I S S U E

84
Vol 27, No. 3, 2005 ISSN 0243-3397

Medicographia
U nmet N eeds in the
T reatment of D epression
S. MONTGOMERY, EDITORIAL 213
UNITED KINGDOM WHY DO WE NEED NEW AND BETTER
ANTIDEPRESSANTS?
POURQUOI AVONS-NOUS BESOIN D’ANTIDÉPRESSEURS
INNOVANTS ET PLUS EFFICACES ?

A. WIRZ-JUSTICE, CHRONOBIOLOGICAL STRATEGIES FOR UNMET NEEDS 223

SWITZERLAND IN THE TREATMENT OF DEPRESSION

M. HAMON, P.-A. BOYER NEW PERSPECTIVES IN THE PATHOPHYSIOLOGY AND 228

AND E. MOCAËR, FRANCE TREATMENT OF AFFECTIVE DISORDERS: THE ROLE
OF MELATONIN AND SEROTONIN

J.-P. OLIÉ, FRANCE SEVERE DEPRESSION: FROM DIAGNOSIS TO TREATMENT 236

S. H. KENNEDY, CANADA SHORTCOMINGS OF CURRENT ANTIDEPRESSANT 240

THERAPIES

D. WINKLER AND SEASONAL AFFECTIVE DISORDER: FROM DIAGNOSIS 247

S. KASPER, AUSTRIA TO TREATMENT

A journal of
medical information D. J. KUPFER AND TRENDS IN DIAGNOSIS AND TREATMENT OF BIPOLAR 254
and international E. FRANK, USA DISORDERS
communication
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Medicographia
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U nmet N eeds in the

Medicographia
T reatment of D epression
a Servier publication
Editor in Chief: Jean-Philippe Seta, MD M. P. DEVA, BRUNEI / CONTROVERSIAL QUESTION 261
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212 MEDICOGRAPHIA, VOL 27, No. 3, 2005


Why do we need
new and better antidepressants?
Stuart MONTGOMERY, MD
Imperial College School
of Medicine
University of London London
UNITED KINGDOM
Address for correspondence:
Prof Stuart Montgomery,
Imperial College School of
Medicine, University of London,
London W13 8WH, UK
(e-mail:
stuart@samontgomery.co.uk)
Medicographia.
2005;27:213-221.
Editorial – Montgomery
E D I T O R I A L
by S. Montgomery, United Kingdom
M AJOR DEPRESSION IS A SERIOUS DISORDER WHOSE LIFE-
time prevalence of 16.2% in the USA1 is being increasingly echoed
in contrasting cultures, eg, Japan and China. The apparent in-
crease requires qualification: people may be readier to discuss
psychological problems than previously, and early studies were probably underestimates. In ad-
dition, differential memory distorts retrospective estimates of lifetime prevalence. People forget
distant episodes of depression and inflate current episodes: follow-up of patients hospitalized for
depression found that 25 years later only half could recall sufficient symptoms to justify a diag-
nosis of major depression.2
Major depression is associated with substantial social and even physical dysfunction, signif-
icantly more than some chronic medical conditions, eg, diabetes. Onset is typically in the teens
and twenties and the course commonly recurrent or chronic, with depressive episodes occupy-
ing 20% of postdiagnosis life. Unsurprisingly, therefore, major depressive disorder is now the
leading cause of disability in those of active working age. Some 10% to 15% of depressed patients
eventually commit suicide. A meta-analysis found a standard mortality rate, calculated by com-
paring the suicide rate in a specific group with that in the general population, of 21.2 among de-
pressives; mood disorders shorten life by 10 years from the combined effect of increased suicide
risk and increased physical illness.3
Not only do current antidepressants not “cure” the underlying condition, they are also only
moderately effective in relieving symptoms during episodes. A National Institute of Mental Health
(NIMH) follow-up of 431 patients seeking treatment found that 12% remained chronically de-
pressed over 5 years, while 55% had suffered a relapse or recurrence, and only one third remained
healthy 4; after 15 years, 82% had had a recurrence, 6% remained chronically depressed, and only
12% remained healthy. Given sufficiently long and careful follow-up, almost all those treated for
major depression will fail to recover, or suffer a recurrence.
Nevertheless, there is an overwhelming case for providing appropriate treatment for depres-
sion, on both personal and socioeconomic grounds. Yet undertreatment remains widespread.
Of the 17% with major depression identified in a European survey of 78 000 adults, 69% were
receiving no medical treatment, 43% had not even consulted a doctor, and under 8% were on an
antidepressant.5 In addition, antidepressant treatment is often suboptimal: in a survey of 1 mil-
lion patients in primary care, 89% were receiving a subtherapeutic dose of tricyclic antidepres-
sant (TCA).6 Fortunately, underprescribing has become less common with newer antidepressants
such as the selective serotonin reuptake inhibitors (SSRIs), which are only marketed at thera-
peutic doses.
Poor treatment response is often due to poor patient compliance: 30% of primary care patients
never fill their first prescription, while a further 25% to 33% stop treatment in the first month,
and 62% fail to inform their physician accordingly. As a result, treatment duration in 55% to
63% of cases is less than the minimum consensus recommendation of 6 months post remis-
sion.7 However, even in well-conducted studies with various classes of antidepressant adminis-
tered for the 6 to 8 weeks generally thought sufficient to show a drug/placebo difference, non-
response rates average 30% to 40%.
MEDICOGRAPHIA, VOL 27, No.3, 2005 213
ED I T O R I A L

Developments of antidepressants
The presumed mechanism of action of both monoamine oxidase inhibitors (MAOIs) and TCAs
was that they blocked the reuptake of the neurotransmitter monoamines, norepinephrine and
serotonin (5-HT), thus increasing their availability in the synaptic cleft. Depression was pre-
sumed due to subnormal neurotransmitter levels. Although oversimple and incomplete, this
theory provided a broad basis for the development of most subsequent antidepressants. Research
focused on the design of compounds with greater selectivity for either monoamine, hence with
fewer side effects. Maprotiline and reboxetine were examples of selective norepinephrine reup-
take inhibitors (SNRIs). But most effort concentrated on the development of SSRIs, culminat-
ing in fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, and escitalopram, which now
dominate the antidepressant market.
Several TCAs were found to act on 5-HT2 receptors: amitriptyline both blocked 5-HT re-
uptake and was a 5-HT2 antagonist. This inspired the development of 5-HT2 antagonists such
as trazodone, followed by compounds more selective still, acting on 5-HT2 receptor subtypes,
such as agomelatine, a 5-HT2C antagonist and melatonin M1/M2 agonist, and mianserin and
mirtazapine, which are 5-HT2A and 5-HT2C receptor antagonists as well as α 2 antagonists and
5-HT1A and 5-HT3 antagonists.

Superiority of particular antidepressants

Clinical trials of antidepressants have failed to demonstrate a consistently superior response to
active treatment versus placebo.8 This is due, irrespective of the inherent (in)efficacy of the an-
tidepressants themselves, to the inappropriate design and conduct of the studies, and some ma-
jor theoretical and practical obstacles. One important failing has been inadequate power, while
a number of “unsuccessful” studies have never been published. Smaller studies demonstrating
significant efficacy were often confined to severely depressed inpatients, whereas the move to
more realistic community-based studies recruited many patients with mild depression for which
drug/placebo difference was difficult to demonstrate. Even the diagnostic criteria for major de-
pressive disorder have proved inadequate, with particular regard to illness duration. Whereas the
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria require only
2 weeks, compatible with a self-limiting disorder, investigators have long since increased the min-
imum episode duration to 1 month to qualify for study inclusion.
Drug/drug difference is even more difficult to demonstrate. SSRIs may be safer and better
tolerated than TCAs, but they appeared significantly less effective than conventional clomipramine
in one key study.9 Despite its methodological weaknesses, this study suggested that selectivity
for the serotonin system might not be universally beneficial. A plausible conclusion was that
selective antidepressants would only be effective in patients with the relevant monoamine defi-
ciency, a theory bolstered by the reports from several subsequent studies that SNRIs such as
venlafaxine were more effective than SSRIs,10 which were themselves significantly better than
placebo. However, this conclusion failed to secure consensus conviction, even with the backing
of a meta-analysis, due to an array of methodological failings.
A rare opportunity for valid interdrug meta-analysis was afforded by the pooled studies of
the SSRIs escitalopram and citalopram, in that all were of the same 8-week duration and used
the Montgomery and Asberg Depression Rating Scale (MADRS): several meta-analyses across
a variety of conditions reached the consensus conclusion that escitalopram was the more effec-
tive agent.11

Early onset of response

A well-recognized shortcoming of antidepressants is that significant difference from placebo can
only be identified reliably some 6 weeks after initiating treatment. The delay is potentially dan-
gerous since suicide risk is highest in the early treatment period when severity is greatest. Ab-
sence of rapid positive feedback also encourages noncompliance. Earlier onset of effect would
therefore be welcome. Unfortunately, however, virtually no studies have investigated this aspect
in individual antidepressants. Retrospective review of placebo-controlled studies with venlafax-
ine indicates simply that response before 2 weeks is seen with early rapid escalation to high doses,
while comparative studies have suggested that escitalopram induces a more rapid response than
citalopram.12

Efficacy of specific symptoms

Some symptoms improve faster with one antidepressant than another.

214 MEDICOGRAPHIA, VOL 27, No.3, 2005 Editorial – Montgomery

 ED I T O R I A L

◆ Sleep
Antidepressants with antihistaminic activity, eg, amitriptyline and mirtazapine, improve sleep
early in treatment, but at the cost of compromised daytime alertness and impaired concentra-
tion. 5-HT2 antagonists, eg, nefazodone, improve sleep with no such penalty, as does the mela-
toninergic agonist and selective 5-HT2C antagonist agomelatine.

◆ Pain and somatic symptoms

SNRIs may be more effective in relieving pain syndromes. Thus, venlafaxine was superior to place-
bo in diabetic neuropathy. In fact, SNRIs may be more effective on the somatic symptoms of de-
pression generally.13 While these are not the core symptoms of the disorder, they may explain
the apparent advantage of SNRIs over SSRIs, particularly when remission is assessed using the
Hamilton Depression Rating Scale (HDRS) with its overrepresentation of somatic symptoms. The
advantage may be less apparent when using a core symptoms scale such as the MADRS.

Discontinuation of medication
Early studies with TCAs established that abrupt treatment withdrawal provoked a syndrome of
nausea, vomiting, headaches, giddiness, chills, weakness, and musculoskeletal pain in some pa-
tients. Symptoms were transient, maximal in the first week and declined thereafter, rarely inter-
fering with function.
A discontinuation syndrome was also reported with the SSRIs, whether withdrawal was grad-
ual or abrupt. Its timing appeared dependent on the half-life of the compound concerned and any
active metabolite. With fluoxetine, for example, the discontinuation syndrome may appear after
4 weeks, whereas with paroxetine it is maximal in the first week. A consistent finding has been that
the syndrome is more frequent with paroxetine than with either sertraline or fluoxetine,14 com-
prising insomnia, dreaming, muscle aches, dizziness, chills, runny nose, nausea, and diarrhea.
The only antidepressant not associated with a discontinuation syndrome is agomelatine.15
This is a distinct advantage in that many patients receiving antidepressants are erratic and forget
to take their medication over a few days during a course of treatment and would therefore be ex-
pected to suffer discontinuation symptoms.

Suicide
Suicide risk is highest early in treatment and related to illness severity. The best predictor is a
history of a previous attempt, although this is absent in over half of suicides. Long-term follow-
up has shown that antidepressants reduce suicide risk 3-fold in unipolar major depression,16 a
statistic confirmed by epidemiological studies in Swedish adults and American adolescents.
Being a rare event in clinical studies, suicide risk for an individual drug cannot be assessed
even from the large datasets contained in the submissions to drug regulatory authorities. How-
ever, a recent meta-analysis of data on over 40 000 patients submitted to licensing authorities
showed nonsignificantly fewer suicides with SSRIs compared with placebo.17 A definitive com-
parison would require the inclusion of millions of patients in placebo-controlled studies.
Results for suicidal thoughts recorded as an adverse event have been similar. Since such
thoughts are measured as part of the pivotal depression severity rating scales, they provide the
best basis for assessment. Several antidepressants, including imipramine, paroxetine, and esc-
italopram, are significantly more effective than placebo in protecting against the emergence
of suicidal thoughts.18

Safety
Side effects are a major cause of treatment noncompliance. TCAs are especially disadvantaged
in this regard, having a broad range of pharmacologic actions in addition to their activity on the
norepinephrine and serotonin systems. Effects on muscarinic receptors produce anticholiner-
gic reactions such as dry mouth, blurred vision, constipation, urinary hesitancy, and cognitive
deficits, while α1-adrenergic receptor effects are responsible for the dizziness and hypotension
that are a particular problem in the elderly because of falls and fractures. Histamine effects cause
sedation and poor concentration. The cumulative result is poor tolerability and compromised
treatment.
The absence of similar receptor effects explains why SSRIs should be better tolerated, with few-
er premature treatment discontinuations.19 However, SSRIs have several characteristic serotoner-
gic side effects; they produce unwanted gastrointestinal effects, for example, nausea and vomit-
ing. Some SSRIs, eg, fluoxetine, cause increased agitation and nervousness, particularly at the

Editorial – Montgomery MEDICOGRAPHIA, VOL 27, No.3, 2005 215

ED I T O R I A L

start of treatment. Their sexual side effects include anorgasmia in women and delayed ejacula-
tion in men. There appears to be some toleration of the nausea, but less of the sexual side effects.
Some antidepressants have been shown to have fewer sexual side effects, eg, nefazodone, pos-
sibly due to its 5-HT2C antagonist properties. Buproprion enjoys a similar advantage over SSRIs,
although it not licensed as an antidepressant in Europe. Agomelatine appears relatively free of
sexual side effects: a specific study found it significantly superior to venlafaxine in patients in re-
mission. There is also evidence that the 5-HT2 antagonist mirtazapine is largely unassociated with
sexual dysfunction.
SNRIs are associated with all the SSRI side effects plus some norepinephrine-related effects
such as dry mouth, constipation, and increased heart rate. Thus, high-dose venlafaxine is likely
to cause excess serotonergic effects. Venlafaxine is also associated with increased blood pressure
and cholesterol, and this must be taken into account when prescribing. Duloxetine is licensed at
a low dose specifically to reduce the risk of excess side effects. Both venlafaxine and duloxetine
appear to be less well tolerated than SSRIs.

Conclusion
Depression is a common and disabling disorder that places a substantial burden on patients, their
relatives and friends, and society as a whole. It is also dangerous, being associated with increased
morbidity and mortality, including from suicide. Depression shortens life by an average of one
decade. The available treatments are largely effective, but their use is compromised by poor tol-
erability and low adherence. Very few depressed individuals receive treatment and, of those who
do, few are prescribed an adequate dose for long enough to secure a full response. There is a clear
need for treatments that are more effective, more rapidly effective, and better tolerated. They
would reduce the number of patients who have a poor or inadequate response and leave fewer
patients with resistant depression. Poor compliance with medication and premature termination
of treatment currently compromise the chance of recovery. Antidepressants with a faster onset
of action would be expected to bring larger numbers of depressed patients to full remission. ❒

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uation study. Int Clin Psychopharmacol. 2004;19:271-280.
16. Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406
mood-disorder patients with and without long-term medication:
a 40 to 44 years’ follow-up. Arch Suicide Res. 2005. In press.
17. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake
inhibitors (SSRIs) and suicide in adults: meta-analysis of drug
company data from placebo controlled, randomised controlled
trials submitted to the MHRA’s safety review. BMJ. 2005;330:385-
388.
18. Montgomery SA, Dunner DL, Dunbar GC. Reduction of suici-
dal thoughts with paroxetine in comparison with reference antide-
pressants and placebo. Eur Neuropsychopharmacol.1995;5:5-13.
19. Anderson IM, Tomenson BM. Treatment discontinuation
with selective serotonin reuptake inhibitors compared with tri-
cyclic antidepressants: a meta-analysis. BMJ.1995;310:1433-1438.

Keywords: antidepressant; tricyclic antidepressant; selective serotonin reuptake inhibitor;

norepinephrine; melatonin

216 MEDICOGRAPHIA, VOL 27, No.3, 2005 Editorial – Montgomery

 ÉD I T O R I A L

Pourquoi avons-nous besoin

d’antidépresseurs innovants et plus efficaces ?
par S. Montgomery, Royaume-Uni

L A DÉPRESSION MAJEURE EST UNE MALADIE GRAVE DONT LA

prévalence au cours de la vie atteint 16,2 % aux États-Unis 1 et qui
s’approche progressivement de cette valeur dans des cultures très
différentes, par exemple au Japon et en Chine. Cette augmentation
apparente nécessite d’être nuancée : les personnes semblent plus enclines à discuter de leurs
problèmes psychologiques qu’auparavant et les études antérieures ont probablement sous-es-
timé l’importance de cette maladie. En outre, la mémoire, sélective, tend vraisemblablement à
fausser les estimations rétrospectives de la prévalence au cours de la vie. Les personnes ont ten-
dance à oublier des épisodes de dépression lointains et à exagérer les épisodes actuels : le suivi
de patients hospitalisés pour dépression a permis de déterminer que, 25 ans plus tard, seulement
la moitié des patients pouvait se rappeler de symptômes suffisants pour justifier un diagnostic
de dépression majeure 2.
La dépression majeure est associée à un dysfonctionnement social et même physique im-
portant, qui dépasse de manière significative celui provoqué par certaines affections médicales
chroniques, par exemple le diabète. Le déclenchement survient généralement au cours de l’ado-
lescence et au début de l’âge adulte, et son déroulement est fréquemment récurrent ou chro-
nique, avec des épisodes dépressifs occupant 20 % de la durée de vie qui suit le diagnostic initial.
Par conséquent, il n’est pas surprenant de constater que le trouble dépressif majeur soit la prin-
cipale cause d’incapacité observée pendant la vie active. Chez environ 10 à 15 % des patients
la dépression aboutit au suicide. Une méta-analyse a établi un taux de mortalité standard, cal-
culé en comparant le taux de suicide dans un groupe spécifique avec celui de la population gé-
nérale, égal à 21,2 chez les dépressifs ; les troubles de l’humeur raccourcissent la vie de 10 ans
à cause de l’effet combiné d’une augmentation du risque de suicide et d’une aggravation des ma-
ladies physiques 3.
Non seulement les antidépresseurs actuels ne « guérissent » pas la maladie sous-jacente,
mais ils ne sont également que modérément efficaces pour soulager les symptômes au cours des
épisodes dépressifs. Un suivi de l’Institut National de la Santé Mentale (National Institute of
Mental Health, NIMH) effectué sur 431 patients en demande thérapeutique a montré que 12 %
de ceux-ci restaient déprimés de manière chronique pendant 5 ans, tandis que 55 % d’entre eux
avaient présenté une récidive ou une rechute, et seulement un tiers restait en bonne santé 4 ;
après 15 ans, 82 % avaient subi une rechute, 6 % souffraient toujours d’une dépression chro-
nique et seulement 12 % étaient restés en bonne santé. Avec un suivi suffisamment long et at-
tentif, il apparaît que la presque totalité des patients traités pour dépression majeure ne gué-
rissent pas, ou présentent une rechute.
Néanmoins, il y a beaucoup d’arguments en faveur de l’administration de traitements ap-
propriés pour la dépression, pour des motifs tant personnels que socio-économiques. Pour-
tant, jusqu’à présent, l’insuffisance de traitement reste très fréquent. Sur les 17 % de personnes
souffrant de dépression majeure identifiées au cours d’une enquête européenne portant sur
78 000 adultes, 69 % ne recevaient aucun traitement médical, 43 % n’avaient même jamais
consulté un médecin, et moins de 8 % recevaient un antidépresseur 5. En outre, le traitement an-
tidépresseur administré est souvent suboptimal : une enquête portant sur un million de patients

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ÉD I T O R I A L

de soins primaires a montré que 89 % d’entre eux recevaient une dose subthérapeutique d’an-
tidépresseur tricyclique (ATC) 6. Heureusement, le sous-dosage est devenu moins fréquent avec
les nouveaux antidépresseurs, notamment les inhibiteurs sélectifs de la recapture de la séro-
tonine (ISRS), qui sont uniquement commercialisés à des doses thérapeutiques.
La mauvaise réponse thérapeutique est fréquemment due à une mauvaise observance du
traitement par le patient : 30 % des patients de soins primaires ne se sont jamais fait délivrer
leur première prescription, tandis que 25 à 33 % de patients supplémentaires interrompent leur
traitement au cours du premier mois, et 62 % n’en informent pas leur médecin. Par conséquent,
la durée du traitement dans 55 à 63 % des cas est inférieure à la recommandation minimale
établie de six mois après la rémission7. Cependant, même dans des études bien conduites portant
sur différentes classes d’antidépresseurs administrés pendant les 6 à 8 semaines généralement
considérées comme suffisantes pour démontrer une différence entre un médicament actif et un
placebo, les taux d’absence de réponse thérapeutique se situent en moyenne entre 30 et 40 %.

Le développement des antidépresseurs

Le mécanisme d’action invoqué pour les des inhibiteurs de la monoamine oxydase (IMAO) et des
ATC était le blocage de la recapture des neurotransmetteurs monoaminergiques, la noradré-
naline et la sérotonine (5-HT), augmentant ainsi leur disponibilité dans la fente synaptique. La
dépression était supposée provenir de concentrations subnormales de neurotransmetteurs. Bien
que simpliste et incomplète, cette théorie a fourni une base fructueuse pour le développement
de la plupart des antidépresseurs découverts par la suite. Les recherches se sont concentrées
sur la découverte de composés présentant une sélectivité supérieure pour l’une ou l’autre des
monoamines, diminuant ainsi les effets indésirables. La maprotiline et la réboxétine sont des
exemples d’inhibiteurs sélectifs de la recapture de la noradrénaline (ISRN). Mais les efforts les
plus importants se sont portés sur le développement des ISRS, et ont culminé avec la mise sur
le marché de la fluoxétine, la paroxétine, la fluvoxamine, la sertraline, le citalopram et l’esci-
talopram qui dominent aujourd’hui le marché des antidépresseurs.
Il a été découvert que plusieurs ATC agissaient sur les récepteurs 5-HT2 : l’amitriptyline
bloque à la fois la recapture de la 5-HT2 et exerce une action antagoniste sur les récepteurs
5-HT2 . Ce phénomène a inspiré le développement d’antagonistes des récepteurs 5-HT2 comme
la trazodone, suivie par des composés encore plus sélectifs agissant sur des sous-types de récep-
teurs 5-HT2 , comme l’agomélatine, un antagoniste des récepteurs 5-HT2C et la mélatonine, un
agoniste des récepteurs de type M1 et M2 , et la miansérine et la mirtazapine, qui sont des anta-
gonistes des récepteurs 5-HT2A et 5-HT2C , ainsi que des antagonistes 2 et des antagonistes des
récepteurs 5-HT1A et 5-HT3 .

Supériorité de certains antidépresseurs particuliers

Les essais cliniques sur les antidépresseurs n’ont pas permis de démontrer une réponse constam-
ment supérieure à un traitement actif par rapport à un placebo 8. Cela est dû, quelle que soit
l’(in)efficacité des antidépresseurs eux-mêmes, au schéma et au déroulement inappropriés des
études, et à certains obstacles théoriques et pratiques majeurs. L’une des insuffisances impor-
tantes a été une puissance inadéquate, tandis qu’un certain nombre d’études « sans succès »
n’ont jamais été publiées. Des études de petite taille démontrant une efficacité significative ont
souvent été limitées à des patients hospitalisés souffrant de dépression sévère, tandis que le pas-
sage à des études plus réalistes sur la population de ville a conduit au recrutement d’un grand
nombre de patients souffrant de dépression légère pour lesquels une différence entre le médi-
cament actif et le placebo a été difficile à mettre en évidence. Même les critères diagnostiques du
trouble dépressif majeur se sont avérés inadéquats, en particulier en ce qui concerne la durée
de la maladie. Tandis que les critères du DSM IV [Diagnostic and Statistical Manual of Mental
Disorders, 4th Edition] ne demandent que deux semaines, une durée compatible avec un trouble
spontanément résolutif, les investigateurs ont depuis longtemps augmenté la durée minimale
d’un épisode à un mois pour justifier d’une inclusion dans ce type d’études.
La différence entre les médicaments est encore plus difficile à démontrer. Les ISRS peuvent
être plus sûrs et mieux tolérés que les ATC, mais ils sont apparus significativement moins effi-
caces que le traitement classique par la clomipramine dans une étude importante 9. Malgré ses
faiblesses méthodologiques, cette étude a suggéré que la sélectivité pour le système de la sé-
rotonine pouvait ne pas s’avérer universellement bénéfique. Une conclusion plausible a été que
les antidépresseurs sélectifs ne pourraient être efficaces que chez les patients présentant un dé-
ficit significatif en monoamines, une théorie corroborée par des comptes rendus de plusieurs

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 ÉD I T O R I A L

études ultérieures selon lesquelles des ISRN, comme la venlafaxine, se sont avérés plus efficaces
que les ISRS 10, qui ont eux-mêmes été significativement plus efficaces que le placebo. Cepen-
dant, cette conclusion n’a pas permis d’établir une conviction consensuelle, même avec le sou-
tien d’une méta-analyse, à cause d’un ensemble d’insuffisances méthodologiques.
Une rare occasion pour effectuer une méta-analyse médicamenteuse valide a été fournie
par les études groupées sur deux ISRS, l’escitalopram et le citalopram, dans la mesure où elles
ont toutes deux été de la même durée de 8 semaines et ont utilisé l’échelle d’évaluation de la dé-
pression de Montgomery & Asberg (Montgomery and Asberg Depression Rating Scale, MADRS) :
plusieurs méta-analyses effectuées pour un certain nombre d’affections sont arrivées à la conclu-
sion générale que l’escitalopram était la substance la plus efficace 11.

Déclenchement précoce de la réponse

L’un des inconvénients bien connus des antidépresseurs est qu’une différence significative avec
le placebo ne peut être mise en évidence de façon fiable qu’environ six semaines après le début
du traitement. Ce délai est potentiellement dangereux, car les risques de suicide sont élevés dans
la période précoce du traitement lorsque la sévérité est maximale. L’absence d’effet positif ra-
pide décourage également l’observance thérapeutique. C’est la raison pour laquelle un déclen-
chement plus précoce de l’effet thérapeutique serait bienvenu. Malheureusement, pratiquement
aucune étude n’a analysé cet aspect sur les antidépresseurs examinés individuellement. Une
analyse rétrospective d’études contrôlées par placebo portant sur la venlafaxine indique sim-
plement qu’une réponse est observée avant deux semaines avec une augmentation précoce et
rapide à des doses élevées, tandis que des études comparatives ont suggéré que l’escitalopram
induisait une réponse plus rapide que le citalopram 12.

Efficacité sur des symptômes spécifiques

Certains symptômes s’améliorent plus rapidement avec un antidépresseur qu’avec un autre.

◆ Sommeil
Les antidépresseurs présentant une activité antihistaminergique, par exemple l’amitriptyline
et la mirtazapine, améliorent le sommeil précocement au cours du traitement, mais au prix
d’une altération de la vigilance diurne et de troubles de la concentration. Les antagonistes des
récepteurs 5-HT2 , par exemple la néfazodone, améliorent le sommeil sans inconvénient de ce
type, de même que l’agomélatine, un agoniste mélatoninergique et un antagoniste sélectif des
récepteurs 5-HT2C .

◆ Symptômes douloureux et somatiques

Les ISRN pourraient être plus efficaces pour soulager les syndromes douloureux. Ainsi, la ven-
lafaxine a été supérieure à un placebo dans la neuropathie diabétique. En fait, les ISRN pour-
raient être plus efficaces d’une manière générale sur les symptômes somatiques de dépression 13.
Bien qu’il ne s’agisse pas des symptômes centraux de ce trouble, ils peuvent expliquer l’avan-
tage apparent des ISRN sur les ISRS, en particulier lorsque la rémission est estimée par l’échelle
d’évaluation de la dépression de Hamilton (Hamilton Depression Rating Scale) avec sa surre-
présentation des symptômes somatiques. L’avantage peut apparaître de façon moins nette en
utilisant une échelle des symptômes centraux, comme l’échelle MADRS.

Interruption du médicament
Des études antérieures sur les ATC ont établi que l’interruption brutale du traitement provo-
quait un syndrome de sevrage se manifestant par des nausées, des vomissements, des maux de
tête, des vertiges, des frissons, une faiblesse et des douleurs musculosquelettiques chez certains
patients. Les symptômes étaient transitoires, atteignant une intensité maximale au cours de la
première semaine puis ont déclinant par la suite, interférant rarement avec le fonctionnement.
Un syndrome de sevrage a également été observé avec des ISRS, que le retrait ait été pro-
gressif ou brutal. Son apparition dépend de la demi-vie du composé considéré et de ses méta-
bolites actifs. Avec la fluoxétine, par exemple, le syndrome de sevrage peut apparaître après
quatre semaines, tandis qu’avec la paroxétine, son intensité est maximale au cours de la pre-
mière semaine. Les résultats montrent de façon constante que le syndrome était plus fréquent
avec la paroxétine qu’avec la sertraline ou la fluoxétine 14, et qu’il se manifestait par une insom-
nie, une augmentation des rêves, des douleurs musculaires, des vertiges, des frissons, une rhi-
norrhée, des nausées et une diarrhée.

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ÉD I T O R I A L

Le seul antidépresseur qui n’est pas associé à un syndrome de sevrage est l’agomélatine 15. Il
s’agit d’un avantage important dans la mesure où de nombreux patients recevant des antidé-
presseurs sont inconstants et oublient de prendre leur médicament pendant quelques jours au
cours du traitement, et seraient, par conséquent, susceptibles de présenter des symptômes de
sevrage.

Suicide
Le risque de suicide est maximal au début du traitement, et il est lié à la sévérité de la maladie.
Le meilleur facteur prédictif est constitué par des antécédents de tentative de suicide, bien qu’ils
soient absents dans plus de la moitié des cas de suicides. Un suivi à long terme a montré que les
antidépresseurs réduisaient le risque de suicide d’un facteur 3 dans la dépression majeure uni-
polaire 16, une statistique confirmée par des études épidémiologiques effectuées chez des adultes
suédois et des adolescents américains.
Dans la mesure où il s’agit d’un événement rare dans les études cliniques, le risque de sui-
cide lié à un médicament individuel ne peut pas être évalué, même à partir des larges ensembles
de données nécessaires aux demandes d’autorisation de mise sur le marché remis aux autorités
réglementaires. Cependant, une récente méta-analyse effectuée sur des données portant sur plus
de 40 000 patients soumises aux autorités sanitaires a montré une réduction non significative
du nombre de suicides avec les ISRS par rapport à un placebo 17. Une comparaison décisive né-
cessiterait l’inclusion de millions de patients dans des études contrôlées par placebo.
Les résultats concernant les pensées suicidaires enregistrées comme événement indésirable
ont été similaires. Ces pensées étant mesurées en utilisant les principales échelles d’évaluation
de la sévérité de la dépression, ces dernières constituent la meilleure base pour l’évaluation. Plu-
sieurs antidépresseurs, notamment l’imipramine, la paroxétine et l’escitalopram, sont signifi-
cativement plus efficaces que le placebo dans la protection contre l’émergence des pensées sui-
cidaires 18.

Sécurité d’emploi
Les effets indésirables constituent une cause majeure de non observance du traitement. Les ATC
présentent un inconvénient particulier à cet égard, dans la mesure où ils exercent une large va-
riété d’actions pharmacologiques outre leur activité sur les systèmes de la noradrénaline et de
la sérotonine. Leurs effets sur les récepteurs muscariniques entraînent des réactions anticho-
linergiques comme une sécheresse buccale, une vision trouble, une constipation, un retard à la
miction et des déficits cognitifs, tandis que les effets sur les récepteurs 1 -adrénergiques sont
responsables de vertiges et d’hypotension, qui représentent un problème particulier chez les per-
sonnes âgées à cause des chutes et des fractures. Les effets histaminiques provoquent une sé-
dation et des troubles de la concentration. Au total, il en résulte une mauvaise tolérance et un
traitement aléatoire.
L’absence d’effets similaires sur ces récepteurs fait que les ISRS devraient être mieux tolé-
rés, et s’accompagner d’un moindre nombre d’interruptions prématurées du traitement 19. Ce-
pendant, les ISRS exercent plusieurs effets indésirables sérotoninergiques caractéristiques ; ils
entraînent des effets gastro-intestinaux indésirables, par exemple des nausées et vomissements.
Certains ISRS, par exemple la fluoxétine, provoquent une augmentation de l’agitation et de la
nervosité, en particulier au début du traitement. Leurs effets indésirables sexuels comprennent
une anorgasmie chez la femme et un retard à l’éjaculation chez l’homme. Il semble que les
nausées puissent être partiellement tolérées, ce qui est moins le cas pour les effets indésirables
sexuels.
Certains antidépresseurs ont montré qu’ils provoquaient moins d’effets indésirables sexuels,
par exemple la néfazodone, ce qui pourrait être lié à ses propriétés antagonistes des récep-
teurs 5-HT2C . Le buproprion présente un avantage similaire par rapport aux ISRS, bien qu’il
ne soit pas commercialisé comme antidépresseur en Europe. L’agomélatine semble relativement
exempte d’effets indésirables sexuels : une étude spécifique a montré sa supériorité significa-
tive par rapport à la venlafaxine chez des patients en rémission. Il existe également des éléments
montrant que la mirtazapine, un antagoniste des récepteurs 5-HT2 , n’avait pratiquement au-
cune association avec un dysfonctionnement sexuel.
Les ISRN sont associés à tous les effets indésirables des ISRS, auxquels s’ajoutent certains
effets liés à la noradrénaline, notamment la sécheresse buccale, la constipation et l’augmenta-
tion de la fréquence cardiaque. Par conséquent, des doses élevées de venlafaxine sont suscep-
tibles de provoquer un excès d’effets sérotoninergiques. La venlafaxine est également associée

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 ÉD I T O R I A L

à une augmentation de la pression artérielle et du cholestérol, ce qui doit être pris en compte
lors de la prescription. La duloxétine est autorisée à faible dose précisément pour réduire les
risques d’effets indésirables excessifs. La venlafaxine et la duloxétine semblent être moins bien
tolérées que les ISRS.

Conclusion
La dépression est un trouble fréquent et invalidant qui impose un lourd fardeau aux patients, à
leurs parents et amis, et à la société dans son ensemble. Elle est également dangereuse, dans la
mesure où elle est associée à une augmentation de la morbidité et de la mortalité, y compris liées
au suicide. La dépression raccourcit la vie en moyenne de 10 ans. D’une manière générale, les
traitements disponibles sont efficaces, mais leur utilisation est compromise par une mauvaise
tolérance et une observance insuffisante. Seul un très petit nombre d’individus déprimés re-
çoivent un traitement, et parmi ceux-ci, il est rare qu’il soit prescrit à une posologie adéquate et
pour une durée suffisante pour assurer une réponse complète. Il existe un besoin manifeste
pour des traitements plus efficaces, plus rapidement efficaces et mieux tolérés. Ils permettraient
de réduire le nombre de patients présentant une réponse insuffisante ou inadéquate, et laisse-
raient moins de patients souffrir d’une dépression réfractaire. La mauvaise observance et l’in-
terruption prématurée du traitement réduisent actuellement les chances de guérison. Des an-
tidépresseurs dont le déclenchement d’action serait plus rapide permettraient d’augmenter le
nombre de patients déprimés bénéficiant d’une rémission complète. ❒

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 UNMET NEEDS IN THE TREATMENT OF DEPRESSION

he field of chronobiology studies 24-hour bio-

T logical clocks (the circadian system) and their

synchronizers (“zeitgebers”) such as light, the
pineal hormone melatonin, food, activity, as well
as the factors regulating sleep.1 Light therapy has
arisen out of this basic research in circadian rhythms,
Anna WIRZ-JUSTICE, PhD whereas, in contrast, sleep deprivation (“wake ther-
Center for Chronobiology apy”) was established by astutely following up clin-
University Psychiatric Hospitals Basel ical observations.2 Chronotherapeutics can be de-
Basel, SWITZERLAND
fined as translating basic chronobiology research
into valid treatments. The term is broad, and the
treatments subsumed under this heading will grow
as the field grows, and are of course not limited to
affective disorders (there is an important body of
evidence, for example, that the correct timing of
cancer treatments augments survival and dimin-
ishes the often potent side effects).
Chronobiological The theme of meeting unmet needs in the treat-
ment of depression is important and timely. The
onset of action of antidepressants is still not rapid

strategies for unmet enough, a proportion of patients do not respond,

others have residual symptoms that predict relapse.
Although medication based on classic neurotrans-

needs in the treatment mitter systems is still a prime focus, drug targets
other than monoamines are under intensive inves-
tigation.3 Strategies promoting adjuvant therapy
are on the increase, whether they encompass com-

of depression bination with other medications (eg, addition of

pindolol, of thyroid hormone) or psychological in-
terventions (eg, cognitive behavioral therapy). Main-
stream psychiatry is becoming more and more
by A. Wirz-Justice, Switzerland eclectic, implementing a variety of approaches to
help the individual patients. The question to be dis-
cussed here is focused on why not also combine the
chronobiological strategies of light therapy and/or
wake therapy with psychopharmacological medica-

C
hronobiological strategies may provide an effective means of address- tion? Light therapy has undergone widespread con-
ing some of the unmet needs in the treatment of depression, such as short- trolled randomized clinical trials, and wake thera-
ening the latency of onset of antidepressant action, combating residual py has been so widely studied over decades that the
symptoms, and preventing relapse in the long term. Light is the treatment of efficacy data are strong. These nonpharmaceutical,
choice for winter depression (or seasonal affective disorder, SAD). Light thera- biologically based therapies are not only powerful
py given as an adjuvant to medication in major nonseasonal depression, as well adjuvants, but also antidepressants in their own
as in chronic and therapy-resistant depression, speeds up and potentiates clin- right.2,4
ical response. Light is also efficacious in bipolar depression; in these patients
“dark therapy” (long nights) can diminish manic symptoms and stop rapid cy- Why are we interested in
cling. Total or partial sleep deprivation in the second half of the night (better biological rhythms?
known as “wake therapy”) induces marked improvement the following day.
This amelioration can be maintained with concomitant treatment with antide- One of the most striking clinical phenomena in af-
pressants, lithium, light therapy, sleep phase advance, or combinations thereof. fective disorders is the periodicity of recurrence—
Careful control of the light-dark cycle and of the timing of mealtimes, activity, ranging from seasonal, as in winter depression, to
and sleep may appear to be old-fashioned methods (“daily structures”) belong- rapid cycling, which can be as short as 48 hours (re-
ing to a long obsolete custodial psychiatry. However, these apparently simple viewed in 5). Other periodic phenomena are found
methods gain new validation when reconsidered within the framework of mod- at the symptom level: diurnal variation of mood,
ern chronobiology, since when appropriately timed, application of “zeitgebers”
can aid treatment of affective disorders.
Medicographia. 2005;27:223-227. (see French abstract on page 227) SELECTED ABBREVIATIONS AND ACRONYMS

5-HT serotonin
Keywords: major depression; circadian rhythm; sleep deprivation;
5-HT2C serotonin receptor (subtype 2C)
light therapy; melatonin
MDD major depressive disorder
PVN paraventricular nucleus
SAD seasonal affective disorder
SCN suprachiasmatic nucleus
Address for correspondence: Prof Dr Anna Wirz-Justice, Center for Chronobiology,
University Psychiatric Hospitals, Wilhelm Klein Straße 27, CH-4025 Basel, Switzerland
SSRI selective serotonin reuptake inhibitor
(e-mail: anna.wirz-justice@unibas.ch)

Chronobiological strategies for unmet needs in the treatment of depression – Wirz-Justice MEDICOGRAPHIA, VOL 27, No. 3, 2005 223
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
early morning awakening, and sleep disturbances.
Abundant research has documented abnormal cir-
cadian rhythms in biochemistry, neuroendocrine
function, physiology, and behavior, often linked to
changes in affective state. These have been reviewed
in detail elsewhere; the findings are not homoge-
neous, even though a certain pattern appears char-
acteristic of depression — there is increased vari-
ability in day-to-day rhythms, decreased circadian
amplitude, and circadian phase that is either ear-
ly (advanced) or late (delayed).5-11 Bipolar disorder
seems to be most clearly linked to abnormal or
changing circadian rhythm phase.6 In addition, al-
terations in the sleep EEG in depression, although
neither pathognomonic nor specific, display recog-
nizable patterns of disturbance.12
Principles of circadian timing
and sleep regulation
The biological timing system is schematically de-
scribed in Figure 1. Circadian oscillators are found
in every organ and every cell — the so-called “pe-
ripheral clocks.”13 A master pacemaker or biologi-
cal clock in the suprachiasmatic nuclei (SCN) coor-
SCN PVN Pineal
Melatonin
Peripheral
Sleep clocks
regulating
centers
Figure 1. Schematic representation of the circadian timing system. Light ( )
is the major zeitgeber reaching the biological clock in the SCN via special-
ized “circadian photoreceptors” in the retina ( ). A multisynaptic pathway to
the pineal gland via the paraventricular nucleus (PVN) drives the nocturnal
synthesis of melatonin and its suppression by light. Melatonin feeds back on
receptors in the SCN. The SCN also synchronizes the timing of peripheral
clocks in other organs and cells, some of which have their own zeitgebers
(eg, food for the liver clock). There are multiple connections from (and to)
the SCN to areas of the brain involved in sleep regulation eg, the preoptic
area, the dorsolateral and posterior hypothalamus, and the raphe nucleus.
dinates these circadian rhythms in brain and body.1
The SCN is synchronized to the external light-dark
cycle primarily by retinal light input. A specialized
(“nonvisual”) retinohypothalamic tract provides di-
rect neuronal connection to the SCN from novel
photoreceptors in the retinal ganglion cells that
measure illuminance.14 Nocturnal synthesis of the
pineal hormone melatonin is driven by the SCN;
melatonin also feeds back on melatonin receptors
in the SCN and thus melatonin belongs to the cat-
egory of synchronizing agents or “zeitgebers” (light
being the major one). A serotoninergic pathway
from the raphe nucleus provides nonphotic input to
the SCN. Nonphotic zeitgebers such as exercise,
sleep, or darkness are probably much weaker zeit-
gebers than light on SCN function. Social zeitgebers
224 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Chronobiological strategies for unmet needs in the treatment of depression – Wirz-Justice
(such as school or work schedules) may act direct-
ly or indirectly on the SCN, since they determine
the timing of meals, sleep, physical exercise, and
outdoor light exposure. The circadian pacemaker
has inputs to sleep regulatory centers (eg, the raphe
nucleus, the dorsolateral hypothalamus [orexin],
ventrolateral preoptic area),15 and sleep centers talk
back to the clock.16 The timing and architecture of
sleep is considered to be a consequence of interac-
tions between the circadian pacemaker and a home-
ostatic process of rising sleep pressure, dependent
on the duration of prior wakefulness, that declines
during sleep (the “two-process model”).17
Mood is dependent on both
time of day and time awake
This parsimonious two-process model has been able
to explain much of the physiology of sleep as well as
of aberrant sleep-wake cycle behavior. Protocols de-
veloped to analyze the contributions of circadian
phase vs the sleep homeostat have provided fasci-
nating information not only about sleepiness—as
might be expected—but also that mood is similarly
regulated by the two processes. This is shown very
clearly in the “forced desynchrony” protocol carried
out in healthy subjects.18 The circadian component
of mood follows the circadian rhythm of core body
temperature rather closely. We wake up in not too
good a mood, but this improves throughout the day
to reach a maximum in the evening, and then mood
declines during the night. The wake-dependent
component reveals that we are quite cheery after a
good night’s sleep when sleep pressure is low, but
that thereafter mood declines monotonically with
time awake. If the temporal alignment between the
sleep-wake cycle and the circadian pacemaker af-
fects self-assessment of mood in healthy subjects,
it might be expected that this is even more impor-
tant for patients with depression. The phenomenon
of diurnal mood variation as a characteristic of de-
pressive state may indeed arise from phase relation-
ships gone awry.
Diurnal mood variation can be manipulated by
shifting or depriving sleep. The improvement after
a night’s wake therapy usually begins in the second
half of the night or the next day, suggesting that
staying awake prevents the nocturnal plunge in
mood.10 Furthermore, a phase advance of sleep tim-
ing has been able to induce a day-by-day change in
diurnal mood patterns over many weeks—evidence
for the profound effect of shifting phase relation-
ships on mood (a more severe form of jet lag).19,20
Similar day-by-day changes in diurnal mood pat-
terns have been found in a “forced desynchrony” ex-
periment carried out in major seasonal depression.21
Shifting rhythms or sleep
can be therapeutic
The above model helps to understand the change of
clinical state with time of day and after manipula-
tions of sleep. The clinical findings, however, are the
important point to be made—extending wakeful-
ness is antidepressant. Wake therapy has been well
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

established as a rapid treatment for depression for

over 30 years, the response being particularly high
2000
in those patients who report daily mood swings.10
Modified protocols have been developed, such as

Estimated CNS serotonin

wake therapy in the second half of the night, or 1500

turnover (pmol/mil)
phase advance of the sleep-wake cycle.10 These two
modifications emphasize the circadian factor— it
being important to remain awake at a particular 1000
time in order to prevent mood decline.
The main reason for the lack of enthusiasm for
wake therapy as a treatment in everyday practice is 500
the equally rapid relapse following recovery sleep.
A number of groups have taken up the challenge of
searching for methods to prevent this: do not give 0
Summer Autumn Winter Spring
up wake therapy as a treatment just because its ef-
fects don’t last long enough! In bipolar patients, the
combination with lithium appears to maintain an-
Figure 2. Average CNS serotonin turnover in vivo in
tidepressant response.22-24 A number of different healthy subjects according to season of measurement.
medications have been tried25; in particular, the use Redrawn from reference 32: Lambert GW, Reid C, Kaye DM, Jen-
of SSRIs or light is recommended following one to nings GL, Esler MD. Effect of sunlight and season on serotonin
turnover in the brain. Lancet. 2002;360:1840-1842. Copyright ©
three episodes of wake therapy.26-29 2002, Elsevier Ltd.

How are circadian rhythms
related to depression?
The basic question of how circadian rhythms are
related to depression has not yet been answered.
Genetic vulnerability and stress influence circadi-
an rhythms and sleep patterns, leading to many of
the symptoms characteristic of affective disorders.
Circadian and seasonal rhythms involve the same
neurotransmitters postulated to be important for
depression — so that changes in one system have
repercussions on the other. For example, it is known
that serotonin concentrations are highest in the
SCN. The SCN also expresses high levels of melato-
nin receptors, and exogenous melatonin is known
to be able to influence the phase and the period of
the circadian clock. In humans, serotonin turnover
changes markedly with time of day and year (Fig-
ure 2),30-32 and light exposure rapidly simulates sero-
tonergic function.32 Serotonin is also important in
sleep regulation, though its role appears complex.
Prefrontal cortical serotonin has been linked with
mood. These interrelationships have been concep-
tualized in a dual model of circadian rhythms and
serotonin in depression (Figure 3).33 The emphasis
is on a system vulnerable to depression—whether
genetic, hormonal, dependent on light availability
and light exposure—and, in parallel, the circadian
system and its phase relationships with sleep and
with the outer world. Concurrent dysfunction can
lead to major depression or its seasonal form. Cir-
cadian abnormalities alone lead to certain forms of
sleep disorders (such as advanced or delayed sleep
phase syndrome) without effects on mood. Seroton-
ergic abnormalities alone lead to other serotonin-
related illnesses (eg, obsessive compulsive disorder)
again, without the mood disorder.
A digression on seasonality
Humans retain their capacity to undergo seasonal
responses, even though their extent has declined
in the last century since the invention of artificial
light and the use of central heating and air condi-
tioning to control environmental temperature. This
is clearly seen in the seasonality of birth (concep-
tion) rates, that had a high spring peak in the 16th
century, but declined to very low amplitude in the
20th century, with a shift to an autumn peak.34 Psy-
chiatrists have long remarked on seasonality in their
patients’ symptoms, for example Esquirol, who not-
ed that the peak admission rates to the Salpêtrière
Altered circadian 5-HT vulnerability
amplitude genetic/gender/
and/or phase light exposure/
relationship season
MDD
Circadian Other 5-HT–related
sleep disorders SAD disorders
Figure 3. Dual model of depression. Both a disturbance in the circadian timing system
and a neurobiological vulnerability (serotonergic [5-HT] hypofunction) are required
for the manifestation of major depressive disorder (MDD) or seasonal affective disorder
(SAD).
Redrawn from reference 33: Lam RW, Tam EM, Yatham LN, Shiah IS, Zis AP. Seasonal depression: the
dual vulnerability hypothesis revisited. J Affect Disord. 2001;63:123-132. Copyright © 2001, Elsevier B.V.
hospital occurred in spring.35 What is not usually
recognized, is that not only depressive symptoms,
but even response to placebo is seasonally modu-
lated. The 10-day response rate to placebo in dou-
ble-blind controlled trials of various antidepressants
carried out at the New York State Psychiatric Insti-
tute was analyzed according to time of year (Fig-
ure 4, page 226).36 Three times higher response rates
occurred in summer than in winter. In conclusion,
many aspects of behavior, physiology, and neuroen-

Chronobiological strategies for unmet needs in the treatment of depression – Wirz-Justice MEDICOGRAPHIA, VOL 27, No. 3, 2005 225
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
40
Placebo response rate (%)
30
20
10
0 “More darkness” is a correlate of the above: pilot
Summer Winter
Autumn
Figure 4. The 10-day response rate to placebo in dou-
ble-blind controlled trials of various antidepressants.
Each point is a single trial.
Redrawn from reference 36: Terman M. On the question of mech-
anism in phototherapy for seasonal affective disorder: considera-
tions of clinical efficacy and epidemiology. In: Rosenthal NE, Ble-
har MC, eds. Seasonal Affective Disorder and Phototherapy. New
York, NY: Guilford Press; 1989:357-376. Copyright © 1989, Guil-
ford Press.
docrine function are sensitive to season. One ex-
ample is presented, that of the in vivo turnover of
central nervous system serotonin in healthy hu-
mans — much higher in summer than in winter
(Figure 2).32
More light!
As for the seasons, the annals of psychiatry abound
with evidence that affective state can be modulated
by exposure to environmental light or darkness.37
The diagnosis of seasonal affective disorder (SAD)
and the development of light therapy was based on
neurobiological models of mammalian seasonali-
ty—the first treatment in psychiatry to be ground-
ed in basic research. Although light therapy was
initially propagated by Kripke for nonseasonal de-
pression,38 initial studies were too short in dura-
tion to provide the convincing results that a single
week of light therapy can now achieve in SAD: it
is only now, 20 years on, that controlled long-term
studies of light at last have been and are being car-
ried out in nonseasonal major depression, with ex-
tremely promising results. For example, the need
for efficacious treatment of depression during preg-
nancy without side effects on the fetus has led to
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17:239-247.
STRATÉGIES CHRONOBIOLOGIQUES POUR LES BESOINS
INSATISFAITS DANS LE TRAITEMENT DE LA DÉPRESSION
L
es stratégies chronobiologiques peuvent représenter un moyen efficace
pour faire face à certains besoins insatisfaits dans le traitement de la dé-
pression. Ce sont : le raccourcissement du temps de latence qui précède
l’apparition de l’effet antidépresseur, la lutte contre les symptômes résiduels
et la prévention de la rechute à long terme. La lumière est le traitement de choix
pour la dépression hivernale (ou trouble affectif saisonnier, TAS). La lumino-
thérapie, comme adjuvant au traitement dans la dépression non saisonnière
majeure comme dans la dépression chronique et résistante au traitement, accé-
lère et potentialise la réponse au traitement. La lumière est aussi efficace dans
la dépression bipolaire ; chez ces patients présentant ce trouble, le « traitement
par l’obscurité » (nuits longues) peut diminuer les symptômes maniaques et
arrêter les cycles rapides. La privation totale ou partielle de sommeil dans la se-
conde partie de la nuit (mieux connue sous le nom de « traitement par l’éveil »)
induit une amélioration marquée le jour suivant. Cette amélioration peut être
maintenue avec des traitements concomitants par les antidépresseurs, le li-
thium, la luminothérapie, l’avance de phase de sommeil ou l’association de plu-
sieurs de ces mesures. Un contrôle soigneux du cycle jour-nuit et de l’heure des
repas, de l’activité et du sommeil peut apparaître comme une méthode démo-
dée (mise en place de « structures journalières ») appartenant à une obsolète
psychiatrie d’institutionnalisation. Cependant, ces méthodes apparemment
simples retrouvent une nouvelle légitimation quand on les reconsidère à l’inté-
rieur du cadre de la chronobiologie moderne, puisque l’utilisation bien réglée de
« synchroniseurs », ou « zeitgebers » peut améliorer le traitement des troubles
affectifs.
✦
MEDICOGRAPHIA, VOL 27, No. 3, 2005 227
UNMET NEEDS IN THE TREATMENT OF DEPRESSION

▲
Michel HAMON, PhD
UMR 677 INSERM-UMPC, Faculté
de Médecine Pitié-Salpêtrière
Paris, FRANCE
Pierre-Alain BOYER, PhD
Elisabeth MOCAËR, PhD
IRIS, 6 place des Pléiades
Courbevoie, FRANCE

New perspectives in the

pathophysiology and treatment
of affective disorders: the role
of melatonin and serotonin
b y M . H a m o n , P. - A . B o y e r ,
a n d E . M o c a ë r, F r a n c e

or over 40 years, research into the pathogenesis of depression and the or almost 50 years, since the empirical dis-

F development of suitable drugs for effective treatment has been domina-

ted by the monoamine hypothesis, which states that depression involves
imbalances in serotonin, norepinephrine, and possibly dopamine function. Al-
F covery of the antidepressant properties of the
monoamine oxidase inhibitors (MAOIs) and
tricyclics, the “monoamine hypothesis,” according
though these monoamine neurotransmitters—the respective roles of which are to which depression involves imbalances in sero-
reviewed—are unquestionably involved, the deficit in monoamines is only part tonergic, noradrenergic, and possibly dopaminer-
of the story, and other events besides monoamine imbalance should be taken gic function, has held sway over the concepts and
into account. There is a clear need for more effective, better tolerated, and more theories put forward to explain the pathophysiolo-
rapidly acting antidepressant agents. The development of new antidepressant gy of depression. More recently, however, other ap-
drugs based on other mechanisms than the monoamine hypothesis holds much proaches to the understanding of the central mech-
promise. Increasing attention is being focused on evidence that various affective anisms of antidepressant drugs have been explored,
disorders, including depression, exhibit abnormal patterns of circadian rhythms. and have revealed the existence of important neu-
This article highlights the impact of melatonin and its receptors on depression, robiological changes in response to chronic treat-
and looks at a recently developed antidepressant with documented clinical ef- ment with these drugs.
ficacy, agomelatine. This agent, characterized by melatonin agonist and 5-HT2C
receptor antagonist properties, heralds a new concept in the treatment of de-
SELECTED ABBREVIATIONS AND ACRONYMS
pression.
Medicographia. 2005;27:228-235. (see French abstract on page 235) 5-HT 5-hydroxytryptamine (serotonin)
BDNF brain-derived neurotrophic factor
Keywords: depression; monoamine hypothesis; neurotransmitter; circadian CREB cyclic (adenosine monophosphate) response
rhythm; melatonin; serotonin; agomelatine element binding (protein)
CRF corticotropin-releasing factor
ECT electroconvulsive therapy
HPA hypothalamo-pituitary-adrenocortical (axis)
MAOI monoamine oxidase inhibitor
MT melatonin (receptor)
NE norepinephrine
NK neurokinin (receptor)
NMDA N-methyl-D-aspartate
SCN suprachiasmatic nuclei
SNRI selective norepinephrine reuptake inhibitor
Address for correspondence: Prof Michel Hamon, UMR 677 INSERM-UMPC,
Faculté de Médecine Pitié-Salpêtrière, 75634 Paris Cedex 13, FRANCE SSRI selective serotonin reuptake inhibitor
(e-mail: hamon@ext.jussieu.fr)

228 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others

The “monoamine hypothesis”
The monoaminergic pathways play a crucial role in
the control of mood and cognition, as well as of en-
docrine secretions and chronobiotic rhythms, all of
which are disrupted in depressive states. It was thus
very logical to postulate a perturbation of mono-
aminergic transmission in the etiology of depres-
sive disorders. This has been consistently borne out
by the findings from monoamine depletion stud-
ies in patients, which confirmed the importance of
functionally competent monoaminergic pathways
for combating depressive states, as well as by the
proven clinical efficacy of available treatments of
depression in restoring the compromised activity of
the corticolimbic monoaminergic pathways. Drugs
facilitating neurotransmission mediated by mono-
amine neurotransmitters, especially serotonin (5-
hydroxytryptamine, 5-HT) and norepinephrine (NE),
generally exert a positive influence on mood. By
blocking the key enzyme in the catabolic pathways
of both 5-HT and NE, MAOIs increase the concen-
trations of these neurotransmitters in the synap-
tic cleft at serotonergic and noradrenergic receptor
level. In contrast, tricyclic antidepressants, which
have also been shown to increase the concentra-
tions of monoamines at the receptor level, act via
blockade of the reuptake process of these neuro-
transmitters from the extracellular space. Several
key observations demonstrated that the resulting
increase in extracellular concentrations of both
5-HT and NE entirely accounted for the antidepres-
sant effects of tricyclics. Drugs were therefore de-
signed to mimic the inhibitory effects of tricyclics
via specific action on the 5-HT transporter (selec-
tive serotonin reuptake inhibitors, or SSRIs) or the
NE transporter (selective norepinephrine reuptake
inhibitors, or SNRIs), or both. These drugs, which
increased extracellular concentrations of 5-HT, NE,
or both, were shown to exert potent antidepressant
actions, and are currently the drugs most widely
used in the treatment of major affective disorders.
Second-generation antidepressants are safer than
first-generation agents because SSRIs and SNRIs
do not generally interact with the various receptor
types (histaminergic, cholinergic, α-adrenergic, etc)
on which tricyclic antidepressants act as antago-
nists. Nevertheless, second-generation antidepres-
sants offer little advantage in terms of efficacy, and
there remains a need for antidepressants that do not
require several weeks of administration prior to full
expression of clinical efficacy.1,2 Furthermore, there
is also a need to reduce undesirable side effects,
such as sexual dysfunction, insomnia, and weight
gain, which make the use of at least some of these
drugs rather delicate, since they compromise pa-
tient compliance and reduce drug efficacy.3
It is now well recognized that synaptic facilita-
tion and augmentation of the levels and effects of
NE and 5-HT are only part of the explanation of the
action of antidepressants. The pure “monoamine
hypothesis” is too restrictive, and depression can-
not be simplistically ascribed to the dysfunction of
monoaminergic systems only. Rather, it reflects a
complex disruption not only of monoaminergic
Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
pathways, but of other pathways as well. In partic-
ular, the “monoamine hypothesis” fails to explain
the 3 to 4 weeks’ delay in the therapeutic efficacy
of MAOIs, tricyclics, SSRIs, and SNRIs. The tempo-
ral mismatch between the rapid elevations in extra-
cellular levels of monoamines induced by antide-
pressant agents, and their slow onset of therapeutic
action reflects the initiation of adaptive mechanisms
involving secondary or even tertiary changes in
receptor density, intracellular signaling, synaptic
transmission, neuronal architecture, and neuroge-
nesis.4
The aforementioned adaptive changes in mono-
aminergic receptors were initially claimed to reflect
therapeutically relevant neurobiological changes
induced by long-term antidepressant treatment.
Downregulation of cortical β1-adrenergic and 5-HT2A
serotonergic receptors was long considered as a bi-
ological marker of effective antidepressant therapy
with tricyclics. This was confirmed by evidence of
postmortem upregulation of these receptors in de-
pressed patients having committed suicide.5 How-
ever, other findings indicated that electroconvulsive
therapy (ECT) was associated with upregulation of
cortical 5-HT2A receptors, and that chronic treat-
ment with most SSRI antidepressants was unable
to downregulate cortical β1-receptors. Furthermore,
functional changes after chronic administration of
at least some classes of antidepressants were evi-
denced for other receptor types, especially 5-HT1A
receptors. In particular, there have been consistent
reports of desensitization of 5-HT1A autoreceptors
in the dorsal raphe nucleus, with no changes in
hippocampal 5-HT1A heteroreceptors, after chronic
treatment with MAOIs, SSRIs, or NK1 receptor an-
tagonists6,7 as well as after transcranial magnetic
stimulation8 and ECT.9 In contrast, hypersensitivi-
ty of hippocampal 5-HT1A receptors with no changes
in 5-HT1A autoreceptors has been found to occur
in response to chronic administration of tricyclic
antidepressants.10,11 Nevertheless, the “monoamine
hypothesis” did not entirely account for the action
of the antidepressants, and researchers began look-
ing for other possible mechanisms of action.
Other approaches to the
understanding of the mechanism
of action of antidepressant drugs
An important consideration was that of the possible
involvement of the hypothalamo-pituitary-adreno-
cortical (HPA) stress axis: upregulation of gluco-
corticoid receptors, notably in the hippocampus,
was evidenced with various antidepressant drugs
following long-term administration. This change
is very probably linked to the therapeutic action of
these drugs, since it contributes to restoring normal
functioning of the depression-associated deficient
negative feedback control of the HPA axis, there-
by decreasing excessive cortisol secretion back to
normal in depressive patients. High levels of gluco-
corticoids are generally associated with a negative
influence upon mood, as well as deleterious struc-
tural changes in the hippocampus, perhaps via re-
duced brain-derived neurotrophic factor (BDNF)
MEDICOGRAPHIA, VOL 27, No. 3, 2005 229
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
synthesis, excessive glutamate release, and/or re-
duced neuronal glucose uptake.4 In line with these
findings, glucocorticoid synthesis inhibitors and
glucocorticoid receptor antagonists have been re-
ported to exert antidepressant-like effects.12,13
Consistent with the hypothesis of a causal rela-
tionship between functional abnormalities in the
HPA stress axis and affective disorders, several stud-
ies have demonstrated elevated levels of cortico-
tropin-releasing factor (CRF) in the cerebrospinal
fluid of patients with moderate-to-severe depres-
sion. Indeed, treatment with antagonists at CRF
receptors were shown to relieve behavioral deficits
in animal models of depression14,15 and to improve
mood in depressed subjects.
Neurokinin type 1 (NK1) receptor antagonists
have been claimed to exert antidepressant activi-
ty independent of monoamines in relevant animal
paradigms as well as in humans, by inhibiting the
action of substance P, a tachykinin neuropeptide
that is localized in brain regions involved in the con-
trol of stress and emotion.16
However, there is a possibility that both CRF and
NK1 antagonists may also act, indirectly, through
monoaminergic mechanisms. Indeed, tachykinin
NK1 receptor antagonists activate noradrenergic
and dopaminergic pathways innervating the hip-
pocampus and the frontal cortex, and long-term
treatments with these antagonists produce the same
adaptive changes in 5-HT neurotransmission (no-
tably, functional desensitization of 5-HT1A auto-
receptors, responsible for increased 5-HT tone) as
those observed after chronic treatment with MAOIs
or SSRIs.17 In addition, recent investigations clear-
ly demonstrated that CRF antagonists indirectly
enhanced the activity of serotonergic pathways4,18
although they do not, unlike tachykinin NK1 recep-
tor antagonists, activate dopaminergic input to the
cortex and may inhibit the activity of noradrener-
gic neurons.19,20
Levels of BNDF are usually found to be increased
in response to long-term antidepressant drug treat-
ment. This is probably related, at least in part, to
the negative influence of glucocorticoids on BDNF
synthesis.21,22 Actually, chronic intracerebroventric-
ular infusion of BDNF exerts antidepressant-like
effects via activation of its receptors, TrkB .23 Find-
ings also suggest that progressive induction of BDNF
and the resulting enhancement of neurogenesis are
causally related to the onset of antidepressant activ-
ity.24 Experimental studies on stress and antidepres-
sant treatment have recently implicated neurogen-
esis in the etiology of major depressive disorders.25,26
So far, all chronic treatments aimed at alleviating
depression, including ECT, have been shown to
stimulate the proliferation of progenitor cells at the
origin of granular neurons in the dentate gyrus of
the hippocampus.27 The precise functional signif-
icance of these newly generated neurons in the
pathophysiology of mood disorders is still disputed,
but a recent study by Santarelli et al28 supports the
idea that granule cell proliferation is directly relat-
ed to the therapeutic action of antidepressant drugs,
since suppression of this process by x-ray exposure
resulted in loss of the antidepressant-related be-
230 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others
havioral effects. In addition, the antidepressants
have been found to modulate the expression of var-
ious factors involved in cell survival and growth,
such as cyclic adenosine monophosphate response
element binding protein (CREB), bcl-2, and mito-
gen-activated protein (MAP) kinases.4,29,30
Finally, the complex pattern of mutual interac-
tions between glutamatergic and monoaminergic
networks plays a crucial role in the control of mood
and cognition.31,32 Excessive corticolimbic gluta-
mate release upon chronic exposure to stress may
contribute to the development of depressive states.33
In this regard, most studies have focused on the
role of detrimental N-methyl-D-aspartate receptor
(NMDA)–mediated alterations in the structure of
hippocampal neurons.4,31 A number of antidepres-
sants, as well as ECT, exert regulatory actions on the
NMDA receptor complex, and some NMDA receptor
antagonists have antidepressant-like properties.34
Depression and abnormal
circadian rhythms
In humans, the circadian pacemaker, or biological
clock, is the site of the generation and entrainment
of circadian rhythms. It is located in the suprachi-
asmatic nuclei (SCN) of the anterior hypothalamus.
The great majority of physiological, metabolic, and
behavioral functions are controlled by the circadian
pacemaker and are often used as circadian phase
markers. The circadian pacemaker is sensitive to
light throughout the 24-h cycle and to the phase-
shifting effects of various chemical and pharmaco-
logical components, including melatonin, which
acts on the circadian clock through melatonin re-
ceptors located in the SCN.35
A wide range of affective disorders, including uni-
polar and bipolar depression, mania, seasonal af-
fective disorder, and premenstrual dysphoric disor-
der, are characterized by disorganization of internal
rhythms.
Disruption of the circadian timing system can
manifest in several ways. The amplitude of an oscil-
lation can be altered, notably through changes in:
(i) the number of SCN neurons or their connections
with other brain areas or peripheral targets; or (ii)
the neuronal traffic to the effector systems. The
phase of the rhythms can also be altered, or there
might be a partial or complete failure to remain
driven by the prevailing light-dark cycle through
disruption of neuronal input pathways that impose
24-h rhythmicity on the intrinsically non–24-h,
rhythmic SCN. A very large number of physiolog-
ical variables showing circadian abnormalities in
depressed patients are described in the literature.
Alterations in circadian rhythms in body tempera-
ture, hormone secretions, and vigilance state very
often accompany endogenous depression,36-39 and
unavoidable alterations in normal circadian rhythms
can trigger depressive episodes in human.40 Most
rhythms are phase advanced with respect to the
sleep-wake cycle, diminished in amplitude, and/or
show day-to-day variability in entrainment. Al-
though altered rhythmicity could be either a cause
or an effect of an altered affective state, the high
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

prevalence of circadian dysfunction in affective states
suggests that the circadian system holds important
clues regarding the etiology and treatment of affec-
tive disorders.
Much less attention has been paid to variations in
circadian amplitude than to those affecting phase
and period, but there has been increasing recogni-
tion that blunted circadian amplitude may be one
of the main chronobiological abnormalities in de-
pression.38,40,41 This suggests that novel treatments
addressing such abnormalities could have poten-
tial value in the management of depression, and
that melatonin could be a target for antidepressant
therapy.
Melatonin: a target
for antidepressant therapy
Melatonin (N-acetyl-5-hydroxytrytamine) is an en-
dogenous neurohormone secreted by the pineal
gland, whose circadian and nocturnal secretion is
controlled by the SCN through β-adrenergic recep-
tors. Melatonin is an endogenous synchronizer of
biological rhythms in mammals and its secretion
and actions are tightly related to seasonal and light-
dark cycles.42-44 Melatonin’s ability to control cir-
cadian rhythm synchronization has triggered nu-
merous studies seeking to determine its role in the
pathogenesis of various psychiatric disorders, in-
cluding depression.45,46
Given the extensive perturbations of circadian
rhythms in depressive disorders on the one hand,
and the chronobiotic properties of melatonin on
the other, it was logical to expect that melatonin
would exhibit potential clinical benefits. Such hopes
were encouraged by reports of alterations of mela-
tonin secretory patterns in various psychiatric dis-
orders.46 Both decreases36,47,48 and increases37,39,49-51
in melatonin plasma levels have been evidenced in
depressed patients. Both a familial vulnerability in
the endogenous melatonin signal in subjects prone
to depression and an abnormal duration of the mela-
tonin signal in subjects with current major depres-
sion have been hypothesized.52
Preclinical studies have demonstrated that mela-
tonin is active in several experimental models re-
sponsive to antidepressant treatment (Table I).53
This antidepressant-like activity of melatonin has
been demonstrated, in particular, during repeated
nighttime administration in a “chronic mild stress”
paradigm with diurnal and sleep rhythm disrup-
tions, in both C3H/He mice54 and rats.37,55 In addi-
tion, melatonin, like effective antidepressants, is
active in the forced swimming test,37,56,57 and N-
acetyltransferase “knocked-down” C57BL/6J mu-
tant mice display a longer immobility time in this
test, regardless of circadian rhythm.58
Although most clinical studies have pointed out
the presence of melatonin secretion disturbances
in depressed patients, the link between melatonin
and clinical depressive states remains unclear. Nev-
ertheless, a relationship between melatonin levels
and depression has been reported by Souetre et al38
who found a correlation between low concentra-
tions of circulating melatonin and the Hamilton
Depression Rating Scale (HDRS) scores in a popu-
lation of patients with symptomatic major depres-
sion and another population in remission. Krahn et
al59 also reported that successful ECT in patients
with major depression is associated with a decrease
in 6-sulfatoxymelatonin urinary excretion.
However, other authors47,49 have unsuccessfully
attempted to find correlations between the clinical
manifestation of depression, intensity of symptoms,
and the course of the disease on the one hand, and
melatonin secretion disturbances on the other. More
recently, Szymanska et al51 have shown that plas-
ma melatonin levels do not differentiate patients
in terms of severity of the depressive symptoms, ab-
normal levels being observed in patients with ma-
jor depression as well as in patients in the remission
phase. Nevertheless, changes in urinary excretion of
6-sulfatoxymelatonin have been reported to enable
the distinction between antidepressant responders
and nonresponders.60
In contrast, other authors hypothesize that the
efficacy of antidepressants of different classes (de-
sipramine, fluvoxamine, mianserin, venlafaxine) is
attributable to the enhancement of melatonin secre-
tion (which could involve monoaminergic mecha-
nisms acting on the pineal gland61-63) and/or the in-
hibition of the degradation of melatonin.64
Melatonin
5-HT2C
Agomelatine
antagonist
Despair test -- -- + Typical
Learned helplessness -- -- + antidepressant
Bulbectomy -- ? + models
Chronic mild stress + ? + Circadian rhythm
Transgenic model + ? + models
Isolated aggressive mice +/-- + + Stress or
Marble burying test +/-- + + anxiety models
Table I. The antidepressant activity of melatonin, 5-HT2c antagonists, and agomelatine.
Reproduced from reference 53: Lanfumey L, Boyer PA, Hamon M, Mocaër E. Antidepressant profile of the
melatonin agonist and 5-HT2C antagonist melatonin (S 20098). Preclinical studies. Eur Neuropsychophar-
macol. 2003;13(suppl 4):S274. Copyright © 2003, Elsevier B. V.
Since melatonin has resynchronizing effects in
both animals and humans suffering from circadi-
an rhythm disorganization, the exciting possibility
was raised that a drug able to mimic the effects of
this neurohormone and easily cross the blood-brain
barrier would be beneficial in the treatment of de-
pression. This hypothesis led to the synthesis of ago-
melatine.
Agomelatine: a new
antidepressant with a novel
mechanism of action
Agomelatine (S 20098) is a potent ligand of mela-
tonin receptors, with agonist properties at cloned
human melatoninergic MT1 and MT2 receptor lev-
el. In addition, it is also endowed with antagonist
properties at cloned human 5-HT2B and 5-HT2C re-
ceptor level.

Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others MEDICOGRAPHIA, VOL 27, No. 3, 2005 231
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
◆ Melatonin agonist properties of agomelatine
◆ Action on circadian rhythms
Behavioral studies in rodents have shown that sys-
temic administration of agomelatine could dose-
dependently alter the functioning of the circadian
clock. The chronobiotic properties of agomelatine
were first demonstrated by its ability to mimic the
action of melatonin in the synchronization of circa-
dian rhythm patterns of locomotor activity, running
wheel activity, and body temperature in rodents.65,66
Agomelatine dose-dependently drives rhythms
by setting up a circadian pattern in free-running
animals. This ability to synchronize rest-activity
rhythms in free-running animals requires the in-
tegrity of the SCN, lending further support to its
action on melatonin receptors. In addition, agome-
latine can reset a preexisting circadian rhythm fol-
lowing a phase shift, since it has the ability to faster
reentrain rats following an 8-h phase advance of the
light-dark cycle in vivo. These effects are dose-de-
pendent, up to a maximum usually obtained with
oral administration of 8 to 10 mg/kg in rodents.67
Similarly, in aged animals, long-term treatment
with agomelatine reduces the time needed for reen-
trainment following a phase advance in the light-
dark cycle.68 Finally, in aged animals with reduced
responsiveness to zeitgebers, agomelatine can re-
store the sensitivity of the circadian clock to envi-
ronmental synchronizers.69
◆ Efficacy of agomelatine in animal models
of depression
Interest in agomelatine has recently increased due
to its potential use as a novel antidepressant agent,
as demonstrated in a number of animal studies
using well-validated animal models of depression
(Table I).53 These findings support the potential use
of agomelatine as an antidepressant in humans, and
indeed, agomelatine has been shown to be clinical-
ly effective in depressed patients.70,71
The antidepressant efficacy of agomelatine was
first investigated using the forced swimming test.
Both acute and repeated treatment with agomela-
tine (2, 10, and 50 mg/kg) showed an antidepres-
sant effect in rats and mice, as evidenced by a sig-
nificantly reduced duration of immobility at all
doses tested. Results following agomelatine admin-
istration were comparable to those with imipramine
and fluoxetine, whereas treatment with melatonin
showed no effect.72
The antidepressant efficacy of agomelatine was
further investigated in a large series of experiments.
Results from the learned-helplessness model of de-
pression also demonstrated agomelatine to be an
effective antidepressant. In this study, agomelatine
(10, 50 mg/kg per os) was shown to be equivalent
to imipramine in its ability to reverse the learning
deficit caused by exposure to aversive stimuli. Once-
daily administration was superior to twice-daily
administration of agomelatine, with the most sig-
nificant antidepressant effects being noted with the
10 mg/kg dose.73 The effects of agomelatine were also
studied in the model of olfactory bulbectomized
rats. Ambulation scores were statistically similar
among animals treated with agomelatine (10 or
50 mg/kg) or imipramine (10 mg/kg). Both treat-
232 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others
ments effectively reduced, to the same extent, the
locomotor hyperactivity caused by bulbectomy.74
To date, the model of chronic mild stress is con-
sidered to be the most reliable model for identifying
the antidepressant-like properties of drugs, because
it focuses on anhedonia, one of the key symptoms
of depression. In addition, antidepressants have to
be administered on a chronic basis in order to re-
verse the induced behavioral deficits, in line with
the delay in the onset of therapeutic action of these
drugs. In this paradigm, rats are subjected for sev-
eral weeks to unpredictable minor stress sessions
that cause behavioral alterations, which closely re-
semble those most frequently observed in depressed
patients. In particular, rats develop anhedonia, as
shown by their decreased voluntary intake of a su-
crose solution. Chronic IP administration of agome-
latine (10 and 50 mg/kg daily) was compared with
treatments with melatonin (10 and 50 mg daily) or
the classic antidepressants imipramine (10 mg/kg
daily) and fluoxetine (10 mg/kg daily), in this mod-
el of depression. Agomelatine reversed anhedonia
induced by chronic mild stress, to a similar extent
to that achieved by the other antidepressant drugs
(Figure 1). Thus, agomelatine was found to be a po-
tent and rapidly acting antidepressant in this mod-
el. Once installed, the effect of agomelatine was
quite robust, with no withdrawal-induced relapse at
1 week after cessation of agomelatine treatment.55
Interestingly, whether agomelatine was adminis-
tered in the morning, ie, at the beginning of the
light period, or in the late evening, just prior to the
start of the dark period, had no influence on its ca-
pacity to restore the rats’ preference for sucrose,
suggesting that the antidepressant-like properties
of this drug involve mechanisms independent of
circadian rhythms. In contrast, under the same con-
ditions, melatonin was found to partially restore the
rats’ preference for sucrose only when the neuro-
hormone was injected just prior to the onset of the
dark phase (Figure 1). This difference clearly indi-
cates that the neurobiological mechanisms under-
lying the antidepressant-like action of agomelatine
are not shared by melatonin. Indeed, blockade of
melatonin receptors by the MT1/MT2 receptor antag-
onist S 22153 failed to reverse the antidepressant-
like effect of agomelatine injected in the morning.55
Finally, alongside agomelatine’s specific proper-
ties linked to its novel antidepressant profile of ac-
tion, agomelatine was shown to exert a stimulatory
influence on cell proliferation within the subgran-
ular layer of the dentate gyrus in rats. Chronic ad-
ministration of agomelatine (40 mg/kg IP daily for
21 days) significantly increased the number of cells
labeled by BrdU (a thymidine analog that is incor-
porated in DNA synthesized during mitosis) in adult
rat brain, within a circumscribed region of the hip-
pocampus, the ventral part of the subgranular lay-
er.75 A 3-week treatment with agomelatine (10 or
50 mg/kg IP daily) also reversed the deficit in gran-
ule cell proliferation that had been induced in adult
rats from a mother subjected to repeated stress dur-
ing gestation.76 With regard to cell proliferation in
the dentate gyrus, agomelatine therefore acts like
all other antidepressant therapies tested to date.
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

18
### Controls
16 ##
Vehicle
#
Melatonin
### ##
14 Agomelatine
Sucrose intake (g)

##

12 **
***
10
*** *** ** Stress
8
+ Vehicle
*** ***
+ Melatonin Figure 1. Agomelatine
+ Agomelatine (morning treatment,
6 *** ***
***
50 mg/kg IP) in chronic
4
*** mild stress (effect on
anhedonia).
0 1 2 3 4 5 6 7 Weeks of treatment
Reproduced from reference 55:
Melatonin antagonist Papp M, Gruca P, Boyer PA,
Mocaer E. Effect of agomelatine
in the chronic mild stress model
** P<0.01, *** P<0.001 relative to vehicle or drug treated control animals at week 0
of depression in the rat. Neuro-
# P<0.05, ## P<0.01, ### P<0.001 relative to drug-treated stressed animals at week 0 psychopharmacology. 2003;28:
694-703. Copyright © 2003,
Elsevier Science, Ltd.

◆ 5-HT2C receptor antagonist properties pressant effects of agomelatine, is a question which

of agomelatine
As mentioned above, agomelatine does more than
simply mimic the action of melatonin, and it has
been hypothesized that the melatonin agonist prop-
erties of agomelatine may not, by themselves, be
sufficient to sustain its clear-cut clinical antidepres-
sant efficacy.
In addition to the properties that led to agome-
latine’s classification as a selective melatonin re-
ceptor agonist, extensive studies have identified an-
other mode of action for this drug. Using a classic
test setting for 5-HT2C antagonists, agomelatine was
found to antagonize the penile erections normally
induced by 5-HT2C receptor activation in Wistar rats.
Penile erections were induced by administration of
the 5-HT2C receptor agonists mCPP and Ro-60-0175,
and diminished, in a dose-dependent manner, when
agomelatine was added. In contrast, melatonin ad-
ministration had no effect in this paradigm. It was
therefore concluded that this effect of agomelatine
did not involve its melatonin receptor agonist prop-
erties, but, instead, that it was due to 5-HT2C recep-
tor antagonism.77
Recent results from receptor binding and signal-
ing studies have lent further support to the hypoth-
esis of a secondary mode of action for agomelatine.
Analyses of receptor binding in transfected Chinese
hamster ovary (CHO) cells showed that agomela-
tine acts as an antagonist at both the 5-HT2C and
5-HT2B receptor subtype level. Agomelatine, there-
fore, has a unique pharmacological profile, result-
ing from stimulation of MT1 and MT2 receptors and
blockade of 5-HT2C and 5-HT2B receptors.78 In vivo
experiments in relevant animal models (see above)
have clearly demonstrated the reality of 5-HT2C re-
ceptor blockade with agomelatine at doses used to
elicit antidepressant-like effects. In contrast, very
little is known to date regarding 5-HT2B receptor
blockade and its possible behavioral consequences
in vivo (on food intake, sleep, etc). Thus, whether or
not blockade of the 5-HT2B receptor subtype, which
is expressed at low levels in the brain, contributes,
to a more or less significant extent, to the antide-
cannot be answered at present.
All new antidepressants for which new mecha-
nisms of action are claimed should be investigated
for the presence of possible interactions with mono-
aminergic systems, since it is unlikely that antide-
pressant efficacy can be achieved without recruit-
ing monoaminergic mechanisms, either directly
or indirectly by actions upstream or downstream of
monoaminergic neurons. Because of its 5-HT2C re-
ceptor antagonist properties, both acute and chron-
ic administration of agomelatine (10-40 mg/kg IP)
produce concomitant dopamine and NE overflow
in the frontal cortex.78 It can be assumed that the
stimulatory effect of agomelatine on these mono-
aminergic systems also contributes to its antide-
pressant action, since these neurotransmitters mod-
ulate cognitive-attentional performance and mood
in the frontal cortex. On the other hand, 5-HT out-
flow is unchanged by agomelatine treatment, which
indicates that mechanisms underlying its antide-
pressant-like action are totally unrelated to those
of tricyclics, SSRIs, and MAOIs,78,79 which all gen-
erally elicit a marked increase in 5-HT outflow.
Conclusion
New antidepressants based on other mechanisms of
action than the monoamine hypothesis are a pro-
mising approach in the development of drugs with
better tolerance and efficacy. One of the most ex-
citing prospects in the treatment of depression has
been the development of the new antidepressant
agomelatine, a compound that exhibits strong mela-
tonin receptor agonist activity and 5-HT2C receptor
antagonist properties. This unique combination of
pharmacological properties very probably explains
the efficacy of agomelatine observed in all validat-
ed animal models of depression. Agomelatine thus
represents a new concept in the treatment of de-
pression, and provides a strong incentive for the
development of antidepressant drugs with mixed
mechanisms of action encompassing monoaminer-
gic as well as nonmonoaminergic systems. ❒

Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others MEDICOGRAPHIA, VOL 27, No. 3, 2005 233
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
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PERSPECTIVES NOUVELLES DANS LA PHYSIOPATHOLOGIE
ET LE TRAITEMENT DES TROUBLES AFFECTIFS :
LE RÔLE DE LA MÉLATONINE ET DE LA SÉROTONINE
D
epuis plus de 40 ans, la recherche sur la pathogenèse de la dépression et
le développement de médicaments adaptés pour un traitement efficace
a été dominée par l’hypothèse monoaminergique, qui stipule que la dé-
pression implique un déséquilibre en sérotonine, noradrénaline, et probable-
ment en dopamine. Bien que ces neurotransmetteurs monoaminergiques – dont
les rôles respectifs sont passés en revue – soient impliqués de façon indiscutable,
le déficit en monoamines ne rend compte seulement que d’une partie des faits,
et d’autres événements hormis le déséquilibre monoaminergique devraient être
pris en compte. Il existe un besoin évident de médicaments antidépresseurs plus
efficaces, mieux tolérés et d’action plus rapide. Le développement de nouveaux
antidépresseurs dont le mécanisme d’action repose sur d’autres bases que l’hy-
pothèse monoaminergique est très prometteur. Le fait que de nombreux troubles
affectifs, y compris la dépression, présentent des anomalies des rythmes circa-
diens suscite une attention croissante. Cet article souligne l’impact de la méla-
tonine et de ses récepteurs sur la dépression et présente un antidépresseur dé-
veloppé récemment possédant une efficacité clinique démontrée, l’agomélatine.
Ce produit, qui se distingue par des propriétés agonistes de la mélatonine et an-
tagonistes des récepteurs 5-HT2C , représente un nouveau concept dans le trai-
tement de la dépression.
✦
MEDICOGRAPHIA, VOL 27, No. 3, 2005 235
UNMET NEEDS IN THE TREATMENT OF DEPRESSION
Jean-Pierre OLIÉ, MD
Hospital-University Department
Mental Health and Therapeutics
Sainte-Anne Hospital
Paris, FRANCE
Severe depression:
from diagnosis to treatment
b y J . - P. O l i é , F r a n c e
he concept of severe depression has several
T clinical connotations: (i) symptom intensi-
ty: sadness, loss of interest, inhibition, and
gloomy thoughts can be evident to variable degrees,
particularly if intense or threatening; the level of in-
tensity or severity is readily measured using quan-
titative scale scores; (ii) threat to life, whether from
the physical impact of appetite loss, intense anxiety
or cognitive disorganization with confusion, or from
the power of suicidal ideas—both series of factors
define the highest emergency level: failure to mount
a rapid medical response can have irreversible con-
sequences, in particular in the elderly; (iii) severi-
ty of the functional impact on daily life, notably on
the work and family level.
Severe depression also has outcome connota-
tions. Certain characteristics compound the prog-
nosis and/or treatment resistance: concomitant
S
evere depression comes in a variety of presentations, from highly acute
intense depression to chronic refractory states complicated by predis-
position or comorbidity. Current antidepressants are often ineffective in
depression with somatic or psychiatric comorbidity, psychotic symptoms, or
imminent threat to life. Pharmacologic efficacy in severe depression is difficult
to demonstrate in children and the elderly for methodological reasons. New an-
tidepressants are as much needed as ever, among other reasons to advance our
understanding of the etiopathogenesis of depressive disease and the mecha-
nism of antidepressant action: an acute increase in synaptic cleft monoamine
levels is a clearly inadequate guide either to understanding depression or to
choosing appropriate drug therapy. Improved tolerability, shortened time to
effect, and efficacy in relieving cognitive and somatic symptoms in emergency
(life-threatening) situations are the criteria for evaluating any potential new
antidepressant.
Medicographia. 2005;27:236-239. (see French abstract on page 239)
Keywords: severe depression; childhood depression; depression in the elderly;
antidepressant; treatment
Address for correspondence: Prof Jean-Pierre Olié, Service Hospitalo-Universitaire,
Santé Mentale et Thérapeutique, Hôpital Sainte-Anne, 7 rue Cabanis, 75684 Paris Cedex 14, France
(e-mail: jp.olie@ch-sainte-anne.fr)
236 MEDICOGRAPHIA, VOL 27, No. 3, 2005
anxiety, pathologic personality traits, alcohol and
psychotropic substance abuse, concomitant phys-
ical disease (organic brain disease, in particular),
and the persistence of negative environmental fac-
tors. Such factors can transform “difficult” or “re-
sistant” depression into severe depression by virtue
of its intra- and interindividual repercussions.
Age of depression onset may influence mood dis-
turbance severity, especially as depressive symp-
toms in children are often associated with other
disturbances, such as attention deficit disorder or
anxiety disorder. Adolescent depression typically
presents as behavioral disturbance, which may not
only delay the diagnosis, but generate consequences
that can be serious and irreversible.
As for the psychotic symptoms that may accom-
pany the depressive episode, they reflect its sever-
ity when mood-congruent (eg, delusional ideas of
guilt or ruin); when noncongruent (eg, delusions
of persecution or of telepathy with hallucinations),
they herald a poor prognosis and are an indication
for immediate first-line therapy with an antide-
pressant+neuroleptic or electroconvulsive therapy
(ECT). Depression associated with delusional hypo-
chondriasis is a more complex presentation, with a
high risk of developing into a chronic delusional
disorder, especially if compounded by pathological
personality traits.
High-intensity depression
This category is readily identified by symptom num-
ber and intensity, producing high scores on the
Montgomery-Asberg Depression Rating Scale
(MADRS) or Hamilton Depression Rating Scale. Not
only low-intensity, but also high-intensity depres-
sion are often observed to respond less well to old-
er antidepressants.1 Studies have revealed that drugs
indeed differ in this context, with some proving
more effective. Thus, certain psychiatrists remain
convinced that selective serotonin reuptake inhib-
itors (SSRIs) are less potent antidepressants than
imipramine. However, this has never been proven.
Severe depression: from diagnosis to treatment – Olié

Imminently
life-threatening depression
In this type of situation, ECT may be necessary, in
particular as malnutrition, dehydration, suicidal in-
tent, and repeated attempted suicide all predict a
favorable response.2 Endogenicity and melancho-
lia, on the other hand, are poorer predictors, in con-
trast to long-held belief.3 The best predictor of re-
sponse to ECT is psychomotor retardation.4 In any
event, ECT is mandatory in imminently life-threat-
ening depression, in particular because of its rapid
onset of effect and the risks of imipramine thera-
py. This underlines the need to identify drugs that
can act rapidly and safely in the (often malnour-
ished) elderly.
The problem of time to antidepressant effect is
clearly critical in severe depression, in particular
when there is an imminent threat to life. At pre-
sent, various chemotherapy strategies can be used
to lower suicide risk: restoration of the sleep-wake
cycle using a hypnotic may help to relieve the de-
pression and pressure of suicidal ideas; reduction
of anxiety using an anxiolytic can prevent impulsive
suicide (in this context, benzodiazepines, with their
potential for paradoxical disinhibitory reactions,
are best avoided in favor of other types of anxiolyt-
ic, eg, levomepromazine or cyamemazine); suici-
dality may also respond to drugs such as lithium.
It is generally agreed that the efficacy of an anti-
depressant can only be assessed after treatment for
4 to 6 weeks. Certain effects may emerge earlier, of
course, heralding greater efficacy at 6 weeks.5 Tol-
erability becomes crucial where the threat to life is
physical. Posttricyclic antidepressants marked a
significant advance in this regard. Safety—cardiac,
hepatic, and neurologic — is mandatory. The new
antidepressants are generally much easier to use
than their predecessors, although renutrition and
gentle sedation often remain necessary to bridge the
gap until the onset of antidepressant effect. Under
such conditions, the ideal antidepressant is one with
rapid onset of effect against anxiety and suicidality,
combined with a high level of tolerability.
Depression with
psychiatric comorbidity
Clinical depression can be associated with psycho-
behavioral symptoms that reverse on effective anti-
depressant treatment. They include obsessive symp-
toms, eating disorders, irritability, and pathological
personality traits.
Depression may also feature in the natural histo-
ry of anxiety disorder or personality disorder. The
classic example is that of panic disorder complicat-
ed by a depressive episode: panic disorder can be di-
agnosed in 20% to 30% of patients with depression;
as a severity factor, it carries considerable psychoso-
cial impact, with a high risk of suicide.6 However,
the prognosis may be better if depression precedes
panic disorder.7 Depression is often associated with
generalized anxiety disorder: early-onset anxiety
disorder may be a severity factor for anxiety and de-
pression.8
Severe depression: from diagnosis to treatment – Olié
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
Depressed patients with personality disorder dif-
fer in several ways from those without: earlier-onset
mood disturbance, less social support, more often
single or divorced, more hospital admissions, and
more severe depressive symptoms with higher sui-
cidality. The personality disorder also compounds
treatment resistance. An antidepressant that would
not only remain effective despite such comorbid-
ity, but could also treat it, would have a definite ad-
vantage.
Depression with psychotic symptoms
Mood-congruent and non–mood-congruent are not
categories cast in stone—they can be influenced by
sociocultural factors.9 For some psychiatrists, the
concept of psychotic depression partly overlaps that
of endogenous depression. Should depression be
viewed as a continuum, stretching from nondelu-
sional depression (Kraepelin’s simple melancholia)
to severe delusional depression or delusional melan-
cholia? Or should delusional depression be consid-
ered a specific category?10
Comparison between delusional and nondelu-
sional depression reveals no differences in sex, age
of onset, number of episodes, or number of suicide
attempts. However, cluster A personality distur-
bances appear more frequent in delusional depres-
sion, and cluster B disturbances more frequent in
its nondelusional counterpart.11 Some psychiatrists
find delusional depression more frequent in bipo-
lar than in unipolar patients.12 Delusions may in-
crease the risk of suicide, in both bipolar and unipo-
lar depressives.13 The risk of mood disturbance in
first-degree relatives may be higher in delusional
than in nondelusional depression.14
Delusions and hallucinations reach critical levels
in the most serious forms of depression in which
obnubilation facilitates the emergence of terrifying
interpretative visions and delusional ideas. Such
delusional presentations have become rare, proba-
bly aborted by psychotropic agents. Thus full-blown
Cotard syndrome, in which delusional negation of
organs or the entire body is combined with delu-
sional ideas of eternal damnation and immortality,
and the negation of family, space, and time, now
tends to be replaced by partial presentations, eg,
delusions of damnation or individual organ nega-
tion. No antidepressant has proved as effective in
delusional depression as in its nondelusional coun-
terpart.
Psychotic symptoms are significantly more fre-
quent in adolescents15 and preadolescents,16 posing
a differential diagnostic quandary with incipient
schizophrenia and raising awkward management
problems: older antidepressant alone, newer anti-
depressant alone, or either in combination with an
antipsychotic?
The concept of schizoaffective disorder introduced
by Kasanin in 1933 raised classification problems
that remain unresolved. In terms of prognosis, de-
pressive schizoaffective disorder falls midway be-
tween schizophrenia and major (psychotic) depres-
sion.17 Here too, treatment is often mixed, combin-
ing an antidepressant with an antipsychotic.
MEDICOGRAPHIA, VOL 27, No. 3, 2005 237
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
Depression in
children and adolescents
Although midterm outcome is often favorable, the
prognosis of depression in the young is often poor,
with 75% relapse at 5 years,18 thus considerably in-
creasing the risk of depression in adulthood.19 In
addition, comorbidity is high, with character or be-
havioral traits that can interfere with the diagnosis
of depression and also its treatment. Hostility by
the child or adolescent generates a vicious circle of
hostile communication that feeds, perpetuates, and
even amplifies the underlying disorder. This may
trigger risk-taking behavior.20 In addition, environ-
mental factors can play a major role in facilitating
suicidal behavior. A history of depressive episode in
childhood is a risk factor for attempted suicide in
adulthood.21 There is also the diagnostic quandary
mentioned earlier: how to differentiate between
mood disorder on the one hand and depression in
an incipient chronic schizophrenic on the other? It
is still difficult to demonstrate antidepressant effi-
cacy in child and adolescent depression.
Depression in the elderly
In the elderly, it is mandatory to test for degenera-
tive disease when depression coexists with psychosis,
especially if there is no history of depression. Delu-
sional hypochondriasis becomes more frequent
with age. Severe cases may present with confusion,
or more commonly hallucinations that can be psy-
chic, auditory-verbal, visual, or involve bodily sen-
sations.
Cognitive and depressive symptoms are frequent-
ly intertwined in this age group. Over 25% of de-
mentia patients first present with altered mood.22
The term depressive pseudodementia is widely used
to reflect the depression/dementia interface. There
are five main clinical variants: (i) depression with
low-grade cognitive impairment; (ii) depressive de-
mentia; (iii) nondepressive dementia; (iv) demen-
tia-induced depression; and (v) comorbidity.
In addition to increased suicide risk in the elder-
ly, the two other factors that compound depression
in this age group are cognitive impairment, which
increases risks such as dehydration, and organic
brain disease, which causes antidepressant resis-
tance and heralds dementia. Because concomitant
physical ailments are so common, it is essential to
select an optimally tolerated antidepressant. The
dream drug in such cases is one that would remain
effective despite organic and psychiatric comorbid-
ity, relieve cognitive impairment, and arrest the risk
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◆ Restore normal psychological and social func-
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Dunner DL. The relationship between anxiety and depression: a
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W. Bipolar II. Combine or keep separate? J Affect Disord.1985;8:
17-28.
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Depression, delusions, and suicide. Am J Psychiatry. 1983;140:
1159-1162.
14. Goldstein RB, Horwath E, Wickramaratne PJ, Wolk SI, War-
ner V, Weissman MM. Familial aggregation of delusional depres-
sion: re-examination in a recent family study. Depress Anxiety.
1998;8:160-165.
15. Carlson GA, Srober M. Affective disorder in adolescence: issue
in misdiagnosis. J Clin Psychiatry. 1978;39:59-66.
16. Chambers WJ, Puig-Antich J, Tabrizi MA. Psychotic symp-
toms in prepubertal major depressive disorders. Arch Gen Psy-
chiatry. 1982;39:921-927.
17. Coryell W, Lavori P, Endicott J, Keller M, Van Eedewegh M.
Outcome in schizoaffective, psychotic and nonpsychotic depres-
sion. Course during a six- to 24-month follow-up. Arch Gen Psy-
chiatry. 1984;41:787-791.
18. Kovacs M, Feinberg TL, Crouse-Novak MA. Depressive dis-
orders in childhood. I. A longitudinal prospective study of char-
acteristics and recovery. Arch Gen Psychiatry.1984;41:229-237.
19. Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult out-
comes of childhood and adolescent depression: II. Links with an-
tisocial disorders. J Am Acad Child Adolesc Psychiatry.1991;30:
434-439.
20. Pesa JA, Cowdery JE, Westerfield RC, Wang M. Self-reported
depression and risk-taking behaviors among Hispanic adoles-
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21. Sechter D, Bonin B, Bertschy G, Vandel S, Bizouard P. [Pre-
diction of suicide risk (French)]. Encephale. 1991;17:361-364.
22. Yesavage J. Differential diagnosis between depression and
dementia. Am J Med. 1993;94(suppl 5A):23-28.
23. Maier W, Philipp M, Schlegel S, Heuser I, Wiedemann K,
Benkert O. Diagnostic determinants of response to treatment
with tricyclic antidepressants: a polydiagnostic approach. Psychi-
atry Res. 1989;30:83-93.
24. Joyce PR, Paykel ES. Predictors of drug response in depres-
sion. Arch Gen Psychiatry. 1989;46:89-99.
25. Kocsis JH. New issues in the prediction of antidepressant re-
sponse. Psychopharmacol Bull. 1990;26:49-53.
26. Charlier C, Pinto E, Ansseau M, Plomteux G. Venlafaxine: the
relationship between dose, plasma concentration and clinical re-
sponse in depressive patients. J Psychopharmacol. 2002;16:369-
372.
27. Thase ME, Kupfer DJ. Recent developments in the pharma-
cotherapy of mood disorders. J Consult Clin Psychol. 1996;64:
646-659.
28. Stahl SM. Essential psychopharmacology. Cambridge, UK:
Cambridge University Press, 2000.
29. De Montigny C, Grunberg F, Mayer A. Lithium induces rapid
relief of depression in tricyclic antidepressant drug nonrespon-
ders. Br J Psychiatry. 1981;138:252-256.
30. Januel D, Poirier MF, D’alche-Biree, Dib M, Olie JP. Multi-
center double-blind randomized parallel-group clinical trial of
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um carbonate (750 mg/day) versus clomipramine (150 mg/day)
plus placebo in the treatment of unipolar major depression. J Af-
fect Disord. 2003;76:191-200.
31. Hatterer JA, Stanley M. Thyroid function in refractory depres-
sion. In: Roose SP, Glassman AH, eds. Treatment Strategies for
Refractory Depression. Washington, DC: American Psychiatric
Press; 1990:169-192.
32. Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S,
Schulze-Monking H. Electroconvulsive therapy vs. paroxetine in
treatment-resistant depression: a randomized study. Acta Psy-
chiatr Scand. 1997;96:334-342.
33. Abrams R, Vedak C. Prediction of electroconvulsive response
in melancholia. Convuls Ther. 1991;7:81-84.
34. Vanelle JM. [Predictive factors of response to electronarcosis
(French)]. Encephale. 1991;17:399-404.
35. Petrides G, Fink M, Husain MM, et al. ECT remission rates in
psychotic versus nonpsychotic depressed patients: a report from
CORE. J ECT. 2001;17:244-253.
36. Rabheru K. The use of electroconvulsive therapy in special pa-
tient populations. Can J Psychiatry. 2001;46:710-719.
37. Benbow SM. The role of electroconvulsive therapy in the treat-
ment of depressive illness in old age. Br J Psychiatry.1989;155:
147-152.

DÉPRESSION SÉVÈRE : DU DIAGNOSTIC AU TRAITEMENT

L
a notion de dépression sévère est polysémique, recouvrant aussi bien des
dépressions particulièrement aiguës et intenses que des états difficiles à
traiter en raison d’un terrain particulier ou d’une comorbidité. Les dé-
pressions avec comorbidité somatique ou psychiatrique, avec symptômes psy-
chotiques, avec risque vital imminent sont souvent peu efficacement traitées
avec les antidépresseurs aujourd’hui disponibles. Chez l’enfant et le sujet âgé
des difficultés méthodologiques rendent difficiles la démonstration d’efficacité
d’un agent pharmacologique dans la dépression sévère. Ainsi de nouveaux an-
tidépresseurs restent-ils nécessaires. Ils devraient aider à progresser dans la
connaissance étiopathogénique du trouble dépressif et du mécanisme d’action
des antidépresseurs, l’augmentation aiguë de taux de monoamines dans la fente
synaptique ne pouvant, à l’évidence, suffire à guider notre compréhension du
trouble dépressif et le choix de nos prescriptions. L’amélioration de la tolérance,
mais aussi le raccourcissement du délai d’action et l’efficacité dans des contextes
d’urgence (risque vital) sur des symptômes tels que les symptômes cognitifs et
somatiques sont des objectifs à la lumière desquels doit être évaluée toute nou-
velle molécule potentiellement antidépressive.

Severe depression: from diagnosis to treatment – Olié MEDICOGRAPHIA, VOL 27, No. 3, 2005 239
UNMET NEEDS IN THE TREATMENT OF DEPRESSION
Sidney H. KENNEDY, MD, FRCPC
Psychiatrist-in-Chief
University Health Network
Professor, Department of Psychiatry
University of Toronto
Toronto, CANADA
Shortcomings of current
antidepressant therapies
by S. H. Kennedy, Canada
his chapter reviews patient variables that in-
T fluence treatment outcomes in Major Depres-
sive Episode (MDE), before focusing on the
current limitations of today’s antidepressant options.
Treatment of depression:
patient variables
◆ Compliance
Compliance reflects the positive or negative inter-
actions among patient, drug, and prescriber vari-
ables and is a significant, but frequently neglected,
reason for poor treatment outcome. Results from
primary care studies indicate that fewer than 50%
of depressed patients continue to take their medi-
cation after 12 weeks.1,2 The reasons cited in both
studies are remarkably similar in content and fre-
quency (Table I).
S
uccessful treatment of a Major Depressive Episode (MDE) is influenced
by many factors beyond the properties of a particular medication. These
include the unique characteristics of each patient; the safety–tolerabil-
ity–effectiveness profile of the drug, and the interaction between patient and
health care professionals. While newer antidepressants represent considerable
advances in safety and tolerability compared with tricyclic (TCA) and mono-
amine oxidase inhibitor (MAOI) agents, the improvement in therapeutic bene-
fit is not substantial. The delay to achieve antidepressant benefit, the percent-
age of patients who do not reach response or remission criteria, the persistence
of unwanted side effects, and concerns about drug discontinuation emergent
effects are all shortcomings of current antidepressants.
Medicographia. 2005;27:240-246. (see French abstract on page 246)
Keywords: antidepressant; major depressive disorder; personality;
compliance; onset of action; side effect
Address for correspondence: Sidney H. Kennedy, MD, FRCPC, University Health Network,
200 Elizabeth St, EN8-222, Toronto, ON M5G 2C4, Canada
(e-mail: sidney.kennedy@uhn.on.ca)
240 MEDICOGRAPHIA, VOL 27, No. 3, 2005
Failure to address compliance at the outset of
treatment and to reinforce its importance through-
out treatment contributes to suboptimal outcomes.
Relatively inexpensive and simple interventions can
make a difference. Patients who received a brief psy-
choeducation program combined with antidepres-
sant medication had a significantly higher response
rate (74%) compared with those who received “usu-
al care” (44%).3 These studies highlight the bene-
fits of spending time with patients, exploring their
beliefs about depression and antidepressants, and
in providing simple “messages” about delayed on-
set of antidepressant action, expected early and late
side effects, as well as the importance of continuing
treatment beyond response.
◆ Personality dimensions
Personality variables also significantly influence a
wide range of treatment-related issues. Different
personality dimensions are easily assessed using a
self-report measure such as the Eysenck Personali-
SELECTED ABBREVIATIONS AND ACRONYMS
5-HT 5-hydroxytryptamine (serotonin)
DESS discontinuation emergent signs and
symptoms
EPQ Eysenck Personality Questionnaire
HRSD Hamilton Rating Scale for Depression
MADRS Montgomery-Asberg Depression Rating
Scale
MAOI monoamine oxidase inhibitor
MDE Major Depressive Episode
NE norepinephrine
NEO-PI Neuroticism, Extraversion, and Openness
Personality Inventory
SNRI serotonin and norepinephrine reuptake
inhibitor
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
TCI Temperament and Character Inventory
Shortcomings of current antidepressant therapies – Kennedy

ty Questionnaire (EPQ),4 Temperament and Charac-
ter Inventory (TCI),5 or the Neuroticism, Extraver-
sion, and Openness Personality Inventory (NEO-PI).6
Although few in number, several studies have eval-
uated the influence of personality on help-seeking
behavior, symptom presentation, compliance, and
ultimately treatment outcomes. In most cases, neu-
roticism and extraversion account for differences
in depressed patients.
For example, men in an urban setting who have
a low level of neuroticism and an external attribu-
tional style are less likely to seek help than men with
higher levels of neuroticism.7 With regard to symp-
tom presentation, a high level of “harm avoidance”
(equivalent to neuroticism) in both men and women
has been shown to predict higher levels of severity,
more physical symptoms including fatigue in de-
pressed patients, while high “novelty seeking” (equiv-
alent to extraversion) is associated with suicide at-
tempts, impaired concentration, and alcohol abuse.8
The influence of neuroticism on side-effect re-
porting was examined in a group of nonpsychiatric
healthy volunteers who received moclobemide or
placebo for 3 weeks under double-blind random-
ized controlled conditions.9 The strongest predictor
of side-effect reporting was baseline neuroticism,
and this relationship increased over time in the
placebo group, but declined in the moclobemide
group, again highlighting the importance of vari-
ables beyond pharmacokinetic and pharmacody-
namic properties of the drug.
The relationship between neuroticism and treat-
ment response has also received considerable atten-
tion. In a large primary care trial involving more
than 300 patients who met diagnostic criteria for
dysthymia, Katon and colleagues10 reported that a
high baseline level of neuroticism was associated
Demyttenaere et al,1 2001 Maddox et al,2 1994
Feeling better 55% Feeling better
Adverse events 23% Adverse events
Fear of dependence 10% Other reasons
Stigma 10% Physician instruction 15%
Lack of effect 10% Lack of effect
Table I. Reasons cited for discontinuation during 12 weeks of anti-
depressant treatment.
with failure to achieve remission, whether treat-
ment involved paroxetine or problem-solving psy-
chotherapy. Although Mulder11 broadly agreed with
this conclusion in the largest systematic review so
far reported, he also noted that personality pathol-
ogy contributed least to outcome prediction in the
better-designed studies.
Importantly, different personality variables can
influence different aspects of the treatment process
in opposing directions. This is particularly true of
extraversion. High baseline scores on extraversion
(particularly the facet identified as gregariousness)
predicted greater symptom reduction during an-
tidepressant treatment,12 while others, using com-
parable measures of extraversion (sensation seeking
or novelty seeking), identified an association be-
Shortcomings of current antidepressant therapies – Kennedy
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
tween high scores and decreased compliance.13,14
This is well illustrated in the following case vignette,
where Mr T’s high level of gregariousness both con-
tributed to an early treatment response and early
drug discontinuation.
Mr T worked in the sales department of a
brewing company. He was a particularly gre-
garious individual. Over a 6-year period, he
had been seen by three different primary care
physicians. On each occasion, he presented
with typical symptoms of a major depressive
episode. For him, the most prominent symp-
tom was losing interest in his normally active
social life.
There was also a pattern to his antidepres-
sant usage. Typically, he responded very quick-
ly, often during the first week. He would re-
gain interest in social activities and increase
his success in sales. At about the same time,
he would start to miss doses of his antidepres-
sant medication for days at a time and even-
tually stop altogether.
Only after a detailed discussion about the
potential negative relationship between his
outgoing personality style and medication
compliance did Mr T agree to comply with an-
tidepressant therapy and he has remained well
for the past 2 years.
◆ Comorbid personality disorders
A related question is whether or not patients with
a diagnosis of MDE and a comorbid personality dis-
order have a worse outcome during antidepres-
sant treatment. Using the Diagnostic and Statistical
Manual of Mental Disorder, 3rd Edition, Revised
(DSM III-R) designation of cluster A
(Paranoid, Schizoid, and Schizotypal),
cluster B (Antisocial, Borderline, Histri-
onic, and Narcissistic), and cluster C
35%
(Avoidant, Dependent, and Obsessive-
30%
Compulsive) personality disorder, Fava
17%
and colleagues15 examined the predic-
tive value of personality disorder comor-
15%
bidity in patients who received fluoxe-
tine. There were no differences in rates
of response between patients with or
without a cluster A or C diagnosis, while
the presence of a cluster B diagnosis before treat-
ment predicted a positive antidepressant response.
Almost a decade later, Mulder and associates16 ex-
amined the interaction between antidepressant class
selection (fluoxetine or nortriptyline), personality
disorder (presence or absence) and drug response.
Although the presence of a comorbid personality
disorder did not have an overall effect on outcome,
those patients with a cluster B personality had a sig-
nificantly better response to fluoxetine compared
with nortriptyline.
While others have reported less favorable out-
comes for depressed patients with personality dis-
orders during continuation therapy,17 the weight of
evidence suggests that such comorbidity does not
adversely affect outcome.
MEDICOGRAPHIA, VOL 27, No. 3, 2005 241
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
◆ Severity of illness
Since there is really no consensus on what consti-
tutes “severe depression,” it is difficult to reach a
conclusion about its impact on treatment outcome.
A predetermined baseline score on the Hamilton
Rating Scale for Depression (HRSD)18 such as scor-
ing 24 or higher at baseline on the 17-item HRSD,
or a score above 28 at baseline on the Montgomery-
Asberg Depression Rating Scale (MADRS),19 are fre-
quently applied criteria for “severe depression.” It
must be pointed out, however, that different symp-
tom weighting on these scales (eg, there are 3 sleep
items on HRSD and 1 sleep item on MADRS) may
result in some patients being considered “severe”
on one scale, but not on another.
Nil
Other
Inconvenient dosing
Poor long-term control
Side effects
Poor predictability of response
Slow onset of action
0 5 10 15 20 25 30 35 40 (%)
Figure 1. Physician-reported preferences for antidepressants: the most significant
disadvantage of the most frequently prescribed antidepressant.
Modified from reference 39: Wade AG. A holistic evaluation of attitudes to depression. Poster presented
at the DURG 16th Annual Meeting; London, UK, 2005. Copyright ©, Drug Utilisation Research Group
(UK & Ireland).
Relatively few studies have been designed to ex-
amine the relationship between severity of symp-
toms and preferential drug response, although it
is generally believed that antidepressant treatments
are less likely to prove superior to placebo in pa-
tients with low pretreatment scores.20,21 Clinical im-
pression that moclobemide is less effective in severe
depression was initially supported in a global re-
view of moclobemide trials, in which imipramine
was superior to moclobemide in the group with
baseline HRSD scores of 28 or higher,22 but not con-
firmed in a subsequent analysis using the same
drug.23 Greater efficacy in more severely depressed
patients is a desirable characteristic of any antide-
pressant. Khan and colleagues24 have also examined
the relationship between severity of depressive
symptoms and response to a range of selective sero-
tonin reuptake inhibitor (SSRI) antidepressants,
venlafaxine, nefazodone, and placebo. Pretreatment
severity was assessed using the 17-item HRSD, and
patients were categorized into 4 groups according
to baseline scores. The drug-placebo difference from
baseline to end of treatment (effect size) was pro-
gressively greater as baseline severity increased.
◆ Melancholic and psychotic features
Other considerations that likely overlap, but are not
synonymous with severity, include inpatient status
and the presence of psychotic or melancholic fea-
242 MEDICOGRAPHIA, VOL 27, No. 3, 2005
tures. While most would agree that a diagnosis of
MDE with psychotic features warrants different
treatment interventions, including combination an-
tidepressant-antipsychotic medications or an early
intervention with electroconvulsive therapy,25 there
is less consensus on the relevance of melancholia.
In a natural practice setting, where patients com-
pleted standard diagnostic and severity measures,
melancholic patients had lower response rates to
paroxetine, sertraline, and venlafaxine compared
with nonmelancholic patients (48% vs 61%).26 In
this study, there was no difference in rate of re-
sponse among drugs in the melancholic subgroup.
However, there is evidence that TCAs, in particular
clomipramine, were more effective than SSRIs in
treating melancholic depression (see Amsterdam27
for a review). In subsequent trials, venlafaxine was
superior to placebo28 and fluoxetine29 in hospitalized
patients with melancholia. Interestingly, Guelfi and
colleagues30 also reported similar outcomes when
mirtazapine was compared with venlafaxine in hos-
pitalized severely depressed patients with melan-
cholic features.
There are also differences between outpatient and
inpatient groups in their response to TCA and MAOI
antidepressants. In a meta-analysis, Thase and col-
leagues31 reported superior response rates to MAOI
antidepressants compared with TCAs among out-
patients, while the converse was true for inpatients.
Likewise, a group of Danish investigators, using
clomipramine as the active comparator, consistent-
ly reported its superiority over the reversible in-
hibitor of MAO-A, moclobemide,32 as well as two
SSRIs—paroxetine33 and citalopram34 —in studies
involving depressed inpatients. However, a variety
of factors including suicidality, social supports, and
differences in practice patterns across countries,
influences the decision to admit a depressed patient
to hospital.
In summary, shortcomings of current antidepres-
sant therapies need to be considered in the context
of treatment adherence, distinct patient profiles in-
cluding personality differences, and illness severi-
ty. One or more of these variables often contribute
to poor treatment outcome.
Unmet needs with current
therapeutic choices
The widespread use of SSRIs to treat patients with
depression in primary care and specialist settings
represents a significant advance in managing one
of the most functionally disabling and frequently
comorbid medical conditions.35,36 With greater safe-
ty and tolerability compared with TCA and MAOI
agents, compliance with SSRI and newer antide-
pressants during acute and maintenance phases has
improved, and the percentage of depressed patients
who are hospitalized for treatment continues to
decline.37 Even so, there are still considerable lim-
itations to SSRI and dual action (duloxetine, ven-
lafaxine, bupropion, milnacipran, and mirtazapine)
antidepressant agents.
The “therapeutic lag” between initiating treat-
ment and achieving clinically meaningful effects
Shortcomings of current antidepressant therapies – Kennedy
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

can still be 3 to 4 weeks.38 Physicians across Europe Weight gain and sexual dysfunction are probably
identified slow onset of action as the most problem- the most unacceptable long-term side effects for
atic issue in current antidepressant therapy, but many patients. Since there are no randomized mul-
also highlighted side effects and predictability of tiple drug, placebo-controlled trials from which to
response as significant shortcomings of current derive comparative rates of side effects, it is neces-
agents (Figure 1).39 There is no overall increase in sary to rely on drug-placebo differences in side ef-
the percentage of responders to SSRIs compared fect reports as a crude method to compare different
with TCAs,40 with a full third of patients in most antidepressants.
clinical trials showing an unsatisfactory response ◆ Selective serotonin reuptake inhibitor antide-
and less than 50% achieving full symptomatic re- pressants
mission.26,41 Greater tolerability and easy once-daily dosing have
contributed to the widespread adoption of SSRIs as
◆ Therapeutic delay first-line therapy. There are six SSRIs available to
Antidepressants with a faster onset of action would treat depression in most countries: citalopram, es-
offer significant benefits to patients. A rapid im- citalopram, fluoxetine, fluvoxamine, paroxetine, and
provement in sleep would reduce the need for co- sertraline. All of these agents block the reuptake
prescription of hypnotic medications and may de- of serotonin, but with differing degrees of selectiv-
crease suicidal ideation in the critical early weeks ity and potency. Gastrointestinal side effects, espe-
of treatment. Although serotonin reuptake occurs cially nausea, are common during the first 1 to 2
almost immediately after antidepressant adminis- weeks of treatment, but usually remit while other
tration, onset of antidepressant action is often 2 to central nervous system effects including alterations
3 weeks later. This coincides with the 2-to-4 week to sleep architecture may persist. Relative frequen-
latency for adaptational downregulation of presy- cies of side effects are reported in Table II.
naptic 5-HT1A receptors, which results in a net in- ◆ Dual action antidepressants
crease in 5-HT release to frontal cortex and limbic Venlafaxine, milnacipran, and duloxetine inhibit
areas.42,43 This latency has also been linked to hippo- both 5-HT and norepinephrine (NE) reuptake, while
campal neurogenesis and other molecular changes mirtazapine acts on both systems through indirect
in gene expression associated with antidepressant noradrenergic mechanisms. The side effects asso-
treatment.44
Based on understanding of 5-HT1A
neurophysiology, pindolol, a 5-HT1A Incidence of side effects
Antidepressant
antagonist and β-blocker, has been ≥30% ≥10%
administered with various SSRIs to
accelerate and augment the effect of Citalopram None Drowsiness, sedation Sweating
SSRIs via blockade of 5-HT1A autore- Escitalopram* Insomnia Tremor
ceptors. Although results have been Headache GI† distress
Asthenia, fatigue Sexual disturbances
inconsistent, this may be partly ex- Dry mouth
plained by differences in patient char-
acteristics. An accelerated response Fluoxetine Sexual disturbances Drowsiness, sedation Dry mouth
was seen in previously untreated pa- Insomnia Tremor
tients, with a relatively short duration Disorientation/confusion Orthostatic hypotension/
and low severity of depression and few Headache dizziness
Asthenia, fatigue GI distress
prior episodes (see review by Segrave
and Nathan45). A further explanation of Fluvoxamine GI distress Drowsiness, sedation Dry mouth
the inconsistent results obtained with Sexual disturbances Insomnia Constipation
pindolol relates to adequacy of the usu- Excitement, hypomania Sweating
ally prescribed dose to bind at 5-HT1A Headache Tremor
sites46). The extent to which mirtaza- Asthenia, fatigue
pine and escitalopram may produce
Paroxetine Sexual disturbances Drowsiness, sedation Sweating
an accelerated response is a matter for Insomnia Tremor
47,48
further exploration. Headache Orthostatic hypotension/
Asthenia, fatigue dizziness
◆ Side effects Dry mouth GI distress
Side effects with SSRIs and dual ac- Constipation
tion agents, although different from
Sertraline GI distress Drowsiness, sedation Dry mouth
those with TCAs, are nevertheless sub- Sexual disturbances Insomnia Tremor
stantial and frequently lead to prema- Excitement, hypomania Orthostatic hypotension
ture drug discontinuation. Anticholin- Headache /dizziness
ergic and cardiovascular side effects
are most prevalent with TCAs, while * Escitalopram is the stereoisomer of citalopram—comparable side effects to citalopram have been reported.
† GI, gastrointestinal.
gastrointestinal and central nervous
system side effects are more problem-
atic with SSRIs. Dual action agents dif- Table II. Frequently reported side effects across selective serotonin reuptake inhibitors (SSRIs).
Modified from reference 53: Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive
fer in side effect profiles according to disorders: IV medications and other biological treatments. Can J Psychiatry. 2001;46(suppl 1):38S-58S. Copyright ©
their mechanism of action. 2001, The Canadian Psychiatric Association.

Shortcomings of current antidepressant therapies – Kennedy MEDICOGRAPHIA, VOL 27, No. 3, 2005 243
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

When structured questionnaires are

Incidence of side effects used to evaluate sexual dysfunction,
Antidepressant 30% to 50% of patients who are treat-
≥30% ≥10%
ed with SSRIs or venlafaxine (compa-
Bupropion None Insomnia Constipation rable duloxetine data are not yet avail-
Excitement, hypomania Sweating able) report impairment of desire and
Headache Tremor orgasm on SSRIs, while bupropion,
Dry mouth GI* distress mirtazapine, and moclobemide cause
Blurred vision significantly less dysfunction (Table
Duloxetine GI distress Drowsiness, sedation Constipation IV).49-51 A potential advantage of the
Insomnia Orthostatic hypotension/ tendency for SSRIs to delay ejacula-
Dry mouth dizziness tion has been demonstrated in the
treatment of premature ejaculation.52
Mirtazapine Drowsiness, sedation Asthenia, fatigue Constipation The development of future antidepres-
Dry mouth Blurred vision
Weight gain (over 6 kg)
sants with favorable effects on sexual
function would be valued by depressed
Nefazodone None Drowsiness, sedation Blurred vision patients and their partners.
Disorientation/confusion Constipation
Headache Orthostatic hypotension/ ◆ Weight gain across antidepressant
Asthenia, fatigue dizziness classes
Dry mouth GI distress
Until recently, weight change received
Trazodone Drowsiness, sedation Asthenia, fatigue Orthostatic hypotension/ minimal attention as an outcome mea-
Dry mouth dizziness sure in antidepressant studies, although
GI distress the tendency for TCA and MAOI agents
to cause substantial weight gain has
Venlafaxine GI distress Drowsiness, sedation Dry mouth
Sexual disturbances Insomnia Constipation been recognized for many years. It is
Excitement, hypomania Sweating estimated that treatment with some
Headache Orthostatic hypotension/ TCAs resulted in a weight gain of ap-
Asthenia, fatigue dizziness proximately 1 kg per month (reviewed
in Kennedy et al53).
* GI, gastrointestinal. While the SSRIs are frequently as-
sociated with modest reductions in
Table III. Frequently reported side effects across dual action agents. weight during the acute phase of treat-
Modified from reference 53: Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive ment, there is some evidence that
disorders: IV medications and other biological treatments. Can J Psychiatry. 2001;46(suppl 1):38S-58S. Copyright © 2001,
The Canadian Psychiatric Association. weight gain may occur during main-
tenance treatment with some, but not
ciated with duloxetine, milnacipran, and venlafax- all, SSRIs.54 Moclobemide and bupropion SR do not
ine are similar to those reported with SSRIs, while appear to be associated with weight gain during
weight gain and sedation are the commonest side maintenance treatment and for some patients may
effects associated with mirtazapine. Nefazodone has be associated with weight reduction. Short-term tri-
weak noradrenergic effects as well as 5-HT2 and als suggest that venlafaxine is weight-neutral; how-
5-HT transporter blockade. It has been withdrawn ever, there is an absence of controlled data on long-
from use in many countries due to rare reports of term weight change.55
liver toxicity. Trazodone is rarely used as an an- Among the currently available SSRI and dual ac-
tidepressant, but also belongs in this group and is tion agents, mirtazapine is most likely to be associ-
often prescribed as a hypnotic in combination with ated with weight gain during acute treatment. This
another antidepressant. Bupropion probably has reflects both histaminergic and 5-HT2C receptor
dual uptake blocking actions on the dopaminergic antagonist properties. During maintenance treat-
and noradrenergic systems. It may cause insomnia ment with mirtazapine, patients who have not ex-
and overarousal. Other side effects are reported in perienced weight gain in the acute phase are un-
Table III. likely to start gaining weight, and those patients

◆ Sexual dysfunction across antidepressant

classes Incidence of sexual dysfunction
Drug-induced sexual dysfunction appears to be more <10% 10%-30% >30%
common in men than women, although levels of
sexual dysfunction are higherin untreated depressed Bupropion Citalopram Fluoxetine
women than in untreated depressed men.49 Preva- Mirtazapine Duloxetine Fluvoxamine
lence rates are lower when studies rely on sponta- Moclobemide Venlafaxine Paroxetine
neous self-report and are higher when specific ques- Nefazodone Sertraline
tions are asked about sexual desire, arousal, orgasm,
and overall satisfaction. Rates of sexual dysfunction Table IV. Frequency of sexual dysfunction during an-
were as high or higher with TCA and MAOI agents, tidepressant treatment.
Modified from reference 61: Kennedy SH, Lam RW, Nutt DJ, Thase
although this issue was usually minimized in the ME. Treating Depression Effectively: Applying Clinical Guidelines.
presence of multiple side effects. London, UK: Martin Dunitz; 2004. Copyright 2004, Martin Dunitz.

244 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Shortcomings of current antidepressant therapies – Kennedy

who initially gained weight are likely to maintain
a plateau after the first few months of treatment.
Nevertheless, for many depressed patients, the pros-
pect of substantial weight gain during antidepres-
sant treatment represents an unacceptable health
burden.
◆ Antidepressant discontinuation emergent
effects
Since the mechanisms of action of reuptake inhib-
itor antidepressants (SSRIs, SNRIs [serotonin and
norepinephrine reuptake inhibitors], and others) in-
volve adaptive downregulation early in the treat-
ment process, it is not surprising that drug discon-
tinuation, particularly abrupt discontinuation,
would result in unpleasant rebound effects. In gen-
eral, the shorter the half-life of the drug, the greater
the likelihood of discontinuation emergent symp-
toms. Such occurrences are not limited to SSRIs or
dual action antidepressants. Cholinergic rebound
was often observed following rapid discontinuation
of amitriptyline or other TCAs with significant an-
ticholinergic effects. Patients reported urinary fre-
quency, headaches, hypersalivation, and diarrhea.
Benzodiazepine withdrawal phenomena have also
been recognized for many decades and include
symptoms of insomnia, nausea, appetite loss, sweat-
ing, and dysphoria.56 Emergent symptoms associat-
ed with drug discontinuation of SSRIs or dual action
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tin Dunitz; 2004.
LIMITES DES TRAITEMENTS ANTIDÉPRESSEURS ACTUELS
efficacité du traitement d’un Épisode Dépressif Majeur (Major Depres-
sive Episode, MDE) est soumise à de nombreuses influences au-delà des
propriétés intrinsèques de tel ou tel médicament. Ces influences com-
prennent les caractéristiques individuelles propres à chaque patient, le profil
sécurité d’emploi/tolérance/efficacité du médicament, ainsi que l’interaction
entre les patients et les soignants. Alors que les antidépresseurs récents ont
permis des avancées considérables en termes de sécurité d’emploi et de tolé-
rance par rapport aux antidépresseurs tricycliques et aux inhibiteurs de la mo-
noamine oxydase (IMAO), l’amélioration du bénéfice thérapeutique n’est pas
probante. Le délai pour l’obtention du bénéfice antidépresseur, le pourcentage
de patients non-répondeurs ou de ceux qui ne présentent pas de rémission, la
persistance d’effets indésirables, et l’apparition d’effets émergents lors de l’ar-
rêt du traitement soulignent les limites des antidépresseurs actuels.
Shortcomings of current antidepressant therapies – Kennedy
 UNMET NEEDS IN
▲
▲ ▲
Siegfried KASPER, MD
Dietmar WINKLER, MD
O Univ Prof Dr Dr hc
Department of General Psychiatry
Medical University of Vienna
AUSTRIA
Seasonal affective disorder:
from diagnosis to treatment
b y D . W i n k l e r a n d S . K a s p e r, A u s t r i a
hysiological functioning of life on earth has
P over eons been influenced by the rising and
setting of the sun. Likewise, it has been known
since ancient times that seasonal changes in the
environment affect humans’ physical and mental
health: Hippocrates of Kos (460-377 BC) and Are-
taeus the Cappadocian (about 150 AD) proposed the
healing powers of sunlight for a range of somatic
illnesses, but also for the state of melancholia.1 The
majority of humans seem to experience seasonal
variations of psychopathological symptoms to some
extent.2 These seasonal changes are of clinical inter-
est if their intensity leads to subjective suffering
and a reduction in psychosocial functioning. Emil
Kraepelin (1856-1926) was one of the first modern
psychiatrists to become aware of a rise in the inci-
dence of affective episodes in manic-depressive pa-
S
easonal affective disorder (SAD, fall-winter depression) is a subtype of
major depressive or bipolar disorder, and has been a subject of psychi-
atric research for over two decades. The prevalence in the general pop-
ulation ranges between 2% and 5% in temperate climates, females are much
more often afflicted by the syndrome. Atypical depressive symptoms with a re-
versed vegetative symptomatology predominate during the depressive episodes
in the darker time of the year, while about one quarter of patients experience
hypomanic (seldom manic) episodes during the successive spring/summer pe-
riod. Bright light therapy (BLT) is generally accepted for depression in SAD, but
psychopharmacological treatment with antidepressants has likewise been found
to be effective and well tolerated. This article reviews the most important patho-
physiological concepts and gives an overview of current diagnostic procedures
and treatment options for SAD.
Medicographia. 2005;27:247-253. (see French abstract on page 253)
Keywords: seasonal affective disorder (SAD); winter depression; light therapy;
antidepressant
Address for correspondence: Prof Siegfried Kasper, Department of General Psychiatry,
Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Wien, Austria
(e-mail: sci-genpsy@meduniwien.ac.at)
Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper
THE TREATMENT OF DEPRESSION
tients in spring and in fall. However, this finding was
not much taken notice of until bright light thera-
py (BLT) was proposed as a possible treatment for
winter depression by Lewy et al,3 followed by the
first systematic study on seasonal affective disorder
(SAD) by Rosenthal et al.4 Scientific research has
been encouraged ever since and has led to the pub-
lication of more than one thousand studies on SAD
and BLT, not only because SAD is clinically impor-
tant, but also because it represents an important
chronobiological paradigm.
Epidemiology
Numerous epidemiological studies have investi-
gated the prevalence of SAD and of its subsyndro-
mal form (s-SAD) in the general population (Fig-
ure 1, page 248).2,5-21 In temperate climates, about
2% to 5% of subjects seem to suffer from SAD, and
the rate of individuals with minor problems dur-
ing the fall-winter period indicating s-SAD is even
higher. A number of reports have documented an
increase in SAD prevalence with northerly lati-
SELECTED ABBREVIATIONS AND ACRONYMS
5-HTTLPR serotonin transporter promoter
repeat length polymorphism
BLT bright light therapy
GSS Global Seasonality Score
HDRS Hamilton Depression Rating Scale
PMDD premenstrual dysphoric disorder
SAD seasonal affective disorder
SIGH-SAD Structured Interview Guide for the
HDRS SAD version
SPAQ Seasonal Pattern Assessment
Questionnaire
S-SAD subsyndromal seasonal affective
disorder
MEDICOGRAPHIA, VOL 27, No. 3, 2005 247
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

USA 64% [5]

USA 42%-50% [6]
USA 42.5% [7]
USA 40% [7]
USA 39% [7]
USA 39% [2]
USA 30%-49% [8]
USA 27% [7]

Finland 60%-70% [9]

Finland 60%-70% [10]
Figure 1. Point prevalence Iceland 62%-67% [11]
of seasonal affective disorder Sweden 55%-58% [10]
(SAD) (dark grey bars)
Sweden 54%-68% [12]
and subsyndromal seasonal
affective disorder (s-SAD) UK 57% [13]
(light grey bars) in the gen- Netherlands 53% [14]
eral population measured in Switzerland 47% [15]
different countries at differ- Switzerland 47% [16]
ent latitudes.2,5-21 Eagles et
Italy 39%-45% [17]
al13 and Ozaki et al18 have
investigated specific popula- Japan 32%-42% [18]
tions. The upper half of the Australia 10%-40% [19]
figure shows studies from Australia 19% [20]
North America,2,5-8 the lower Philippines 15% [21]
half below the dotted line
shows mainly studies from 0% 5% 10% 15% 20%
Europe,9-17 but also from
Asia18,21 and Australia.19,20

Clinical picture in
seasonal affective disorder
100%
The prevalence of SAD is higher in female than in
male patients.24 In most clinical samples, women
80%
outnumber men by about 3.5:1 to 9:1,25 which is by
far higher than the 2:1 ratio commonly found in
nonseasonal depression.26 Psychiatric classification
60%
distinguishes between a winter type of SAD (fall-
winter depression), and summer SAD,27,28 which is
rare and will not be further discussed in this report.
40%
According to most clinical and epidemiological stud-
ies, the majority of patients experience their first
affective episode in their late twenties or early thir-
20%
ties. The symptom pattern found in a clinical sam-
ple of 610 SAD patients is shown in Figure 2.29 Sea-
0%
sonal depressive episodes share the core symptoms
with nonseasonal major depression. Depressed mood
gy

ue

ite

e
or
lit

tit
sio

id
oo

ni

in

et
tig
er

bi

pe
om

av
lib

and reduced drive (subjectively experienced as loss

m

p
en

ita

fa
e

ap

ap
cr
at
rs

of
rt
d

Irr

e
of

se

pe

te
es
ne

im

d
ss

of energy) are reported by almost all patients. How-

es

ra

se

ce
ss

lti
Hy

Lo
in

yt
pr

yd
cu
Lo

ea

du
Da
y,
De

ffi

oh

cr

ever, most SAD patients display a reversed vegeta-

Re
et

Di

In
xi

rb
An

Ca

tive symptom pattern and fulfill the criteria of the

Figure 2. Distribution
of symptoms in a cohort
of 610 seasonal affective
disorder (SAD) patients
from Austria and Ger-
many. Data for generation
of this bar chart are from
Winkler et al.29
tude.22 In fact, the relationship between prevalence
and latitude seems to be more established in North
America.7 The overall prevalence of SAD is consis-
tently higher in North America compared with Eu-
rope. In contrast, prevalence rates have been found
to be unexpectedly low in Scandinavia, a fact that
might be explained by a natural selection of the pop-
ulation toward increased tolerance of winter dark-
ness.11
SAD is quite frequent in psychiatric populations:
Kasper and Kamo23 examined the rate of seasonal
depression in a sample of inpatients suffering from
major depression. Their survey showed that 11.4%
of patients suffered from a fall-winter pattern of feel-
ing worse similar to that of patients with SAD.
atypical feature specifier of DSM-IV-TR.30 Symptoms
of atypical depression include hypersomnia, day-
time fatigue, heaviness in the limbs (termed “lead-
en paralysis”), increased appetite, changed eating
habits (mostly cravings for carbohydrates or fatty
foods), weight gain, and interpersonal rejection sen-
sitivity. In contrast, melancholic depression, which
is more often found in patients with nonseasonal
depression, is characterized by markedly depressed
mood, complete loss of pleasure, reduced appetite,
and, consecutively, loss of weight, insomnia (diffi-
culty falling asleep, waking up several times during
the night and in the early morning hours), feelings
of guilt, and psychomotor agitation or retardation.
About three quarters of patients report increased ir-
ritability,29 and many SAD patients suffer from anger

248 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

Table I. Diagnostic criteria for a major depressive episode

◆ A. At least five of the following symptoms have been present during the same
two-week period, nearly every day, and represent a change from previous
functioning. At least one of the symptoms is either (1) depressed mood
or (2) loss of interest or pleasure.
NOTE: Do not include symptoms that are clearly due to a general medical
condition, or mood-incongruent delusions or hallucinations
(1) Depressed mood (or alternatively can be irritable mood in children
and adolescents)
(2) Markedly diminished interest or pleasure in all, or almost all, activities
(3) Significant weight loss when not dieting or weight gain or decrease
or increase in appetite
(4) Insomnia or hypersomnia
(5) Psychomotor agitation or retardation
(6) Fatigue or loss of energy
(7) Feelings of worthlessness or excessive or inappropriate guilt
(8) Diminished ability to think or concentrate, or indecisiveness
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or a specific
plan for committing suicide
◆ B. The symptoms are not better accounted for by a mood disorder due to a
general medical condition, a substance-induced mood disorder, or bereave-
ment (normal reaction to the death of a loved one)
◆ C. The symptoms are not better accounted for by a psychotic disorder like
schizoaffective disorder
according to DSM-IV-TR.30
Reproduced from reference 30: American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders, 4th edition,
text revision (DSM-IV-TR). Washington, DC: American Psychiatric
Press; 2000. Copyright © 2000, American Pychiatric Press.
◆ A. Regular temporal relationship between the
onset of major depressive episodes and a
particular time of the year (unrelated to ob-
vious season-related psychosocial stressors)
◆ B. Full remissions (or a change from depression
to mania or hypomania) also occur at a
characteristic time of the year
◆ C. Two major depressive episodes meeting crite-
ria A and B in last 2 years and no nonsea-
sonal episodes in the same period
◆ D. Seasonal major depressive episodes substan-
tially outnumber the nonseasonal episodes
over the individual’s lifetime
Table II. Diagnostic criteria of the seasonal pattern
specifier according to DSM-IV-TR.30
Reproduced from reference 30: American Psychiatric Association.
Diagnostic and Statistical Manual of Mental Disorders, 4th edition,
text revision (DSM-IV-TR). Washington, DC: American Psychi-
atric Press; 2000. Copyright © 2000, American Pychiatric Press.

attacks, consisting of intense spells of inappropri-

ate anger or rage.31 Furthermore, nearly half of all
female SAD patients suffer from premenstrual dys-
phoric disorder (PMDD).32 The severity of seasonal
depressive episodes ranges mostly between mild and
moderate. However, severe depression, occasional-
ly with suicidal ideations requiring inpatient treat-
ment, is possible. About one quarter of SAD patients
suffer from bipolar affective disorder with hypoman-
ic or (rather seldom) manic episodes during spring
or summer in addition to depressive symptoms dur-
ing the fall-winter period.
Diagnostic procedure
As SAD is either a form of recurrent major depres-
sive or bipolar disorder with onset and remission
of the affective episodes at a specific time of the year,
patients have to fulfill the diagnostic criteria of these
disorders (see Table I 30 for the diagnostic criteria
for major depression). According to the Diagnostic
and Statistical Manual of Mental Disorders, Fourth
Edition, Revised (DSM-IV-TR), it is possible to ap-
ply a seasonal pattern specifier to diagnose SAD
(Table II).30
The Global Seasonality Score (GSS), which is
calculated from the Seasonal Pattern Assessment
Questionnaire (SPAQ),33,34 has frequently been used
to assess the degree of seasonal change in psycho-
pathology in the past. According to the Rosenthal
criteria, patients have to obtain a GSS of at least 10
to qualify for SAD. Furthermore, the overall degree
of impairment during the worst time of the year
has to be at least “moderate” to establish the diag-
nosis. This is the most important difference between
SAD and s-SAD.35,36 Patients with the subsyndromal
form report differences in several psychopatholog-
ical items, however they experience no or only mild
◆ 1. A history of some difficulty during the winter months that had
occurred on a regular basis (at least two consecutive winters)
and had lasted for a sustained period of time (at least 4 weeks).
Examples of these difficulties are decreased energy, decreased
efficiency at work (eg, concentration, completing tasks), de-
creased creativity or interest in socializing, and change in
eating habits (eg, eating more carbohydrates), weight (gaining
weight), or sleep patterns (more sleep)
◆ 2. Subjects have to regard themselves as normal, ie, not suffering
from an illness or disorder
◆ 3. They have not sought medical or psychological help specifically
for the above difficulties, nor has anyone else suggested that
they do so
◆ 4. People who do not know them well do not recognize that they
have a problem, or if they do, easily attribute it to circum-
stances such as “flu” or “overwork”
◆ 5. The symptoms experienced by the subjects have not disrupted
their functioning to a major degree, eg, calling in sick several
times per winter, or severe marital discord
◆ 6. No history of major affective disorder in wintertime
◆ 7. No serious medical illness
Table III. Diagnostic criteria for subsyndromal seasonal affective disorder
(s-SAD) according to Kasper et al.35
Reproduced from reference 35: Kasper S, Rogers SL, Yancey A, Schulz PM, Skwerer RG,
Rosenthal NE. Phototherapy in individuals with and without subsyndromal seasonal affec-
tive disorder. Arch Gen Psychiatry. 1989;46:837-844. Copyright ©, 1989 JAMA & Archives.
difficulties during fall and winter. The diagnostic
criteria for s-SAD are presented in Table III.35 To ex-
amine the severity of seasonal depression, a mod-
ified version of the Hamilton Depression Rating
Scale (HDRS) has been recommended: the Struc-
tured Interview Guide for the HDRS–SAD version
(SIGH-SAD), which contains 29 items and covers
not only melancholic symptomatology of depres-
sion, but also contains 8 items for atypical depres-

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UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
sive symptoms, which are frequently found in SAD.
For many patients it takes years until the correct
diagnosis is made: the mean diagnostic latency in
a German-speaking sample was approximately 10
years after the first depressive episode.37 This is still
unacceptably long. However, since the early 1990s,
the diagnostic latency has decreased by about 3
years, probably due to education of medical profes-
sionals and increased awareness of patients.
Pathogenesis of SAD
It is supposed that the shorter photoperiod during
fall and winter triggers the onset of depressive symp-
toms in predisposed individuals. Light is one of the
most important zeitgebers and is able to reliably al-
ter the length and phase of the human circadian
rhythm by affecting the main circadian pacemaker
in the diencephalon, the suprachiasmatic nucleus.
Scientific research has focused especially on the
hormone melatonin (5-methoxy-N-acetyltrypt-
amine), which is produced in the pineal gland and
thought to mediate the photoperiod signal by the
onset and duration of nocturnal secretion. Studies
measuring dim light melatonin onset have found a
phase delay in SAD patients that was successfully
reversed with BLT.38-40 However, there is a subset of
SAD patients who do not display any circadian ab-
normalities, so other mechanisms may also be in-
volved in the pathogenesis of SAD.41
There is converging evidence that alteration of
monoaminergic neurotransmitters, such as sero-
tonin, norepinephrine, or even dopamine, may be
involved in the pathophysiology of SAD. Tryptophan
depletion has been used to selectively reduce the
plasma tryptophan concentration by administration
of a mixture of amino acids free of tryptophan, which
is a precursor of serotonin. Studies using neuro-
imaging techniques have been able to show that
serotonin synthesis is reduced for a few hours in
the human brain after this procedure.42 Additional-
ly, two further studies have demonstrated that SAD
patients in stable remission during summer time43
and after successful BLT44 experience a temporary
depressive relapse after tryptophan depletion. To
investigate the role of norepinephrine in SAD, Neu-
meister et al45 conducted a study comparing the ef-
fects of tryptophan depletion with catecholamine
depletion and sham depletion in SAD patients in
remission with BLT: Both active depletion protocols
resulted in temporary depressive relapses provid-
ing evidence that brain catecholaminergic systems
may also be involved in the mechanism of action of
BLT. Interestingly, another study in SAD was able
to demonstrate that monoamine depletion led to
alterations in several humoral and cellular immuno-
logic parameters, suggesting a potential role of the
immune system in the pathogenesis of the disorder.46
Several neuroimaging studies have investigat-
ed the importance of specific molecular targets in
the pathophysiology of SAD. Binding studies using
123I-β-CIT and single photon emission computed
tomography (SPECT) have found that depression in
SAD is associated with reduced serotonin trans-
porter availability in the thalamus and hypothala-
250 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper
mus.47 A further study was likewise able to show
reductions in the availability of striatal dopamine
transporter binding sites in untreated depressed
SAD patients.48 This study provides evidence that
the dopaminergic systems may also be involved in
the pathogenesis of SAD. However, these findings do
not explain whether lowered availability of mono-
amine transporters in the synaptic cleft represents
a primary defect or an attempt to overcome a state
of possible lowered dopamine/serotonin availability
during a depressive episode.
There is evidence that specific genetic factors may
lead to increased vulnerability for developing SAD.
Genetic association studies have examined the role
of several candidate genes: a number of surveys have
investigated the serotonin transporter promoter re-
peat length polymorphism (5-HTTLPR), but the re-
sults of these studies are inconsistent.49,50 One study
examined the relationship between SAD and PMDD
and found an association between the presence of
PMDD and family history and 5-HTTLPR long/short
allele-heterozygosity in females with SAD.51 PMDD
and SAD may thus share some genetic vulnerabil-
ity factors such as the 5-HTTLPR. A higher rate of
affective disorders in relatives of patients with SAD
and PMDD may be indicative of higher genetic vul-
nerability in this subgroup when compared with pa-
tients with SAD alone. A further interest-deserving
study investigated the association of the 5-HTTLPR
with the DSM-IV clinical subtypes of depression:
Willeit et al52 were able to demonstrate that melan-
cholic depression is associated with the 5-HTTLPR
long allele and atypical depression with the short
allele.
Apart from the 5-HTTLPR several other candidate
genes have been investigated: guanine nucleotide-
binding proteins (G-proteins) have been implicated
in affective disorders, with reports of altered signal
transduction and G-protein levels.53 The higher ac-
tivity T-allele of the G-protein beta-3-subunit C825T
polymorphism has been found to be associated with
SAD54; however, other authors have failed to repli-
cate these findings.55 The investigation of genetic
variations in clock-genes deserves specific attention
as SAD is thought to be a circadian rhythm disor-
der: indeed, Johansson et al56 were able to demon-
strate a significant association between the NPAS2
471 Leu/Ser polymorphism and SAD, and with the
Period3 647 Val/Gly polymorphism and diurnal pref-
erences (morningness-eveningness tendencies). In
conclusion, the results of these genetic association
studies have been most promising so far. However,
each of these studies has to be considered prelim-
inary and replicated in larger samples before defi-
nite conclusions may be drawn.
Treatment of SAD
Even one of the oldest written resources of man-
kind, the Bible, mentions the beneficial effects of
light: “Truly the light is sweet, and a pleasant thing
it is for the eyes to behold the sun.” (Ecclesiastes
11:7). From the first reports of SAD,4,57 bright arti-
ficial light has been proposed as a most promising
therapeutic method. Further studies58,59 have ac-
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

knowledged BLT as the first-line treatment for SAD

(Table IV). Light boxes emitting full-spectrum bright ◆ Intensity of BLT 2500 to 10 000 lux (measured at the level of the eyes
white light of an intensity of 2500 to 10 000 lux in a device of the patient)
distance of 60 to 80 cm have been most frequently
◆ Wavelength Full spectrum of visible light (no ultraviolet component)
used for BLT. Patients have to be instructed to use
BLT for half to 1 hour on a daily basis during the ◆ Distance from The patient should remain seated at about 60 to 80 cm
whole fall and winter season. The duration of treat- light source from the light source
ment can be gradually increased to 2 hours and 1/2
◆ Duration to 2 hours per day (depending on the intensity of
more per day in case of partial or insufficient re- the light source); from fall to spring on a daily basis
sponse. It has been demonstrated that the antide-
pressant effect of BLT is higher when it is used in ◆ Daytime Morning BLT exceeds the efficiency of evening BLT
the morning.60,61 BLT has a very high acceptance
◆ During light Patient can be active in a seated position, but should
among patients; side effects are mostly mild and
therapy maintain the therapeutic distance to the light source
transient and rarely lead to discontinuation of ther-
apy (Table V).62-67 The combination of BLT with oth- ◆ Latency to thera- 3 to 7 days until onset of antidepressant action
er nonpharmacological treatment approaches, such peutic response
as therapeutic sleep deprivation,68 has been recom-
mended to increase its efficacy. In spite of the sig- Table IV. Guidelines for
nificance of BLT, it is also important to recognize the use of bright light
62,63
the limitations: Pjrek et al69 reviewed the clinical ◆ Common side effects therapy (BLT) for sea-
– Headache sonal depression.
course of 553 SAD patients and found that only
about half of them were sufficiently treated with BLT – Eye strain, vision problems
as monotherapy. Forty-nine percent of patients in – Insomnia
this study received psychopharmacological medi- – Irritability
cation and 35.4% had to be treated with antidepres- – Agitation, restlessness
sants in addition to BLT. – Nausea
Despite the clinical importance of antidepressants – Photophobia
and in contrast to the numerous reports of BLT,
there have been relatively few studies on the effica- ◆ Rare side effects (casuistic reports)
cy of psychopharmacological medication for SAD.70,71 – Hypomania64
To our knowledge, there is only one placebo-con- – Suicidal ideations65
Table V. Adverse
trolled trial on the selective serotonin reuptake in- – Menstrual disturbances66 effects associated
hibitor (SSRI) sertraline72 that has been able to suc- – Retinal damage? (no certain proof until now)67 with bright light
cessfully confirm the superiority of the compound therapy.62-67
under consideration. Some other trials, like the
study of Lam et al73 on fluoxetine or that of Ling-
◆ Prior positive response to antidepressants or
jaerde et al74 on moclobemide have shown a higher mood stabilizers
rate of responders or more rapid remission of atyp-
ical symptoms, respectively. However, these results ◆ Bipolar disorder (phase prophylaxis, treatment
are not statistically significant due to small sam- of acute manic or hypomanic episodes)
ple sizes and a very high rate of placebo responders, ◆ Melancholic features specifier (predicts non-
which is a common methodological issue in sam- response to bright light therapy [BLT]80)
ples mostly consisting of patients with mild-to-mod-
◆ Severe subtypes of depression (eg, psychotic)
erate depression. Besides, there have been several
case reports and open studies investigating the use- ◆ History of recurrent depression in the moderate-
fulness of different antidepressant drugs, eg, citalo- to-severe range (need for psychopharmaco-
pram,75 Hypericum extract,76,77 mirtazapine,78 and logic long-term treatment?)
reboxetine.79 Table VI 80 summarizes potential indi- ◆ High suicide risk (assess the need for hospitali-
cations for pharmacological treatment of SAD. zation, avoid tricyclic antidepressants to pre-
While there is at least a scientific basis for the vent overdose)
treatment of SAD with a unipolar course of illness, ◆ Marked impairment in occupational functioning,
a search of the available literature reveals a lack of in usual social activities, or in relationships
studies on specific psychopharmacological treat- with others Table VI.
ment for bipolar SAD. Furthermore, few bipolar Indications for
◆ Patient preference pharmacotherapy
SAD patients are willing to accept treatment with in patients with
phase prophylactic medication.69 However, in the ◆ Intolerable side effects of BLT seasonal affective
absence of controlled trials it seems reasonable to disorder (SAD).
adapt guidelines for the treatment of nonseasonal
bipolar affective disorder 81,82 for bipolar SAD. Conclusions
Recently, there have been reports on the use of
transcranial magnetic stimulation (TMS) in patients SAD is a rather frequent psychiatric disorder in the
with SAD.83 While these preliminary data suggest general population,2 but it is inadequately identi-
that TMS is effective and lacks major side effects, fied, with a diagnostic latency of about 10 years af-
future studies have to evaluate the importance of ter the first depressive episode. Besides, seasonal
this method in the clinical management of SAD. changes in mood also impair social functioning and

Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper MEDICOGRAPHIA, VOL 27, No. 3, 2005 251
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
reduce patients’ performance at work.84 SAD, in its
most frequent manifestation, fall-winter depression,
is characterized in most cases by reverse vegetative
symptoms such as increased appetite, carbohydrate
craving, hypersomnia, daytime fatigue, and loss of
energy. However, the most important clinical feature
is that patients feel worst in the fall-winter months,
ie, in the time of light deficiency. Changes in hor-
monal and monoaminergic neurotransmitter func-
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252 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper
tion as well as an underlying genetic predisposition
have been implicated in the pathogenesis of SAD.
Antidepressant psychopharmacotherapy is used for
the treatment of SAD depression similar to other
forms of depression; however, BLT is now recog-
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search should aim at investigating specific treat-
ment options for SAD patients with a bipolar course
of illness. ❒
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66. Pjrek E, Winkler D, Willeit M, Konstantinidis A, Thierry N,
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RM. Ophthalmologic examination of patients with seasonal affec-
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of light treatment with citalopram in winter depression: a longitu-
dinal single case study. Int Clin Psychopharmacol.1992;7:109-116.
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the treatment of seasonal affective disorders. J Geriatr Psychia-
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Hypericum extract. Pharmacopsychiatry. 1997;30(suppl):89-93.
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ter A, Kasper S. Reboxetine in seasonal affective disorder: an open
trial. Eur Neuropsychopharm. 2001;11:1-5.
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sponse and nonresponse to light treatment for winter depression.
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81. American Psychiatric Association. Practice Guideline for the
Treatment of Patients With Bipolar Disorder [Revision]. Am J
Psychiatry. 2002;159:1-50.
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sensus Group on Bipolar I Depression Treatment Guidelines (Aca-
demic highlights). J Clin Psychiatry. 2004;65:569-579.
83. Konstantinidis A, Heiden A, Stastny J, et al. Rapid transcra-
nial magnetic stimulation (r-TMS): a novel treatment option for
seasonal affective disorder (SAD)? Eur Neuropsychopharm. 2002;
12(suppl):252.
84. Booker JM, Roseman C. A seasonal pattern of hospital med-
ication errors in Alaska. Psychiatry Res.1995;57:251-257.
TROUBLE AFFECTIF SAISONNIER :
DU DIAGNOSTIC AU TRAITEMENT
L
e trouble affectif saisonnier (TAS, ou « blues de l’hiver ») est un sous-
type de la dépression majeure ou du trouble bipolaire qui fait l’objet de
recherches en psychiatrie depuis plus de 20 ans. La prévalence dans la
population générale varie entre 2 % et 5 % dans les pays à climat tempéré, les
femmes étant beaucoup plus souvent touchées par le syndrome. Des symptômes
dépressifs atypiques accompagnés d’une symptomatologie végétative inversée
prédominent pendant les épisodes dépressifs au cours de la période obscure de
l’année, tandis qu’un quart des patients environ présentant des épisodes hypo-
maniaques (rarement maniaques) pendant la période printemps/été. La lumi-
nothérapie est généralement admise comme traitement de la dépression du TAS,
mais le traitement psychopharmacologique par les antidépresseurs s’est éga-
lement montré efficace et bien toléré. Cet article passe en revue les concepts
physiopathologiques les plus importants et donne un aperçu des méthodes dia-
gnostiques actuelles ainsi que des options thérapeutiques pour les TAS.
MEDICOGRAPHIA, VOL 27, No. 3, 2005 253
UNMET NEEDS IN THE TREATMENT OF DEPRESSION

ipolar disorder (manic-depressive illness) is

B a chronically recurring subtype of mood dis-

orders with considerable psychiatric and med-
ical comorbidity. As contrasted with the diagnosis
▲ and treatment of nonbipolar depression, which of-
David J. KUPFER, MD ten occurs in the primary care sector, the treatment
Ellen FRANK, PhD
Department of Psychiatry of bipolar disorder has often required great diag-
University of Pittsburgh School of Medicine nostic skill and sophisticated therapeutic interven-
Western Psychiatric Institute and Clinic tions by specialists. Even among specialists bipolar
Pittsburgh, Pa, USA
disorder is routinely not recognized or misdiag-
nosed.

Diagnostic characteristics
and potential etiology

As shown in Figure 1, bipolar disorder can be char-

acterized by varying degrees of symptomatology in

Trends in diagnosis several symptom domains: the manic mood and be-
havior domain, the psychotic symptom domain, the
dysphoric or negative mood and behavior domain,

and treatment and the cognitive dysfunctioning domain. Not ev-

ery one of the symptoms within a domain is pres-
ent at the same time; however, it is important to
recognize that symptoms from each of these do-
of bipolar disorders mains may be present at the same time, along with
neurovegetative symptoms including changes in
sleep, appetite, and energy. Indeed, some experts
argue that bipolar disorder always presents with a
by D. J. Kupfer symptom picture that is mixed to a greater or less-
er extent. Generally, however, the major symptom
and E. Frank,USA set in each of these domains leads to the diagnosis
of a particular phase of the disorder, usually con-
sidered to be mania with psychosis or without
psychosis, depression with or without psychosis, or

B
ipolar disorder (manic-depressive illness) is a chronically recurring sub- a fully mixed state. The Diagnostic and Statistical
type of mood disorders that is associated with considerable psychiatric Manual of Mental Disorders, 4th Edition (DSM-IV)
and medical comorbidity. Psychiatric comorbidity, such as alcohol or nosology lays out criteria for the diagnosis of bipo-
drug abuse, anxiety, and panic disorder adversely influences outcomes. Medi- lar I disorder, bipolar II disorder, cyclothymic disor-
cal disease and medical risk factors are common in bipolar disorder and lead der, and also bipolar disorder, not otherwise speci-
to even greater morbidity and mortality in this population. Associated with a fied (NOS). In a similar fashion, a diagnosis of bipolar
high rate of suicide, bipolar disorder is a potentially lethal disease. In consid- spectrum disorder is included to subsume all pa-
ering appropriate interventions for bipolar disorder, it is easiest to group them tients who meet DSM-IV criteria for one of the above
as treatment of acute mania or mixed states, treatment of acute depression, and diagnoses, as well as some patients who do not meet
treatment for the prevention of both manic and depressive recurrence. Mono- the criteria for either mania or hypomania. As
therapy, usually in the form of lithium, valproate, or one of the atypical anti- shown in Figure 2, the age of onset for bipolar dis-
psychotic medications, is initially recommended for the treatment of mania order is much earlier than previously assumed. In
and mixed states. The treatment of acute depression is generally longer and a 3000-person cohort who were self-identified as
more difficult than mania. Many expert clinicians have recommended opti- having bipolar disorder,1 the onset appears to peak
mization of a mood stabilizer and, if this strategy is ineffective, adding an anti- between the ages of 15 and 19. This report is con-
depressant to the mood stabilizer. Mood stabilizer monotherapy was once con- sistent with other new data sets suggesting that,
sidered the ideal maintenance treatment; however, considerable attention has with or without comorbid psychiatric disease, bipo-
now been devoted to the conduct of controlled trials of atypical antipsychotic lar disorder first appears much more frequently now
medications in the maintenance phase. In considering future trends, the in- in the teen years and in the twenties.
creased use of atypical antipsychotics and their possible efficacy, not only for Given the often confusing range of symptoms as
stabilization of mania, but for depressive symptomatology, is an important well as the early onset, it is not surprising that bipo-
area of further investigation. Furthermore, the use of agents with a regulatory lar disorder is often unrecognized or misdiagnosed,
effect on biological rhythms deserves further exploration. and consequently mismanaged. In one study, 69%
Medicographia. 2005;27:254-260. (see French abstract on page 260) of the 600 respondents were initially misdiagnosed.2
These patients waited almost 10 years to receive the
Keywords: bipolar disorder; atypical antipsychotic; mania; depression; correct diagnosis, with an average of 3.5 prior mis-
maintenance treatment diagnoses. Nonbipolar depression diagnoses were
made 60% of the time, followed by anxiety disorder.
Failure to recognize and treat bipolar disorder adds
Address for correspondence: David J. Kupfer, MD, Department of Psychiatry, Western Psychiatric
Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, to the huge clinical and human costs associated
PA 15213, USA (e-mail: kupferdj@upmc.edu) with this disorder.

254 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank
 UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

Another major feature of bipolar disorder is the

level of psychiatric and medical comorbidity. Com-
munity-based studies indicate that 60% to 70% of Manic mood and behavior Dysphoric or negative
◆ Euphoria mood and behavior
individuals with bipolar illness meet diagnostic cri- Depression
◆ Grandiosity ◆
teria for a lifetime history of substance abuse or de- ◆ Pressured speech ◆ Anxiety
pendence.3,4 The risk for alcohol or drug abuse is 6 ◆ Impulsivity ◆ Irritability
to 7 times greater in patients with bipolar disorder ◆ Excessive libido ◆ Hostility
than would be expected in the general population.5 ◆ Recklessness ◆ Violence or suicide
◆ Social intrusiveness
A more recent investigation from the Stanley Foun- ◆ Diminished need for sleep Bipolar
dation Bipolar Network reports 2 to 3 times the pop- disorder
ulation rate of alcohol abuse in men with bipolar Cognitive symptoms
disorder and 7 times the frequency in women.6 ◆ Racing thoughts
Among other psychiatric comorbidities, anxiety, Psychotic symptoms ◆ Distractibility
panic disorder, and panic spectrum disorder are ◆ Delusions ◆ Disoganization
◆ Hallucinations ◆ Inattentiveness
common and adversely influence bipolar outcomes.
Angst and colleagues have reported that the asso-
ciation with panic is greater in patients with bipo- Figure 1. Bipolar disorder symptom domains.
lar disorder than in patients with major depression
(J. Angst, personal communication). Panic and oth- intervention. As highlighted recently,13 progress has
er forms of anxiety significantly delay remission of been made in understanding the role of genetics
acute bipolar episodes.7,8 The presence of somatic in bipolar disorder and complemented by findings
symptoms in bipolar disorder, particularly cardio- from the neuroimaging field, both functional mag-
vascular symptoms, is increased in the presence of netic resonance imaging (fMRI) and structural
panic disorder. McElroy and colleagues9 have high- imaging. First, studies repeatedly confirm that bi-
lighted the frequency of eating problems in bipolar polar disorder has extremely high heritability.14 Sec-
disorder, including symptoms of bulimia nervosa ond, they demonstrate increased frequency of bipo-
and, in particular, binge eating. lar disorder in family members, but also of other
Associated with a high rate of suicide, bipolar dis- disorders that are primarily psychotic disorders
order is a potentially lethal disease.1,10,11 Medical dis- (schizoaffective disorder and schizophrenia).15 Spe-
ease and medical risk factors are present in bipolar
disorder and lead to even greater morbidity and
mortality in this population. The most commonly
30
reported problems are cardiovascular disease, dia-
betes, obesity, and thyroid disease. The accumula-
25
tion of key medical risk factors related to excessive
nicotine use, alcohol and drug use, concomitant
20
anxiety, and eating disorders, lead to the early onset
Percentage

of medical diseases with poor long-term outcomes.

Furthermore, because patients with bipolar disor- 15

der spend most of their time in the depressive phase

of the illness, there is often a loss of the discipline
and motivation required to reduce such medical
risk factors. Katon12 has established the clear rela-
tionship between depression and a host of negative
health behaviors including smoking, poor diet, over-
eating, and sedentary lifestyle and has shown that
depression has a maladaptive effect on adherence
to medical regimens and direct adverse physiolog-
ic effects including decreased heart rate variability
and increased adhesiveness of platelets.
Bipolar I disorder is almost always treated in men-
tal health settings, with patients viewing their psy-
chiatric care as their most important form of med-
ical care. This has led to a relative underrecognition
of and inattention to the many physical diseases
from which these patients suffer. Only recently has
a greater awareness of medical burden and medi-
cal risk factors, stimulated by the introduction of
atypical antipsychotic medication for bipolar I dis-
order with its attendant medical problems, led clin-
icians and investigators to focus on these issues. To-
day there is broad recognition that advances in the
treatment of bipolar disorder must go together with
increased medical risk factor assessment, ongoing
laboratory surveillance, and integrated treatment
10
5
0
0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45+
Age of first onset (y)
Figure 2. Distribution of bipolar symptom onset by age.
cific chromosomal regions have been identified, but
only 5 out of 16 chromosomal regions currently
meet criteria for significant linkage.13 Complement-
ing this work on genetics, anatomical and MRI neu-
roimaging studies have demonstrated functional
abnormalities of the medial prefrontal cortex.16 Neu-
ropsychological dysfunction, including abnormal-
ities in cognitive and memory activity,17,18 but par-
ticularly in social cognition,19 have been found in
individuals with bipolar disorder. This is consistent
with work of others, including Phillips,20 who has
been particularly interested in alterations in emo-
tional perception. Neurocognitive deficits and, per-
haps, deficits in social cognition may represent, if
not specific, at least consistent findings in bipolar

Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank MEDICOGRAPHIA, VOL 27, No. 3, 2005 255
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N

Psychiatric comorbidity Medical comorbidity

◆ Panic ◆ Obesity
◆ Ethyl alcohol ◆ Thyroid disease
◆ Substance disorders ◆ Diabetes
◆ Personality disorders ◆ Cardiovascular

Psychotic symptoms Manic mood and

Background of social developmental/

◆ Delusions behavior
◆ Hallucinations ◆ Euphoria
◆ Grandiosity
◆ Pressured speech
maturational deficits

◆ Impulsivity
◆ Excessive libido Poor
Early Array of ◆ Recklessness treatment
onset of bipolar disorder ◆ Intrusiveness adherence
illness symptoms ◆ Reduced need
for sleep

Dysphoric or negative
mood and behavior Cognitive symptoms
◆ Depression ◆ Racing thoughts
◆ Anxiety ◆ Distractibility
◆ Irritability ◆ Disoganization
◆ Hostility ◆ Inattentiveness
◆ Violence or suicide

Limited educational Unemployment

attainment and poverty

Figure 3. A model of intervention points for improving treatment outcomes in bipolar disorder.

disorder. The possible linkage of individual genes Treatment paradigms

with neuroanatomical findings and cognitive def-
icits represents a potential cascade of processes deal-
ing with gene-environmental interaction, similar
to the research ongoing in the area of schizophre-
nia.21
A second area of interest in bipolar disorder has
emerged from the long-standing research in bio-
logical rhythms and bipolar disorder. Ehlers and
colleagues22 hypothesized that biological dysregu-
lation, both at the level of neurobiology and also at
the level of social rhythms, may be responsible for a
cascade of events leading to episodes of mania and
depression and proposed a “social zeitgeber theo-
ry,” to explain the onset of bipolar disorder.23 In sup-
port of this concept, Malkoff-Schwartz and others24
demonstrated that events associated with changes
in social routines were common prior to the onset
of a manic episode. The social rhythm disruption
concept led to the design and implementation of a
psychosocial intervention specifically tailored for
the treatment of bipolar disorder that has been de-
veloped both from interpersonal psychotherapy 25
and social rhythm theory.26 Consistent with this bi-
ological rhythms perspective, a host of biological
clock genes has been studied in both families and
patients with bipolar disorder, suggesting a vulner-
ability in certain patient groups or groups at risk for
bipolar disorder.
in bipolar disorder
Once thought of as our “good prognosis” illness in
psychiatry, bipolar disorder has emerged in the last
decade as one of our most significant treatment
challenges. Thinking back to what it must have
been like to try to manage this condition in the pre-
lithium era, it is easy to understand how, once lithi-
um was introduced, the field was lulled into a false
sense of complacency. In the late 1980s and early
1990s, however, both naturalistic data27,28 and data
from controlled trials (eg, Prien et al,29 1984) made
it clear that bipolar disorder was not a problem
solved. This led a relatively small group of investi-
gators in the US and abroad to take a renewed in-
terest in developing treatment strategies for bipolar
disorder, both psychopharmacologic and psycho-
therapeutic.30 As we have entered the 21st century,
we have come to recognize the multiple factors that
complicate the process of achieving ideal outcomes
for those that suffer from bipolar disorder.
Our model for understanding these complexities
is illustrated in Figure 3. According to our model,
the early age of onset typical of bipolar disorder
means that early years spent in coping with the ill-
ness often lead to social developmental/matura-
tional deficits. Future experience of the illness often,
then, takes place against a background of such defi-

256 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank

cits making rational decision-making and coping
with difficult challenges more difficult for the in-
dividual even during euthymic periods. The com-
plexity of the disorder itself (as discussed earlier),
involving as it does an ever-changing mix of psy-
chotic symptoms, dysphoric or negative mood and
behavior, manic mood and behavior, and cognitive
symptoms makes treatment decision-making a con-
stantly ongoing process in which no sooner is a
symptom or group of symptoms effectively ad-
dressed than others appear which require new treat-
ment decisions. Further complicating the picture
are the psychiatric and medical comorbidities com-
monly encountered in bipolar disorder: panic, al-
cohol abuse, substance abuse, and personality dis-
orders (particularly Cluster B disorders) as well as
obesity, thyroid disease, diabetes, and cardiovascu-
lar disease. Each of these comorbidities can have
important impact on treatment decisions. For ex-
ample, we have observed that patients with panic
comorbidity are much more sensitive to medica-
tion side effects, often necessitating lower starting
doses and slower titration of new treatments.8 In
the area of medical comorbidity, those patients with
thyroid disease or diabetes also warrant special clin-
ical attention if their bipolar disorder treatment is
to be benign with respect to these medical condi-
tions. Finally, although treatment adherence is an
issue in all of medicine, it seems to be a particular
challenge for patients with bipolar disorder. As Fig-
ure 3 illustrates, multiple factors in the model in-
cluding the poor judgment brought on by mania or
substance use, the medication sensitivity brought
on by panic comorbidity, and the desire to limit
weight gain in an already obese individual, may all
contribute to the challenges to treatment adherence
in this population. Thought of in this way, there are,
then, a series of potential targets for improving
treatment paradigms for bipolar disorder.
In considering appropriate interventions for bi-
polar disorder, it is easiest to group them as treat-
ment of acute mania or mixed states, the treatment
of acute depression, and the treatment for the pre-
vention or prophylaxis of both mania and depres-
sion in the future (maintenance treatment). The
treatment of acute mania involves the following
aims: the improvement of manic symptoms, possi-
bly requiring rapid tranquillization; the resolution
of manic symptomatology avoiding both the onset
of new depressive symptomatology or the unmask-
ing of depressive symptomatology; and finally, the
consideration of mood stabilization and subsequent
treatment. With respect to rapid tranquillization,
Cookson and others have demonstrated that hal-
doperidol, as well as the new atypical antipsychotics,
have immediate antimanic effects independent of
sedation.31 Other drugs often used in the treatment
of acute mania may not act as quickly and there-
fore have delayed antimanic effects. The American
Psychiatric Association (APA) Guidelines suggest
that for mild mania, lithium or valproate or an atyp-
ical antipsychotic can be utilized.32 For severe ma-
nia, they recommend the immediate combination
of a mood stabilizer and an atypical antipsychotic.
The recent British Guidelines33 conclude that for
Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
less ill manic patients, lithium, valproate, or carba-
mazepine can be administered; for more severe ma-
nia, atypical antipsychotics or valproate are rec-
ommended. For mania associated with psychosis,
atypical antipsychotics are preferred.
Monotherapy is initially recommended to address
manic features. The use of lithium, valproate, as well
as of a number of atypical antipsychotics, including
olanzapine, risperidone, quetiapine, nefazodone, and
aripiprazole is recommended. If patients do not im-
prove on any of these drugs, a number of clinical
specialists have suggested that the addition of olan-
zapine, risperidone, or quetiapine to lithium or val-
proate confers an additional effect, as does the addi-
tion of valproate. The avoidance of major depressive
symptomatology as an outcome in the successful
0.0 Depressed
Mixed/cycling
Manic
Cumulative proportion of patients remitted
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50
Weeks of preliminary phase treatment
*P<0.0001 vs manic; **P<0.001 vs manic; and P<0.05 vs depressive
Figure 4. Bipolar depressive and mixed episodes are difficult to treat.
Reproduced from reference 34: Kupfer DJ, Frank E, Grochocinski VJ, et al. Stabilization in the treatment
of mania, depression and mixed states. Acta Neuropsychiatrica. 2000;12:110-114. Copyright © 2000,
Blackwell Publishing.
resolution of manic symptoms could be helped by
use of antipsychotics, which may have antidepres-
sant effects of their own. It is further recommend-
ed that after acute treatment, on the way to stabi-
lization and maintenance treatment, patients and
family members receive psychoeducation, with par-
ticular emphasis on recognition of early symptoms
of mania. Many clinicians also further recommend
the availability of rescue medication, such as small
doses of an atypical antipsychotic.
The treatment of acute depression is longer and
more difficult than that of mania, as shown in Fig-
ure 4.34 Many expert clinicians have recommended
the initial optimization of a mood stabilizer and, if
this strategy is ineffective, adding an antidepressant
to the mood stabilizer. If this second step does not
work, then there are a variety of recommendations
including adding a second mood stabilizer.35 Re-
cently, it has been shown that an atypical antipsy-
chotic plus an selective serotonin reuptake inhib-
MEDICOGRAPHIA, VOL 27, No. 3, 2005 257
UN M E T NE E D S I N T H E TR E AT M E N T O F DE P R E S S I O N
itor (SSRI) is effective in acute bipolar depression,36
leading to Food and Drug Administration (FDA) ap-
proval of this combination for treatment of bipolar
depression. In considering alternatives involving
mood stabilizers, various controlled trials have sug-
gested that lithium may have antidepressant effica-
cy. Similarly, lamotrigine may possess antidepres-
sant efficacy in acute bipolar depression. Recent
reviews of controlled trials of antidepressants versus
placebo37 have demonstrated a mild positive effect
for antidepressants, accompanied by a relatively low
switch rate from depression to mania with antide-
pressants (except for the tricyclics). Two clinical tri-
als with quetiapine have shown efficacy in acute
bipolar depression (J. R. Calabrese, personal com-
munication). The failure to respond to a mood sta-
bilizer (or an atypical antipsychotic) with or with-
out an antidepressant leads the clinician to consider
substituting another antidepressant or mood sta-
bilizer, as well as the use of electroconvulsive ther-
apy (ECT) and/or adjunctive psychological interven-
tions. Finally, a key unanswered question is how
long one should continue an antidepressant follow-
ing resolution of a bipolar depressive episode. No
guidelines, similar to those available for the treat-
ment of acute unipolar depression, exist.
When we review options for long-term treatment,
one important issue is that we need to deal with the
prevention of both manic and depressive episodes.
Indeed, one could list the therapeutic objectives in
the following manner: to achieve symptom control
of all four domains that have been mentioned pre-
viously; to prevent syndromal recurrence; and to
reduce or oblate all subsyndromal symptomatology
because this is often related to significant function-
al impairment. Finally, it is important to minimize
the risk of cycling, which, when it occurs, makes it
more difficult to treat both the acute manic or de-
pressive state and to manage the illness over the
long term.
Complicating the treatment of bipolar disorder,
both acutely and long term, is the presence of con-
siderable psychiatric and medical comorbidity.
Therefore, a successful long-term treatment ap-
proach will also assist in treating the psychiatric
and medical comorbidities. Underscoring the im-
portance of complete symptomatic relief is the asso-
ciated functional recovery as manifested by return
to work, family, and schooling for younger people.
Another important consideration in maintenance
treatment is a reduction in overall mortality. While
a great deal of appropriate attention has been de-
voted to suicide prevention, bipolar patients also die
of other causes, especially medical disease.38 Con-
sequently, a major goal of maintenance treatment
is to reduce overall mortality. This goal is compli-
cated by the fact that adherence to treatments for
both medical and psychiatric disorders for patients
with bipolar disorder is very poor and, therefore,
we must pay specific attention to treatment adher-
ence principles.
In reviewing the possibilities of long-term treat-
ment in bipolar disorder, at the present time we
have the following information: lithium appears to
be effective for the prevention of manic episodes,
258 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank
but not necessarily depressive episodes39; the data
for valproate for long-term treatment are minimal
despite its wide use40; the data for lamotrigine for
long-term treatment support a specific indication
for the prevention of depressive as compared with
manic episodes.41,42 Recently, attention has been de-
voted to the conduct of controlled trials of atypical
antipsychotics in the maintenance phase. The ma-
jority of such controlled studies have been carried
out with olanzapine, with one recent trial of aripi-
prazole.43 Studies of olanzapine demonstrate supe-
rior efficacy to valproate; and comparisons of olan-
zapine to lithium show an advantage of olanzapine
with respect to study completion.44,45 An olanzapine
versus placebo study for relapse prevention demon-
strated efficacy for olanzapine in preventing relapse
into mania as well as into depression.46 Finally, a
study comparing olanzapine plus lithium or val-
proate versus placebo plus lithium or valproate
showed the advantage of the addition of olanzapine
as compared with placebo, suggesting the possibil-
ity of combined long-term treatment.47 Recently, a
26-week trial comparing aripiprazole to placebo has
been reported demonstrating a significant advan-
tage for this atypical antipsychotic.43
Maintenance treatment should include, at the
minimum, patient management strategies33 con-
sisting of five specific areas: establishment and
maintenance of a therapeutic alliance; education of
patients and their families about the disorder; ef-
forts to enhance treatment adherence; promotion
of awareness of stresses, sleep disturbance, and ear-
ly signs of relapse and regular patterns of activity;
and finally, evaluation and management of func-
tional impairment. Furthermore, targeted psycho-
social interventions are now being studied in the
treatment of bipolar disorder that may be very ap-
plicable to larger groups of patients suffering from
this illness.26,48 Interestingly, these approaches gen-
erally include strong emphasis on improving treat-
ment adherence.
Future trends
In considering future trends, the increased use of
atypical antipsychotics and their possible utility,
not only for stabilization of mania, but for depres-
sive symptomatology, is an important area of fur-
ther investigation. That monotherapy may not be
the optimal way to proceed with patients with bipo-
lar disorder is becoming clearer, making it very like-
ly that an increased emphasis will be placed on com-
bination treatments in the next 5 years. It is hoped
that controlled clinical trials will be available to
guide the clinician. With respect to the treatments
specifically for bipolar depression, it is likely that
a novel serotonin receptor agonist or antagonist
will be used to treat bipolar depression. Some of the
other novel treatments being suggested for unipo-
lar depression may also be useful for bipolar depres-
sion. In assessing the risk-benefit ratio of the use
of any medication in bipolar disorder, it is important
to consider the level of medical risk factors that may
make patients more vulnerable to the adverse effects
of certain atypical antipsychotics and to the devel-

opment of medical diseases. Consequently, patients
with bipolar disorder should receive careful medi-
cal monitoring throughout the period of treatment.
While we have considered the need for new drug
treatment targets, it is also clear that our under-
standing of bipolar disorder will also be facilitated
by paying more careful attention to a better defini-
tion of behavioral phenotypes as well as to identify-
ing markers for intermediate endophenotypes. This
will require the use of pharmacogenomic strategies,
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DIAGNOSTIC ET TRAITEMENT DES TROUBLES BIPOLAIRES :

TENDANCES ACTUELLES

L
e trouble bipolaire (psychose maniacodépressive) est un sous-type des
troubles de l’humeur chroniquement récurrent associé à une considé-
rable comorbidité psychiatrique et médicale. La comorbidité psychia-
trique, telle que l’abus d’alcool ou autres substances, l’anxiété et les troubles
paniques influent défavorablement sur l’évolution. Une affection médicale et
des facteurs de risque médicaux sont fréquents au cours des troubles bipolaires
et conduisent à une morbidité et une mortalité encore plus importantes dans
cette population. Associé à un taux élevé de suicide, le trouble bipolaire est une
maladie potentiellement létale. À la lumière des attitudes thérapeutiques adap-
tées aux troubles bipolaires, il est plus facile de les regrouper en traitement pour
les états maniaques ou mixtes aigus, traitement de la dépression aiguë et trai-
tement préventif de la récurrence dépressive et maniaque. La monothérapie,
habituellement administrée sous la forme de lithium, de valproate ou d’un mé-
dicament antipsychotique atypique, est recommandée dans un premier temps
pour le traitement des états maniaques et mixtes. Le traitement de la dépres-
sion aiguë est généralement plus long et plus difficile que celui des états ma-
niaques. De nombreux cliniciens experts ont recommandé l’utilisation optimisée
d’un régulateur de l’humeur et, si cette stratégie n’est pas efficace, l’associa-
tion d’un antidépresseur au régulateur de l’humeur. La monothérapie par ré-
gulateur de l’humeur était considérée autrefois comme le traitement d’entre-
tien idéal ; toutefois, l’intérêt se porte désormais de plus en plus sur des études
contrôlées de médicaments antipsychotiques atypiques dans la phase d’entre-
tien. L’utilisation croissante des antipsychotiques atypiques et leur possible ef-
ficacité, non seulement pour stabiliser les états maniaques, mais aussi pour la
symptomatologie dépressive, constitue un important champ d’investigation
pour les orientations ultérieures. Enfin, l’utilisation d’agents ayant une action
régulatrice sur les rythmes biologiques mérite d’être explorée plus avant.
✦

260 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank

What are the core symptoms
of depression?
1 ◆ M. P. Deva, Brunei
M. Parameshvara DEVA, MD
FRCPsych, FRANZCP, FAMM
Hon Professor of Psychiatry
UPNG, SSB Hospital
Kuala Belait, KA 1131
BRUNEI
(e-mail: devaparameshvara@
yahoo.com)
2 ◆ T. Partonen, Finland
Timo PARTONEN, MD
Associate Professor of
Psychiatry at the University
of Helsinki, and
Academy Research Fellow
at the National Public Health
Institute
Department of Mental Health
and Alcohol Research
Helsinki, FINLAND
(e-mail:
timo.partonen@ktl.fi)
What are the core symptoms of depression?
C O N T R O V E R S I A L
he problem with core symptoms is the
T availability of acceptable guidelines and
classifications of depressive illnesses. Many
nonpsychiatrist doctors consider any patient who
is distressed as depressed, especially if the patient
is crying! Suicide attempts or parasuicides are
always equated by nonpsychiatrists as depression.
Persons who are irritable and angry and easily
provoked are often seen as either normal or psy-
chotic, but seldom considered to be depressed.
Such looseness in diagnosis leads to injudicious
use and noneffectiveness of antidepressant medi-
cines. Thus, a review of the current concepts in
recognizing depressive illnesses and treating them
is needed. The answer lies in a good history taking
through a good interview of the patient. The core
symptoms include a history of at least 3 weeks
(but usually 6 weeks) of low mood and negative
thoughts, gloomy outlook on everyday topics,
sleep patterns disturbed without reason, lack of
interest in eating, some loss of weight, poor inter-
est in work, recreation, sexual function. To pa-
tients, everything looks gray, hopeless, useless,
they have vague thoughts of leaving their job,
going somewhere else, or even “ending it all.”
epression is heterogeneous in terms of
D etiology and phenotype. Depressions are
many; they vary according to profile and
intensity of symptoms, and course and cause of
illness. Symptoms may be melancholic, atyp-
ical, psychotic, or mild; there may be one or nu-
merous episodes; the course may be recurrent
or chronic; the depression may be reactive or en-
dogenous in nature. Thus, trying to pin down the
core of depression is like peeling an onion. The
essential characteristic of depression is the feel-
ing of loss: the core symptoms of depressive dis-
order are therefore lack of pleasure and sadness,
in other words, anhedonia and depressed mood.
These constitute the key criteria for a major de-
pressive episode, not only in terms of diagnosis,
but also of evolution. However, this point of view
has been challenged by recent findings suggesting
a need to focus on core pathways in the patho-
genesis of illness rather than on manifestations
of individual disorders. Several arguments can be
Q U E S T I O N
Core symptoms of depressive illnesses
Depression is characterized by the following
symptoms, whether in developing countries or
in other countries.
◆ Lowering of mood, volition and outlook. The
patient has a negative outlook, a low mood, a
feeling of loss, of despondency. Everything is col-
orless, negative, gray, and gloomy.
◆ Inability to deal with normal work, play, and
social obligations satisfactorily.
◆ Preoccupation with bodily functions and phys-
ical symptoms. Patients often want their doctor
to prove they have a physical disease that is not
there.
◆ Sleep disturbances. Patients usually report
early morning awakening, but many experience
difficulty in falling asleep.
◆ Disturbances in eating. Patients show a lack
of interest in food and therefore usually lose
weight; occasionally, they eat too much and put
on weight.
◆ In severe and prolonged depressive illnesses
there may be suicidal ideas, a stuporous state. ❒
put forward in favor of this. For instance, depres-
sive disorders and generalized anxiety disorder
tend to be related to the same genetic factors and
may be interpreted as different manifestations of
the same predisposition.1 This predisposition could
involve mutations in the so-called circadian clock
genes and result in errors in regulation of the cir-
cadian pacemaker.2 This would lead to abnormal
circadian rhythms and alteration of the sleep-
wake cycle, resulting in changes in core body
temperature and short latencies to rapid eye
movement (REM) sleep,3-6 the outcome of which
is compromised mood regulation and ultimately,
feelings of depression and anxiety. One way to
look at the question is to analyze the individual
domains that may show differing trajectories rath-
er than the overall severity of depression reflecting
a summation of these domains.7 Severe depres-
sions are characterized by two symptoms only
that commonly occur in both typical and atypi-
cal depressive disorders. These key symptoms—
MEDICOGRAPHIA, VOL 27, No.3, 2005 261
CO N T R O V E R S I A L QU E S T I O N
feelings of depression and loss of interest— are
reported by 9 patients out of 10.8 Are these the
core symptoms of depression? Not necessarily,
since in addition to these two symptoms, severe
typical depression is characterized by difficulty
in concentrating, insomnia, and loss of pleasure.
Moreover, major depressive episodes with a sea-
sonal pattern (seasonal affective disorder) are
frequently accompanied by atypical symptoms of
depression such as prolonged sleep, weight gain,
carbohydrate craving, and increased appetite.9
Nevertheless, a simple two-question screening tool
inquiring about the presence of depressed mood
and anhedonia may be just as effective as a more
complex questionnaire.10 Despite its limitations,
such a screening tool is certainly a useful, more
pragmatic, and less time-consuming method for
detecting depression in the primary care setting.
Specific groups of individuals with depressive dis-
order, including children and adolescents, wom-
en after delivery, and the elderly, need specific
attention in clinical practice, since their clinical
picture may differ, and therefore can be missed by
the usual case-finding instruments, thereby de-
REFERENCES
1. Vollebergh WA, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J.
The structure and stability of common mental disorders: the
NEMESIS study. Arch Gen Psychiatry. 2001;58:597-603.
2. Johansson C, Willeit M, Smedh C, et al. Circadian clock-re-
lated polymorphisms in seasonal affective disorder and their
relevance to diurnal preference. Neuropsychopharmacology.
2003;28:734-739.
3. Schulz H, Lund R. Sleep onset REM episodes are associated
with circadian parameters of body temperature: a study in de-
pressed patients and normal controls. Biol Psychiatry. 1983;18:
1411-1426.
4. Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafael-
sen OJ. REM latency and core temperature relationships in
primary depression. Acta Psychiatr Scand. 1986;74:269-280.
5. Czeisler CA, Kronauer RE, Mooney JJ, Anderson JL, Allan JS.
Biologic rhythm disorders, depression, and phototherapy: a
new hypothesis. Psychiatr Clin North Am. 1987;10:687-709.
6. Schwartz PJ, Rosenthal NE, Kajimura N, et al. Ultradian
oscillations in cranial thermoregulation and electroencephalo-
graphic slow-wave activity during sleep are abnormal in humans
with annual winter depression. Brain Res. 2000;866:152-167.
7. Parker G, Roy K. The development of a six-item daily self-
report measure assessing identified depressive domains. J Affect
Disord. 2003;73:289-294.
8. Sullivan PF, Kessler RC, Kendler KS. Latent class analysis
of lifetime depressive symptoms in the national comorbidity
survey. Am J Psychiatry. 1998;155:1398-1406.
262 MEDICOGRAPHIA, VOL 27, No.3, 2005
flating scores on the routinely administered rating
scales.11-13 For example, depressive elderly persons
with mild cognitive impairment tend to report
sadness, anhedonia, and pessimistic thoughts.14
Self-reports of depression may be of benefit in
terms of both expense and time, and a valuable
substitute for clinician-based ratings in treatment
trials of outpatients with major depressive disor-
der, but no psychotic symptoms or cognitive im-
pairment.15 Global ratings, however, seem to pro-
duce less valid findings than specific item-based
ratings. To ensure optimal control of the core
symptoms of depression, an antidepressant should
have mood-lifting and energizing effects, in other
words it needs to achieve elation and activation.
Rapid relief from anxiety and insomnia are nat-
urally of great help for a good outcome. In the
long run, the patient will recover feelings of plea-
sure and optimistic thoughts. However, it is neces-
sary to realize that no treatment—not even the
most potent one—stands a true chance of success
if resources in terms of health-care professionals
are insufficient to ensure an adequate follow-up
of patients suffering from depression.16 ❒
9. Partonen T, Lönnqvist J. Seasonal affective disorder. Lancet.
1998;352:1369-1374.
10. Whooley MA, Avins AL, Miranda J, Browner WS. Case-find-
ing instruments for depression: two questions are as good as
many. J Gen Intern Med. 1997;12:439-445.
11. Timbremont B, Braet C, Dreessen L. Assessing depression
in youth: relation between the Children’s Depression Inventory
and a structured interview. J Clin Child Adolesc Psychol.
2004;33:149-157.
12. Teissedre F, Chabrol H. Detecting women at risk for post-
natal depression using the Edinburgh Postnatal Depression Scale
at 2 to 3 days postpartum. Can J Psychiatry. 2004;49:51-54.
13. Watson LC, Pignone MP. Screening accuracy for late-life
depression in primary care: a systematic review. J Fam Pract.
2003;52:956-964.
14. Gabryelewicz T, Styczynska M, Pfeffer A, et al. Prevalence
of major and minor depression in elderly persons with mild
cognitive impairment—MADRS factor analysis. Int J Geriatr
Psychiatry. 2004;19:1168-1172.
15. Rush AJ, Trivedi MH, Carmody TJ, et al. Self-reported de-
pressive symptom measures: sensitivity to detecting change
in a randomized, controlled trial of chronically depressed,
nonpsychotic outpatients. Neuropsychopharmacology.
2005;30:105-116.
16. Scott J, Thorne A, Horn P. Quality improvement report:
Effect of a multifaceted approach to detecting and managing
depression in primary care. BMJ. 2002;325:951-954.
What are the core symptoms of depression?

3 ◆ A. Soykan, Turkey
Attila SOYKAN, MD
Associate Professor
Division of Consultation
Liaison Psychiatry
Department of Psychiatry
Ankara University
School of Medicine
Ankara
TURKEY
What are the core symptoms of depression?
epression has been a long-standing focus
D of attention for writers, poets, philoso-
phers, artists, and, eventually, scientists.
The theories proposed to explain depression have
shed light on the many facets of the disease and
contributed to increase our awareness, under-
standing, and conceptualization of it. Thus, Freud
stressed the importance of grieving in depression,
in the absence of any obvious loss. Beck, a psy-
choanalyst and the father of the Depression In-
ventory that bears his name, started investigating
the role of aggression directed toward self in de-
pression, and ended up by formulating a cognitive
theory of depression. Interestingly, almost all
theories have emphasized two symptoms of de-
pression; depressed mood and anhedonia/loss of
interest. These symptoms are also included in the
core of Hamilton’s conceptualization of depres-
sion as presented in the Hamilton Depression Rat-
ing Scale.1 Eventually, the Diagnostic and Statis-
tical Manual of Mental Disorders (DSM) approach
highlighted depressed mood and anhedonia/loss
of interest as the cardinal features of depression.2
Since the third edition of the DSM in 1980, the
differences among cultures have gradually sub-
sided, mainly due to the widespread acceptance
of the conceptual framework enshrined in the
DSM classification system. Recent studies indicate
that, although culture can affect the expression
of depressive mood and symptoms, there appears
to be a “core syndrome” of depression, regardless
of sociocultural context.3 Current classification
systems consider depressed mood and anhedonia/
loss of interest as the “core” symptoms of depres-
sion. Classification systems relying on clinical
presentation need to identify “core” symptoms to
differentiate individual “disorders,” which are
accordingly defined. However, major drawbacks
are associated with the DSM approach regarding
the conceptualization of depression, and, as the
etiopathology of depressive disorders is increas-
ingly elucidated, the concept of “core” symptoms
tends to be replaced with etiologically relevant
symptom profiles. First of all, the DSM approach
relies heavily on “clinical” observations, and in
terms of etiology—the ultimate goal of any clas-
sification—this hardly allows to go beyond syn-
drome level. Secondly, the description of depres-
sion is best adapted to middle-aged patients
without comorbid psychiatric or physical disor-
ders. Even when only anxiety disorders are taken
into account, at least 50% of depressive patients
present with symptoms of anxiety that interact
with the symptomatology produced by depression.
Last but not least, in describing a common “ma-
jor depressive episode” syndrome, the DSM em-
phasizes similarities more than differences among
CO N T R O V E R S I A L QU E S T I O N
disorders, thus decreasing the possibility of de-
tecting differences in underlying etiopathology.
In all, the drawbacks of the DSM system restrict
the number and power of the studies investigat-
ing the heterogeneity of depressive disorders. All
symptoms are the end-product or by-product of
pathological or functional changes in organs. The
brain is an organ with highly specialized functions
assigned to different areas of the hemispheres.
Unlike most other organs, expansion or a slight
change in the location of pathology can result in
very different clinical presentations. In regard to
depression, great variability of symptoms and
high frequency of comorbid diseases could well
be related to the extent of the areas affected. To
date, although much remains to be learned, we do
have some clues about the possible brain loca-
tions that control some of functions that are af-
fected in depression. For example, depressed mood
possibly originates in increased activity of the
limbic cortex, specifically, the anterior cingulate
cortex and the limbic orbital cortex. Abnormal
neuronal activity in the hypothalamus and other
limbic areas could lead to anhedonia/loss of in-
terest, decreased libido, and dysregulation of ap-
petite and sleep. We also know some of the areas
involved in other psychiatric disorders as well.
For example, the hippocampal region is affected
in dementia, and mesolimbocortical dopaminer-
gic pathways and the prefrontal cortex are af-
fected in schizophrenia. I fully expect that, in
future, new syndromes will be defined according
to the affected brain areas and circuits, and that
this will lead to a thorough overhaul of current
diagnostic criteria for psychiatric disorders. In
conclusion, although we still need to rely on
“core” and other symptoms for the differential
diagnosis of depression, we should also bear in
mind that the current conceptualization of de-
pression limits our understanding of depression
and how to treat it. Once the diagnosis of depres-
sion has been established, all the symptoms and
signs presented by the patient should be consid-
ered as “core” symptoms. Every single symptom
should receive clinical attention regardless of
severity. We should rethink our current partially
successful concept of medical treatment that con-
siders depression as a whole. Instead, we should
focus on individual symptoms and new thera-
peutic strategies to address them. ❒
REFERENCES
1. Hamilton M. Development of a rating scale for primary
depressive illness. Br J Soc Clin Psychol. 1967;6:278-296.
2. American Psychiatric Association. Diagnostic and Statisti-
cal Manual of Mental Disorders. 4th ed. Washington, DC:
American Psychiatric Association; 1994.
3. Douki S, Tabbane K, Taktak MJ. Cross-cultural aspects of
depressive disorders. Eur Psychiatry. 1997;12(suppl 2):124s.
MEDICOGRAPHIA, VOL 27, No.3, 2005 263
CO N T R O V E R S I A L
4 ◆ A. C. Altamura, Italy
A. Carlo ALTAMURA, MD
Chairman Department of
Psychiatry
Center for Diagnosis and
Treatment of Mood Disorders
University of Milan
Hospital Luigi Sacco
Milan, ITALY
(e-mail:
c.altamura@hsacco.it)
264 MEDICOGRAPHIA, VOL 27, No.3, 2005
QU E S T I O N
t is well known that the word depression refers
I both to a full-fledged clinical condition and
to brief, mild downward mood swings that
we all experience as a part of daily living. In the
clinical context, the term depression refers not
simply to a state of depressed mood, but to a syn-
drome comprising mood disorders, psychomotor
changes, and various types of somatic (neuroveg-
etative) dysfunction and cognitive impairment.1
According to the 4th edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV),
all these changes may occur (they should be pre-
sent for at least 2 weeks), but none except “de-
pressed mood” and “loss of interest or pleasure in
nearly all activities,” are essential for the diagno-
sis of Major Depression. DSM-IV and the Inter-
national Statistical Classification of Diseases and
Health-Related Problems, 10th Revision (ICD-10)
show some degree of divergence in their criteria
for depression, regarding type and number of
symptoms. ICD-10 contains 10 items, in contrast
to the 9 DSM-IV items (loss of self-esteem is in a
separate category from inappropriate guilt in
ICD-10). Also, in ICD-10, the severity of Major
Depressive Episodes is rated according to an in-
cremental number of criteria: mild depression
starts from 4 out of 10 symptoms, moderate de-
pression from 6 out of 10 symptoms, and severe
depression from 8 out of 10 symptoms. Finally, in
ICD-10, the diagnostic algorithm differs by re-
quiring the presence of at least 2 out of the follow-
ing 3 symptoms: depressed mood, loss of interest,
and decreased energy for mild and moderate de-
pressive episodes, and all 3 for severe depressive
episodes. ICD-10 episodes with psychotic features
exclude first-rank symptoms and bizarre delu-
sions. In terms of core or nuclear symptoms, both
DSM-IV and ICD-10 include the following symp-
toms: (i) psychic (eg, mood or anxiety or suicidal
ideation and guilt feelings); (ii) psychomotor (eg,
retardation or agitation); (iii) somatic/neuroveg-
etative (eg, sweating, tachycardia, dryness of
mouth); (iv) diurnal variation; (v) insomnia/hy-
persomnia; (vi) loss of energy; and (vii) cognitive
symptoms (eg, difficulty concentrating and loss
of memory). All these components can be present
REFERENCES
1. Altamura AC, Montresor C, Salvadori D, Mundo E. Does
comorbid subthreshold anxiety affect clinical presentation and
treatment response in depression? A preliminary 12-month
naturalistic study. Int J Neuropsychopharmacol. 2004;7:1-7.
2. Altamura AC. Anxious-depressive syndromes in the elderly.
Assessment, clinical course and treatment. In: Racagni G,
Smeraldi E, eds. Anxious Depression: Assessment and Treat-
ment. New York, NY: Raven Press; 1987:209-216.
3. Lepine JP, Altamura AC, Ansseau M et al. Tianeptine and
paroxetine in major depressive disorder, with a special focus
on the anxious component in depression: an international,
6-week double-blind study. Hum Psychopharmacol Clin Exp.
2001;16:219-227.
4. Judd LL, Akiskal HS, Paulus MP. The role and clinical sig-
nificance of subsyndromal depressive symptoms (SSD) in uni-
polar major depressive disorder. J Affect Disord. 1997;45:5-17.
5. Altamura AC, Percudani M. The use of antidepressants for
in the same patient (this is more likely to happen
in the most severe forms), but more often some
aspects (besides depressed mood or loss of inter-
est or pleasure) are predominant, particularly in
the early phase, where some patients can be “pau-
cisymptomatic,” with a more prominent psychic
or somatic or cognitive expression.2,3 However,
along with the development of a full-blown major
depressive syndrome, all core or nuclear symp-
toms tend to occur. Thus, depression is like the
rings that a pebble makes in a pond, which en-
large progressively from the center (depressed
mood and loss of interest), to progressively include
more and more symptoms (psychic, somatic, and
cognitive). In other words, depression evolves from
an initial “paucisymptomatological” presentation
to the full-blown, multisymptomatic form usu-
ally seen by the GP. Psychiatrists usually see pa-
tients at a later stage, after weeks of suffering, if
they are not adequately diagnosed and treated by
GPs.4 It is of paramount importance that GPs be
aware that patients with a monosymptomatic
presentation (depressed mood/anxiety and reduced
interest or anhedonia), even though the 2-week
criterion is not fulfilled or other symptoms are not
present, may present subclinical signs that can
quickly develop into the core or nuclear symp-
toms of a major depressive episode. The final point
we must address is whether an antidepressant
should be active on the core symptoms of depres-
sion.5,6 We favor a “holistic” approach to the psy-
chobiology of depression taking into account
dysfunctions of the serotonergic (5-HT) or nora-
drenergic (NA) pathways, as well as the fine reg-
ulation of disturbed biological rhythms involved
in the pathogenesis of depression (such as the
hypothalamopituitary axis [HPA], melatonin,
etc), which are responsible for diurnal variations
in mood, sleep disorders, anxiety, neurovegetative
symptoms, etc.7 Future approaches should ad-
dress not only the classic monoaminergic path-
ways, but also other neurotransmitters and/or
neuromodulators involved in the dysregulation of
biological rhythms, which influence, at least in
part, the pathophysiology and outcome of major
depression.8,9 ❒
long term treatment of recurrent depression: rationale, cur-
rent methodologies and future directions. J Clin Psychiatry.
1993;54(suppl 8):29-37.
6. Paykel ES. Treatment of depression: the relevance of research
for clinical practice. Br J Psychiatry. 1989;155:754-763.
7. Maes M, Meltzer HY. The serotonin hypothesis of major de-
pression. In: Maes M, Meltzer HY, eds. Psychopharmacology:
The Fourth Generation of Progress. New York, NY: Raven
Press; 1994:933-944.
8. Altamura AC, Carta MG, Carpiniello B, Piras A, Maccio MV,
Marcia M. Lifetime prevalence of brief recurrent depression
(results from a community survey). Eur Neuropsychophar-
macol. 1995;5(suppl):99-102.
9. Frank E, Prien RF, Jarret RB, et al. Conceptualization and
rationale for consensus definitions of terms in major depres-
sive disorder: remission, recovery, relapse, and recurrence.
Arch Gen Psychiatry. 1991;48:851-855.
What are the core symptoms of depression?

5 ◆ A. B. Smulevitch, Russia
he concept of “depression” embraces a wide
T range of states of pathologically changed
affects (from typical melancholic forms to
atypical, masked, and seasonal, depressions). The
core symptoms of depression determine the patho-
logical course and the type of response to thera-
py, and form the basis of the psychopathological
structure of depression. These manifestations of
depression are also the main measures of compli-
ance used to evaluate the action of psychotropic
Anatoly B. SMULEVITCH, drugs (target symptoms). The basic symptoms of
MD typical depression include positive affectivity man-
National Mental Health
Research Center
ifestations (mentally oppressive depressive hyper-
Kachirskoe Shosse 34 esthesia (eg, heartache, suffering) or somatic dis-
115522 Moscow orders, which determine the clinical presentation
RUSSIA of typical (vital) depressions. These core diagnos-
tic features include: (i) melancholy, ie, an uncer-
tain (protopathic) feeling of intolerable pressure
in the chest or epigastrium (precardiac or epi-
gastric melancholy) accompanied by low spirits,
despondency, despair, hopelessness; (ii) intellec-
tual and motor retardation, ie, difficulties in con-
centration and attention, delayed responses, slow-
ness of movements, loss of spontaneous activity;
(iii) pathological circadian rhythm, ie, mood
swings during the day with maximum symptom
severity early in the morning; (iv) ideas of self-
inferiority, ie, persisting thoughts of self-useless-
ness and self-accusation, depreciation of personal
successes in the past, pessimistic thoughts about
the future; and (v) suicidal thoughts, ie, psycho-
logically not derivable wish to die, thoughts that
life is not worth living, suicidal ideation, occasion-
ally an irresistible urge to commit suicide). The
diagnosis of atypical depressions is based on neg-
ative affectivity manifestations, involving mental
alienation (persisting feeling of impoverished
and altered mental life, loss of motivation to any
activity). The symptom complexes of negative af-
fectivity include: (i) anaesthesia psychica dolorosa,
ie, a painful feeling of loss of emotions, inability
to feel love, hatred, empathy, anger; (ii) depres-
sive devitalization, ie, loss of life instinct, instinct
of self-preservation, vital inclinations (sleep, ap-
petite, libido); (iii) apathy, ie, appetency deficit
accompanied by a loss of zest for life, lack of en-
ergy, indifference to everything; (iv) dysphoria,
gloominess, “anger attacks,” querulousness; and
(v) anhedonia, ie, inability to experience plea-
sure, joy, and delight. The difficulty of detecting
masked depressions (or “latent,” “alexithymic”),
which are prevalent in general medical practice,
is related to the predominance of neurotic symp-
tom complexes (anxiety, phobic, hypochondriac,
What are the core symptoms of depression?
CO N T R O V E R S I A L QU E S T I O N
neurasthenic, autonomic and somatoform dis-
orders, algias, sleep disturbances, mainly in the
form of insomnia/hypersomnia), while the basic
affect manifestations (melancholy, psychomotor
disturbances, ideas of guilt) are moderate. In
these cases, the diagnosis of depression is made
easier by evidence of a circadian rhythm, pes-
simistic thoughts about the persons’ own health
and future, passive suicidal thoughts (desirability
of an accident, sudden death, etc). The diagnos-
tic criteria for seasonal depressions are based on
chronobiological characteristics, as these types
of affective disorders manifest during the autumn
and winter period. During spring and summer,
depressions can be followed by a remission or
hypomania. The peculiarities of the psychopatho-
logical structure of seasonal depressions should
be taken into account. Two types of somatovege-
tative symptom complex can be distinguished in
seasonal depressions: hyperesthetic (increase in
appetite, including appetency for carbohydrate-
rich meals, increase in weight, hypersomnia) and
anesthetic (reduction in appetite and taste, ac-
com-panied by a nutrition deficit and consider-
able loss of weight, insomnia with absence of
feeling of sleep and reduction of sleep duration).
The choice of antidepressants is based on the
psychopathological manifestations of depressions
as describe above. Effective control of typical de-
pression with basic symptomatology is achieved
with the majority of current thymoanaleptics.
Severe depression with agitation or marked psy-
chomotor retardation requires use of potent psy-
chotropic medications: injectable tricyclic anti-
depressants are preferable. In mild or moderate
depressions, as well as atypical depressions, with
predominance of negative affectivity, the recent
antidepressants are the drugs of choice. Com-
pared with tricyclic antidepressants these are
much more neurochemically selective and pro-
duce fewer side effects (selective stimulators and
inhibitors of serotonin reuptake, fluoxetine,
paroxetine, etc; dual action antidepressants, in-
cluding venlafaxine, mirtazapine, etc; selective,
reversible monoamine oxidase A–type inhibitors
like pirlindole, or other antidepressants like tia-
neptine). Finally, the acute treatment and pre-
vention of seasonal affective disorder, which is
associated with dysfunction of the serotonergic
system and pineal gland, as well as of other de-
pressions characterized by abnormal biological
rhythms, relies on new therapeutic strategies
interacting with circadian rhythms and other
targets. ❒
MEDICOGRAPHIA, VOL 27, No.3, 2005 265
CO N T R O V E R S I A L
6 ◆ B. Millet, France
W background to a modern definition of
Bruno MILLET, MD
Service Universitaire de
Psychiatrie
CHS Guillaume Régnier
108 avenue du Général
Leclerc
35011 Rennes Cedex
FRANCE
(e-mail: b.millet@ch-guillau-
meregnier.fr)
266 MEDICOGRAPHIA, VOL 27, No.3, 2005
QU E S T I O N
hat is the epidemiologic and historical
depression?
Given its huge epidemiologic variation, with point
prevalences of Major Depressive Episode in the
general population over 1 year ranging from 0.6%
in Taiwan through 5% in France to 10% in the
United States, it is essential to define the core
symptoms of depression if we are to identify a nu-
cleus of depression for use as a model in clinical
psychiatric research and operating criteria for
appropriate antidepressant treatment. The defini-
tion of depression is grounded in Ey’s description
of melancholia as a state of “intense depression
experienced with psychic pain and characterized
by psychomotor inhibition.”1 The concepts of
neurasthenia, neurotic depression, and anxiety
and depression were then coined to characterize
syndromes falling outside this definition. Since
these comprised symptoms such as insomnia,
functional somatic complaints and anxiety, clin-
icians were led to differentiate between “endoge-
nous” and “psychogenic” depression—only for
this distinction to be swept aside after 1960 by the
arrival of the first antidepressants that proved
active against all forms of depression, irrespec-
tive of their cause. International classification
systems subsequently jettisoned the concept of
endogenicity so dear to Kraepelin.2
Core symptoms of depression
However, a number of psychiatric manuals differ-
entiate between endogenous depression (whether
unipolar or manic-depressive bipolar) and a much
more mixed presentation extending from reac-
tive depression to neurotic depression.3 Clinical
studies have identified the following core symp-
toms across a multiplicity of presentations 4,5:
◆ Depressed mood (expressed in its most severe
form as convictions of unworthiness, incurability,
and guilt).
◆ Inhibition or loss of élan vital (asthenia, global
disinterest, loss of initiative, impaired intellectual
performance and motor function).
◆ Somatic symptoms (anorexia, weight loss, con-
stipation, sleep disturbance).
◆ Anxiety and personality disturbances (irritabil-
ity, impulsiveness, social withdrawal).
◆ Ideas of death and suicidal thoughts (often as-
sociated with depressed mood).
◆ Delusional ideas (in the most severe forms of
depression): mood-congruent (guilt, ruin, mourn-
ing, misfortune, hypochondria) or mood-incon-
gruent (ideas of influence and possession).6
The introduction of international criteria advanced
the understanding of depression by assembling
experts who reanalyzed the literature data and
drew on new studies. It was thus no surprise when,
in 1994, the 4th edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV)
required at least either depressed mood or loss of
interest to meet the criteria for Major Depressive
Episode.7 Cognitive symptoms (diminished ability
to think, concentrate, or take decisions) were also
given a major role. It was specified that depres-
sive symptoms vary with the branch of medicine
concerned (in general medicine patients with de-
pressive disorder report more pain and somatic
illness than others) and age (predilections for ir-
ritability and social withdrawal in children, im-
pulsiveness and toxic substance use in adoles-
cents, and cognitive impairment in the elderly).
Disruption of circadian rhythm as a major symp-
tom of depression appears only in the form of
sleep disturbance (maintenance insomnia, early
morning awakening insomnia, or, conversely,
hypersomnia).
Response to antidepressants and clinical
profile
Antidepressant response profiles appear to differ
with the clinical characteristics of the depression:
monoamine oxidase inhibitors in atypical de-
pression (mood reactivity, increased appetite or
body weight, hypersomnia, impression of limb
anesthesia, oversensitivity to rejection); tricyclics
and electroconvulsive therapy in melancholic
depression; selective serotonin reuptake inhibitors
in nonmelancholic depression.8 Depression with
anxiety and sleep disturbance appears sensitive
to the more sedative antidepressants.
Neuroimaging and understanding of the patho-
physiology of depressive symptoms
The key to future breakthroughs could lie in the
ability to identify specific symptoms with certain
neuronal circuits and develop substances to target
those circuits.9 The demonstration of structures
mediating the self-referential processing of emo-
tional stimuli10 and of corticosubcortical circuits
involved in depression justifies further research
into the connections between clinical symptoms
and functional neurology.11,12 Depressive symp-
toms may thus be divided into spheres:
◆ Emotion: depressed mood, self-depreciation,
guilt.
◆ Motivation: loss of interest, loss of affect, psy-
chomotor retardation.
◆ Association: abnormal executor function, with
each sphere being concerned by a neighboring,
but different, neuronal circuit.
A pathophysiologic approach to depression brings
the clinical targets of antidepressants into sharper
focus. Depression is a clinically mixed syndrome
with core characteristics that are recognized by
all clinicians. The next step is to establish clini-
coneurophysiologic correlates that optimize the
deployment of our therapeutic arsenal. ❒
What are the core symptoms of depression?
 CO N T R O V E R S I A L QU E S T I O N
▲

REFERENCES
1. Ey H, Bernard P, Brisset C. Manuel de Psychiatrie. Paris,
France: Masson; 1963.
2. Sartorius N. Classification: an international perspective.
Psychiatr Ann. 1976;6:22-35.
3. Lempérière T , Féline A, Gutman A, Adès J, Pilate C.
Abrégé de Psychiatrie de l’Adulte. Paris, France: Masson;
1977.
4. Guelfi JD. Psychiatrie de l’Adulte. Paris, France: Editions
Ellipses; 1985.
5. Gelder M, Gath D, Mayou R. Oxford Textbook of Psychiatry.
2nd ed. Oxford, UK: Oxford University Press; 1989.
6. De Carvalho W, Cohen D. États dépressifs chez l’adulte. In:
Olié JP, Poirier MF, Lôo H, eds. Les Maladies Dépressives. 2nd
ed. Paris, France: Éditions Médecine Sciences Flammarion;
2003:3-19.
7. American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV). 4th ed. Washington, DC:
American Psychiatric Association; 1994.
8. Esposito K, Goodnick P. Predictors of response in depres-
sion. Psychiatr Clin N Am. 2003;26:353-365.
9. LeDoux JE. Synaptic Self. New York, NY: Viking; 2001.
10. Fossati P, Hevenor SJ, Graham SJ, et al. In search of the
emotional self: an fMRI study using positive and negative
emotional words. Am J Psychiatry. 2003;160:1938-1945.
11. Seminowicz DA, Mayberg HS, McIntosh AR, et al. Limbic-
frontal circuitry in major depression: a path modeling meta-
nalysis. Neuroimage. 2004;22:409-418.
12. Mayberg HS. Positron emission tomography imaging in
depression: a neural systems perspective. Neuroimaging Clin
N Am. 2003;13:805-815.

7 ◆ J. Saiz-Ruiz, Spain
here are two possible presentations of de- ◆ Somatic: anorexia, asthenia, weight loss, sleep

T pression:
Jerónimo SAIZ-RUIZ,
MD, PhD
Hospital Ramón y Cajal
Head, Psychiatric
Department, and
University of Alcalá
Vice-Dean and Professor
of Psychiatry
Ca Colmenar, km 9,1
28034 Madrid
SPAIN
(e-mail:
jsaiz.hrc@salud.madrid.org)
◆ Presence of one symptom (or a group of
symptoms) pathognomonic for depression, which
leads to an immediate diagnosis of depression; or
◆ Absence of characteristic symptoms, in which
case it is the ensemble of a more or less variable
clinical picture that leads to diagnosis of the
disorder.
The first presentation is the classic one in psychi-
atry. Since Kurt Schneider,1 “vital sadness” has
been considered as a fundamental symptom of
depression. Depressed mood is described as hav-
ing a “different quality” than “normal sadness.”
It is sadness that is nonreactive, internal, “cor-
poralized,” persistent, not voluntarily changeable.
For these authors, this symptom is the very core
of depression, it is depression itself. This type of
depression is described as endogenous,2,3 and is
characterized by inhibition, lack of emotional re-
activity, and loss of interest and pleasure in things.
The second presentation is increasingly at the
forefront in current practice. Modern operating
classifications have switched from the former en-
dogenous (melancholy)/reactive (neurotic) dis-
tinction to that between major depression and
dysthymia. They postulate a sequential develop-
ment of the different subtypes of depression
throughout the subject’s evolution. These classifi-
cations do not take into account the subtle phe-
nomenological distinction of the “different quali-
ty” of the depressive mood, which is so difficult to
detect.4 It has been claimed that this devaluates
the symptom, and blurs the limits between the
syndrome and the pathological entity and the dif-
ferent types of mood disorder. However, the basic
diagnostic criteria continue to include an alter-
ation of mood and a lack of pleasure, with various
combinations of the following symptomatic com-
plexes later completing the picture:
◆ Psychic: sadness, demoralization, lack of inter-
est, negative thoughts, low self-esteem, decreased
attention and memory, etc, and
disorders, pains, psychomotor retardation, etc.
From a practical perspective, the high incidence
of depression has resulted in its being treated es-
sentially at primary health care level. This patient
population has a lesser prevalence of dysphoria
or ideas of guilt, but a high incidence of fatigue,5
which has been proposed as the primordial symp-
tom of major depression.6 We need to improve the
early diagnosis and recognition of depression in
this setting, for example, by using certain simple
epidemiological screening tools and evaluation
scales (Primary Care Evaluation of Mental Disor-
ders [PRIME-MD], Mini-Mental Status Examina-
tion [MMSE], Zung Self-rating Depression Scale
[SDS], etc).7,8 Physicians need to carry out appro-
priately detailed clinical interviews that cover the
full psychopathological gamut of symptoms in
order to improve the detection rates of depression.
Another factor that adds to the difficulties is the
lack of stability in symptoms throughout the
course of the depression. This was clearly shown
in a recent study,9 with respect to both the con-
tinuity of symptoms in successive recurrences and
the subtypes of depression. Variations based on
gender have also been reported.10 Likewise, trans-
cultural divergences have been pointed out when
studying samples in different populations.11 How-
ever, all of these studies suffer from having been
performed on samples of severe patients, frequent-
ly in hospital, which may not be very representa-
tive of the usual setting in which depression oc-
curs. One field of interest over recent years is that
of the importance of residual symptoms (fatigue,
anxiety, sexual dysfunction, sleep disorders, etc),12
which may persist after partial relief from symp-
toms following treatment of the episode. These
residual symptoms multiply the risk of relapse by
three, worsen social and occupational function-
ing, favor chronic depression, and increase the
risk of suicide. Although it is debated whether
these residual symptoms are caused by comorbid-
ity with personality or anxiety disorders, they are

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 267
CO N T R O V E R S I A L QU E S T I O N

now considered a prime target of antidepressant
treatment, with the aim of achieving total remis-
sion and/or effective treatment of these symp-
toms.13 Further research is necessary, in particu-
lar through naturalistic studies, in order to gain
a clearer picture of the clinical reality of depres-
sion. Reliable biological markers to validate clin-
ical diagnoses are still lacking. Hopes have been
placed on research into molecular genetics, neu-
roimaging, and neuropsychology, and new dis-
coveries are expected, which should lead to a bet-
ter understanding and delimitation of depression,
as well as to benefits in the field of antidepressant
treatment. ❒

REFERENCES
1. Schneider, K. Clinical Psychopathology. New York, NY: Grune
and Stratton; 1959
2. Mendels J, Cochrane C. The nosology of depression: the en-
dogenous-reactive concept. Am J Psychiatry. 1968;124(suppl):
1-11.
3. Nelson JC, Charney DS. Primary affective disorder criteria
and the endogenous-reactive distinction. Arch Gen Psychiatry.
1980;37:787-793.
4. Carroll BJ. Problems with diagnostic criteria for depression.
J Clin Psychiatry. 1984;45(7 pt 2):14-18.
5. Suh T, Gallo JJ. Symptom profiles of depression among gen-
eral medical service users compared with specialty mental
health service users. Psychol Med. 1997;27:1051-1063.
6. Demyttenaere K, De Fruyt J, Stahl SM. The many faces of
fatigue in major depressive disorder. Int J Neuropsychophar-
macol. 2005;8: 93-105.
7. Magruder-Habib K, Zung WW, Feussner JR. Improving
physicians’ recognition and treatment of depression in gen-
eral medical care. Results from a randomized clinical trial.
Med Care. 1990;28:239-250.
8. Colon de Marti LN, Guzman Yunque FS, Guevara-Ramos
LM. Early detection of depression using the Zung Self-Rating
Depression Scale. P R Health Sci J. 1997;16:375-379.
9. Oquendo MA, Barrera A, Ellis SP, et al. Instability of symp-
toms in recurrent major depression: a prospective study. Am
J Psychiatry. 200;161:255-261.
10. Winkler D, Pjrek E, Heide A, et al. Gender differences in
the psychopathology of depressed inpatients. Eur Arch Psychi-
atry Clin Neurosci. 2004;254:209-214.
11. Fleck MP, Chaves ML, Poirier-Littre MF, Bourdel MC,
Lôo H, Guelfi JD. Depression in France and Brazil: factorial
structure of the 17-item Hamilton Depression Scale in inpa-
tients. J Nerv Ment Dis. 2004;192:103-110.
12. Boulenger JP. Residual symptoms of depression: clinical
and theoretical implications. Eur Psychiatry. 2004;19:209-213.
13. Menza M, Marin H, Opper RS. Residual symptoms in de-
pression: can treatment be symptom-specific? J Clin Psychiatry.
2003;64:516-523.

8 ◆ V. N. Vahia, India
epression with accompanying biological, disorder strive to find a physical cause for their

D behavioral, and cognitive changes is the

Vihang N. VAHIA, MD
Professor of Psychiatry
(University of Bombay)
G. S. Medical College
& Cooper Hospital
Lilavati Hospital
Mumbai 400 054
INDIA
(e-mail: vahia@vsnl.com)
most common form of mental disorder in
the community.1-4 A vigilant primary care physi-
cian, the “gatekeeper” of health care, 5 is crucial
in early detection, prompt and effective treatment,
adequate rehabilitation, and prevention of de-
pression. Proverbially, the term “depression” is
equated with a feeling of sadness.4 Variability in
clinical manifestations, natural course, comorbid-
ity, associated disability, or impairment, and its
impact on the considerable underrecognition of
the disorder is well documented.5 Guidelines for
diagnosis and detection of depression emphatical-
ly state that not all clinically depressed patients
are sad and that many sad patients are not clin-
ically depressed.4 Depression is not a normal re-
action to life’s difficulties.2,4 Depressive disorder
consists of a group of symptoms and signs lasting
2 weeks or more.6 Presence of pervasive sadness
or lack of interest in pleasurable activities or its
equivalents is essential for the diagnosis of de-
pression.6 Diagnosis is easier when the patient
mentions feeling sad or depressed.5 Apathy, anx-
iety, irritability, and reduced interest or capacity
for pleasure or enjoyment may be experienced in
addition to or instead of sadness.4 Though affec-
tive symptoms are cardinal, cognitive, behavioral,
and somatic symptoms are integral to the clinical
presentation.4,7,8 Social stigma, or viewing depres-
sion as personal weakness, results in reluctance
to seek or accept the diagnosis.5 Victims of the
discomfort. Hence sleep disorders or vague somat-
ic symptoms tend to be frequent presentations.5,9
Pain, particularly if the patient reports three si-
multaneous pain symptoms, indicates depressive
disorder.4 Standardized classification systems like
the Diagnostic and Statistical Manual of Mental
Disorders, 4th Edition, Text Revision (DSM-IV-TR)6
specify that besides reduced interest or sadness,
at least four additional symptoms drawn from a
list that includes vegetative symptoms, psycho-
motor activity, cognitive symptoms, and suicidal
ideation, are a diagnostic requirement. Children
and adolescents tend to describe their mood as
irritable rather than sad.6 In addition to the con-
text of primary mood disorders, symptoms of
depression can occur in the context of obsessive,
panic, eating, and generalized anxiety disorders,
as well as drug and alcohol abuse. Symptoms
and typical syndromes of depression are frequent
in nonpsychiatric disorders 2 such as grief reac-
tion, substance abuse, intoxication, or withdraw-
al, and in purely physical disorders like diabetes,
cancer, heart attack, stroke, and after use of pre-
scription drugs for some of these disorders.4,10 The
treating physician should thus determine whether
there is a relationship between the symptoms of
the primary physical illness, the effects of the
administered drugs, and affective symptoms. The
sequence of occurrence of symptoms, and the
nature, intensity, diurnal fluctuations, past and
family history of depression, help to diagnose

268 MEDICOGRAPHIA, VOL 27, No.3, 2005 What are the core symptoms of depression?

depression.4,5 Instruments like the Depression
Screening Questionnaires5 facilitate the diagno-
sis of depression. Ultimately, the combination of
clinical awareness, vigilance, and diagnostic ori-
entation of the primary care physician is critical
to early recognition of a depressive disorder. 2,5
Once the presence of a depressive disorder is di-
agnosed, a finer analysis is required to subtype
the disorder.4,10 Age, education, race, income, and
marital status are related to the outcome more
than the presentation.4 Psychosocial events may
influence the first few episodes, but do not have
much relevance in subsequent episodes.4 An ideal
antidepressant drug is definitely on any clini-
cian’s wish list.11 The ten tenets for an ideal an-
tidepressant drug should be:
◆ Rapid onset, broad spectrum of action in all
REFERENCES
1. Ustun TB. The world-wide burden of depression in the 21st
century. In: Weissman MM, ed. Treatment of Depression. Bridg-
ing the 21st Century. Bombay, India: First Indian Edition;
2003:35.
2. Murthy RS, Bertolote JM, Eppig Jordan J, eds. World Health
Report 2001. Geneva, Switzerland: World Health Organization;
2001.
3. Chisholm D, Sanderson K, Ayuso-Mateos JL, Saxena S. Re-
ducing the global burden of depression population–level analy-
sis of intervention cost-effectiveness in 14 regions. Br J Psy-
chiatry. 2004;184:393-403.
4. Depression Guidelines Panel. Depression in Primary Care.
Vol 1. Detection and Diagnosis. Clinical Practice Guideline,
Number 5. Rockville, MD. U.S. Department of Health and Hu-
man Service, Agency for Health Care Policy and Research.
AHCPR Publication No. 93-0550. April 1993.
5. Wittchen HU, Beesdo K, Bittner A. Depression, an under-
diagnosed disease. Medicographia. 2003;25:9-18.
6. American Psychiatric Association. Diagnostic and Statisti-
What are the core symptoms of depression?
CO N T R O V E R S I A L QU E S T I O N
subtypes of depression.
◆ Achieve complete remission, promote function-
al recovery, prevent relapse.
◆ Safe in overdose, pregnancy, lactation, and in
cardiac, respiratory, autoimmune, skin, hepatic,
renal, and other systemic disorders.
◆ Minimal drug interactions.
◆ Established safety for long-term use in all age
groups.
◆ Absent or minimal adverse and emergent ef-
fects on weight, hair growth, appetite, libido,
and others.
◆ No diurnal sedation.
◆ Easy to administer, preferably once daily
standard dose, no dose titration.
◆ Cost-effective, easily available.
◆ Low risk of breakthrough mania. ❒
cal Manual of Mental Disorders. 4th Edition, Text Revision.
Washington DC; American Psychiatric Association; 2000.
7. Akiskal HS. Mood disorders: clinical features. In: Sadock BJ,
Sadock VA, eds. Comprehensive Textbook of Psychiatry. 7th
Edition, Vol 1. Philadelphia, Pa: Lippincott Williams & Wilkins;
2000:1341.
8. Depression Research at National Institute of Mental Health.
Depression Fact Sheet 1999. Available at http://www.loren-
bennett.org/depfactsheet.htm. Accessed on 04/20/2005.
9. Greunberg AM, Goldstein RD. Mood Disorders: Depression.
In: Tasman A, Kay J, Lieberman JA, eds. Psychiatry. Vol 2, 2nd
edition. Indian Reprint. Bangalore, India: Panther Publishers
Private Ltd; 2004:1217-1218.
10. Greunberg AM, Goldstein RD. Mood Disorders: Depression.
In Tasman A, Kay J, Lieberman JA, eds. Psychiatry. Vol 2, 2nd
edition. Indian Reprint. Bangalore, India: Panther Publishers
Private Ltd; 2004:1210-1213.
11. Lôo H. Antidepressants of the future: a clinician’s wish list.
Medicographia. 2003;25:3-8. Editorial.
MEDICOGRAPHIA, VOL 27, No.3, 2005 269
I N T E R V I E W

UNMET NEEDS IN DEPRESSION

(AND OTHER MENTAL DISORDERS)
Interview with N. Sartorius
Switzerland

Prof Norman
SARTORIUS, MD, PhD
Former Director, WHO
Division of Mental Health
Past President, World Psychiatric Association (WPA)
and Association of European Psychiatrists (AEP)
Geneva, SWITZERLAND
Needs for mental health services have
been traditionally expressed in terms
of frequency of mental disorders. Is
this the best way of measuring needs?
ify” them as having a mental disorder.
They, however, request a service, get it,
and feel better. It is therefore more use-
ful not to equate prevalence data with
needs—were that done, there would also
be the danger that every change of diag-
nostic criteria would change the assess-
ment of needs—but to define mental
health needs as demands for care made
by people who have a mental disorder for
which the health services have an effec-
tive response acceptable to the persons
demanding help and to the society in
significantly impaired and who require
medical help necessary to prevent them
from harming themselves or those around
them. These cases, however, represent
only a relatively small proportion of the
total numbers of people who are using
mental health services.
Are there any problems that make the
assessment of needs defined in this way
difficult?
he main difficulty does not lie

o. Needs for mental health ser-

N vices cannot be equated with
the prevalence of mental disorders. There
are mental disorders for which health
services can do little and social services
a great deal: in such cases, counting
these disorders as being mental health
services needs is not relevant: they are
social service needs. There are also people
who suffer from mental disorders that
do not diminish their insight and who
prefer to deal with their problems them-
selves, and should therefore not be count-
ed as needing a mental health service.
On the other hand, there are also people
who ask for help and advice of mental
health services although they do not have
the array of symptoms that would “qual-
which they live. To the estimate of needs
defined in this way, it is necessary to add
T in the assessment of needs and
demands, but in the fact that the needs
work that should be done to look after
persons whose mental disorder is of such
and demands of the various stakeholders
in mental health care are not the same
severity that insight into their state is (see Figure).
What patients want overlaps
only partially with what families
and society want. Patients, for ex-
ample, may demand the best of
Needs Needs
expressed by expressed by
care regardless of its cost. Fami-
patients families lies may be keen on preserving
their prestige and avoiding em-
barrassment from the unusual
behavior sometimes seen in
Needs Needs
expressed by mental illness (regardless of the
common to all
society/government type of treatment) and would
not object to hospitalization far
from home or other ways of hid-
ing the patient. Governments

M
ental health needs should no longer be expressed in
terms of prevalence of mental disorders as such, but in
terms of demands for which an adequate response is
available to mental health services. Therefore, assessment of needs
should take into account not only what the patient wants, but
also the needs of families, doctors, and society. The main diffi-
culty in the application of this definition is that the needs and
demands of each party may be conflicting or show only partial
overlap. What patients want, for example, is to be treated with
dignity, to be free of symptoms, and to retain their source of in-
come (jobs). Family needs include the preservation of their rep-
utation and financial situation. Doctors want to be effective, avoid
litigation, be confident that the risk of suicide is low, and that
treatment will have a rapid onset of action and not be unduly
long. Governments (voicing society’s demands) want to reduce
the cost of care, while remaining in tune with their election plat-
form. Governmental policies contain the solution to some, but
certainly not all, health issues. Although the development of new
and better medications is unquestionably useful, it is by no means
the only solution to the needs for better mental health services.
Knowledge about mental illnesses and ways of dealing with men-
tally ill people should also be improved. Therapeutic advances
must be accompanied by an adjustment of the health system and
an active commitment of society to deal with mental disorders
in the best way known.
Medicographia. 2005;27:270-272. (see French abstract on page 272)
Keywords: depression; mental disorder; patient; family; society;
government; health service; cultural setting
Address for correspondence: Prof Norman Sartorius, 14 Chemin Colladon,
1209 Geneva, Switzerland
(e-mail: mail@normansartorius.com)

270 MEDICOGRAPHIA, VOL 27, No.3, 2005 Unmet needs in depression (and other mental disorders) – Sartorius

may want to reduce costs for care by
focusing on certain groups of disorders
and providing the least expensive service.
All three would like to see the illness dis-
appear, but in its presence will demand
or do different things to resolve the
problems.
Can you give us another example illus-
trating the relevance of this approach
to the assessment of needs?
nother example is the often
A quoted desideratum that treat-
ment must be simple. The argument is
that this will allow less well-trained per-
sonnel to apply the treatment and that
compliance with the instructions of the
service provider to the patient will be
better. The requirement that treatment
be simple stems from priorities of the
health service, which aims to simplify
training and to delegate treatment re-
sponsibility to less expensive staff. Pa-
tients do not express that need. In fact,
both the experience of traditional prac-
titioners and of medical practice seem to
indicate that patients are prepared to
follow very complex treatment regimens
provided that they have received instruc-
tions about the treatment and that they
believe that, if taken in the specified way,
the treatment will help.
Another common example is the fami-
ly’s demand to the health worker to find
a treatment that will make the patient’s
sleep/wake rhythm predictable and co-
inciding with theirs. While a patient may
not feel the need to take sleeping pills
and might even prefer being awake for a
great part of the night, the family finds
this difficult to tolerate because of their
obligations during the day. Recognizing
the difference between what patients and
families need and taking it into account
will require that doctors use their nego-
tiating skills with both parties in order
to find a compromise solution. If they do
not, they will lose the good will and con-
fidence of one or both of the crucial par-
ties involved in the treatment process—
the patients and/or their families.
Tell us more about the needs that
patients express?
esearch on expressed needs
R and demands has only recently
begun to take on more serious dimen-
sions. Until now, such studies were not
seen as a priority and it was difficult to
find funding for them. What we do know
is that patients wish to be treated with
due respect to their dignity; that they
want to be involved in decisions about
Unmet needs in depression (and other mental disorders) – Sartorius
their treatment; that they demand easy
access—whenever necessary—to the
service providers; that they wish to be
freed from symptoms that are severely
disturbing (some symptoms of mental
disorders are not experienced as too
much of a nuisance by the patient); that
their disease—if it cannot be eliminat-
ed—does not affect functions that they
consider most important (for example,
their thinking or their sexual function-
ing); that they do not remain for ever
marked by the disease; and that their
sources of income — eg, their job — is
not affected by the illness.
These examples of patients’ wishes and
expectations were found in a major pro-
ject against stigma started a decade ago
and currently under way in some 18
countries. These findings may not be
valid everywhere, and it is therefore ex-
tremely useful to carry out local studies
to find out what the patients’ needs are.
What about families’ needs?
ere, even more than with pa-
H tients’ needs, it is important
to carry out assessments in the cultural
setting in which the service is provided
because the needs of families tend to be
profoundly affected by traditions and
other cultural markers of a community.
In many countries, families are reported
to go to extreme lengths to protect their
good reputation; they try to avoid finan-
cial crises because of one of its members’
sickness; they will often have only a lim-
ited amount of patience in waiting for
their sick member to reassume his/her
role in the family; and they will insist on
having a decisive word in decisions about
the patient’s treatment. They will also
often refuse to take on—forever—the
burden that a sick member imposes; for
the family as well as for the patient it is
incomparably easier to fight if the end
of the disease is in sight, even if very
distant.
And what about the doctors’s needs?
octors want to help their pa-
D tients, but also want to avoid
litigation; they want to be reassured that
the risk of suicide in a patient they have
to treat is low; they want to see a rapid
onset of treatment—not only because
they want to help the patient, but also
because they want to see the good results
of their work; they want to learn about
techniques that can shorten the duration
of their intervention; and they want to be
able to refer away patients whose treat-
ment is beyond their competence.
IN T E RV I E W
And society’s needs?
n democratic societies, govern-
I ments are “spokespersons” for so-
ciety as a whole (or at least 51% of it).
Governments, however, rarely have the
luxury of fulfilling long-range plans and
usually have to change them for political
reasons. This also changes governments’
demands on the health sector. Still, it
seems that some demands are becoming
universal. Governments want health ser-
vices to help them contain disruptions of
communities that they fear might arise if
patients with mental illnesses were to be
allowed to go about unattended; they want
to reduce the cost of care and keep it low
in all sectors with the exception of those
that are politically very important and
therefore often very visible; they want to
build and retain their image in harmony
with their election platform, which often
contains the solution of some, but certain-
ly not all, health problems; and they want
to avoid scandals which involve them.
What about unmet needs concerning
treatment?
oday’s array of medications
T and techniques that have been
shown to be effective and safe is consid-
erable, certainly larger than ever before.
The main challenge therefore does not lie
in the development of better treatments,
but in the equitable use of those available.
Stigma of mental illness reduces the pri-
ority given to the development of effec-
tive mental health services. Burnout of
personnel in institutions dealing with
mental illness is on the increase, fueled
by an excessive amount of work (with
continuous reduction of personnel and
other resources) and unrealistic expecta-
tions. Ignorance about mental illness and
ways of dealing with people who have it
is monumental. Also, the disintegration
of families and communities reduces their
capacity to deal with their ill members.
These are challenges that have to be
addressed if the currently available treat-
ment techniques are to give maximum
benefit and satisfy the mental health ser-
vice needs of the population.
Does this mean that we do not need to
improve treatment techniques?
o, improvement of therapy is
N very useful, but it will not be
sufficient. Advances must go hand in
hand with an adjustment of the health
system and an active commitment of
society to deal with mental disorders in
the best way known. ❒
MEDICOGRAPHIA, VOL 27, No.3, 2005 271
IN T E RV I E W
BESOINS INSATISFAITS DANS LA DÉPRESSION (ET AUTRES TROUBLES MENTAUX)
L
es besoins dans le domaine des maladies mentales ne de-
vraient plus être exprimés en termes de prévalence des
troubles mentaux en tant que tels, mais en termes de de-
mandes pour lesquelles il existe une réponse adéquate sur le plan
des services de santé mentale. L’évaluation des besoins doit prendre
en compte non seulement les souhaits du patient, mais égale-
ment ceux exprimés par les familles, les médecins et la société.
La difficulté principale liée à l’application de cette définition est
que les besoins et les demandes de chaque partie peuvent être en
conflit ou ne se recouvrir que de façon partielle. Ce que deman-
dent les patients, par exemple, c’est d’être traités avec dignité,
d’être soulagés de leurs symptômes, et d’être sûrs que leurs sources
de revenus (emplois) ne soient pas affectées par leur maladie.
L’évaluation des besoins des familles comprennent entre autres
272 MEDICOGRAPHIA, VOL 27, No.3, 2005
de maintenir leur réputation et leur situation financière. Les mé-
decins veulent être efficaces, éviter litiges et procès, être assurés
que le risque de suicide est bas, que le traitement agira rapide-
ment et ne s’étendra pas sur une durée trop longue. Les gouver-
nements (représentant la société) cherchent à réduire les coûts
de santé, tout en restant à l’unisson de leurs plates-formes élec-
torales. Si nul ne nie l’utilité de développer des médicaments
nouveaux et plus efficaces, ceci ne peut en aucun cas constituer
la seule solution aux besoins des services de santé mentale. La
connaissance des maladies mentales et la manière de soigner les
patients qui en souffrent doivent également être améliorées. Les
avancées thérapeutiques doivent s’accompagner des révisions
nécessaires des systèmes de santé et d’une implication active de
la société dans la prise en charge des troubles mentaux.
Unmet needs in depression (and other mental disorders) – Sartorius

THE IMPACT OF SLEEP DISORDERS ON
THE COURSE OF DEPRESSION
by R. Emsley, South Africa
his article looks at the pivotal importance of
T depression-associated sleep abnormalities
throughout their course: from diagnosis at
the early stage of depression to initial treatment,
and to their long-term outcome.
The quality of life of depressed patients is dimin-
ished by a variety of factors, sleep disturbances be-
ing one of the most prominent among these. Very
few patients with depression do not experience dis-
turbance of sleep pattern in one form of another.
Sleep disturbances in depression comprise insom-
nia and, less commonly, hypersomnolence. Some
patients actually fluctuate between these two pat-
terns of sleep disturbance during the course of an
episode of depression, reflecting the psychobiolog-
ical heterogeneity of major depressive episodes.1
Whether as insomnia or hypersomnia, it has be-
come clear that sleep dysregulation is more than
just an epiphenomenon of depression. Thus, not
only is disturbed sleep one of the most common
concomitants of a persistent depressed mood—ad-
ditional associations include the following: (i) the
presence of sleep abnormality in depressed patients
has prognostic and outcome implications; (ii) the
majority of antidepressants cause substantial chang-
es in polysomnographic measures as well as in sub-
jective and objective aspects of sleep; and (iii) var-
ious sleep manipulations can alleviate or exacerbate
symptoms of depression in a subset of patients. For
these reasons it has been suggested that changes in
A
lmost all patients with major depression experience a dis-
turbance of sleep pattern. Sleep disturbance is a core fea-
ture of major depression, and is associated with important
prognostic and outcome implications. While sleep abnormalities
with major depression are seen across the age spectrum, aging is
associated with more prominent insomnia. Disordered sleep pre-
cedes the onset of a depressive episode, and the reemergence of
insomnia may herald the onset of a new episode of recurrent
depression. While insomnia often resolves with successful treat-
ment of the depressive episode, most polysomnographic sleep ab-
normalities persist after recovery, suggesting that they are more
trait-like than state-like. Excessive daytime sleepiness and fa-
tigue are consequences of insomnia, and can result in decreased
productivity and an increased risk of accidents. Persistent sleep
disturbance is associated with significant risk of recurrence, an
increased risk of suicide, and poorer overall outcome. Most anti-
depressants cause substantial changes in subjective aspects of
sleep as well as in polysomnographic measures. Tricyclic antide-
pressants and the conventional monoamine oxidase inhibitors
The impact of sleep disorders on the course of depression – Emsley
F O C U S
sleep physiological processes may be intimately in-
volved in the pathophysiological and recovery pro-
cesses of major depression.2 Insomnia associated
with depression can be categorized as follows: diffi-
culty initiating sleep, difficulty maintaining sleep
(or continuity disturbances), and early morning
awakening. Difficulty initiating sleep is the least
specific, and early morning awakening the most
Robin EMSLEY, MB ChB, specific to major depression. Factors such as age,
MMed, FCPsych, MD sex, severity of the episode, and comorbid anxiety
Department of Psychiatry
Faculty of Health Sciences
play a role in determining the incidence, severity,
University of Stellenbosch and nature of sleep disturbances associated with
Cape Town, SOUTH AFRICA major depression.
Time course
Sleep abnormalities in depression are seen across
the age spectrum, from an early age, ie, in adoles-
cence,3 to the elderly. The bidirectional risk rela-
SELECTED ABBREVIATIONS AND ACRONYMS
HPA hypothalamic-pituitary-adrenal (axis)
MAOI monoamine oxidase inhibitor
N-REM non–rapid eye movement (sleep)
REM rapid eye movement (sleep)
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
suppress rapid eye movement (REM) sleep to varying degrees.
Selective serotonin reuptake inhibitors (SSRIs) generally sup-
press REM sleep, but are often associated with subjective reports
of insomnia. Insomnia in patients with major depression requires
careful assessment. Exclusion of primary insomnia, as well as of
general medical and substance-related causes, is important. Treat-
ment strategies involve pharmacological and nonpharmacolog-
ical interventions. Some clinicians prescribe an antidepressant
with sedative properties. Alternatively, a hypnotic can be copre-
scribed. Neither of these approaches is without problems. Sleep
hygiene and other behavioral treatments may be helpful adjuncts.
Medicographia. 2005;27:273-278. (see French abstract on page 278)
Keywords: sleep; insomnia; depression; major depression;
antidepressant
Address for correspondence: Prof Robin Emsley, Department of Pyschiatry, Faculty
of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505
South Africa (e-mail: rae@sun.ac.za)
MEDICOGRAPHIA, VOL 27, No. 3, 2005 273
FO C U S
tionship between sleep and depression may be par-
ticularly strong in older adults.4 Aging is associated
with more prominent insomnia in depression, while
hypersomnolence is relatively more common ear-
lier in life and may even be nearly as prevalent as in-
somnia among younger depressed women.1 There
is considerable evidence to suggest that disordered
sleep actually precedes the onset of a depressive
episode. In a longitudinal epidemiological study
investigating the association between sleep distur-
bance and psychiatric disorders in young adults,
prior insomnia was a significant predictor of subse-
quent major depression. On the basis of their find-
ings, the authors suggested that complaints of 2
weeks or more of insomnia nearly every night might
be a useful marker of subsequent onset of a major
depressive episode.5 In the National Institute of Men-
tal Health Epidemiologic Catchment Area study,
10.2% and 3.2% of a community sample noted in-
somnia and hypersomnia, respectively. The risk of
developing new major depression was significantly
higher in those who had insomnia compared with
those without insomnia, but this risk was much re-
duced if the insomnia had resolved at a follow-up
visit.6 In subjects with preexisting major depression
the reemergence of insomnia can similarly herald
the onset of a new episode of recurrent depression.7
Considerable research attention has focused on
whether sleep changes occurring in major depres-
sion are state-related (ie, emerge during the episode
only) or trait-related (ie, whether they persist after
full remission of the episode). Research to date has
produced mixed results. On the one hand, improve-
ment in subjective insomnia was found to be close-
ly related to global improvement in depression,8 and
it was originally thought to be a state marker. This
is also supported by findings that hypothalamic-
pituitary-adrenal (HPA) axis changes appear to be
specifically state-related.3 On the other hand, lon-
gitudinal studies in fact indicate that most EEG
sleep measures persist after episode recovery, sug-
gesting that they are more trait-like.3,9,10 There are
indications that the type of treatment may have an
effect on sleep in the postrecovery phase of depres-
sion. A study reported quantitative differences in
EEG sleep measures in subjects who had recovered
from a major depressive episode after treatment
with interpersonal therapy and those who recov-
ered after treatment with interpersonal therapy plus
fluoxetine.11
Classification
Sleep EEG changes, together with HPA axis changes
associated with major depressive disorder are among
the best replicated biological findings in psychia-
try.12 Sleep disturbances in patients with major de-
pressive disorders can be classified according to
polysomnographic studies as: (i) difficulties initiat-
ing and maintaining sleep; (ii) abnormal sleep ar-
chitecture; and (iii) disruptions in the timing of
rapid eye movement (REM) sleep13:
◆ Difficulties with sleep initiation and maintenance
include prolonged sleep latency (ie, sleep-onset in-
somnia), intermittent wakefulness and sleep frag-
274 MEDICOGRAPHIA, VOL 27, No. 3, 2005
mentation during the night, early morning wak-
ening with an inability to return to sleep, reduced
sleep efficiency, and decreased total sleep time.
◆ Regarding abnormal sleep architecture, abnor-
malities have been reported in the amounts and
distribution of non-rapid eye movement (N-REM)
sleep stages throughout the night, including an
increase in the amount of light stage 1 sleep and
reduction of deep, slow-wave (stages 3 and 4) sleep.
◆ REM sleep disturbances in patients include a
shortening of REM latency (<65 minutes), a pro-
longation of the first REM sleep period, and in-
creased REM density (ie, increased total REM sleep
time), particularly in the first half of the night.14,15
Sleep disturbances can be verified with polysom-
nography in 90% of patients with major depression.
They are most pronounced in melancholic depres-
sion16 and in bipolar and psychotic depression.17
The underlying mechanisms involved in the
pathogenesis of sleep abnormalities in major de-
pression are not known. In cases of early morning
wakening and decreased REM latency there may be
a phase advance of the sleep-wake cycle.18 Although
not fully elucidated, a recent study involving EEG
sleep and regional metabolism assessments with
positron emission tomography reported interest-
ing findings regarding the underlying neurobiology
of disturbed REM sleep in depression. Depressed pa-
tients showed signs of altered function of limbic/
anterior paralimbic, and prefrontal circuits during
the REM sleep state, possibly reflecting an imbal-
ance in monoaminergic/cholinergic function af-
fecting not only the brainstem generation of REM
sleep, but also the manner in which the forebrain
responds to the stimuli of REM sleep.19
Sleep disturbances seem to be more prominent in
patients with more severe depression, as suggested
by the finding that they were reported in 80% in-
patients with depression (presumably more severe)
compared with only 40% to 60% depressed outpa-
tients. About 30% depressed patients actually have
hypersomnia.13 When EEG sleep profiles were com-
pared in the first 6 weeks of a depressive episode in
a group of subjects with recurrent depression and
compared with their sleep profiles as measured
during their previous episode at a later stage, it was
found that REM sleep abnormalities were more pro-
nounced earlier in the course of a depressive epi-
sode.20 Deficiencies in sleep efficiency may explain
why depressed patients often feel fatigued even
when they appear to sleep excessively. However, the
diagnostic specificity of the sleep disturbances is
poor. It has been reported that no single sleep vari-
able reliably distinguishes patients with major de-
pression from healthy controls or from patients
with other psychiatric disorders.21
Clinical implications
Excessive daytime sleepiness and fatigue are un-
avoidable consequences of insomnia, and are there-
fore common features of patients suffering from
depression.22 This in turn can result in impaired oc-
cupational and social functioning, with decreased
productivity and an increased risk of accidents.23
The impact of sleep disorders on the course of depression – Emsley

There are other important clinical implications
for sleep disturbances in depression. Persistent sleep
disturbance is associated with significant risk of re-
currence.6 Also, recurrent depression is associated
with a more severe neurophysiologic substrate than
phenotypically similar single-episode cases.24 Two
studies have reported an association between sleep
disturbance and suicide. The first found that both
insomnia and hypersomnia are associated with sui-
cidal behavior in patients with major depression,25
and the second reported an association between
poor subjective sleep quality and suicidal behavior
in patients with major depressive disorder.26 Poly-
somnographic sleep changes such as REM latency
have also been reported to predict treatment re-
sponse and the clinical course of illness.27
Effects of antidepressants on sleep
All antidepressants have some effects on sleep ar-
chitecture.28 In fact, in early studies, suppression of
REM sleep was regarded as necessary for the anti-
depressant action, based on a finding of a correla-
tion between clinical response and REM suppres-
sion as well as a temporal relationship between the
onset of clinical response and REM suppression.
However, this was later found not to be the case.1
Clinical trials investigating the effects of antide-
pressants in patients with major depressive disor-
der have reported varying effects of these agents on
sleep latency and sleep efficiency, as well as on day-
time somnolence.29 Some antidepressants have pro-
found effects on sleep regulation, and others min-
imal. Specific antidepressants also vary in their
effects from individual to individual. An antidepres-
sant may produce a strong sedative effect in one
individual, and no effect or even an activating effect
in another. Clinicians have traditionally selected
an antidepressant with a more sedative profile for
depressed subjects with prominent insomnia, while
a more activating antidepressant may be prescribed
in cases where hypersomnia is a significant prob-
lem. It has also been suggested that the nature of
the sleep disturbance at initial clinical presenta-
tion may be relevant to the choice of antidepres-
sant medications and the likelihood of experiencing
treatment-emergent side effects.30
◆ Tricyclics
The tricyclic antidepressants (TCAs) primarily in-
hibit the reuptake of the neurotransmitter nore-
pinephrine, and to a lesser extent serotonin.31 They
have additional effects on a variety of other recep-
tors. Most of the TCAs are potent suppressors of
REM sleep, although some do so only moderately.32
Clomipramine and desipramine are the most po-
tent in this regard. REM suppression is usually more
pronounced during the first few hours of sleep and
there is some accommodation to these effects with
continuation therapy.1 TCAs also prolong REM la-
tency and decrease the total amount of REM sleep
time.13 Clomipramine, desipramine, and amitripty-
line increase stage 1 sleep and decrease sleep effi-
ciency over baseline levels.33 Clomipramine, with
the strongest serotonergic effects of all of the TCAs,
The impact of sleep disorders on the course of depression – Emsley
FO C U S
has the most prominent alerting effect on sleep.28
The clinical response to amitriptyline34 and clo-
mipramine35 may be related to the degree of REM
sleep suppression, with better outcome being as-
sociated with a greater degree of REM suppression.
One curious TCA is trimipramine. Although a clas-
sic TCA, trimipramine shows unusual pharmaco-
logical properties. Rather than reducing, it increas-
es, REM sleep. This property has important clinical
implications. Clinicians have for many years found
trimipramine particularly useful in depressed pa-
tients with prominent insomnia, and in addition
it has been shown to be effective in treating non-
depressed patients with primary insomnia.36
◆ Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs) have been
found to also suppress REM sleep in patients with
major depression.28 The onset of the suppressant ef-
fect is delayed, however, and there is considerable
associated REM rebound upon withdrawal.37 Unlike
in the case of TCAs, the antidepressant response to
phenelzine treatment is not correlated with the de-
gree of suppression of REM sleep.38 MAOIs also re-
duce total sleep time and may decrease sleep effi-
ciency.39 Different findings to the classic MAOIs have
been reported with the reversible MAOI moclobe-
mide. One study reported improved sleep continu-
ity in depressed subjects, particularly during the in-
termediate and late stages of drug administration
in a 4-week trial. This was accompanied by signif-
icant improvements in the symptoms of depres-
sion.40 A second study found an activating effect
with moclobemide, most marked during the early
phase of treatment. The most noticeable effects were
on REM sleep, affecting polysomnographic and spec-
tral sleep EEG parameters. A REM sleep habituation
phenomenon was observed, and a slight REM sleep
rebound effect occurred early during withdrawal.41
◆ Selective serotonin reuptake inhibitors
Serotonergic neurons play a critical role in modu-
lating the onset and maintenance of sleep, and it is
thought that insomnia in depression is linked to
dysfunction of central nervous system serotonergic
systems.31 Selective serotonin reuptake inhibitors
(SSRIs) generally suppress REM sleep. However,
they have variable effects on subjective reports of
effects on sleep. Between 10% and 15% of patients
treated with an SSRI complain of insomnia during
the early stages of treatment. As a consequence,
clinicians often coprescribe concomitant hypnotic
medication. One source found that 35% patients
prescribed an SSRI also received a sedative/hypnot-
ic.42 Studies have highlighted increased wakeful-
ness with SSRIs, particularly on fluoxetine. A study
investigating the longer-term effects of fluoxetine in
patients with major depression who were treatment
responders reported significantly reduced sleep ef-
ficiency, decreased stage 2 sleep, increased stage 1
sleep, prolonged REM latency, and a 3.4% reduction
in REM time at 10 weeks of treatment. This study
showed that these effects persist, as even after 30
weeks of treatment there were still alerting effects
on sleep.43 Paroxetine is also associated with an
MEDICOGRAPHIA, VOL 27, No. 3, 2005 275
FO C U S
alerting effect44 as well as a significant REM rebound
with discontinuation.44 Fluvoxamine also appears to
have an alerting effect in patients with major de-
pression. This effect was found to have a fast onset,
being evident even after the first day or two of treat-
ment.45 Citalopram did not appear to have any dele-
terious effects on sleep continuity or wakefulness
during the night in a study of patients over 6 weeks
of treatment.46 Escitalopram is reported to cause in-
somnia at a greater rate than placebo.47
◆ Other antidepressants
Mirtazapine is a potent blocker of 5-HT2 , 5-HT3 and
histamine receptors, and it has the strongest ini-
tial sedative effects among the newer antidepres-
sants. These effects cause daytime sedation in about
half of patients during the first 2 weeks of treat-
ment,48 but they may be very useful for depressed
patients with prominent insomnia. In a study em-
ploying low doses of venlafaxine, the effects on sleep
architecture were similar to those of the SSRIs.49
Bupropion is generally considered to be an activat-
ing antidepressant, and has been reported to short-
en REM latency and increase REM sleep.50 Rebox-
etine, a selective norepinephrine reuptake inhibitor,
has been reported to induce sleep-EEG changes
similar to those after SSRIs by increasing intermit-
tent wakefulness and decreasing REM time.51
Treatment options for insomnia
associated with depression
Insomnia is a symptom with many possible under-
lying causes. Careful assessment and establishment
of a differential diagnosis is necessary. It is impor-
tant to rule out a primary sleep disorder as the
cause of the insomnia as one of the first steps. A sig-
nificant association has been reported between pri-
mary sleep disorder and major depression. There is
an increased risk of depression in patients with rest-
less legs syndrome52 as well as sleep apnea,53 and ef-
fective treatment of sleep apnea appears to improve
depression in these patients. A further important
reason for ruling out primary sleep disorders is be-
cause some of the medications used to treat insom-
nia associated with depression can actually exacer-
bate the primary sleep disorders.1 Once identified,
primary sleep disorders should be referred to a sleep
specialist. There are numerous other possible caus-
es of insomnia. Insomnia may also be related to a
general medical condition, whether due to pain,
discomfort, or a more direct physiological mecha-
nism. Examples of the latter include hyperthyroid-
ism and pheochromocytoma. Insomnia may be re-
lated to a side effect of medication, or to the use of
some other substance. Both substance (eg, alcohol)
intoxication and withdrawal may cause insomnia.
In attempting to improve sleep patterns, patients
with insomnia may sometimes use medications in-
appropriately. This may include the use of hypnotics
or alcohol to help them sleep at night, as well as caf-
feine or other stimulants to combat excessive day-
time fatigue. Alcohol dependence is often associat-
ed with prominent, persistent insomnia. Insomnia
may also be related to a psychiatric disorder other
276 MEDICOGRAPHIA, VOL 27, No. 3, 2005
than depression (eg, anxiety disorder, mania, psy-
chosis). There are various strategies for treating pa-
tients with insomnia in major depression. First, an
antidepressant with sedative properties can be pre-
scribed. Mirtazapine is commonly used these days,
although sedative TCAs such as amitriptyline and
trimipramine, trazodone, and nefazodone have also
been used. Patients successfully treated with an
SSRI, but who experience persistent insomnia, may
be treated with a hypnotic such as zolpidem or zopi-
clone. Alternatively, they may be switched to a se-
dating antidepressant. Finally, combinations of an-
tidepressants (ie, adding a sedative antidepressant
at night to a patient being treated with an SSRI) can
be considered as a last resort in patients responding
inadequately to the above strategies.1 However, cau-
tion is necessary with the TCAs because of poten-
tially toxic effects due to drug-drug interactions,
and combination of an SSRI with mirtazapine is
likely to be safer.
In addition to pharmacologic management, sleep-
hygiene and other behavioral strategies can be help-
ful in treating insomnia associated with major de-
pression. Activities that may be detrimental to op-
timal nighttime sleep should be eliminated. These
include things such as daytime napping, excessive
alcohol consumption and brisk exercise in the
evening, and excessive daytime caffeine intake.22
Other behavioral treatments include stimulus con-
trol therapy (aimed at breaking the cycle of prob-
lems commonly associated with initiating sleep),
sleep restriction therapy, relaxation and biofeedback
therapy, and chronotherapy (resetting the biolog-
ical clock by progressively phase-delaying sleep).
Conclusion
Since insomnia associated with major depression
causes subjective distress and is associated with
many risks, its optimal management must be an
important clinical goal. Clinicians have for a long
time been aware of the importance of the effects of
antidepressants on sleep when choosing a drug to
treat major depression. Previously, such decisions
were based largely on clinical experience. Today,
much research has been conducted, and we have a
better understanding of the specific effects of indi-
vidual antidepressants on sleep regulation. Howev-
er, there is still a lack of consensus on the manage-
ment of insomnia associated with major depression.
Consequently, long-term treatment of insomnia is
driven primarily by the individual choices of patients
and their clinicians.54 Clinicians are frequently faced
with a difficult choice when dealing with depressed
patients with prominent insomnia. Prescribing an
antidepressant with an activating effect may exac-
erbate the sleep disturbance, and coprescription of
a hypnotic goes against the basic principle of avoid-
ing polypharmacy where possible, as well as intro-
ducing the inherent risks of hypnotic therapy. Us-
ing a sedative antidepressant is therefore often re-
garded as a better option. However, this may result
in a spillover of daytime sedation, and also com-
plicate the return of normal sleep-cycle in recover-
ing patients. ❒
The impact of sleep disorders on the course of depression – Emsley

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34. Gillin JC, Wyatt RJ, Fram D, et al. The relationship
between changes in REM sleep and clinical improve-
ment in depressed patients treated with amitriptyline.
Psychopharmacology (Berl). 1978;59:267-272.
35. Hochli D, Riemann D, Zulley J, et al. Is there a re-
lationship between response to total sleep deprivation
and efficacy of clomipramine treatment in depressed
patients? Acta Psychiatr Scand. 1986;74:190-192.
36. Berger M, Gastpar M. Trimipramine: a challenge
to current concepts on antidepressives. Eur Arch Psy-
chiatry Clin Neurosci. 1996;246:235-239.
37. Dunleavy DL, Oswald I. Phenelzine, mood response,
and sleep. Arch Gen Psychiatry. 1973;28:353-356.
38. Landolt HP, Raimo EB, Schnierow BJ, et al. Sleep
FO C U S
and sleep electroencephalogram in depressed patients
treated with phenelzine. Arch Gen Psychiatry. 2001;
58:268-276.
39. Kupfer DJ, Bowers MB Jr. REM sleep and central
monoamine oxidase inhibition. Psychopharmacolo-
gia. 1972;27:183-190.
40. Monti JM. Effect of a reversible monoamine oxi-
dase-A inhibitor (moclobemide) on sleep of depressed
patients. Br J Psychiatry. 1989(suppl)6:61-65
41. Minot R, Luthringer R, Macher JP. Effect of mo-
clobemide on the psychophysiology of sleep/wake cy-
cles: a neuroelectrophysiological study of depressed
patients administered with moclobemide. Int Clin
Psychopharmacol. 1993;7:181-189.
42. Rascati K. Drug utilisation review of concomi-
tant use of specific serotonin reuptake inhibitors or
clomipramine with antianxiety/sleep medications.
Clin Ther. 1995;17:786-790.
43. Trivedi MH, Rush AJ, Armitage R, et al. Effects of
fluoxetine on the polysomnogram in outpatients with
major depression. Neuropsychopharmacology. 1999;
20:447-459.
44. Staner L, Kerkhofs M, Detroux D, et al. Acute, sub-
chronic and withdrawal sleep EEG changes during
treatment with paroxetine and amitriptyline: a dou-
ble-blind randomized trial in major depression. Sleep.
1995;18:470-477.
45. Kupfer DJ, Perel JM, Pollock BG, et al. Fluvox-
amine versus desipramine: comparative polysomno-
graphic effects. Biol Psychiatry. 1991;29:23-40.
46. van Bemmel AL, van den Hoofdakker RH, Beers-
ma DG, et al. Changes in sleep polygraphic variables
and clinical state in depressed patients during treat-
ment with citalopram. Psychopharmacology (Berl).
1993;113:225-230.
47. Waugh J, Goa KL. Escitalopram: a review of its use
in the management of major depressive and anxiety
disorders. CNS Drugs. 2003;17:343-362.
48. Holm KJ, Markham A. Mirtazapine: a review of its
use in major depression. Drugs. 1999;57:607-631.
49. Luthringer R, Toussaint M, Schaltenbrand N, et
al. A double-blind, placebo-controlled evaluation of
the effects of orally administered venlafaxine on sleep
in inpatients with major depression. Psychopharma-
col Bull. 1996;32:637-646.
50. Nofzinger EA, Reynolds CF 3rd, Thase ME, et al.
REM sleep enhancement by bupropion in depressed
men. Am J Psychiatry. 1995;152: 274-276.
51. Kuenzel HE, Murck H, Held K, et al. Reboxetine
induces similar sleep-EEG changes like SSRIs in pa-
tients with depression. Pharmacopsychiatry. 2004;37:
193-195.
52. Saletu B, Anderer P, Saletu M, et al. EEG mapping,
psychometric, and polysomnographic studies in rest-
less legs syndrome (RLS) and periodic limb movement
disorder (PLMD) patients as compared with normal
controls. Sleep Med. 2002;3(suppl):S35-S42.
53. Millman RP, Fogel BS, McNamara ME, et al. De-
pression as a manifestation of obstructive sleep ap-
nea: reversal with nasal continuous positive airway
pressure. J Clin Psychiatry. 1989;50:348-351.
54. Jindal RD, Buysse DJ, Thase ME. Maintenance
treatment of insomnia: what can we learn from the de-
pression literature? Am J Psychiatry. 2004;161:19-24.
MEDICOGRAPHIA, VOL 27, No. 3, 2005 277
FO C U S
L’IMPACT DES TROUBLES DU SOMMEIL SUR L’ÉVOLUTION DE LA DÉPRESSION
a plupart des patients atteints de dépression majeure ont
L une perturbation du tracé du sommeil. Le trouble du som-
meil est une caractéristique essentielle de la dépression ma-
jeure et il est associé à d’importantes implications pronostiques
et évolutives. Alors que les anomalies du sommeil accompagnant
une dépression majeure sont retrouvées à tout âge, le vieillisse-
ment est associé à une insomnie plus marquée. Les troubles du
sommeil précèdent l’installation de l’épisode dépressif et la réap-
parition de l’insomnie peut annoncer le début d’un nouvel épi-
sode de dépression récurrente. Alors qu’un traitement efficace de
l’épisode dépressif résout souvent l’insomnie, la plupart des ano-
malies polysomnographiques du sommeil persistent après la gué-
rison, suggérant qu’elles seraient plus liées au profil du malade
qu’à l’épisode lui-même. Une fatigue et une somnolence diurnes
excessives sont les conséquences de l’insomnie, et peuvent provo-
quer une baisse de productivité et un risque accru d’accidents. Un
trouble du sommeil persistant est associé à un risque significa-
tif de récurrence, un risque accru de suicide et une évolution glo-
278 MEDICOGRAPHIA, VOL 27, No. 3, 2005
bale plus mauvaise. La plupart des antidépresseurs provoquent
des changements substantiels des aspects subjectifs du sommeil
ainsi que des paramètres polysomnographiques. Les antidépres-
seurs tricycliques et les inhibiteurs de la monoamine-oxydase
classiques suppriment à des degrés divers le sommeil paradoxal
(REM sleep). Les inhibiteurs sélectifs de la recapture de la séro-
tonine (ISRS) suppriment généralement le sommeil paradoxal,
mais sont souvent accompagnés de plaintes subjectives d’insom-
nies. L’insomnie chez les patients atteints de dépression majeure
requiert une évaluation rigoureuse. Il est important d’exclure une
insomnie primaire, ainsi que les causes médicales générales et
celles liées à une substance. Les interventions pharmacologiques
et non pharmacologiques font partie des stratégies thérapeu-
tiques. Certains praticiens prescrivent un antidépresseur ayant
des propriétés sédatives. Autrement, un hypnotique peut être as-
socié. Aucune de ces approches n’est dépourvue d’inconvénient.
Une bonne hygiène du sommeil et d’autres traitements compor-
tementaux peuvent être des auxiliaires utiles.
The impact of sleep disorders on the course of depression – Emsley
 A T O U C H O F F R A N C E

Christian RÉGNIER, MD
Praticien Attaché des Hôpitaux de Paris
Société Internationale d’Histoire de la Médecine
9, rue Bachaumont 75002 Paris, FRANCE
(e-mail: dr.christian.regnier@wanadoo.fr)

Hygeia versus Polymnia *

Some French painters

and their diseases
b y C . R é g n i e r, F r a n c e

I
n the year 1700, Bernardino Ramazzini (1633-1714), doc-
17th century
watercolor entitled tor of medicine and philosophy, holder of the chair of prac-
The Drip. A painter tical medicine in Padua, published De Morbis Artificium
(with his canvas un- Diatriba [Concerning Work-Related Diseases], the first
der his arm) moves
with difficulty lean- “modern” work devoted to occupational illnesses. A second
ing on a cane, his edition was published on the year of his death (with 12 ad-
hands and back- ditional chapters), and was translated into French in 1777. The
bone are deformed,
he has a drip at the author had ventured into several artists’ studios in the republic
end of his nose. of Venice, and described many ailments induced by noxious sub-
© Private collection. stances, unhealthy working conditions, and the repetition of un-
All rights reserved.
usual movements.1
Ramazzini noted a marked similarity between the clinical manifestations of painters and those of metal
workers, “which differed only by their lesser intensity in painters.” Chapter 8 of his work was devoted to
painters’ diseases such as “tremor, cachexia, black teeth, pallor, melancholy, and loss of sense of smell.”
“Often, Ramazzini noted, when painting portraits, they endow their sitters with greater beauty and color

* Hygeia, daughter of Asclepius, the Greek god of medicine, was renowned for her ability to prevent disease; in classical times she
was known as the goddess of health. Originally, Polymnia was the muse of lyrical poetry and glorified the gods and heroes. She
became the muse of painting in the 17th century when the painter Jacques de Stella portrayed her in his painting Minerva visit-
ing the Muses (1640). Jacques de Stella wanted to show that the art of painting ought to be raised to the same rank as the other
intellectual/artistic disciplines.

P
ainters are not an exception, they also suffer from diseases. Some occur due to chance or ge-
netics, others are related to their artistic activity (professional diseases). The repeated use of
organic solvents and pigments containing heavy metals or harmful substances have in the past
caused a multitude of diseases due to intoxication (then not understood). The occurrence of disease in
an artist inevitably upsets his or her perception of the world; this upset can prove critical in painters who
express their impressions and feelings in their work. Psychiatric disturbance, loss of vision, neurological
disorders, articular ailments, and painful syndromes can transform, modify, or even interrupt a painter’s
oeuvre. Several French painters have been affected by diseases that gradually influenced their artistic work.
For example: Édouard Manet (locomotor ataxia), Edgar Degas (loss of vision), Auguste Renoir (rheuma-
toid arthritis), Vincent van Gogh (character disorders), Henri de Toulouse-Lautrec (pyknodysostosis),
and Raoul Dufy (rheumatoid arthritis). However, the different histories show that disease was never an
obstacle to the expression of true artistic genius; in the best case, the painter adapted to his condition by
finding new ways to express his art, or, in the worst case, died young while exploiting the time he had left
by an explosion of creativity.
Medicographia. 2005;27:279-287. (see French abstract on page 287)

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A T O U C H O F FR A N C E

than nature has in fact endowed them, as they them-

selves lack color and portliness.” Ramazzini also claimed
that the sedentary life that painters led and “the fantas-
tic ideas that perturb them resulted in a sort of melan-
choly genius.” He remarked on the “obnoxious smell of
latrines that permeated artists studios (…) they contin-
ually breathe in these pernicious vapors that (…) disturb
the management of the natural functions and lead to all
the diseases we have noted.”1
A Danish study of 1988 confirmed these observations:
painters who used bright colors (rich in metallic pig-
ments) were frequently affected with articular disease.2
There were also the “lead colics” (known since ancient
Greece) and observed in the 16th century by Jean Fernel,
personal physician to Henry II, who described a painter
of Angers who had the habit of sucking his paintbrushes
to clean them.1

Edouard Manet’s ergotism

Manet died on April 30, 1883 at the age of 51 years. His
left leg had been amputated several days previously be-
cause of gangrene.
In 1880, Manet’s doctor, François Siredey (specialist in
women’s diseases), advised him to start hydrotherapy to Man on Crutches, sketch by Édouard Manet (1878).
© Metropolitan Museum of Arts. New York.
treat clinical signs of incipient locomotor ataxia. Were
these in fact manifestations of tertiary syphilis, which is characterized by disorders of coordination and
equilibrium, paralysis, and proximal anesthesia of the lower limbs? Manet regularly attended shower ses-
sions in the hydrotherapeutic establishment of Doctor Joseph Béni-Barde in Auteuil. “When the Béni-
Bardeuses (thus he nicknamed the female attendants) see me running down the steps of the swimming
pool and laughing, I will have won—and that could be quite soon,” he wrote to his friend Antonin Proust,
who had been a school pal at Rollina College when they were ten. When Proust became minister of arts,
in 1880, he awarded Manet the Legion of Honor.3-5
In 1881, Manet was treated in Meudon at the Bellevue Clinic. These cures failed to provide the hoped-
for benefits, so he switched to another doctor who prescribed rye smut (ergot), of which there then three
forms: Bonjean’s Ergotin, Yvon’s Ergotin, and Tanret’s Ergotinin. The results were spectacular, and Manet
decided to increase the dosage to what were horrifying levels according to his friend, the painter Camille
Pissarro.6 The clinical signs of ergotism soon set in: hallucinations, delirium, circulatory disorders of the
lower limbs, and the famous Saint Anthony’s fire that burned his legs.
From 1881, Manet regularly used a walking stick, and the following year he had great difficulty getting
about. Doctor Siredey warned Antonin Proust that Manet should avoid such blatant overdosing. Holi-
daying in Meudon in the summer of
1882, Manet had become almost im-
potent.4,7 At the end of march 1883,
his left foot had become gangrenous.
Manet’s surgeon René Marjolin and
doctors Siredey and de Berio, were in
favor of amputation. On April 10, they
called in Paul Tillot, a well-known sur-
geon at Beaujon Hospital, and Aristide
Verneuil, professor of clinical surgery
at La Pitié Hospital, both members of
the French Academy of Medicine, for
Ergot a consultation at Manet’s home in
(rye smut).
Engraving
taken from Spontaneous arterial gangrene,
the Littré engraving taken from the atlas Patho-
dictionary logical Anatomy of the Human Body,
(1865). by Jean Cruveihlier (published between
© Coll. Inter- 1830 and 1842 by J.-B. Baillière, Paris,
Activités. France). © BIUM Paris.

280 MEDICOGRAPHIA, VOL 27, No.3, 2005 Hygeia versus Polymnia: some French painters and their diseases – Régnier
 A T O U C H O F FR A N C E

Paris. The two surgeons decided that amputation of the left leg was necessary and urgent, and this was
carried out, one week later, at the painter’s home, under anesthesia with chloroform. However, his condi-
tion did not improve. Racked with fever chills, Manet suffered stoically while the world of art came to pay
a final visit. A medical bulletin was regularly posted on the front door of his house.5,7 His sister-in-law,
Berthe Morisot, described the two days he took to die as unbearable. On April 30, at 7 o’clock in the evening,
Manet died in the arms of his son all the while complaining about pain in his absent leg.8
Ergot is a parasitic fungus, Claviceps purpurea, of the rye seed. It is known for its action on smooth mus-
cle fibers (uterus, arteries), but when ingested in large amounts it causes ergotism. Known in the Middle
Ages as Saint Anthony’s fire, the disease ultimately led to dry gangrene of the feet and hands. The French
Littré dictionary (1865) noted: “in the presence of gangrene, the strongest antiseptics must be used; am-
putation is rarely successful.”9

Edgar Degas’s loss of vision: the art

of adapting
To the attentive observer, the creative evolution of
Edgar Degas (1834-1917) and the variety of tech-
niques he used were clearly shaped by the course
of his eye ailment, a handicap that he adroitly
managed to turn to his advantage. The painter and
critic André Lhote extolled “the second Degas, that
of the latter years, when his failing eyes forced
him to embrace the essential,”10 and for Auguste
Renoir, “Degas painted his best canvases when he
could no longer see.”11 Degas was treated by two
of the most famous ophthalmologists of his day,
Edmond Landolt and Charles Abadie, but no med-
ical record has yet been found. It was during the
Franco-Prussian war that Degas, then aged 35,
became aware of a loss of vision in his right eye
during firing practice. His contemporaries, no-
tably Edmond and Jules de Goncourt, noticed that
the painter half shut his eyes when looking at dis-
tant objects. This was diagnosed as myopia, a vague
term, which at the end of the 19th century loose-
ly applied to a great number of cases of “poor vi-
sion.”12 In his study Les Yeux des Peintres [The
Eyes of Painters] (1999), Philippe Lanthony, an
ophthalmologist who specializes in color vision
Absinth (1876), canvas by Edgar Degas; has the artist
at the Quinze-Vingts Hospital in Paris, has reser- depicted himself on the right of the drinker? All the
vations about the diagnosis even though it was techniques used to compensate for his visual difficulties
compatible with Degas’s habit of painting subjects are present: depth (with presence of the window), unusual
viewing angle. © Musée du Louvre, RMN. Paris.
close up (and his horror of painting in the open
air). Examination of the glasses prescribed by Landolt (now in the Orsay Museum) revealed only a small
correction of 1.5 diopters. The hundred or so portraits of Degas show him wearing glasses outside only
twice and never when he is reading.13 According to Dr Lanthony, two diagnoses can be excluded: ambly-
opia, which normally does not develop at a late age, and myopic maculopathy, in which the myopia is
much more severe.12 The very special lighting and the representation of space in Degas’s work suggest
monocular vision; this defect in the perception of depth could also explain the frequent presence of mir-
rors in his paintings.
In November 1871, writing to his friend James Tissot, Degas described a sudden loss of vision in his left
eye: I recently suffered, and still do, from a sudden weakening and disorder in my eyes. It began beside the
lake at Chatou under a bright sun while painting a watercolor. And it made me lose three weeks, during
which I couldn’t read, travel, or even go outside.”13 The clinical details are precise: sudden loss of vision,
a disorder resolving spontaneously in a few weeks, and absence of other clinical signs (pain, watery eyes,
edema). Degas’s ophthalmic disorder developed progressively, with loss of sharpness of vision, photopho-
bia (circa 1873), scotoma (circa 1884), and reduced color vision (circa 1895).
His eyes saw only one part of an object at a time; planes were cut up like a trellis (…) He saw some parts very
clearly while others were a complete blur (…). He told a young painter, Maurice Denis, I see your nose, but
I do not see your mouth.12

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A T O U C H O F FR A N C E

Despite considering himself nearly totally blind (he had his newspaper read to him by his housekeep-
er), Degas nonetheless continued his social activities: visits to the Opera, journeys to Spain and Morocco
(1889), participation in and organization of impressionist exhibitions. Similarly, his production of paint-
ings was considerable up until 1895. Working in semidarkness, wearing glasses with strongly tinted lenses,
Degas used magnifying glasses to examine photographs and drawings that he enlarged himself by succes-
sive tracings and used for painting. His last portraits (Renoir, Mallarmé, Halévy, Rouart) were all painted
from enlarged photographs.12,13
Some people even went so far as to doubt whether Degas really had poor vision, like Claude Monet, who
considered him a “joker,” or the art dealer Ambroise Vollard who said, “Degas pretended not to see in or-
der to avoid being obliged to recognize people.”14 Even his brother was a doubter: “He does not suffer from
any disease, except deafness.”13 However, Degas’s productivity and social activity declined after 1895; he
then began modeling statuettes, which gave him a better perception of three-dimensional objects thanks
to the sense of touch. Degas noted: “My infirmities have prevented me from continuing to paint with oils,
so I have to be satisfied with pastels.” By adopting this technique and using bright colors, he could carry
one, but he finally had to give up when he could no longer see
them.15 The diagnosis of retinochoroiditis was put forward by the
painter Maurice Denis who suffered from the same condition; to-
day this hypothesis seems the most probable.12

Auguste Renoir: “one does not need hands

In the movie Ceux
de Chez Nous (1917),
Sacha Guitry filmed
Pierre-Auguste Renoir,
whose fingers, deformed
by polyarthritis, can be
clearly seen. © Ciné-
mathèque Française.
in order to paint!”
The first symptoms of polyarthritis struck the painter in 1901.
His hands with their protruding bones beneath the wrinkled skin
had fingers that were twisted forward and wrapped in tight ban-
dages to prevent the nails from penetrating the palms. The first
phalanx of the right thumb was bent back, having been dislocat-
ed and badly reduced. It was separated from the paintbrush in-
serted between thumb and forefinger by a thin corn plaster. It was
under such conditions that Renoir painted during the last years
of his life, without being the least discouraged, with the same pas-
sion as in his youth, the same love of life, the same fervor, and the
same enjoyment.16 Renoir was treated with antipyrine, an analgesic
much in fashion at the start of the 19th century. He also took the waters at the spa towns of Bourbonne-
les-Bains and Aix-les-Bains. He consulted the famous Doctor Gachet, physician and “protector” of Honoré
Daumier, Vincent van Gogh, Édouard Manet, Armand Guillaumin, Paul Cézanne, Gustave Courbet, Claude
Monet, Alfred Sisley, and Camille Pissaro.17
When his art dealer, Vollard, visited him in Cagnes, Renoir declared, “As you can see, hands are not need-
ed for painting! The hand, it’s a lot of nonsense.”14 His son, the filmmaker Jean Renoir, noted in his mem-
oirs that from 1911 on his father was not mobile, even with the aid of crutches. Contrary to legend, the
paintbrushes were not fixed to his hands, simply his palms were protected by a gauze bandage and tal-
cum powder. Every day, Renoir was carried from his bed to his wheelchair and settled in front of his can-
vas.11,18 Despite his physical sufferings and the difficulty of finding the ideal body position for applying the
brush, he painted right up to the end of his life without his work suffering from his deforming arthropa-
thy. On the morning of his death, he painted a bouquet of anemones with shimmering colors.
A lover of bright tints (cinnabar, Naples yellow, ultramarine), Renoir naturally used numerous metallic
pigments. A chain-smoker, he rolled his own cigarettes, unaware that each time he deposited the toxic
compounds of his paint-impregnated fingers on the cigarette paper. In fact, 0.05 mL of red cinnabar con-
tains 100 to 150 mg of mercury sulfide, and repeated inhalation several times a day would be 100 times
more toxic than the official toxic limit of mercury permitted in the air (0.01-0.1 g/m3). Painters ingested
metallic pigments by smoothing their paintbrush with their mouth, and by drinking, eating, and smoking
without washing their hands. The drying of clothes stained with paint and the burning of old canvases
in the stove also gave off toxic metallic vapors.2
In 1988, two doctors and two professors of the Copenhagen School of Fine Arts published in the Lancet
a study that established a correlation between the onset of certain rheumatic diseases in painters and in-
toxication by metallic pigments (cobalt, copper, manganese, lead, chromium) present in certain bright
colors. The Danish authors compared the use of colors in two paintings by Claude Monet with the palette
of Renoir. Thus, in the Skaters in the Bois de Boulogne (1868) and in the Woman with Umbrella (1875),
Monet used very few bright colors such as blue, red, and yellow. The dominant colors were gray, olive green
(iron silicates), ochre (iron oxide), blue gray and black (bone), which contain very little or no toxic heavy

282 MEDICOGRAPHIA, VOL 27, No.3, 2005 Hygeia versus Polymnia: some French painters and their diseases – Régnier
 A T O U C H O F FR A N C E

metals. The same comparison can be made with Edgar Degas who used more pigments containing iron
and carbon than his contemporary Renoir who was very exposed to heavy metals (mercury, arsenic, cad-
mium, tin, antimony, cobalt). The authors showed that heavy metals that entered the organism induced
enzymatic inhibition, denaturation of proteins, or immunosuppression, all pathophysiologic processes
implicated in the onset of certain rheumatologic diseases.2

The Yellow Room by

Vincent van Gogh
(Arles, 1888) where the
drama of the ear
unfolded. © Musée
van Gogh, Amsterdam.

Vincent van Gogh: a victim of pathologists?

Vincent van Gogh (1853-1890) was the son of a Calvinist preacher, and three of his paternal uncles were
art dealers. The life of the painter was punctuated with tragic adventures and dismal experiences, which
led to him killing himself with a bullet to the thorax on July 27, 1890 in Auvers-sur-Oise, where he was be-
ing treated by Doctor Paul Gachet. His physician was a cultivated art collector and depressive freethinker,
who was infatuated with psychiatry and a mediocre practitioner. van Gogh’s tragic end contributed to
the legend of the artist who had painted 44 self-portraits and kept up a regular correspondence with his
younger brother Théodore, who died in the Utrecht asylum one year later.7,19,20
It all began with the “drama of the excised ear.” At Arles, on the evening of December 23, 1888, Vincent
van Gogh went up to his room in the Yellow House, sharpened his razor, and cut off the lower half of his
left ear. He then covered his head with damp towels and a bonnet, wrapped the piece of ear in paper and
went to a brothel in the rue Bout d’Arles where he frequently visited a certain Rachel. He found the young
girl, offered her his grisly present and declared: this is a souvenir of me, look after it carefully. Rachel im-
mediately fainted. The next morning, van Gogh was found unconscious at his lodgings, his head wrapped
in bloodstained towels. Agitated and menacing when awoken, he was taken to Arles Hospital and put in
a padded cell. The amputated ear was collected by a policeman, and the intern, Félix Rey rapidly sutured

SOME METALLIC PIGMENTS USED IN PAINTING

Known in Egypt around 8000 years BC, certain metallic salts (mercury, copper, arsenic, tin, iron)
mixed with linseed oil, which forms nearly 80% of the pigment. From the Roman Empire to the Re-
naissance, new metals were used as pigments (lead, antimony, cobalt, chrome, cadmium, manganese,
aluminum).
◆ Cinnabar: a red vermilion color, derived from mercuric sulfide (HgS).
◆ White lead: white pigment composed of lead carbonate (2PbCO3 ; Pb(OH)2).
◆ Bright yellow: cadmium or lead sulfide (Pb CrO4).
◆ Naples yellow: prepared from lead antimonate (Pb3 (SbO4)2).
◆ Violet: prepared from manganese ammonium phosphate and cobalt arsenate.
◆ Verdigris: copper acetate.
◆ Cobalt blue: composed of cobalt oxide and alumina (CoO; Al2O3).
◆ Ultramarine: aluminum-based (Na 6 -10 Al6 Si6 O2 4 S2-4).
◆ Oxide blue: prepared by exposing silver strips to a mixture of salt, vinegar, alkali, and alum.

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A T O U C H O F FR A N C E

the missing part back into place, and the wound healed without complications. On January 7, 1889, the
intern noted in the discharge register: “A form of epilepsy characterized by hallucinations and episodes of
confused agitation that were precipitated by alcohol excess.” During his stay in Arles, van Gogh had been
encouraged by Paul Gauguin to consume quantities of alcohol and to frequent the bordellos. Having gone
to Provence in the hope of founding a painting workshop like the school at Pont-Aven (where Gauguin had
been a leading light), van Gogh had been profoundly disappointed by the hostility of Gauguin to the pro-
ject. The two men had separated on bad terms a few days before the “drama of the severed ear,” whose ver-
sions are as numerous (and contradictory) as the hypotheses explaining the event.17,19,21
On May 8, 1889, van Gogh was interned, at his own request, in the Saint-Paul-de-Mausole Asylum at
Saint-Rémy-de-Provence. For one year he enjoyed the tranquillity and the comprehension of the nuns
and personnel of the establishment. Appreciating the quality of the light and the glowing beauty of the set-
ting (the asylum is a jewel of Provençal Romanesque art), van Gogh produced nearly 150 paintings and
drawings, including Irises and Vincent’s Room in Arles. This year spent in Saint-Rémy is considered one
of the important creative periods in the oeuvre of Vincent van Gogh.
The first diagnoses of the painter’s neuropsychiatric disorders were made by Doctors Rey and Urpar (Arles)
and Peyron (Saint Rémi), who suggested epilepsy with visual and auditory hallucinations associated with
acute mania with generalized delirium.22 Gachet spoke simply of unwise exposure to the sun plus chronic
intoxication with turpentine and camphor (with which he impregnated his pillow in order to find sleep).
Numerous other hypotheses by a host of doctors followed: cerebral tumor (Bader), psychomotor temporal
epilepsy (Gastaut), schizoid syphilis (Eichbaum), precocious dementia (Bychowski), degenerative psychosis
(Hutter), Ménière’s disease (Yasuda then Arenberg and colleagues), tuberculous meningoencephalitis
(Dupinet), thujone intoxication (Arnold), schizophrenia (Kahn et Jaspers), melancholia (Michel).21-25
It seems that van Gogh was treated for psychomotor epilepsy with extracts of digitalis, and some believe
that the intoxication could explain the visual disorders like dyschromatopsia and xanthopsia, and hence
the painter’s trademark yellow suns surrounded with circles and haloes, and the extraordinary yellow of
the cornfields.26 In the two portraits of Doctor Gachet, van Gogh depicted a flower of the purple foxglove
(Digitalis purpurea). Other “pathobiographies” attribute the chro-
matic particularities of the painter’s palette to cataract, corneal dys-
trophy, or glaucoma (Maire).12,21 In a work devoted to van Gogh,
Professor Henri-André Martin, painter, otorhinolaryngologist, hon-
orary professor at the Lyon Faculty of Medicine, concluded:
It is wrong to want to understand everything and resolve van Gogh
like an elementary mathematical problem. It would be unseemly to
want to inflict a positivist analysis on his person and on his work.20
This small low chair
(12 inches), purchased in Henri-Marie de Toulouse-Lautrec: the misfortunes
1876 in Bagnères de of the “little chap”
Bigorre, is the chair from The Montmartre painter Toulouse-Lautrec (1864-1901) suffered all
which Toulouse-Lautrec fell
and began the series of acci- his life from his ungracious appearance. When about 8 years old,
dents contributing to his his weak health and multiple fractures had already given him a
disability. © Albi. Maison close acquaintance with doctors and spas. A victim of all kinds of
Natale de Toulouse-Lautrec.
abuses, he died aged 37, worn out and in despair.
His father, Alphonse de Toulouse-Lautrec Montfa, descendant of Raymond IV, Count of Toulouse, and
his mother Adèle Tapié de Céleyran were first cousins. Henri-Marie was born on November 24, 1864, in
the family mansion of Bosc situated on the ramparts of Albi. The baby seemed so healthy that he was nick-
named “lou poulit” (patois for little beauty) and because of his insatiable appetite he was deemed worthy
of the “legendary Lautrec stomach.” 27-29
In 1872, Toulouse-Lautrec studied at the Lycée Fontanes (now Condorcet) in Paris — where his pals
called him “little chap.” He then suddenly began to suffer from unexplained feverish attacks with severe
pains in the knees and hips. On the advice of doctors, he began taking thermal cures at Amélie-les-Bains,
Plombières, Lamalou-les-Bains, Evian, Guyon, and Barèges, accompanied by his mother. In March 1877,
he was subjected to an “electric brush treatment” that had previously cured his uncle Charles.30
In Albi, on May 30, 1878, Toulouse-Lautrec slipped, fell, and fractured his left thighbone. The family doc-
tor set the limb with a plaster cast. After one month of immobilization and an equally long convales-
cence, he could only walk lopsidedly, “like a duck,” as he noted in a letter to a friend. A Toulouse-Lautrec
does not walk with a cane! roared his father when he happened to notice the instrument unworthy of the
sporting reputation of the family (to the great despair of the count, his son had never mounted a horse).
During the holidays in July 1879, at Barèges (Hautes-Pyrénées) while walking with his mother, he slipped
into a ravine and fractured his right thighbone; another immobilization, another convalescence. From

284 MEDICOGRAPHIA, VOL 27, No.3, 2005 Hygeia versus Polymnia: some French painters and their diseases – Régnier
 A T O U C H O F FR A N C E

Henri Toulouse-Lautrec taking

the pulse of his friend Maurice
Guibert under the watchful eye
of his cousin Gabriel Tapié de
Céleyran, who was an intern.
Lautrec often said: If I wasn’t
a painter, I would like to be a
doctor, and his insatiable pencil
often sketched the interns in
the staff waiting room or in the
wards. In Paris he dined every
Friday evening at Drouant’s
Restaurant in the company of
artists and doctors, including
Georges Clemenceau and
Henri Vaquez. From 1891 to
1895, every Saturday morning,
he accompanied his cousin
Gabriel (who was completing
his medical studies) to the
department of Docteur Émile
Péan in the Saint-Louis Hos-
pital.32 © Albi. Maison Natale
de Toulouse-Lautrec.

Henri de Toulouse-Lautrec
in the company of Zidler,
manager of the Moulin Rouge
around 1891. © Albi. Musée
Toulouse-Lautrec.

that date on, his growth suddenly slowed. His lower and upper limbs ceased to grow even though his trunk
gained 5 cm. When 20 years old, in 1884, Toulouse-Lautrec was only 5 feet tall, about one inch less than
that required for military service (decree of November 30, 1872). The average height of conscripts in 1885
was about 64 inches. He was already what would later be called: the “greatest dwarf of the century.” 28-30
In addition to his small size, Toulouse-Lautrec’s physical appearance was unsightly: he concealed his
vast head beneath a large hat and hid the hypoplasia of his lower jawbone with an abundant beard. He also
had to wear glasses in order to paint. Yvette Guilbert, his favorite model, described him thus:
He was small in size, had an enormous brown head, a heavily colored face and black beard, greasy, oily skin, a
nose big enough for two people, with a mouth slashing the face from one side to the other, and pinkish-violet,
flat and flabby lips that lined his fearful orifice.27,31

Toulouse-Lautrec sketched his muse as he saw her: because he had exaggerated her scrawniness and
pointed nose, Yvette Guilbert revenged herself by calling him “the little monster,” without realizing it was
the artist’s talent that would save her from oblivion.32
The etiology of the disease remains hypothetical. The consanguinity, the bone fragility, the late and un-
equal bone growth, and the craniofacial deformations are the main characteristics of Toulouse-Lautrec’s
disease. After having eliminated the diagnoses of premature puberty and ricketts, biographers unani-
mously class the disease among the genotypic chondrodystrophies. In the absence of x-rays and biological
or genetic examinations, the retrospective diagnoses are as follows:
– osteogenesis imperfecta (Seedorf - 1949),27
– achondroplasia (Séjournet - 1955),29
– Morquio’s disease (Lévy - 1957),33
– multiple epiphyseal dysplasia (Flament - 1965),27
– pyknodysostosis (Marotteaux and Lamy - 1966),27,34 to-
day this diagnosis is the unanimously accepted diagnosis.
Séjournet, the biographer of Toulouse-Lautrec, wrote,
“Like Goya, like Ensor, he draws from his despair a force
against the destiny that isolates him. Thus to our eyes
and forever, his paintings: Mélinite (an explosive), Jane
Avril, cabaret dancer; La Goulue (The Glutton), Louis
Weber, lead dancer at the Moulin Rouge; Grille d’Égout
(The Sewer Grating), a dancer with terrible teeth; Valen-
tin le Désossé (The Boneless One) male dancer; seem to
An Examination at the Faculty of Medicine. Oils on canvas
(26  32 inches) painted in July 1901, the year Toulouse- echo the pathetic and derisory vortex of his own dance
Lautrec died. © Albi. Musée Toulouse-Lautrec. with death.”29

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A T O U C H O F FR A N C E

The Dufy “miracle”

Raoul Dufy (1877-1953) suffered his first arthralgias in childhood. His rheumatoid polyarthritis devel-
oped slowly from 1935 until 1948, when his functional disability was already well advanced. He was treat-
ed with injections of gold salts, underwent vertebral manipulations, and was treated at spas in Spain. In
1948, he suffered very intense articular pains in the wrists, knees, and ankles. However, he could still use
his left hand. He has not lost his subtle touch with lines or his fine strokes. “He draws with a pencil, and
just lightly strokes the paper, using his right hand as a support,” noted his friend Pierre Courthion, a well-
known art critic.35
Since he used bright colors in his work, the painter was also a great consumer of metallic pigments.
Dufy, as everyone knows, is one of our greatest colorists. He has the magic touch. It is his favorite form of
expression, and it takes precedence over all the other forms, which explains his novelty. Color gleams in his
work, light spreads out with a richness, warmth, and life that are comparable, in their own way, to the colors
of Veronese and Rubens that Delacroix so admired. Everything is fresh, alive, clear, joyful as the spring in na-
ture or youthfulness in life,

wrote Pierre Camo in 1947 in his Dufy the Enchanter.36 The following year, Jean Cocteau wrote a pamphlet
on the painter and reminisced on his intense physical suffering:
He had the appearance of a red devil always ready to emerge from a green box. Since then, we have each grown
older in or own corner and in our own way. Dufy became an invalid who fought, and this battle with evil re-
placed in a way the youthful ardor.35

On April 11, 1950, the painter, almost bedridden, embarked for Boston to consult Doctors Homburger
and Bonner of the Jewish Memorial Hospital. Raoul Dufy was already famous on the other side of the
Atlantic, and his photograph had appeared in Life Magazine. Homburger and Bonner had noted the de-
formed joints and suggested he should come to the United States and be treated with a “revolutionary”
therapy.36 Several days before his departure, Dufy wrote a poem that could be considered his artistic legacy:
“Tomorrow, I sail to Boston in search of my hands…” He also painted a superb bunch of brightly colored
flowers entitled Cortisone (which harks back to the flowers painted by Auguste Renoir on the morning of
the day he died). That same year, 1950, Philip Hench, Head of the Department of Rheumatic Disease at
the Mayo clinic in Rochester, received the Nobel Prize for Medicine or Physiology for his discovery of the
hormones of the suprarenal cortex (cortisone and adrenocorticotropic hormone [ACTH]), together with
their structures and biological effects. He shared the prize with the biochemists Edward Calvin Kendall
and Tadeus Reichstein, professor in Zurich and Basel.
At the beginning of June 1950, Raoul Dufy began a series of injections of 100 mg per day of cortisone
acetate for 3 weeks. On his return to France at the end of July, he took cortisone by mouth at the dose

POEM WRITTEN BY RAOUL DUFY IN CHANTILLY

SEVERAL DAYS BEFORE HIS DEPARTURE FOR THE UNITED STATES IN
Yesterday the invitation arrived
Drawing me to Dr Homburger
And his hospital in America.
Tomorrow I sail to Boston in search
Of my hands.
Forty years ago I painted with Braque
at l’Estaque.
The cubist edges cut too deep into
my palette
And I joined Matisse and became a Fauve.
I covered my canvases only with the
colors that I could feel
Avoiding those that I couldn’t see.
Unsatisfied I traveled to Munich,
Normandy, Marseille
Saw the terrible women of Avignon
And found myself on the Riviera in Vence.
Fifteen years ago the attacks began.
Disfiguring my hands
As if I were painting with leaden gloves.
APRIL 1950
I sought gold To color silk scarves and dresses
Injections. Underwent spinal And finally saw my work sail with the
manipulations wind.
And made a pilgrimage to a Spanish spa. Now my hands are splinted
Yet my hands grew And I have become disjointed
Still. An old man whose hands will not obey
I continued studies in my mind his heart.
Waiting for the time Rheumatism loosened Renoir’s brush
When my brush could be awakened from his grasp
To decorate the canvas And his son bound the bristles to the
With arabesques and flourishes. hollow of his hand.
I have long tried to capture But Dr Perles has assured me
The motion of race horses and regattas That the new remedy, cortisone and ACTH,
The movements of the orchestra Will release the bonds
As musicians chase the notes Of the arthritis that have held me in place.
In concertos of yellow and red. My only wish: to draw freehand
I have painted Electricity Following the wind
With dynamos and electrons moving Flowers that beckon me
at the speed of light. And capturing them
Craving more speed I released my canvases In a vase of Anemones.

286 MEDICOGRAPHIA, VOL 27, No.3, 2005 Hygeia versus Polymnia: some French painters and their diseases – Régnier
 A T O U C H O F FR A N C E

of 100 mg twice a week.37,38 Dufy also received ACTH, but the form and dosage are not known. To express
his thanks, Dufy painted the portrait of the American Doctor Freddy Homburger, his “savior.”
Despite the occurrence of secondary complications, Dufy benefited very rapidly from the revolutionary
treatment: he was again able to move around on his crutches, draw, squeeze the tubes of paint by himself,
and renew work on abandoned canvases such as Amphitrite begun in 1935.14,37 Fully aware that he had
benefited from a “therapeutic miracle,” Dufy wrote: “Is it a rebirth or a swan song?” Indeed, he was to suf-
fer from many complications, such as abscess at the injection site, diarrhea, and severe stomachache.38
Raoul Dufy died on March 23, 1953, in his house at Forcalquier (Haute Provence Alps) of intestinal
hemorrhage probably related to corticotherapy. ❒

REFERENCES
1. Ramazzini B. De Morbis Artificum Diatriba [Des Maladies du
Travail] 1700, translated into French by de Fourcroy A. Paris,
France: AleXitère; 1990.
2. Pedersen LM, Permin H. Rheumatic diseases, heavy-metal
pigments, and the great masters. Lancet. 1988;4:1267-1269.
3. Manet J. Journal (1893-1899). Paris, France: Scala; 1987.
4. Moreau-Nelaton E. Manet Raconté par Lui-Même. Paris,
France: Plon; 1926.
5. Proust A. Edouard Manet—Souvenirs. Paris, France: L’Échoppe;
1996.
6. Duret T. Histoire d’Edouard Manet et de son Œuvre. Paris,
France: Hachette; 1906.
7. Darragon E. Manet. Paris, France: Fayard; 1989.
8. Perruchot H. La Vie de Manet. Paris, France: Gallimard; 1959.
9. Littré E, Robin C. Dictionnaire de Médecine, de Chirurgie,
de Pharmacie, des Sciences Accessoires et de l’Art Vétérinaire.
Paris, France: J.-B. Baillière et fils; 1865.
10. Lhote A. Peinture d’Abord. Paris, France: Denoël; 1942.
11. Renoir J. Pierre-Auguste Renoir, Mon Père. Paris, France: Gal-
limard; 1981.
12. Lanthony P. Les Yeux des Peintres. Lausanne, Switzerland:
L’Âge d’Homme; 1999.
13. Boggs JS, Loyrette H, Pantazzi M, Tinterow G. Degas. Paris,
France: Réunion des Musées Nationaux; 1988.
14. Vollard A. Souvenirs d’un Marchand de Tableaux. Paris,
France: Albin Michel; 1937.
15. Rouart D. Degas à la Recherche de sa Technique. Geneva,
Switzerland: Skira; 1988.
16. Certigny H, Deslandres Y, Leprohon P. La Vie des Grands
Peintres Impressionnistes. Paris, France: Éditions du Sud; 1964.
17. Porot D. Van Gogh ou le Hollandais Volant. Rueil-Malmaison:
Ceigy; 1989.
19. Lossouarn M. Médecine et Peinture. Rapports Historiques et
Actualisation. Medical Thesis No. 323; Brest, France. 1976.
20. Van Gogh V. Lettres à Théo. Paris, France: Gallimard, L’Ima-
ginaire; 1988.
21. Martin HA. La Maladie de van Gogh: Le Mystère d’une Fin
Tragique. Paris, France: Buchet-Chastel; 1994.
22. Lee TC. Ce que voyait van Gogh: une intoxication digitalique?
JAMA (French edition). 1981;3:1389-1392.
23. Arnold WN. Vincent van Gogh and the thujone connection.
JAMA. 1988;260:3042-3044.
24. Arenberg K, Countryman LF, Bernstein LH, Shambaugh GE
Jr. Van Gogh had Meniere’s disease and not epilepsy. JAMA.1990;
264:491-493.
25. Gastaut H. La Maladie de Vincent van Gogh Envisagée à la
Lumière des Conceptions Nouvelles sur l’Épilepsie Psycho-Mo-
trice. Cahors, France: Coueslant; 1956.
26. Michel FB. La Face Humaine de Vincent van Gogh. Paris,
France: Grasset; 1999.
27. Corcos M. Van Gogh, une étrange flamboyance. Gazette Med.
1990;97:73.
28. Darley P. La Pycnodysostose. Approche Diagnostique à Pro-
pos d’une Nouvelle Observation et Revue de Littérature. La Ma-
ladie de Toulouse-Lautrec? Medical Thesis. Dijon, France; 1978.
29. Flament E. Henri de Toulouse-Lautrec. Pathologie de sa
Croissance. Hypothèses. Medical Thesis. Paris, France; 1966.
30. Sejournet G. La maladie de Toulouse-Lautrec. Presse Med.
1955;63:1866-1867.
31. Desvoisins L. Henri de Toulouse-Lautrec, Essai d’Étude Cli-
nique, ses Maladies, sa Mort. Medical Thesis, Montpellier, France;
1958.
32. Beaute G. Toulouse-Lautrec Vu par les Photographes. Lau-
sanne, Switerland: Edita; 1988.
33. Pasteur Valéry-Radot L. La médecine et les médecins dans
l’œuvre de Toulouse-Lautrec. Presse Med. 1951;59:1021-1022.
34. Levy G. Réflexions sur la maladie de Toulouse-Lautrec. Sem
Hop. 1957;33:2691-2696.
35. Lamy M Marotteaux P. Les Chondrodystrophies Génoty-
piques. Paris, France: L’expansion scientifique française; 1960.
36. Courthion P. Raoul Dufy. Geneva, Switzerland: P. Cailler; 1951.
37. Camo P. Dufy l’Enchanteur. Paris, France: Éditions Margue-
rat; 1947.
38. Cogniat R. Dufy. Paris, France: Flammarion; 1962.
39. Homburger F, Bonner CD. The treatment of Raoul Dufy’s ar-
thritis. N Engl J Med. 1979;301:669-673.

HYGIE CONTRE POLYMNIE : DES MALADIES DE QUELQUES PEINTRES FRANÇAIS

C
omme tous les hommes, les peintres ont souffert de maladies: les unes survenant selon les lois
du hasard ou de la génétique, les autres étant liées à leur activité artistique (maladies « profes-
sionnelles »). L’emploi répété de solvants organiques et de pigments contenant des métaux lourds
ou des substances délétères ont probablement généré quantité de pathologies par intoxication
(alors inconnues). La survenue d’une maladie chez un artiste brouille inéluctablement sa percep-
tion au monde; ce bouleversement prend toute son importance pour le peintre qui restitue ses im-
pressions et ses sentiments par des techniques plastiques. Troubles psychiatriques, malvision, affections
neurologiques, maladies articulaires, syndromes douloureux constituent des évènements susceptibles de
transformer, modifier ou interrompre une œuvre. Parmi les peintres français, plusieurs d’entre eux fu-
rent affectés par des maladies qui influencèrent peu ou prou leur production artistique. On peut citer les
exemples d’Édouard Manet (ataxie locomotrice), d’Edgar Degas (troubles de la vision), d’Auguste Renoir
(polyarthrite rhumatoïde), de Vincent van Gogh (troubles du caractère), d’Henri de Toulouse-Lautrec
(pycnodysostose ?), de Raoul Dufy (polyarthrite rhumatoïde). Pour autant, les différentes pathobiogra-
phies présentées montrent que la maladie ne fut jamais un obstacle à l’expression du génie artistique; au
mieux, le peintre s’adaptait à sa pathologie en trouvant de nouveaux moyens pour exprimer son art, au
pire, il disparaissait prématurément en profitant de sa courte vie pour faire exploser sa créativité.

Hygeia versus Polymnia: some French painters and their diseases – Régnier MEDICOGRAPHIA, VOL 27, No.3, 2005 287
A T O U C H O F F R A N C E

Isabelle SPAAK
37 rue des Plantes
75014 Paris, France
(e-mail: isabelle.spaak@wanadoo.fr)

In van Gogh’s footsteps

in Auvers-sur-Oise
by I. Spaak, France

I
n the lovely cemetery in Auvers-sur-Oise stand two graves, leaning against the wall. They are cov-
ered with a mantle of ivy giving the impression that there is in fact just one grave. Only the simple
inscriptions on the gravestones and the rather sad bunch of plastic sunflowers indicate that under
this little corner of soil and sand facing the gentle valleys of the Oise lie the remains of Vincent van
Gogh and his brother Theo. Auvers is only 30 kilometers north of Paris, and it was to this village set in
the peaceful countryside that Vincent van Gogh arrived by train on May 21, 1890. It was here, too, 70
days later, on July 29, that he died in the arms of his brother. During this short period of time, Vincent
produced 77 paintings, some of which feature among
his most important works, as well as 30 drawings and
an engraving.
Grief-stricken, Theo died six months later in Utrecht,
on January 21, 1891. His widow, Johanna requested that
Theo’s remains be buried alongside his brother’s in the
graveyard of this charming French village. His ashes
were in fact transferred to Auvers-sur-Oise in 1914.

View of the charming village of Auvers-sur-Oise, which lies

to the north of Paris in the valley of the river Oise. It was
here that Vincent van Gogh spent the last few months of his
life. The village itself and the surrounding countryside pro-
vided van Gogh with inspiration for some of his most famous
paintings. The Oise region was in fact much frequented by
painters in the latter part of the 19th century. In particular,
Cézanne painted a view of the village. © Moulu/Sunset.

J
ust 30 kilometers (19 miles) from Paris lies the pretty valley of the Oise where Vincent van Gogh
spent the last weeks of his life before committing suicide. After mutilating his ear on Decem-
ber 24, 1888, he entered the Saint-Paul-de-Mausole Asylum in Provence where he spent nearly
one year. He had only one wish: to flee the heat and blinding sunlight of the south for the milder
climes of the north. This he managed to do thanks to his brother Theo, who recommended him to
a physician — Dr Gachet — who could look after him in the attractive little village of Auvers-sur-
Oise where he had a house. Vincent arrived on May 20, 1890 full of enthusiasm for this peaceful, verdant
region. He thought it was just the place he needed and threw himself into his work with zeal. But the respite
did not last long. After alternating between moments of great happiness and periods of profound anguish,
Vincent finally shot himself in the chest on the afternoon of July 27, 1890, and died in the night two days
later in the arms of his brother. During the 2 months he spent at Auvers, he did about 30 drawings, one
engraving, and 77 paintings, out of the 879 that have been attributed to him. The Portrait of Dr Gachet,
The Church at Auvers, Daubigny’s Garden, and Wheat Field with Crows, are essential landmarks in the
history of painting.
Medicographia. 2005;27:288-295. (see French abstract on page 295)

288 MEDICOGRAPHIA, VOL 27, No.3, 2005 In van Gogh’s footsteps in Auvers-sur-Oise – Spaak
 A T O U C H O F FR A N C E

Steeped in memories of its famous adopted son

In the village, each alleyway, each meadow, and each empty lane,
seems to recall the passage of one of the greatest painters of the
19th century. “It was at this window on the first floor that Vincent
painted his only painting of the interior,” explains Maryvonne
Grandfils, who shows visitors round the Auberge Ravoux, an un-
pretentious building where the artist rented a garret. It was here,
under the rooftops, after a night and day of agony, that he died in
his little iron bed. On the afternoon of July 27, 1890, in a field of
wheat and under a burning sun, van Gogh shot himself in the
chest before dragging himself back to the inn to die.
Today, 125 years later, on a beautiful September afternoon,
Madame Grandfils, the faithful and respectful guardian of the
memory of this vulnerable person whose life she knows by heart
suggests we walk round the village and the surrounding country-
side, before introducing us to the intimacy of the upstairs gar-
ret that has been faithfully restored to give the impression that
Vincent has just left it. “Make the most of the beautiful light, go
wherever your feet lead you,” she advises. “Don’t hesitate to en-
ter the little wood, you will find a quite charming walk.” She is
right. The locality exudes calm and peace. Especially off-season,
this pilgrimage is a must. One almost wonders whether van Gogh,
a Dutchman, has not been adopted as a son of the village given
Self-Portrait With Straw Hat. 1887. This is one of several the many tributes that are paid to him.
self-portraits that van Gogh painted during his lifetime, and
was executed during his stay in Paris, the painter’s most
prolific time in terms of output, two years before the famous The village and the paintings: mirror images
incident when Vincent cut off his left ear. Oil on canvas, First of all there are the panels to which his paintings are fixed.
54  46 cm. Rijksmuseum Vincent van Gogh, Amsterdam They are to be found everywhere in the village, in the main street,
(Vincent van Gogh Foundation).
and at vantage points. They show exactly where van Gogh’s can-
vases were painted, allowing the person viewing to contrast the reality with the artist’s interpretation,
like an art history lesson in front of the original subject. The panels are located in front of the church, op-
posite the town hall, and facing Daubigny’s Garden, and are all examples of the chromatic intensity and
swirling touch of the “man suicided by society” as Antonin Artaud described him. The poet had been in
a state of ecstasy before the work of van Gogh at an exhibition in the Musée de l’Orangerie in Paris in 1947.
Artaud was fascinated by “the most genuine painter of all painters, who did not paint lines or forms, but
inert natural things that seem to be in a state of violent convulsion.” It is this representation of the world
that confronts the visitor each time he or she comes across one of these metallic panels and tries to work
out the viewing angle and the position of the easel, and looks for differences between the painting and per-
spective, until finally one is won over by the “bludgeon with which van Gogh never ceases to strike all forms
of nature and objects.” In his paintings, reality is transformed by anguish, by the fundamental anxiety of
all beings confronted by an object. Even the most innocent view of a tumbledown cottage could conceal a
secret. The church, peaceful on its
hillock, seems twisted in the paint-
ing by a mystical force. It vibrates
with an internal light against a
background of a tortured, almost
black, sky. The town hall proudly
displaying its red, white, and blue
flag for the 14th of July celebration
becomes, in the hands of the painter,

Thatched Cottages at Cordeville.

Painted in June 1890. On his arrival in
the Auvers region, Vincent van Gogh
was immediately struck by the number
of buildings with thatched roofs in the
area, as they were becoming a rarity, and,
indeed, he produced several canvases of
thatched cottages during his brief spell
there. Oil on canvas, 72  91 cm.
Musée d’Orsay, Paris. © AKG Images.

In van Gogh’s footsteps in Auvers-sur-Oise – Spaak MEDICOGRAPHIA, VOL 27, No.3, 2005 289
A T O U C H O F FR A N C E

Below: photograph showing the church at

Auvers-sur-Oise made famous by the paint-
ing by Vincent van Gogh. © Paul Cooper/
Rex Features/Sunset.
Right: van Gogh’s representation in his
painting The Church at Auvers, one of
his best-known works. Painted June
1890. The rather crooked church and
the dark swirling sky create a
sinister, violent effect. Oil
on canvas, 94  74 cm.
Musée d’Orsay, Paris.
© AKG Images.

a sinister scene, the representation of infinite solitude in this square with its pennants drooping sadly
between two spindly trees. This is the state of abandonment that the artist must have felt in this peace-
ful village where he continued to fight against the demons he thought he had got away from after his year
at the Saint-Paul-de-Mausole Asylum in Provence.

A safe haven from depression?

It was to escape from the blinding light of the south of France that he had taken refuge in this village in the
clement Oise valley. But to no avail. Even the innocent Daubigny’s Garden—“one of my most sought-after
canvases,” he wrote to Theo around July 23, 1890—was metamorphosed under his paintbrush into a series
of disturbing convolutions among an overabundance of flowers. “Everywhere,” according to Artaud, “the
landscape paintings reveal their hostile tones, their anger at being disemboweled.” Above the village, it is
finally the Wheat Field with Crows that greets the visitor. The place has not changed. No building has come
to disfigure the plot of ploughed land. Even though we know today that this canvas is not the last one paint-
ed by van Gogh, there is no denying that references to his suffering are everywhere in the dramatic portray-
al of this landscape that at first glance seems innocuous. “There are vast fields of wheat beneath a tortured
sky,” Vincent wrote to Theo, “and I did not need to look far to capture the extreme sadness and loneliness.”
Each stroke of his paintbrush breathes disquiet, the aberrations of a lost man. Beyond the more or less fan-

Wheat Field With Crows. This picture, which van Gogh painted in July 1890, is considered by many to be his last
painting before his suicide, although there is no evidence for this. This belief stemmed from the turbulent style in
which he painted this piece with its darkening blue sky and the black of the crows, which were thought to portend
an ill omen. The three paths in the painting leading to nowhere are believed by some to reflect the impasse van
Gogh felt he had reached in his life. Oil on canvas, 50  100.5 cm. Rijksmusem Vincent van Gogh, Amsterdam;
Vincent van Gogh Foundation.© AKG Images.

290 MEDICOGRAPHIA, VOL 27, No.3, 2005 In van Gogh’s footsteps in Auvers-sur-Oise – Spaak
 A T O U C H O F FR A N C E

ciful interpretations that this painting attracts, it nonetheless undoubtedly conceals a few symbolic keys in-
cluding the three tracks that disappear in three different directions, all without an exit. Does this reflect the
point of no return that van Gogh had reached? This is entirely possible. Then there are the crows painted,
in the words of Artaud, “truffle black, rich banquet black.” Birds of ill omen that “did not open the door to
posthumous glory,” but which allowed him to open “…the door…to an enigmatic and sinister afterlife.”
Though the fields have changed little since van Gogh knew them in the summer of 1890, the reputation
of this tortured man has changed dramatically. It was a broken painter who stepped down onto the rail-
way platform on May 20, 1890, a hard-up artist who, in his life, had sold only one single painting, The Red
Vineyard, for 400 francs, but whose works today are among the most expensive on the market.
The 427 million francs paid in New York on May 15, 1990, for the Portrait of Dr Gachet painted 100 years
earlier, from June 3 to 5, 1890, seem indecent when one remembers the misery of the painter’s existence.
The price makes a mockery of the measly 150 francs a month that Theo managed to scrape together as a
kind of allowance for his brother—a more than modest sum that the painter did not always receive and
for which he felt guilty, especially after Theo became the father of a son, Vincent, born on January 31, 1890,
and was having difficulty feeding his little family.

The controversial Doctor Gachet

The main figure during the painter’s last few weeks was Dr Gachet, a rather strange character. An eccen-
tric practitioner, he befriended the numerous impressionists who lived in the Oise area and collected their
works. He was also a painter in his spare time, and signed his few inferior works “P. van Ryssel.” Initially,
Theo had hoped that a mutual friend, Camille Pissarro, would be able to look after his brother. However,
married, with six children, and having just lost his mother, and himself unwell, Pissarro felt he could not
take on someone who needed a lot of attention and was often subject to violent attacks. So, instead, Theo
recommended Dr Gachet who had a medical practice in Paris and a house in Auvers-sur-Oise, a favorite
spot for painters and Parisians in
search of green fields. Since April
1889, Vincent had dreamed of leav-
ing the asylum at Saint-Rémy-de-
Provence where he had stayed for
one year. He wanted to get back to
work as quickly as possible after
his last attack, and take advantage
of a period of calm. “I am sure that
in the north I will recover rapidly,
and will be well for at least some
time, even though I may relapse
Village Street and Steps in in a year or two.” He encouraged
Auvers With Figures. This
painting dates from late May Theo to write to Gachet, and, to
1890, just after van Gogh’s speed things up, even suggested
arrival in Auvers-sur-Oise. what should go in the letter: “My
© AKG Images.
brother would very much like to
meet you…, he hopes you will approve of his spending several weeks in your village where he wants to
do some studies. He is sure he will get on well with you, and believes that his return to the north will ben-
efit his illness, whereas a longer stay in the Midi would risk harming his health.”
On May 20, his wish was granted and he finally met Dr Gachet. After an exhausting journey, he had ar-
rived in Paris three days earlier, on May 17, weighed down with about 60 pounds of luggage and impatient
to see Theo again, and to meet Johanna, his sister-in-law, and of course little Vincent, now 6 months old.
He made a good impression on Theo’s young wife, but could not stand the noise and bustle of the city for
long. After remaining shut in for a whole day in the apartment at 8, Cité Pigalle, while he contemplated
his paintings spread out on the floor, he agreed the following day to visit his brother’s stock of paintings,
where the works of Guillaumin, Gauguin, and Russel were piled up with his own. The two brothers also
visited an exhibition at the Salon du Champ-de-Mars, then the time came for Vincent to leave for the coun-
tryside exhausted. He finally arrived at Auvers with three paintings under his arm and a letter of intro-
duction for the doctor whom he found “rather eccentric.” This first impression is even rather reserved,
since he wrote to Theo that the doctor “appeared to be afflicted at least as seriously as I am.” Full of “black,
black antiquities,” his large white house built at the foot of a chalk cliff did not impress Vincent either. Was
it by prudence, the need for independence, or for reasons of economy that he opted to take a room at the
Auberge Ravoux that was cheaper, only 3.50 francs per day compared with 6 francs, and was further away
from Gachet’s house than the inn at Saint-Aubin that the doctor had recommended?

In van Gogh’s footsteps in Auvers-sur-Oise – Spaak MEDICOGRAPHIA, VOL 27, No.3, 2005 291
A T O U C H O F FR A N C E

Solace in a frenzy of paintings

Though he was seduced by the village and its “many thatched roofs, which is becoming rare,” and by
the region “...it is extremely beautiful, a typical picturesque open countryside,” his relations with Gachet
were not what he had hoped for. “I cannot rely on Dr Gachet at all,” he wrote several weeks after his ar-
rival. Yet, to begin with, he thought he could make a real friend of this old man who loved art and seemed
to have known Manet, who had discovered the works of Monet and Renoir at the Impressionist Exhibition
of 1874, and who also had a long friendship with Pissarro. Cézanne regularly visited Dr Gachet’s house
in 1873 during the year he spent at Auvers with his partner and son, and later Guillaumin. Having been
plunged into grief by the death of his wife in 1875, Gachet was a sad person “with a haggard face.” How-
ever, van Gogh adapted to the doctor. He even followed some of his recommendations: going to bed at
9 o’clock, getting up at 5 o’clock, and warding off the return of attacks by hard work. Gachet let Vincent use
a printing press he had in his attic to etch a self-portrait he was working on. Vincent also lunched with
Gachet every Sunday and sometimes on Mondays or Tuesdays to finish a canvas of Marguerite at the Piano,
the doctor’s daughter, or of his daughter in their
The Auberge Ravoux,
garden. He also decided to do a portrait of Gachet,
Auvers-sur-Oise. and was only too happy to have a model who actu-
Van Gogh spent the last ally wanted to pose. The painting shows the doctor
few months of his life at
this inn, where he rented
with “a white cap on his head, light-colored, and
an attic room, eking out very prominent, the hands in clear flesh tints, and
a meager existence on wearing a blue tail coat, against a cobalt back-
the allowance that his
brother Theo was able to ground.” More than a portrait, it is a manifesto, a
give him. The inn is today kind of social icon, whereby van Gogh expressed
an essential stop on the the misfortune that haunted this disillusioned and
itinerary of the many
visitors to the village in sad human being. The features transcend those of
search of the places that just the doctor. “I want,” explained Vincent, “to paint
van Gogh made so famous portraits that one century later people will view as
through his paintings.
© Paul Cooper/Rex apparitions. I now have a portrait of Dr Gachet bear-
Features/Sunset. ing the heartbroken expression of our time.” The

MILESTONES
March 30, 1853: Birth of Vincent at Groot-
Zundert, in the south of Holland
May 1, 1857: Birth of his brother Theodorus.
Of the five brothers and sisters, Theo was the
closest to Vincent
1869: Vincent is employed by Goupil & Co, a
company specializing in art and run by his un-
cle in The Hague
1872: Begins his lifelong correspondence with
his brother Theo
1873: He joins the London branch of the Goupil
company. First unhappy love affair with Ursula,
the daughter of his landlady
1874: He is sent to Paris by Goupil and returns
to London in December. Begins to lose interest
in his work
1875: Returns to Paris
From 1876 to 1880: Sacked by Goupil for neg-
ligence. Returns to England to become assis-
tant to a clergyman. Goes to Amsterdam to
prepare for entry to a seminary. Travels to the
mining region of Borinage to help the disad-
vantaged miners. Wears himself out. His reli-
gious fanaticism reaches its peak. He breaks
off all contact with his family during 1879
1880: Decides to devote himself to art
1881 to 1882: Falls in love with his cousin
Kee, who rejects him. Sinks into depression.
Returns to The Hague and the studio of Anton
Mauve. Takes up with a prostitute, Sien, who
breaks with him in 1882. Theo pays Vincent
an allowance of 150 francs/month
1883: Seeks solitude. Returns to his parents at
Nuenen
1885: Sudden death of his father. Leaves for
Antwerp in Belgium
1886-1887: Theo and Vincent settle in Paris.
His first attacks occur. Alcoholism. Frequents
the boutique of Julien (“Père”) Tanguy, a dealer
in paintings and art
February 1888: Settles in Arles
October 1888: Arrival of Paul Gauguin
December 1888: Severs his ear after a violent
dispute with Gauguin
1889: Vincent enters the asylum at Saint-Rémy
and leaves it one year later
March 1890: Ten of van Gogh’s paintings are
exhibited at the Salon des Indépendants
May 20, 1890: Arrives at Auvers-sur-Oise
July 27, 1890: Shoots himself in the chest
July 29, 1890: Dies at dawn. He is 37 years
old

292 MEDICOGRAPHIA, VOL 27, No.3, 2005 In van Gogh’s footsteps in Auvers-sur-Oise – Spaak
 A T O U C H O F FR A N C E

Portait of Doctor Gachet. Van Gogh painted two versions of this portrait,
at the request of the subject, both in June 1890. Dr Gachet, a painter
himself, was a friend of several of the Impressionists and invited them
to stay with him Auvers-sur-Oise (Cézanne did a painting of his house).
Vincent initially had high hopes of Dr Gachet, but came to realize that
he could not rely on him. In this portrait, van Gogh captured some of
the melancholic, contemplative mood to which the doctor was prone. On
the table can be seen a sprig of purple foxglove, the source of digitalis.
Dr Gachet was the only male sitter that van Gogh painted in Auvers.
Oil on canvas, 68  57 cm. Musée d’Orsay, Paris. © AKG Images.

painting showed him “leaning against a red table on which there

is a yellow book and purple foxglove” (in homage to his interest in
homeopathy). Gachet loved the portrait so much that he imme-
diately asked Vincent to paint another one for him. This second
painting is today in the Musée d’Orsay in Paris, thanks to the do-
nation made by Gachet’s son in 1949, while the first painting was
sold by Christie’s.

The tragic climax

At about this time, van Gogh’s reputation was starting to be estab-
lished through the efforts of Theo. Several artists including Guil-
laumin wanted to exchange canvases with him. In a very laudatory
article, the art critic Albert-Émile Aurier thanked him for a work painted at Saint-Rémy-de-Provence. But
the praise fell on deaf ears, all Vincent wanted was for his brother and family to come and live near him
in the country. On June 8, they all arrived after being invited to lunch by Gachet. It was a beautiful day,
Vincent was in relaxed mood and played with his little nephew, showing him the hens and ducks. The
happiness he dreamed of was within his reach. But not for long. Several days later, little Vincent became
ill and nearly died. Anxious and himself short of money, Theo made it clear to his brother that it was be-
coming more and more difficult to provide the monthly allowance. He invited him to come to Paris on
July 6 to try to find a solution, and to introduce him to Albert-Émile Aurier, and the painters Émile Bernard
and Toulouse-Lautrec. But Vincent could not stand the pressure. He cut short his visit that was meant
to last several days and took the evening train back to Auvers the very same day. He was devastated. Was it
because he had seen his paintings decaying in the squalid storeroom belonging to the art-dealer Julien
(Père) Tanguy? Was it his fear for the life of little Vincent and for his mother exhausted after nights of
watching over her son? Was it the prospect of being alone for several days while Theo and his family were
in Holland? Was it, above all, the prospect of having to stop painting due to lack of money? In spite of a
letter from Johanna that comforted and reassured him concerning little Vincent, he did not recover from
the storm that was threatening his livelihood. He did not know how to react. He felt helpless confronted

Marguerite Gachet in
the Garden. Executed in
June 1890, this was one
of two paintings van
Gogh did of Dr Gachet’s
daughter. Oil on canvas,
46  55.5 cm. Musée
d’Orsay, Paris. © Photo
RMN - Gérard Blot.

In van Gogh’s footsteps in Auvers-sur-Oise – Spaak MEDICOGRAPHIA, VOL 27, No.3, 2005 293
A T O U C H O F FR A N C E

Vase With Irises Against a Yellow Background.

This still life was painted in Saint-Rémy,
in May 1890, just before Vincent left to live in
Auvers-sur-Oise. He discovered the iris motif
in the garden at the asylum at Saint-Rémy and
produced several pictures with these flowers as
the main subject during this period. Oil on canvas,
92  73.5 cm. Rijksmuseum Vincent van Gogh,
Amsterdam. Vincent van Gogh Foundation.

with problems of money and reproached his broth-

er for leaving him stranded. “My own existence is
threatened at its very roots, my future too is totter-
ing.” He could not see any way out, except to con-
tinue working relentlessly “even though the paint-
brush is falling from my hands.” On July 14, Theo
left Paris for Holland instead of taking several days’
rest at Auvers as Vincent had so desperately hoped.
Was it the coup de grâce for this abandoned soul?
We will never know. Even though on his return Theo
immediately sent his brother a 50 franc note, noth-
ing could stop Vincent from taking the fatal step.
He left his little garret at the Auberge Ravoux after
lunch, took the street that runs through the village, climbed the hill, and there, alone, facing the fields,
shot himself in the chest. It was July 27, 1890 and Vincent was just 37 years old. The innkeeper, seeing he
had not returned for supper, was starting to worry, when Vincent finally arrived and went straight upstairs
to his room. It is in this little garret under the roof with its cracked walls, splashes of grayish paint, and
faithfully restored mildew that all visits to Auvers-sur-Oise end. It was here that Ravoux found the painter
in agony. He summoned the doctor who lived opposite, then Dr Gachet, who administered first aid, but
they decided not to remove the bullet as it was lodged just below the heart. Theo was informed in Paris and
arrived panic-stricken late the following morning. Despite Vincent’s strong constitution, he was writhing
“in terrible agony.” He died on July 29 at 1:30 AM leaving an unfinished letter to his brother in which he
explained: “In my kind of work, I risk my life.” ❒

PRACTICAL GUIDE TO AUVERS-SUR-OISE

◆ How to get there
By road: Take the A15, direction Cergy Pontoise, leave
the A15 at exit 7, direction Méry and Auvers.
By train (about one hour). Leave from Gare Saint-Lazare.
Change at Pontoise for Auvers.
Information: Tourist office: 00 33 1 30 36 10 06,
E-mail: otsi.auvers@wanadoo.fr

Photograph showing the gravestones of Vincent van Gogh and
his brother Theo, in the cemetery at Auvers-sur-Oise. Theo died
just 6 months after Vincent’s death in Utrecht, the Netherlands,
on January 21, 1891. His wife, Johanna, requested that Theo
be buried alongside his beloved brother, which was finally
achieved in 1914 when his ashes were transferred to Auvers.
© Rasmussen/Diaporama.
◆ What to see
The Château d’Auvers. Visit with spectacle “In the foot-
steps of the impressionists.”
Tel: 00 33 1 34 48 48 45. www.château-auvers.fr
Auberge Ravoux, called the Maison van Gogh.
Tel: 00 33 1 30 36 60 60
Musée Daubigny. Tel: 00 33 1 30 36 80 20
Atelier Daubigny (workshop). Open only from Easter to
All Saint’s Day (November 1). Tel: 00 33 1 34 48 03 03
Musée de l’Absinthe. Tel: 00 33 1 30 36 83 26

294 MEDICOGRAPHIA, VOL 27, No.3, 2005 In van Gogh’s footsteps in Auvers-sur-Oise – Spaak
 A T O U C H O F FR A N C E

WORK AS A TREATMENT FOR “MENTAL WEAKNESS”

No idea was more disagreeable to van Gogh
than Cézanne’s belief that he would produce “the
paintings of a madman.” And, in August 1889,
while in the asylum at Saint-Rémy, Vincent wrote
that he hated nothing more “than having to ask
a doctor for permission to do a painting,” and was
convinced “that if sooner or later I am more or
less cured, it will be because I have cured myself
by working.” Though the genius of the painter is
beyond question, it is evident that this fragile per-
son painted despite (or perhaps because of) the
more or less clear-cut symptoms of his mental
illness manifested by the mutilation of his ear at
Arles in 1888, his repeated attacks, his confine-
ment in the asylum at Saint-Rémy-de-Provence
in 1889, and his suicide in Auvers in 1890. Ac-
cording to a study by Doctor Jean-Marc Boulon,*
Concerning the Clinical Case of Vincent van
Gogh, the diagnoses of contemporary psychia-
trists suggest “manic-depressive psychosis with
acute mania with hallucinations and delusions
complicated by epileptic fits that are exacerbated
during periods of undernutrition, overwork, or
intoxication with absinth, digitalis, potassium
bromide (prescribed at Arles), camphor, and car-
bon monoxide, as well as by his excessive addic-
tion to coffee and smoking.” The cause of the bi-
polar disorder should be looked for, as in all
patients with alternating periods of euphoria and
depression, in the family history and a probable
genetic origin. These periods of intense depres-
sion with mutism, nonproductivity, and melan-
cholia, that can even lead to suicide, alternate
with moments of hyperactivity (also called hypo-
mania), thanks to which van Gogh was able to
create his large number of paintings and to pen
his voluminous correspondence.
*Association Saint-Paul-de-Mausole, Route des Baux
BP 39, 13532 Saint-Rémy-de-Provence Cedex.
Tel: 00 33 4 90 92 77 00.

SUR LES TRACES DE VAN GOGH À AUVERS-SUR-OISE

C’
est à trente kilomètres de Paris, dans une jolie vallée de l’Oise que le peintre Vincent van
Gogh passera ses dernières semaines avant de se donner la mort. Après avoir été interné près
d’un an à l’asile de Saint-Paul-de-Mausole, en Provence, suite à la mutilation de son oreille le
24 décembre 1888, il ne rêve que d’une chose : fuir la chaleur et la lumière trop brutale du sud
pour retrouver la douceur du nord. C’est chose faite grâce à son frère Théo qui le recommande
à un médecin – le Dr Gachet – qui pourra s’occuper de Vincent dans le joli petit village d’Auvers-
sur-Oise où il possède une maison. Le peintre arrive le 20 mai 1890 plein d’enthousiasme pour cette ré-
gion paisible et verdoyante. Il pense avoir trouvé la paix et se remet au travail avec fougue. Mais, le répit
est de courte durée. Alternant des moments de grands bonheur avec d’autres d’angoisse profonde, il finit
par se tirer une balle dans la poitrine le 27 juillet 1890 dans l’après-midi et rendra l’âme dans les bras de
son frère dans la nuit du 29. Durant les deux mois qu’il passe à Auvers il aura réalisé quelques 30 dessins,
une gravure et 77 tableaux, sur les 879 qu’on lui connaît. Essentiels dans l’histoire de la peinture mo-
derne, « Le portrait du Dr Gachet », « L’Église à Auvers », « Le jardin de Daubigny » et « Champs de blé aux
corbeaux », font partie de ceux-là.
✦

In van Gogh’s footsteps in Auvers-sur-Oise – Spaak MEDICOGRAPHIA, VOL 27, No.3, 2005 295
Medicographia
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