistic features in WS is a

controversial issue. Children with WS are described

as outgoing, overfriendly, communicative, and hy-

persocial with good empathic skills. The excessively

social behaviour repertoire represents an important

component of its phenotype that distinguishes WS

from other developmental disorders (Jones et al.

2000). On the grounds of these features, it is

believed that WS is the opposite phenotype of

autism (Peterson and Panksepp 2004). On the other

hand, a recent study that compared subjects with

WS and other developmental disorders found that

WS group had more pragmatic language impair-

ments, poor social relationships and restricted inter-

ests. The researchers concluded that WS would

seem to share many characteristics of autistic dis-

order (Laws and Bishop 2004).

To our knowledge, there are only three case

reports about the concurrence of WS and AD

(Gillberg and Rasmussen 1994; Gosch and Pankau

1994; Reiss et al. 1985) without any specific genetic

information. Reiss et al. (1985) described two cases

with 46 XY karyotypes and one of the cases showed

pericentric inversion of chromosome 9 which had no

clinical significance. Gillberg and Rasmussen (1994)

reported four cases and examined them for chromo-

some 15 abnormalities but failed to demonstrate any

Correspondence: Dr Sabri Herguner, Istanbul Tip Fakultesi, Cocuk-Ergen Psikiyatrisi Anabilim Dali, 34393 � Capa, Istanbul, Turkey.

Tel: +90 533 7428150. Fax: +90 212 2349208. E-mail: [email protected]

The World Journal of Biological Psychiatry, 2006; 7(3): 186�188

(Received 21 September 2005; accepted 11 January 2006)

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

DOI: 10.1080/15622970600584221

finding. The present case describes a child with WS

and AD who had 7q11.23 deletion.

Case report

EK, a 12-year-old boy, referred to our clinic due to

parental concerns regarding his impairment in

language development, social�emotional reciprocity,

and repetitive and self-mutilative behaviours. His

language was severely delayed, he had only 10 single

words and his speech was echolalic. He started using

single words at the age of 5 years and never used

two-word phrases. He had limited non-verbal com-

munication with poor eye contact and his response

to instructions was inconsistent. He had no pretend

play; his plays were mostly repetitive (like shaking

toys) and he had an unusual preoccupation with

collecting buttons, watching spinning wheels and

washing machines. He was not able to join his peers

or interact with them. He had stereotypic behaviours

such as peripheral gazing, rocking his head, and his

body, and self-mutilative behaviours including head-

banging and finger-biting.

EK was born at term after a normal pregnancy by

an unremarkable delivery. His motor development

was severely delayed; he sat at 12 months, first

walked at 40 months of age, and became continent

when he was 6 years old. He was referred to a

child neurology and genetic department at the age of

6 years for his psychomotor retardation. He was

diagnosed as WS due to his physical features; wide

mouth with thick lips, long philtrum, prominent

cheeks, periorbital fullness, epicanthal folds, long

neck, hypoplastic nails, hoarse voice, short stature

and microcephaly. His genetic analysis by fluores-

cence in situ hybridization (FISH) using a bio-

tin-labelled probe revealed hemizygosity at the

elastin locus with a karyotype of 46,XY,del(7)

(q11.21q11.23). In his family history, his aunt and

uncle had motor developmental delay. There was no

evidence of autistic spectrum disorders in his family

history.

His weight and height were below the 3rd percen-

tile, and his head circumference was at the 3rd

percentile. Blood chemistry analysis yielded normal

values. His cardiological examination and echocar-

diography revealed tricuspid insufficiency. His

neurological and ophthalmological examinations,

abdominal ultrasonography, electrocardiography,

cranial tomography and electroencephalography

were normal.

His total score in the Childhood Autism Rating

Scale (CARS) (Schopler et al. 1980) was 44,

indicating severe autism and total score on the

Autism Behavior Checklist (ABC) (Krug et al.

1980) was 111 points. He was diagnosed as AD

according to DSM-IV criteria (APA 1994).

Discussion

We present a case that was diagnosed as WS at 6

years and as AD at 12 years. This is the first case

with autistic disorder and WS with 7q11.23 deletion.

Deletions that span a number of genes and cause a

constellation of symptoms are called contiguous

gene syndromes. WS is one such disorder, caused

by the hemizygous deletion of a 1.5-Mb interval

encompassing at least 17 genes at 7q11.23 (Osborne

1999). In over 95% of the cases, the elastin gene

which encodes the major component of skin, blood

vessels, and lung tissues, is deleted. The deletion at

the elastin locus may account for the cardiac

abnormalities, most commonly supravalvular aortic

stenosis, but none of the other features seen in WS.

Supravalvular aortic stenosis also can occur as an

isolated trait with 7q11.23 deletion (Curran et al.

1993). Because it is expressed in high concentrations

in the brain, deletion in the LIM kinase 1 (LIMK1)

gene may be responsible for the impaired visuo-

spatial constructive cognition in this disorder (Don-

nai and Karmiloff 2000). In addition to ELN and

LIMK1, several genes have been described, but

whether their haploinsufficiency contributes to the

WS phenotype is not yet known (Wu et al. 1998).

But it had been postulated that other genes in this

region including CYLN2, RFC2, and STX1A could

account for the remaining features of WS such as

mental retardation, growth deficiency, infantile hy-

percalcaemia, and neurological alterations (Meng et

al. 1998). Taken together, autistic features may also

be caused by other genes flanking ELN.

Even though several full genome scans have failed

to identify susceptibility loci with certainty, numer-

ous genetic studies showed the presence of chromo-

some 7 abnormalities, mainly in 7q22.33, in autistic

spectrum disorders (Muhle et al. 2004). However,

no study has found 7q11.23 as a susceptible region.

Although it seems premature to mention clearly that

deleted genes in 7q11.23 are attributable for the

autism phenotype, increasing reports on autistic

features in WS raise the question of the probable

contribution of genes in 7q11.23 in the genetic

aetiology of AD.

Another important point in this case is the delayed

diagnosis of autistic disorder. Although he was

referred to the neurology clinic for his psychomotor

developmental retardation and had undergone neu-

rological and genetic investigations at age of 6 years,

his autistic features were not evaluated carefully by

the medical professionals until his referral to the

child psychiatry clinic at the age of 12 years. There

Autism and Williams Syndrome 187

may be several reasons for the delay in the diagnosis

of AD. Firstly, when a medical doctor makes a

diagnosis of a medical disorder in a child with

autistic disorder, it is quite likely that the medical

diagnosis will take precedence and the child will not

be referred for examination of the autistic symptoms

(Kielinen et al. 2004). Secondly, it could be related

to the lack of information and awareness on autism

in our society. Our clinical experience shows that

children with a medical condition and AD refer to

the child psychiatry clinics in older ages because

their behavioural symptoms are usually attributed to

their physical problems. It seems that both paedia-

tricians and parents mostly focus on the medical

problems than the behavioural�social development

of these children. To sum up, the case described here

highlights the need for consideration of the presence

of autism in sufferers of other medical conditions.

Since early diagnosis and intervention of autism

significantly improve patients’ long-term outcome,

multidisciplinary and comprehensive evaluation of

children with developmental delays appears vital.

Statement of interest

The authors have no conflict of interest with any

commercial or other associations in connection with

the submitted article.

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Reiss AL, Feinstein C, Rosenbaum KN, Borengasser-Caruso MA.

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Schopler E, Reichler RJ, DeVellis RF, Daly K. 1980. Toward

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188 S. Herguner & N. M. Mukaddes

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Brain WR. 1958. The physiological basis of consciousness. Acritical review. Brain 81:426 �455.

Kuhlenbeck H. 1954. The human diencephalon. A summary ofdevelopment, structure, function and pathology. Basel: Karger.

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5. Tables should be typed on separate sheets and numbered consecutivelywith Arabic numbers. All tables should include a brief descriptivecaption.

6. Figures. All illustrations, whether photographs, graphs or diagrams,should be numbered consecutively with Arabic numerals and sub-mitted on separate sheets. Each illustration should be referred to in thetext as ‘Figure 1’, ‘Figures 1�4’, etc. The figures should have a shorttitle followed by a concise description. All abbreviations and symbolsappearing in the figure must be explained in the legend. Remarks suchas ‘for explanation (or details) see text’ should be avoided. Each figureshould have a legend containing sufficient information to render thefigure intelligible without reference to the text. If a figure has beenpublished previously, acknowledge the original source and submitwritten permission from the copyright holder to reproduce it. Ifphotographs of persons are used, either the subjects must not beidentifiable or their written permission to use the photographs mustaccompany the manuscript. Figures can be sent electronically asseparate files in EPS or TIFF format.

7. Copyright. It is a condition of publication that authors vest copyrightin their articles, including abstracts, in Taylor & Francis GroupLtd. This enables us to ensure full copyright protection and todisseminate the article, and the journal, to the widest possiblereadership in print and electronic formats as appropriate. Authorsmay, of course, use the material elsewhere after publication providingthat prior permission is obtained from Taylor & Francis GroupLtd. Authors are themselves responsible for obtaining permission toreproduce copyright material from other sources. To view the ‘Copy-right Transfer Frequently Asked Questions’ please visit http://www.tandf.co.uk/joumals/copyright.asp

8. Proofs and offprints. Proofs will be sent as a PDF file to thecorresponding author’s e-mail address unless otherwise requested.The corrected proof must be returned to the publisher within 3 days.Authors will be liable to pay for excessive alterations in the proof.Offprints can be ordered by filling out the form accompanying theproofs. The corresponding authors will be supplied with a free copy ofthe relevant issue.

9. For further information about the journal, including links to the onlinesample copy and contents pages, visit the journal homepage:www.tandf.no/wjbp or contact the Editorial Office at the followingaddress:

Jacqueline Klesing, Editorial Assistant, Department of Psychiatry,Ludwig-Maximilians-University, Nussbaumstrasse 7, 80336 Munich,Germany. Tel: +49 89 5160 5531 Fax: +49 89 5160 5530. E-mail:[email protected]