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

U nmet N eeds in the
T reatment of D epression










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U nmet N eeds in the

T reatment of D epression
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212 MEDICOGRAPHIA, VOL 27, No. 3, 2005


Why do we need
new and better antidepressants?
by S. Montgomery, United Kingdom

Imperial College School
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
of Medicine
University of London London depression found that 25 years later only half could recall sufficient symptoms to justify a diag-
UNITED KINGDOM 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.
Address for correspondence:
Poor treatment response is often due to poor patient compliance: 30% of primary care patients
Prof Stuart Montgomery, never fill their first prescription, while a further 25% to 33% stop treatment in the first month,
Imperial College School of
Medicine, University of London,
and 62% fail to inform their physician accordingly. As a result, treatment duration in 55% to
London W13 8WH, UK 63% of cases is less than the minimum consensus recommendation of 6 months post remis-
stuart@samontgomery.co.uk) sion.7 However, even in well-conducted studies with various classes of antidepressant adminis-
Medicographia. tered for the 6 to 8 weeks generally thought sufficient to show a drug/placebo difference, non-
2005;27:213-221. response rates average 30% to 40%.

Editorial – Montgomery MEDICOGRAPHIA, VOL 27, No.3, 2005 213


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

Efficacy of specific symptoms

Some symptoms improve faster with one antidepressant than another.

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


◆ 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 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

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
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


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.

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. ❒

1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of 11. Einarson TR. Evidence based review of escitalopram in treat-
major depressive disorder: results from the National Comorbid- ing major depressive disorder in primary care. Int Clin Psycho-
ity Survey replication (NCS-R). JAMA. 2003;289:3095-3105. pharmacol. 2004;19:305-310.
2. Andrews G, Anstey K, Brodaty H, Issakidis C, Luscombe G. Re- 12. Lepola U, Wade AG, Andersen HF. Do equivalent doses of es-
call of depressive episode 25 years previously. Psychol Med.1999; citalopram and citalopram have similar efficacy? A pooled analy-
29:787-791. sis of two positive placebo-controlled studies in major depressive
3. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients disorder. Int Clin Psychopharmacol. 2004;19:149-155.
with mood disorders: follow-up over 34-38 years. J Affect Disord. 13. Detke MJ, Wiltse CG, Mallinckrodt CH, et al. Duloxetine in the
2002;68:167-181. acute and long-term treatment of major depressive disorder: a
4. Keller MB, Lavori PW, Mueller TI, et al. Time to recovery, placebo- and paroxetine-controlled trial. Eur Neuropsychophar-
chronicity, and levels of psychopathology in major depression: macol. 2004;14:457-470.
a 5-year prospective follow-up of 431 subjects. Arch Gen Psychi- 14. Montgomery SA, Huusom AK, Bothmer J. A randomised
atry. 1992;49:809-816. study comparing escitalopram with venlafaxine XR in primary
5. Lepine JP, Gastpar M, Mendlewicz J, Tylee A. Depression in the care patients with major depressive disorder. Neuropsychobiol-
community: the first pan-European study DEPRES (Depression ogy. 2004;50:57-64.
Research in European Society). Int Clin Psychopharmacol.1997; 15. Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M,
12:19-30. Hindmarch I. Absence of discontinuation symptoms with agome-
6. Donoghue JM, Tylee A. The treatment of depression: prescrib- latine and occurrence of discontinuation symptoms with paroxe-
ing patterns of antidepressants in primary care in the UK. Br J tine: a randomized, double-blind, placebo-controlled discontin-
Psychiatry. 1996;168:164-168. uation study. Int Clin Psychopharmacol. 2004;19:271-280.
7. CINP Task Force. Impact of neuropharmacology in the 1990s— 16. Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide in 406
strategies for the therapy of depressive illness. Eur Neuropsycho- mood-disorder patients with and without long-term medication:
pharmacol. 1993;3:153-156. a 40 to 44 years’ follow-up. Arch Suicide Res. 2005. In press.
8. Khan A, Khan S, Brown WA. Are placebo controls necessary 17. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake
to test new antidepressants and anxiolytics? Int J Neuropsycho- inhibitors (SSRIs) and suicide in adults: meta-analysis of drug
pharmacol. 2002;5:193-197. company data from placebo controlled, randomised controlled
9. Danish University Antidepressant Group. Paroxetine: a selec- trials submitted to the MHRA’s safety review. BMJ. 2005;330:385-
tive serotonin reuptake inhibitor showing better tolerance, but 388.
weaker antidepressant effect than clomipramine in a controlled 18. Montgomery SA, Dunner DL, Dunbar GC. Reduction of suici-
multicenter study. J Affect Disord. 1990:18:289-299. dal thoughts with paroxetine in comparison with reference antide-
10. Clerc GE, Ruimy P, Verdeau Pailles J. A double-blind compar- pressants and placebo. Eur Neuropsychopharmacol.1995;5:5-13.
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9:139-143. 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


Pourquoi avons-nous besoin

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


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

Éditorial – Montgomery MEDICOGRAPHIA, VOL 27, No.3, 2005 217


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

218 MEDICOGRAPHIA, VOL 27, No.3, 2005 Éditorial – Montgomery


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.

Éditorial – Montgomery MEDICOGRAPHIA, VOL 27, No.3, 2005 219


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

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
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

220 MEDICOGRAPHIA, VOL 27, No.3, 2005 Éditorial – Montgomery


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.

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. ❒

Éditorial – Montgomery MEDICOGRAPHIA, VOL 27, No.3, 2005 221


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-
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-

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

early morning awakening, and sleep disturbances. (such as school or work schedules) may act direct-
Abundant research has documented abnormal cir- ly or indirectly on the SCN, since they determine
cadian rhythms in biochemistry, neuroendocrine the timing of meals, sleep, physical exercise, and
function, physiology, and behavior, often linked to outdoor light exposure. The circadian pacemaker
changes in affective state. These have been reviewed has inputs to sleep regulatory centers (eg, the raphe
in detail elsewhere; the findings are not homoge- nucleus, the dorsolateral hypothalamus [orexin],
neous, even though a certain pattern appears char- ventrolateral preoptic area),15 and sleep centers talk
acteristic of depression — there is increased vari- back to the clock.16 The timing and architecture of
ability in day-to-day rhythms, decreased circadian sleep is considered to be a consequence of interac-
amplitude, and circadian phase that is either ear- tions between the circadian pacemaker and a home-
ly (advanced) or late (delayed).5-11 Bipolar disorder ostatic process of rising sleep pressure, dependent
seems to be most clearly linked to abnormal or on the duration of prior wakefulness, that declines
changing circadian rhythm phase.6 In addition, al- during sleep (the “two-process model”).17
terations in the sleep EEG in depression, although
neither pathognomonic nor specific, display recog- Mood is dependent on both
nizable patterns of disturbance.12 time of day and time awake

Principles of circadian timing This parsimonious two-process model has been able
and sleep regulation to explain much of the physiology of sleep as well as
of aberrant sleep-wake cycle behavior. Protocols de-
The biological timing system is schematically de- veloped to analyze the contributions of circadian
scribed in Figure 1. Circadian oscillators are found phase vs the sleep homeostat have provided fasci-
in every organ and every cell — the so-called “pe- nating information not only about sleepiness—as
ripheral clocks.”13 A master pacemaker or biologi- might be expected—but also that mood is similarly
cal clock in the suprachiasmatic nuclei (SCN) coor- 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
SCN PVN Pineal
good a mood, but this improves throughout the day
Melatonin 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
Peripheral time awake. If the temporal alignment between the
Sleep clocks
regulating sleep-wake cycle and the circadian pacemaker af-
centers 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
Figure 1. Schematic representation of the circadian timing system. Light ( ) of diurnal mood variation as a characteristic of de-
is the major zeitgeber reaching the biological clock in the SCN via special- pressive state may indeed arise from phase relation-
ized “circadian photoreceptors” in the retina ( ). A multisynaptic pathway to
the pineal gland via the paraventricular nucleus (PVN) drives the nocturnal ships gone awry.
synthesis of melatonin and its suppression by light. Melatonin feeds back on Diurnal mood variation can be manipulated by
receptors in the SCN. The SCN also synchronizes the timing of peripheral shifting or depriving sleep. The improvement after
clocks in other organs and cells, some of which have their own zeitgebers a night’s wake therapy usually begins in the second
(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
half of the night or the next day, suggesting that
area, the dorsolateral and posterior hypothalamus, and the raphe nucleus. staying awake prevents the nocturnal plunge in
mood.10 Furthermore, a phase advance of sleep tim-
dinates these circadian rhythms in brain and body.1 ing has been able to induce a day-by-day change in
The SCN is synchronized to the external light-dark diurnal mood patterns over many weeks—evidence
cycle primarily by retinal light input. A specialized for the profound effect of shifting phase relation-
(“nonvisual”) retinohypothalamic tract provides di- ships on mood (a more severe form of jet lag).19,20
rect neuronal connection to the SCN from novel Similar day-by-day changes in diurnal mood pat-
photoreceptors in the retinal ganglion cells that terns have been found in a “forced desynchrony” ex-
measure illuminance.14 Nocturnal synthesis of the periment carried out in major seasonal depression.21
pineal hormone melatonin is driven by the SCN;
melatonin also feeds back on melatonin receptors Shifting rhythms or sleep
in the SCN and thus melatonin belongs to the cat- can be therapeutic
egory of synchronizing agents or “zeitgebers” (light
being the major one). A serotoninergic pathway The above model helps to understand the change of
from the raphe nucleus provides nonphotic input to clinical state with time of day and after manipula-
the SCN. Nonphotic zeitgebers such as exercise, tions of sleep. The clinical findings, however, are the
sleep, or darkness are probably much weaker zeit- important point to be made—extending wakeful-
gebers than light on SCN function. Social zeitgebers ness is antidepressant. Wake therapy has been well

224 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Chronobiological strategies for unmet needs in the treatment of depression – Wirz-Justice

established as a rapid treatment for depression for

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

trials of monotherapy with light.39 Double-blind

placebo-controlled studies have now shown that
light therapy combined with an SSRI leads to more
rapid (within 1 week) and more profound (by ca

Placebo response rate (%)

30%) improvement in patients with nonseasonal
major depression.27,40 Recently, a study of light treat-
ment in chronic depression (of greater than 2 years
20 duration) yielded impressive results in this often
treatment-resistant group.41 Thus, a new genera-
tion of clinical trials supports the therapeutic effi-
10 cacy of light, alone or in combination with medica-
tion, for a variety of psychiatric disorders, and it is
to be hoped that more will follow.
0 “More darkness” is a correlate of the above: pilot
Summer Winter studies suggest that the simple measure of promot-
Autumn Spring ing long nights (more rest, more sleep, no light) can
stop rapid cycling in bipolar patients,42,43 or dimin-
Figure 4. The 10-day response rate to placebo in dou- ish manic symptoms44 — intriguing findings that
ble-blind controlled trials of various antidepressants. require replication.
Each point is a single trial.
Redrawn from reference 36: Terman M. On the question of mech- Can chronotherapeutics
anism in phototherapy for seasonal affective disorder: considera-
tions of clinical efficacy and epidemiology. In: Rosenthal NE, Ble- provide new drugs as well?
har MC, eds. Seasonal Affective Disorder and Phototherapy. New
York, NY: Guilford Press; 1989:357-376. Copyright © 1989, Guil-
ford Press. Not only are the described chronotherapeutic ap-
proaches efficacious antidepressants in themselves,
docrine function are sensitive to season. One ex- but they also offer new models for pharmaceutical
ample is presented, that of the in vivo turnover of research. Is part of the usefulness of light due to its
central nervous system serotonin in healthy hu- zeitgeber function of stabilizing phase? Is part of its
mans — much higher in summer than in winter efficacy due to serotonergic mechanisms? Given
(Figure 2).32 that the antidepressant properties of selective sero-
tonin (5-HT) reuptake–inhibiting drugs are con-
More light! sidered to be related to the 5-HT2C receptor subtype,
it is interesting that 5-HT2C receptor agonists in the
As for the seasons, the annals of psychiatry abound rat SCN mimic the effects of light.45 Serotonergic
with evidence that affective state can be modulated drugs and melatonin improve entrainment. In this
by exposure to environmental light or darkness.37 respect, the pharmacological profile of agomelatine
The diagnosis of seasonal affective disorder (SAD) fits the above model, as it is a melatonin receptor
and the development of light therapy was based on type 1 and 2 (MT1 and MT2) agonist with 5-HT2C
neurobiological models of mammalian seasonali- properties.46 Melatonin itself has no antidepressant
ty—the first treatment in psychiatry to be ground- characteristics.
ed in basic research. Although light therapy was In summary, circadian rhythm and sleep research
initially propagated by Kripke for nonseasonal de- have led to nonpharmacological therapies of de-
pression,38 initial studies were too short in dura- pression (light therapy, wake therapy) that can be—
tion to provide the convincing results that a single and should be — used in everyday practice.2,4 The
week of light therapy can now achieve in SAD: it rationale for attempting to resynchronize disturbed
is only now, 20 years on, that controlled long-term phase relationships between the clock and sleep is
studies of light at last have been and are being car- the concomitant improvement in mood. Chrono-
ried out in nonseasonal major depression, with ex- biological concepts emphasize the importance of
tremely promising results. For example, the need zeitgebers and provide psychopharmacology with
for efficacious treatment of depression during preg- a novel approach for developing “chronobiotic”
nancy without side effects on the fetus has led to drugs. ❒
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mortem. Acta Psychiatr Scand. 1980;61(suppl 280):75-85.
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Lancet. 2002;360:1840-1842. induit une amélioration marquée le jour suivant. Cette amélioration peut être
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simples retrouvent une nouvelle légitimation quand on les reconsidère à l’inté-
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« synchroniseurs », ou « zeitgebers » peut améliorer le traitement des troubles

Chronobiological strategies for unmet needs in the treatment of depression – Wirz-Justice MEDICOGRAPHIA, VOL 27, No. 3, 2005 227

Michel HAMON, PhD
UMR 677 INSERM-UMPC, Faculté
de Médecine Pitié-Salpêtrière
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-
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” pathways, but of other pathways as well. In partic-

ular, the “monoamine hypothesis” fails to explain
The monoaminergic pathways play a crucial role in the 3 to 4 weeks’ delay in the therapeutic efficacy
the control of mood and cognition, as well as of en- of MAOIs, tricyclics, SSRIs, and SNRIs. The tempo-
docrine secretions and chronobiotic rhythms, all of ral mismatch between the rapid elevations in extra-
which are disrupted in depressive states. It was thus cellular levels of monoamines induced by antide-
very logical to postulate a perturbation of mono- pressant agents, and their slow onset of therapeutic
aminergic transmission in the etiology of depres- action reflects the initiation of adaptive mechanisms
sive disorders. This has been consistently borne out involving secondary or even tertiary changes in
by the findings from monoamine depletion stud- receptor density, intracellular signaling, synaptic
ies in patients, which confirmed the importance of transmission, neuronal architecture, and neuroge-
functionally competent monoaminergic pathways nesis.4
for combating depressive states, as well as by the The aforementioned adaptive changes in mono-
proven clinical efficacy of available treatments of aminergic receptors were initially claimed to reflect
depression in restoring the compromised activity of therapeutically relevant neurobiological changes
the corticolimbic monoaminergic pathways. Drugs induced by long-term antidepressant treatment.
facilitating neurotransmission mediated by mono- Downregulation of cortical β1-adrenergic and 5-HT2A
amine neurotransmitters, especially serotonin (5- serotonergic receptors was long considered as a bi-
hydroxytryptamine, 5-HT) and norepinephrine (NE), ological marker of effective antidepressant therapy
generally exert a positive influence on mood. By with tricyclics. This was confirmed by evidence of
blocking the key enzyme in the catabolic pathways postmortem upregulation of these receptors in de-
of both 5-HT and NE, MAOIs increase the concen- pressed patients having committed suicide.5 How-
trations of these neurotransmitters in the synap- ever, other findings indicated that electroconvulsive
tic cleft at serotonergic and noradrenergic receptor therapy (ECT) was associated with upregulation of
level. In contrast, tricyclic antidepressants, which cortical 5-HT2A receptors, and that chronic treat-
have also been shown to increase the concentra- ment with most SSRI antidepressants was unable
tions of monoamines at the receptor level, act via to downregulate cortical β1-receptors. Furthermore,
blockade of the reuptake process of these neuro- functional changes after chronic administration of
transmitters from the extracellular space. Several at least some classes of antidepressants were evi-
key observations demonstrated that the resulting denced for other receptor types, especially 5-HT1A
increase in extracellular concentrations of both receptors. In particular, there have been consistent
5-HT and NE entirely accounted for the antidepres- reports of desensitization of 5-HT1A autoreceptors
sant effects of tricyclics. Drugs were therefore de- in the dorsal raphe nucleus, with no changes in
signed to mimic the inhibitory effects of tricyclics hippocampal 5-HT1A heteroreceptors, after chronic
via specific action on the 5-HT transporter (selec- treatment with MAOIs, SSRIs, or NK1 receptor an-
tive serotonin reuptake inhibitors, or SSRIs) or the tagonists6,7 as well as after transcranial magnetic
NE transporter (selective norepinephrine reuptake stimulation8 and ECT.9 In contrast, hypersensitivi-
inhibitors, or SNRIs), or both. These drugs, which ty of hippocampal 5-HT1A receptors with no changes
increased extracellular concentrations of 5-HT, NE, in 5-HT1A autoreceptors has been found to occur
or both, were shown to exert potent antidepressant in response to chronic administration of tricyclic
actions, and are currently the drugs most widely antidepressants.10,11 Nevertheless, the “monoamine
used in the treatment of major affective disorders. hypothesis” did not entirely account for the action
Second-generation antidepressants are safer than of the antidepressants, and researchers began look-
first-generation agents because SSRIs and SNRIs ing for other possible mechanisms of action.
do not generally interact with the various receptor
types (histaminergic, cholinergic, α-adrenergic, etc) Other approaches to the
on which tricyclic antidepressants act as antago- understanding of the mechanism
nists. Nevertheless, second-generation antidepres- of action of antidepressant drugs
sants offer little advantage in terms of efficacy, and
there remains a need for antidepressants that do not An important consideration was that of the possible
require several weeks of administration prior to full involvement of the hypothalamo-pituitary-adreno-
expression of clinical efficacy.1,2 Furthermore, there cortical (HPA) stress axis: upregulation of gluco-
is also a need to reduce undesirable side effects, corticoid receptors, notably in the hippocampus,
such as sexual dysfunction, insomnia, and weight was evidenced with various antidepressant drugs
gain, which make the use of at least some of these following long-term administration. This change
drugs rather delicate, since they compromise pa- is very probably linked to the therapeutic action of
tient compliance and reduce drug efficacy.3 these drugs, since it contributes to restoring normal
It is now well recognized that synaptic facilita- functioning of the depression-associated deficient
tion and augmentation of the levels and effects of negative feedback control of the HPA axis, there-
NE and 5-HT are only part of the explanation of the by decreasing excessive cortisol secretion back to
action of antidepressants. The pure “monoamine normal in depressive patients. High levels of gluco-
hypothesis” is too restrictive, and depression can- corticoids are generally associated with a negative
not be simplistically ascribed to the dysfunction of influence upon mood, as well as deleterious struc-
monoaminergic systems only. Rather, it reflects a tural changes in the hippocampus, perhaps via re-
complex disruption not only of monoaminergic duced brain-derived neurotrophic factor (BDNF)

Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others MEDICOGRAPHIA, VOL 27, No. 3, 2005 229

synthesis, excessive glutamate release, and/or re- havioral effects. In addition, the antidepressants
duced neuronal glucose uptake.4 In line with these have been found to modulate the expression of var-
findings, glucocorticoid synthesis inhibitors and ious factors involved in cell survival and growth,
glucocorticoid receptor antagonists have been re- such as cyclic adenosine monophosphate response
ported to exert antidepressant-like effects.12,13 element binding protein (CREB), bcl-2, and mito-
Consistent with the hypothesis of a causal rela- gen-activated protein (MAP) kinases.4,29,30
tionship between functional abnormalities in the Finally, the complex pattern of mutual interac-
HPA stress axis and affective disorders, several stud- tions between glutamatergic and monoaminergic
ies have demonstrated elevated levels of cortico- networks plays a crucial role in the control of mood
tropin-releasing factor (CRF) in the cerebrospinal and cognition.31,32 Excessive corticolimbic gluta-
fluid of patients with moderate-to-severe depres- mate release upon chronic exposure to stress may
sion. Indeed, treatment with antagonists at CRF contribute to the development of depressive states.33
receptors were shown to relieve behavioral deficits In this regard, most studies have focused on the
in animal models of depression14,15 and to improve role of detrimental N-methyl-D-aspartate receptor
mood in depressed subjects. (NMDA)–mediated alterations in the structure of
Neurokinin type 1 (NK1) receptor antagonists hippocampal neurons.4,31 A number of antidepres-
have been claimed to exert antidepressant activi- sants, as well as ECT, exert regulatory actions on the
ty independent of monoamines in relevant animal NMDA receptor complex, and some NMDA receptor
paradigms as well as in humans, by inhibiting the antagonists have antidepressant-like properties.34
action of substance P, a tachykinin neuropeptide
that is localized in brain regions involved in the con- Depression and abnormal
trol of stress and emotion.16 circadian rhythms
However, there is a possibility that both CRF and
NK1 antagonists may also act, indirectly, through In humans, the circadian pacemaker, or biological
monoaminergic mechanisms. Indeed, tachykinin clock, is the site of the generation and entrainment
NK1 receptor antagonists activate noradrenergic of circadian rhythms. It is located in the suprachi-
and dopaminergic pathways innervating the hip- asmatic nuclei (SCN) of the anterior hypothalamus.
pocampus and the frontal cortex, and long-term The great majority of physiological, metabolic, and
treatments with these antagonists produce the same behavioral functions are controlled by the circadian
adaptive changes in 5-HT neurotransmission (no- pacemaker and are often used as circadian phase
tably, functional desensitization of 5-HT1A auto- markers. The circadian pacemaker is sensitive to
receptors, responsible for increased 5-HT tone) as light throughout the 24-h cycle and to the phase-
those observed after chronic treatment with MAOIs shifting effects of various chemical and pharmaco-
or SSRIs.17 In addition, recent investigations clear- logical components, including melatonin, which
ly demonstrated that CRF antagonists indirectly acts on the circadian clock through melatonin re-
enhanced the activity of serotonergic pathways4,18 ceptors located in the SCN.35
although they do not, unlike tachykinin NK1 recep- A wide range of affective disorders, including uni-
tor antagonists, activate dopaminergic input to the polar and bipolar depression, mania, seasonal af-
cortex and may inhibit the activity of noradrener- fective disorder, and premenstrual dysphoric disor-
gic neurons.19,20 der, are characterized by disorganization of internal
Levels of BNDF are usually found to be increased rhythms.
in response to long-term antidepressant drug treat- Disruption of the circadian timing system can
ment. This is probably related, at least in part, to manifest in several ways. The amplitude of an oscil-
the negative influence of glucocorticoids on BDNF lation can be altered, notably through changes in:
synthesis.21,22 Actually, chronic intracerebroventric- (i) the number of SCN neurons or their connections
ular infusion of BDNF exerts antidepressant-like with other brain areas or peripheral targets; or (ii)
effects via activation of its receptors, TrkB .23 Find- the neuronal traffic to the effector systems. The
ings also suggest that progressive induction of BDNF phase of the rhythms can also be altered, or there
and the resulting enhancement of neurogenesis are might be a partial or complete failure to remain
causally related to the onset of antidepressant activ- driven by the prevailing light-dark cycle through
ity.24 Experimental studies on stress and antidepres- disruption of neuronal input pathways that impose
sant treatment have recently implicated neurogen- 24-h rhythmicity on the intrinsically non–24-h,
esis in the etiology of major depressive disorders.25,26 rhythmic SCN. A very large number of physiolog-
So far, all chronic treatments aimed at alleviating ical variables showing circadian abnormalities in
depression, including ECT, have been shown to depressed patients are described in the literature.
stimulate the proliferation of progenitor cells at the Alterations in circadian rhythms in body tempera-
origin of granular neurons in the dentate gyrus of ture, hormone secretions, and vigilance state very
the hippocampus.27 The precise functional signif- often accompany endogenous depression,36-39 and
icance of these newly generated neurons in the unavoidable alterations in normal circadian rhythms
pathophysiology of mood disorders is still disputed, can trigger depressive episodes in human.40 Most
but a recent study by Santarelli et al28 supports the rhythms are phase advanced with respect to the
idea that granule cell proliferation is directly relat- sleep-wake cycle, diminished in amplitude, and/or
ed to the therapeutic action of antidepressant drugs, show day-to-day variability in entrainment. Al-
since suppression of this process by x-ray exposure though altered rhythmicity could be either a cause
resulted in loss of the antidepressant-related be- or an effect of an altered affective state, the high

230 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others

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

Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others MEDICOGRAPHIA, VOL 27, No. 3, 2005 231

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

232 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others

### Controls
16 ##
### ##
14 Agomelatine
Sucrose intake (g)


12 **
*** *** ** Stress
+ Vehicle
*** ***
+ Melatonin Figure 1. Agomelatine
+ Agomelatine (morning treatment,
6 *** ***
50 mg/kg IP) in chronic
*** mild stress (effect on
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 cannot be answered at present.
As mentioned above, agomelatine does more than All new antidepressants for which new mecha-
simply mimic the action of melatonin, and it has nisms of action are claimed should be investigated
been hypothesized that the melatonin agonist prop- for the presence of possible interactions with mono-
erties of agomelatine may not, by themselves, be aminergic systems, since it is unlikely that antide-
sufficient to sustain its clear-cut clinical antidepres- pressant efficacy can be achieved without recruit-
sant efficacy. ing monoaminergic mechanisms, either directly
In addition to the properties that led to agome- or indirectly by actions upstream or downstream of
latine’s classification as a selective melatonin re- monoaminergic neurons. Because of its 5-HT2C re-
ceptor agonist, extensive studies have identified an- ceptor antagonist properties, both acute and chron-
other mode of action for this drug. Using a classic ic administration of agomelatine (10-40 mg/kg IP)
test setting for 5-HT2C antagonists, agomelatine was produce concomitant dopamine and NE overflow
found to antagonize the penile erections normally in the frontal cortex.78 It can be assumed that the
induced by 5-HT2C receptor activation in Wistar rats. stimulatory effect of agomelatine on these mono-
Penile erections were induced by administration of aminergic systems also contributes to its antide-
the 5-HT2C receptor agonists mCPP and Ro-60-0175, pressant action, since these neurotransmitters mod-
and diminished, in a dose-dependent manner, when ulate cognitive-attentional performance and mood
agomelatine was added. In contrast, melatonin ad- in the frontal cortex. On the other hand, 5-HT out-
ministration had no effect in this paradigm. It was flow is unchanged by agomelatine treatment, which
therefore concluded that this effect of agomelatine indicates that mechanisms underlying its antide-
did not involve its melatonin receptor agonist prop- pressant-like action are totally unrelated to those
erties, but, instead, that it was due to 5-HT2C recep- of tricyclics, SSRIs, and MAOIs,78,79 which all gen-
tor antagonism.77 erally elicit a marked increase in 5-HT outflow.
Recent results from receptor binding and signal-
ing studies have lent further support to the hypoth- Conclusion
esis of a secondary mode of action for agomelatine.
Analyses of receptor binding in transfected Chinese New antidepressants based on other mechanisms of
hamster ovary (CHO) cells showed that agomela- action than the monoamine hypothesis are a pro-
tine acts as an antagonist at both the 5-HT2C and mising approach in the development of drugs with
5-HT2B receptor subtype level. Agomelatine, there- better tolerance and efficacy. One of the most ex-
fore, has a unique pharmacological profile, result- citing prospects in the treatment of depression has
ing from stimulation of MT1 and MT2 receptors and been the development of the new antidepressant
blockade of 5-HT2C and 5-HT2B receptors.78 In vivo agomelatine, a compound that exhibits strong mela-
experiments in relevant animal models (see above) tonin receptor agonist activity and 5-HT2C receptor
have clearly demonstrated the reality of 5-HT2C re- antagonist properties. This unique combination of
ceptor blockade with agomelatine at doses used to pharmacological properties very probably explains
elicit antidepressant-like effects. In contrast, very the efficacy of agomelatine observed in all validat-
little is known to date regarding 5-HT2B receptor ed animal models of depression. Agomelatine thus
blockade and its possible behavioral consequences represents a new concept in the treatment of de-
in vivo (on food intake, sleep, etc). Thus, whether or pression, and provides a strong incentive for the
not blockade of the 5-HT2B receptor subtype, which development of antidepressant drugs with mixed
is expressed at low levels in the brain, contributes, mechanisms of action encompassing monoaminer-
to a more or less significant extent, to the antide- 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

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19. Lejeune F, Gobert A, Millan MJ. The selective neurokinin (NK) 46. Pacchierotti C, Lapichino S, Bossini L, Pieraccini F, Castro-
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tical dopaminergic transmission in the rat: a combined dialysis melatonin involvement in psychiatry. Front Neuroendocrinol.
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20. Millan MJ, Lejeune F, De Nanteuil G, Gobert A. Selective 47. Beck-Friis J, Kjellman BF, Aperia B, et al. Serum melatonin
blockade of neurokinin (NK)(1) receptors facilitates the activity in relation to clinical variables in patients with major depressive
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glucocorticoids affect the expression of brain-derived neurotroph- and depression are associated with low levels of urinary mela-
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22. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and roendocrine aspects of primary endogenous depression. XI. Serum
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pressives and normal controls. Psychiatry Res.1997;69:143-153. 70. Lôo H, Hale A, D’haenen H. Determination of the dose of ago-
51. Szymanska A, Rabe-Jablonska J, Karasek M. Diurnal profile melatine, a melatoninergic agonist and selective 5-HT2C antag-
of melatonin concentrations in patients with major depression: onist, in the treatment of major depressive disorder: a placebo-
relationship to the clinical manifestation and antidepressant treat- controlled dose range study. Int Clin Psychopharmacol. 2002;17:
ment. Neuroendocrinol Lett. 2001;22:192-198. 239-247.
52. Tuunainen A, Kripke DF, Elliott JA, et al. Depression and en- 71. Emsley R. Efficacy and safety of agomelatine (25 mg/50 mg),
dogenous melatonin in postmenopausal women. J Affect Disord. a melatonergic and specific serotonergic antidepressant, in the
2002;69:149-158. treatment of major depressive disorder: a randomised, double
53. Lanfumey L, Boyer PA, Hamon M, Mocaër E. Antidepressant blind placebo-controlled study. Int J Neuropsychopharmacol.
profile of the melatonin agonist and 5-HT2C antagonist melatonin 2004;7(suppl 1):S350-S351.
(S 20098). Preclinical studies. Eur Neuropsychopharmacol. 2003; 72. Bourin M, Mocaer E, Porsolt R. Antidepressant-like activity
13(suppl 4):S274. of S 20098 (agomelatine) in the forced swimming test in rodents:
54. Kopp C, Vogel E, Rettori MC, Delagrange P, Misslin R. The involvement of melatonin and serotonin receptors. J Psychiatry
effects of melatonin on the behavioural disturbances induced by Neurosci. 2004;29:126-133.
chronic mild stress in C3H/He mice. Behav Pharmacol.1999;10: 73. Bertaina-Anglade V, Mocaer E, Drieu-La-Rochelle C. Anti-
73-83. depressant-like action of agomelatine (S20098) in the learned
55. Papp M, Gruca P, Boyer PA, Mocaer E. Effect of agomelatine helplessness test. Int J Neuropsychopharmacol. 2002;5(suppl 1):1.
in the chronic mild stress model of depression in the rat. Neuro- 74. Norman TR, Cranston I, Irons J. Effect of the novel antide-
psychopharmacology. 2003;28:694-703. pressant agomelatine in the olfactory bulbectomised rat. Int J
56. Overstreet DH, Pucilowski O, Retton MC, Delagrange P, Neuropsychopharmacol. 2004;7(suppl):S461.
Guardiola-Lemaitre B. Effects of melatonin receptor ligands on 75. Daszuta A, Banasr M, Hery M, Mocaer E. Agomelatine, a new
swim test immobility. Neuroreport. 1998;9:249-253. antidepressant drug, increases cell proliferation in adult hippo-
57. Shaji AV, Kulkarni SK. Central nervous system depressant ac- campus. Society for Neuroscience 33rd Annual Meeting of the
tivities of melatonin in rats and mice. Indian J Exp Biol.1998;36: Society for Neuroscience, New Orleans, La, USA, November 8th-
257-263. 13th, 2003. 849.3.
58. Uz T, Manev H. Prolonged swim-test immobility of serotonin 76. Morley-Fletcher S, Mairesse J, Mocaer E, Darnaudery M, Vil-
N-acetyltransferase (AANAT)-mutant mice. J Pineal Res. 2001; tart O, Maccari S. Chronic treatment with agomelatine increases
30:166-170. hippocampal cell proliferation in prenatally stressed rats. Society
59. Krahn LE, Gleber E, Rummans TA, Pileggi TS, Lucas DL, Li H. for Neuroscience 33rd Annual Meeting of the Society for Neuro-
The effects of electroconvulsive therapy on melatonin. J Electro- science, New-Orleans, La, USA, November 8th-13th. 2003. 506.20
convuls Ther. 2000;16:391-398. 77. Chagraoui A, Protais P, Filloux T, Mocaer E. Agomelatine
60. Miller HL, Ekstrom RD, Mason GA, Lydiard RB, Golden RN. (S 20098) antagonizes the penile erections induced by the stim-
Noradrenergic function and clinical outcome in antidepressant ulation of 5-HT2C receptors in Wistar rats. Psychopharmacology
pharmacotherapy. Neuropsychopharmacology. 2001;24:617-623. (Berl). 2003;170:17-22.
61. Durlach-Misteli C, Van Ree JM. Dopamine and melatonin in 78. Millan MJ, Gobert A, Lejeune F, et al. The novel melatonin ag-
the nucleus accumbens may be implicated in the mode of action onist, agomelatine (S 20098, is an antagonist at 5-hydroxytryp-
of antidepressant drugs. Eur J Pharmacol. 1992;217:15-21. tamine 2C receptors, blockade of which enhances the activity of
62. Franklin M, Clement EM, Campling G, Cowen PJ. Effect of frontocortical dopaminergic and adrenergic pathways. J Phar-
venlafaxine on pineal melatonin and noradrenaline in the male macol Exp Ther. 2003;306:954-964.
rat. J Psychopharmacol. 1998;12:371-374. 79. Hanoun N, Mocaer E, Boyer PA, Hamon M, Lanfumey L. Dif-
63. Palazidou E, Papadopoulos A, Ratcliff H, Dawling S, Checkley ferential effects of the novel antidepressant agomelatine (S 20098)
SA. Noradrenaline uptake inhibition increases melatonin secre- versus fluoxetine on 5-HT1A receptors in the rat brain. Neuro-
tion, a measure of noradrenergic neurotransmission, in depressed pharmacology. 2004;47:515-526.
patients. Psychol Med. 1992;22:309-315.
64. Hartter S, Wang X, Weigmann H, et al. Differential effects of
fluvoxamine and other antidepressants on the biotransformation
of melatonin. J Clin Psychopharmacol. 2001;21:167-174. PERSPECTIVES NOUVELLES DANS LA PHYSIOPATHOLOGIE
65. Krauchi K, Cajochen C, Mori D, Graw P, Wirz-Justice A. Ear-
ly evening melatonin and S-20098 advance circadian phase and
nocturnal regulation of core body temperature. Am J Physiol. LE RÔLE DE LA MÉLATONINE ET DE LA SÉROTONINE

66. Van Reeth O, Olivares E, Zhang Y, et al. Comparative effects of epuis plus de 40 ans, la recherche sur la pathogenèse de la dépression et
a melatonin agonist on the circadian system in mice and Syrian
hamsters. Brain Res. 1997;762:185-194.
le développement de médicaments adaptés pour un traitement efficace
67. Redman JR, Guardiola-Lemaitre B, Brown M, Delagrange P, a été dominée par l’hypothèse monoaminergique, qui stipule que la dé-
Armstrong SM. Dose dependent effects of S-20098, a melatonin pression implique un déséquilibre en sérotonine, noradrénaline, et probable-
agonist, on direction of re-entrainment of rat circadian activity ment en dopamine. Bien que ces neurotransmetteurs monoaminergiques – dont
rhythms. Psychopharmacology (Berl). 1995;118:385-390.
68. Weibel L, Turek FW, Mocaer E, Van Reeth O. A melatonin les rôles respectifs sont passés en revue – soient impliqués de façon indiscutable,
agonist facilitates circadian resynchronization in old hamsters le déficit en monoamines ne rend compte seulement que d’une partie des faits,
after abrupt shifts in the light-dark cycle. Brain Res. 2000;880: et d’autres événements hormis le déséquilibre monoaminergique devraient être
69. Van Reeth O, Weibel L, Olivares E, Maccari S, Mocaer E, Turek
pris en compte. Il existe un besoin évident de médicaments antidépresseurs plus
FW. Melatonin or a melatonin agonist corrects age-related changes efficaces, mieux tolérés et d’action plus rapide. Le développement de nouveaux
in circadian response to environmental stimulus. Am J Physiol antidépresseurs dont le mécanisme d’action repose sur d’autres bases que l’hy-
Regul Integr Comp Physiol. 2001;280:R1582-R1591. 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.

Pathophysiology and treatment of affective disorders: melatonin and serotonin – Hamon and others MEDICOGRAPHIA, VOL 27, No. 3, 2005 235

Jean-Pierre OLIÉ, MD
Hospital-University Department
Mental Health and Therapeutics
Sainte-Anne Hospital

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 anxiety, pathologic personality traits, alcohol and

T clinical connotations: (i) symptom intensi-

ty: sadness, loss of interest, inhibition, and
gloomy thoughts can be evident to variable degrees,
psychotropic substance abuse, concomitant phys-
ical disease (organic brain disease, in particular),
and the persistence of negative environmental fac-
particularly if intense or threatening; the level of in- tors. Such factors can transform “difficult” or “re-
tensity or severity is readily measured using quan- sistant” depression into severe depression by virtue
titative scale scores; (ii) threat to life, whether from of its intra- and interindividual repercussions.
the physical impact of appetite loss, intense anxiety Age of depression onset may influence mood dis-
or cognitive disorganization with confusion, or from turbance severity, especially as depressive symp-
the power of suicidal ideas—both series of factors toms in children are often associated with other
define the highest emergency level: failure to mount disturbances, such as attention deficit disorder or
a rapid medical response can have irreversible con- anxiety disorder. Adolescent depression typically
sequences, in particular in the elderly; (iii) severi- presents as behavioral disturbance, which may not
ty of the functional impact on daily life, notably on only delay the diagnosis, but generate consequences
the work and family level. that can be serious and irreversible.
Severe depression also has outcome connota- As for the psychotic symptoms that may accom-
tions. Certain characteristics compound the prog- pany the depressive episode, they reflect its sever-
nosis and/or treatment resistance: concomitant ity when mood-congruent (eg, delusional ideas of
guilt or ruin); when noncongruent (eg, delusions
of persecution or of telepathy with hallucinations),

evere depression comes in a variety of presentations, from highly acute they herald a poor prognosis and are an indication
intense depression to chronic refractory states complicated by predis- for immediate first-line therapy with an antide-
position or comorbidity. Current antidepressants are often ineffective in pressant+neuroleptic or electroconvulsive therapy
depression with somatic or psychiatric comorbidity, psychotic symptoms, or (ECT). Depression associated with delusional hypo-
imminent threat to life. Pharmacologic efficacy in severe depression is difficult chondriasis is a more complex presentation, with a
to demonstrate in children and the elderly for methodological reasons. New an- high risk of developing into a chronic delusional
tidepressants are as much needed as ever, among other reasons to advance our disorder, especially if compounded by pathological
understanding of the etiopathogenesis of depressive disease and the mecha- personality traits.
nism of antidepressant action: an acute increase in synaptic cleft monoamine
levels is a clearly inadequate guide either to understanding depression or to High-intensity depression
choosing appropriate drug therapy. Improved tolerability, shortened time to
effect, and efficacy in relieving cognitive and somatic symptoms in emergency This category is readily identified by symptom num-
(life-threatening) situations are the criteria for evaluating any potential new ber and intensity, producing high scores on the
antidepressant. Montgomery-Asberg Depression Rating Scale
Medicographia. 2005;27:236-239. (see French abstract on page 239) (MADRS) or Hamilton Depression Rating Scale. Not
only low-intensity, but also high-intensity depres-
Keywords: severe depression; childhood depression; depression in the elderly; sion are often observed to respond less well to old-
antidepressant; treatment 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-
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 itors (SSRIs) are less potent antidepressants than
(e-mail: jp.olie@ch-sainte-anne.fr) imipramine. However, this has never been proven.

236 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Severe depression: from diagnosis to treatment – Olié

Imminently Depressed patients with personality disorder dif-

life-threatening depression fer in several ways from those without: earlier-onset
mood disturbance, less social support, more often
In this type of situation, ECT may be necessary, in single or divorced, more hospital admissions, and
particular as malnutrition, dehydration, suicidal in- more severe depressive symptoms with higher sui-
tent, and repeated attempted suicide all predict a cidality. The personality disorder also compounds
favorable response.2 Endogenicity and melancho- treatment resistance. An antidepressant that would
lia, on the other hand, are poorer predictors, in con- not only remain effective despite such comorbid-
trast to long-held belief.3 The best predictor of re- ity, but could also treat it, would have a definite ad-
sponse to ECT is psychomotor retardation.4 In any vantage.
event, ECT is mandatory in imminently life-threat-
ening depression, in particular because of its rapid Depression with psychotic symptoms
onset of effect and the risks of imipramine thera-
py. This underlines the need to identify drugs that Mood-congruent and non–mood-congruent are not
can act rapidly and safely in the (often malnour- categories cast in stone—they can be influenced by
ished) elderly. sociocultural factors.9 For some psychiatrists, the
The problem of time to antidepressant effect is concept of psychotic depression partly overlaps that
clearly critical in severe depression, in particular of endogenous depression. Should depression be
when there is an imminent threat to life. At pre- viewed as a continuum, stretching from nondelu-
sent, various chemotherapy strategies can be used sional depression (Kraepelin’s simple melancholia)
to lower suicide risk: restoration of the sleep-wake to severe delusional depression or delusional melan-
cycle using a hypnotic may help to relieve the de- cholia? Or should delusional depression be consid-
pression and pressure of suicidal ideas; reduction ered a specific category?10
of anxiety using an anxiolytic can prevent impulsive Comparison between delusional and nondelu-
suicide (in this context, benzodiazepines, with their sional depression reveals no differences in sex, age
potential for paradoxical disinhibitory reactions, of onset, number of episodes, or number of suicide
are best avoided in favor of other types of anxiolyt- attempts. However, cluster A personality distur-
ic, eg, levomepromazine or cyamemazine); suici- bances appear more frequent in delusional depres-
dality may also respond to drugs such as lithium. sion, and cluster B disturbances more frequent in
It is generally agreed that the efficacy of an anti- its nondelusional counterpart.11 Some psychiatrists
depressant can only be assessed after treatment for find delusional depression more frequent in bipo-
4 to 6 weeks. Certain effects may emerge earlier, of lar than in unipolar patients.12 Delusions may in-
course, heralding greater efficacy at 6 weeks.5 Tol- crease the risk of suicide, in both bipolar and unipo-
erability becomes crucial where the threat to life is lar depressives.13 The risk of mood disturbance in
physical. Posttricyclic antidepressants marked a first-degree relatives may be higher in delusional
significant advance in this regard. Safety—cardiac, than in nondelusional depression.14
hepatic, and neurologic — is mandatory. The new Delusions and hallucinations reach critical levels
antidepressants are generally much easier to use in the most serious forms of depression in which
than their predecessors, although renutrition and obnubilation facilitates the emergence of terrifying
gentle sedation often remain necessary to bridge the interpretative visions and delusional ideas. Such
gap until the onset of antidepressant effect. Under delusional presentations have become rare, proba-
such conditions, the ideal antidepressant is one with bly aborted by psychotropic agents. Thus full-blown
rapid onset of effect against anxiety and suicidality, Cotard syndrome, in which delusional negation of
combined with a high level of tolerability. organs or the entire body is combined with delu-
sional ideas of eternal damnation and immortality,
Depression with and the negation of family, space, and time, now
psychiatric comorbidity tends to be replaced by partial presentations, eg,
delusions of damnation or individual organ nega-
Clinical depression can be associated with psycho- tion. No antidepressant has proved as effective in
behavioral symptoms that reverse on effective anti- delusional depression as in its nondelusional coun-
depressant treatment. They include obsessive symp- terpart.
toms, eating disorders, irritability, and pathological Psychotic symptoms are significantly more fre-
personality traits. quent in adolescents15 and preadolescents,16 posing
Depression may also feature in the natural histo- a differential diagnostic quandary with incipient
ry of anxiety disorder or personality disorder. The schizophrenia and raising awkward management
classic example is that of panic disorder complicat- problems: older antidepressant alone, newer anti-
ed by a depressive episode: panic disorder can be di- depressant alone, or either in combination with an
agnosed in 20% to 30% of patients with depression; antipsychotic?
as a severity factor, it carries considerable psychoso- The concept of schizoaffective disorder introduced
cial impact, with a high risk of suicide.6 However, by Kasanin in 1933 raised classification problems
the prognosis may be better if depression precedes that remain unresolved. In terms of prognosis, de-
panic disorder.7 Depression is often associated with pressive schizoaffective disorder falls midway be-
generalized anxiety disorder: early-onset anxiety tween schizophrenia and major (psychotic) depres-
disorder may be a severity factor for anxiety and de- sion.17 Here too, treatment is often mixed, combin-
pression.8 ing an antidepressant with an antipsychotic.

Severe depression: from diagnosis to treatment – Olié MEDICOGRAPHIA, VOL 27, No. 3, 2005 237

Depression in of dementia, and even—for good measure— cor-

children and adolescents rect the biological parameters that tend to decline
with age.
Although midterm outcome is often favorable, the
prognosis of depression in the young is often poor, Treatment strategies
with 75% relapse at 5 years,18 thus considerably in-
creasing the risk of depression in adulthood.19 In No one antidepressant has proved more effective
addition, comorbidity is high, with character or be- than the others, including in severe depression. Cer-
havioral traits that can interfere with the diagnosis tain markers of endogenicity may predict a good
of depression and also its treatment. Hostility by response to antidepressants: absence of mood re-
the child or adolescent generates a vicious circle of activity to the environment, circadian variation,23
hostile communication that feeds, perpetuates, and psychomotor retardation, anorexia, and weight
even amplifies the underlying disorder. This may loss.24 Resistance may simply reflect greater sever-
trigger risk-taking behavior.20 In addition, environ- ity.25 Various treatment strategies are available:
mental factors can play a major role in facilitating ◆ Increasing the dose of antidepressant (the ad-
suicidal behavior. A history of depressive episode in vantages of this approach were shown with ven-
childhood is a risk factor for attempted suicide in lafaxine26).
adulthood.21 There is also the diagnostic quandary ◆ Using a different antidepressant, including a
mentioned earlier: how to differentiate between monoamine oxidase inhibitor (MAOI).27
mood disorder on the one hand and depression in ◆ Combining two drugs with complementary phar-
an incipient chronic schizophrenic on the other? It macologic effects, eg, an SSRI with an β-blocker
is still difficult to demonstrate antidepressant effi- (mianserin, mirtazapine).28
cacy in child and adolescent depression. ◆ Combining an antidepressant with lithium.29,30
◆ Combining an antidepressant with T3 thyroid
Depression in the elderly hormone.31
◆ Combining an antidepressant with a partial sero-
In the elderly, it is mandatory to test for degenera- tonin 1A receptor agonist.28
tive disease when depression coexists with psychosis, ECT is the last resort, the only therapy that has
especially if there is no history of depression. Delu- proved superior to an antidepressant.32 In severe de-
sional hypochondriasis becomes more frequent pression the predictors of response to ECT are:
with age. Severe cases may present with confusion, ◆ Presence of melancholic symptoms.33
or more commonly hallucinations that can be psy- ◆ Threat to life (malnutrition, high suicide risk).34
chic, auditory-verbal, visual, or involve bodily sen- ◆ Psychotic symptoms.35
sations. ◆ Catatonic symptoms.3
Cognitive and depressive symptoms are frequent- ◆ Pregnancy or severe postpartum depression.36
ly intertwined in this age group. Over 25% of de- ◆ Advanced age.37
mentia patients first present with altered mood.22 This highlights the urgent need for new antide-
The term depressive pseudodementia is widely used pressant treatments that ideally:
to reflect the depression/dementia interface. There ◆ Advance our understanding of the mechanism
are five main clinical variants: (i) depression with of mood-elevating activity: this requires the devel-
low-grade cognitive impairment; (ii) depressive de- opment of drugs with novel neurobiologic actions,
mentia; (iii) nondepressive dementia; (iv) demen- given that the mere increase in monoamine levels
tia-induced depression; and (v) comorbidity. in the synaptic cleft is a far from adequate account
In addition to increased suicide risk in the elder- of antidepressant effect.
ly, the two other factors that compound depression ◆ Can be tailored to a patient or a type of depres-
in this age group are cognitive impairment, which sion; a current difficulty is our inability to predict
increases risks such as dehydration, and organic which antidepressant will actually be best for a par-
brain disease, which causes antidepressant resis- ticular patient or for a particular phase in the disease.
tance and heralds dementia. Because concomitant ◆ Restore normal psychological and social func-
physical ailments are so common, it is essential to tion by doing more than achieving symptom remis-
select an optimally tolerated antidepressant. The sion.
dream drug in such cases is one that would remain If such drugs could be identified, today’s severe
effective despite organic and psychiatric comorbid- depression could be more easily treated and no
ity, relieve cognitive impairment, and arrest the risk doubt prevented. ❒

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16. Chambers WJ, Puig-Antich J, Tabrizi MA. Psychotic symp- fect Disord. 2003;76:191-200.
toms in prepubertal major depressive disorders. Arch Gen Psy- 31. Hatterer JA, Stanley M. Thyroid function in refractory depres-
chiatry. 1982;39:921-927. sion. In: Roose SP, Glassman AH, eds. Treatment Strategies for
17. Coryell W, Lavori P, Endicott J, Keller M, Van Eedewegh M. Refractory Depression. Washington, DC: American Psychiatric
Outcome in schizoaffective, psychotic and nonpsychotic depres- Press; 1990:169-192.
sion. Course during a six- to 24-month follow-up. Arch Gen Psy- 32. Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S,
chiatry. 1984;41:787-791. Schulze-Monking H. Electroconvulsive therapy vs. paroxetine in
18. Kovacs M, Feinberg TL, Crouse-Novak MA. Depressive dis- treatment-resistant depression: a randomized study. Acta Psy-
orders in childhood. I. A longitudinal prospective study of char- chiatr Scand. 1997;96:334-342.
acteristics and recovery. Arch Gen Psychiatry.1984;41:229-237. 33. Abrams R, Vedak C. Prediction of electroconvulsive response
19. Harrington R, Fudge H, Rutter M, Pickles A, Hill J. Adult out- in melancholia. Convuls Ther. 1991;7:81-84.
comes of childhood and adolescent depression: II. Links with an- 34. Vanelle JM. [Predictive factors of response to electronarcosis
tisocial disorders. J Am Acad Child Adolesc Psychiatry.1991;30: (French)]. Encephale. 1991;17:399-404.
434-439. 35. Petrides G, Fink M, Husain MM, et al. ECT remission rates in
20. Pesa JA, Cowdery JE, Westerfield RC, Wang M. Self-reported psychotic versus nonpsychotic depressed patients: a report from
depression and risk-taking behaviors among Hispanic adoles- CORE. J ECT. 2001;17:244-253.
cents. Psychol Rep. 1997;81:235-243. 36. Rabheru K. The use of electroconvulsive therapy in special pa-
21. Sechter D, Bonin B, Bertschy G, Vandel S, Bizouard P. [Pre- tient populations. Can J Psychiatry. 2001;46:710-719.
diction of suicide risk (French)]. Encephale. 1991;17:361-364. 37. Benbow SM. The role of electroconvulsive therapy in the treat-
22. Yesavage J. Differential diagnosis between depression and ment of depressive illness in old age. Br J Psychiatry.1989;155:
dementia. Am J Med. 1993;94(suppl 5A):23-28. 147-152.


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


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- Failure to address compliance at the outset of

T fluence treatment outcomes in Major Depres-

sive Episode (MDE), before focusing on the
current limitations of today’s antidepressant options.
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-
Treatment of depression: choeducation program combined with antidepres-
patient variables sant medication had a significantly higher response
rate (74%) compared with those who received “usu-
◆ Compliance al care” (44%).3 These studies highlight the bene-
Compliance reflects the positive or negative inter- fits of spending time with patients, exploring their
actions among patient, drug, and prescriber vari- beliefs about depression and antidepressants, and
ables and is a significant, but frequently neglected, in providing simple “messages” about delayed on-
reason for poor treatment outcome. Results from set of antidepressant action, expected early and late
primary care studies indicate that fewer than 50% side effects, as well as the importance of continuing
of depressed patients continue to take their medi- treatment beyond response.
cation after 12 weeks.1,2 The reasons cited in both
studies are remarkably similar in content and fre- ◆ Personality dimensions
quency (Table I). Personality variables also significantly influence a
wide range of treatment-related issues. Different
personality dimensions are easily assessed using a

uccessful treatment of a Major Depressive Episode (MDE) is influenced self-report measure such as the Eysenck Personali-
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 SELECTED ABBREVIATIONS AND ACRONYMS

health care professionals. While newer antidepressants represent considerable 5-HT 5-hydroxytryptamine (serotonin)
advances in safety and tolerability compared with tricyclic (TCA) and mono-
DESS discontinuation emergent signs and
amine oxidase inhibitor (MAOI) agents, the improvement in therapeutic bene- symptoms
fit is not substantial. The delay to achieve antidepressant benefit, the percent- EPQ Eysenck Personality Questionnaire
age of patients who do not reach response or remission criteria, the persistence
HRSD Hamilton Rating Scale for Depression
of unwanted side effects, and concerns about drug discontinuation emergent
MADRS Montgomery-Asberg Depression Rating
effects are all shortcomings of current antidepressants.
Medicographia. 2005;27:240-246. (see French abstract on page 246)
MAOI monoamine oxidase inhibitor
Keywords: antidepressant; major depressive disorder; personality; MDE Major Depressive Episode
compliance; onset of action; side effect NE norepinephrine
NEO-PI Neuroticism, Extraversion, and Openness
Personality Inventory
SNRI serotonin and norepinephrine reuptake
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
Address for correspondence: Sidney H. Kennedy, MD, FRCPC, University Health Network,
200 Elizabeth St, EN8-222, Toronto, ON M5G 2C4, Canada
TCI Temperament and Character Inventory
(e-mail: sidney.kennedy@uhn.on.ca)

240 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Shortcomings of current antidepressant therapies – Kennedy

ty Questionnaire (EPQ),4 Temperament and Charac- tween high scores and decreased compliance.13,14
ter Inventory (TCI),5 or the Neuroticism, Extraver- This is well illustrated in the following case vignette,
sion, and Openness Personality Inventory (NEO-PI).6 where Mr T’s high level of gregariousness both con-
Although few in number, several studies have eval- tributed to an early treatment response and early
uated the influence of personality on help-seeking drug discontinuation.
behavior, symptom presentation, compliance, and
ultimately treatment outcomes. In most cases, neu- Mr T worked in the sales department of a
roticism and extraversion account for differences brewing company. He was a particularly gre-
in depressed patients. garious individual. Over a 6-year period, he
For example, men in an urban setting who have had been seen by three different primary care
a low level of neuroticism and an external attribu- physicians. On each occasion, he presented
tional style are less likely to seek help than men with with typical symptoms of a major depressive
higher levels of neuroticism.7 With regard to symp- episode. For him, the most prominent symp-
tom presentation, a high level of “harm avoidance” tom was losing interest in his normally active
(equivalent to neuroticism) in both men and women social life.
has been shown to predict higher levels of severity, There was also a pattern to his antidepres-
more physical symptoms including fatigue in de- sant usage. Typically, he responded very quick-
pressed patients, while high “novelty seeking” (equiv- ly, often during the first week. He would re-
alent to extraversion) is associated with suicide at- gain interest in social activities and increase
tempts, impaired concentration, and alcohol abuse.8 his success in sales. At about the same time,
The influence of neuroticism on side-effect re- he would start to miss doses of his antidepres-
porting was examined in a group of nonpsychiatric sant medication for days at a time and even-
healthy volunteers who received moclobemide or tually stop altogether.
placebo for 3 weeks under double-blind random- Only after a detailed discussion about the
ized controlled conditions.9 The strongest predictor potential negative relationship between his
of side-effect reporting was baseline neuroticism, outgoing personality style and medication
and this relationship increased over time in the compliance did Mr T agree to comply with an-
placebo group, but declined in the moclobemide tidepressant therapy and he has remained well
group, again highlighting the importance of vari- for the past 2 years.
ables beyond pharmacokinetic and pharmacody-
namic properties of the drug.
The relationship between neuroticism and treat- ◆ Comorbid personality disorders
ment response has also received considerable atten- A related question is whether or not patients with
tion. In a large primary care trial involving more a diagnosis of MDE and a comorbid personality dis-
than 300 patients who met diagnostic criteria for order have a worse outcome during antidepres-
dysthymia, Katon and colleagues10 reported that a sant treatment. Using the Diagnostic and Statistical
high baseline level of neuroticism was associated Manual of Mental Disorder, 3rd Edition, Revised
(DSM III-R) designation of cluster A
(Paranoid, Schizoid, and Schizotypal),
Demyttenaere et al,1 2001 Maddox et al,2 1994 cluster B (Antisocial, Borderline, Histri-
onic, and Narcissistic), and cluster C
Feeling better 55% Feeling better 35%
(Avoidant, Dependent, and Obsessive-
Adverse events 23% Adverse events 30%
Compulsive) personality disorder, Fava
Fear of dependence 10% Other reasons 17%
and colleagues15 examined the predic-
Stigma 10% Physician instruction 15%
tive value of personality disorder comor-
Lack of effect 10% Lack of effect 15%
bidity in patients who received fluoxe-
tine. There were no differences in rates
Table I. Reasons cited for discontinuation during 12 weeks of anti-
depressant treatment. of response between patients with or
without a cluster A or C diagnosis, while
with failure to achieve remission, whether treat- the presence of a cluster B diagnosis before treat-
ment involved paroxetine or problem-solving psy- ment predicted a positive antidepressant response.
chotherapy. Although Mulder11 broadly agreed with Almost a decade later, Mulder and associates16 ex-
this conclusion in the largest systematic review so amined the interaction between antidepressant class
far reported, he also noted that personality pathol- selection (fluoxetine or nortriptyline), personality
ogy contributed least to outcome prediction in the disorder (presence or absence) and drug response.
better-designed studies. Although the presence of a comorbid personality
Importantly, different personality variables can disorder did not have an overall effect on outcome,
influence different aspects of the treatment process those patients with a cluster B personality had a sig-
in opposing directions. This is particularly true of nificantly better response to fluoxetine compared
extraversion. High baseline scores on extraversion with nortriptyline.
(particularly the facet identified as gregariousness) While others have reported less favorable out-
predicted greater symptom reduction during an- comes for depressed patients with personality dis-
tidepressant treatment,12 while others, using com- orders during continuation therapy,17 the weight of
parable measures of extraversion (sensation seeking evidence suggests that such comorbidity does not
or novelty seeking), identified an association be- adversely affect outcome.

Shortcomings of current antidepressant therapies – Kennedy MEDICOGRAPHIA, VOL 27, No. 3, 2005 241

◆ Severity of illness tures. While most would agree that a diagnosis of

Since there is really no consensus on what consti- MDE with psychotic features warrants different
tutes “severe depression,” it is difficult to reach a treatment interventions, including combination an-
conclusion about its impact on treatment outcome. tidepressant-antipsychotic medications or an early
A predetermined baseline score on the Hamilton intervention with electroconvulsive therapy,25 there
Rating Scale for Depression (HRSD)18 such as scor- is less consensus on the relevance of melancholia.
ing 24 or higher at baseline on the 17-item HRSD, In a natural practice setting, where patients com-
or a score above 28 at baseline on the Montgomery- pleted standard diagnostic and severity measures,
Asberg Depression Rating Scale (MADRS),19 are fre- melancholic patients had lower response rates to
quently applied criteria for “severe depression.” It paroxetine, sertraline, and venlafaxine compared
must be pointed out, however, that different symp- with nonmelancholic patients (48% vs 61%).26 In
tom weighting on these scales (eg, there are 3 sleep this study, there was no difference in rate of re-
items on HRSD and 1 sleep item on MADRS) may sponse among drugs in the melancholic subgroup.
result in some patients being considered “severe” However, there is evidence that TCAs, in particular
on one scale, but not on another. 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
Other colleagues30 also reported similar outcomes when
mirtazapine was compared with venlafaxine in hos-
Inconvenient dosing pitalized severely depressed patients with melan-
Poor long-term control
cholic features.
There are also differences between outpatient and
Side effects inpatient groups in their response to TCA and MAOI
antidepressants. In a meta-analysis, Thase and col-
Poor predictability of response leagues31 reported superior response rates to MAOI
Slow onset of action
antidepressants compared with TCAs among out-
patients, while the converse was true for inpatients.
0 5 10 15 20 25 30 35 40 (%) Likewise, a group of Danish investigators, using
clomipramine as the active comparator, consistent-
Figure 1. Physician-reported preferences for antidepressants: the most significant ly reported its superiority over the reversible in-
disadvantage of the most frequently prescribed antidepressant. hibitor of MAO-A, moclobemide,32 as well as two
Modified from reference 39: Wade AG. A holistic evaluation of attitudes to depression. Poster presented SSRIs—paroxetine33 and citalopram34 —in studies
at the DURG 16th Annual Meeting; London, UK, 2005. Copyright ©, Drug Utilisation Research Group involving depressed inpatients. However, a variety
(UK & Ireland).
of factors including suicidality, social supports, and
Relatively few studies have been designed to ex- differences in practice patterns across countries,
amine the relationship between severity of symp- influences the decision to admit a depressed patient
toms and preferential drug response, although it to hospital.
is generally believed that antidepressant treatments In summary, shortcomings of current antidepres-
are less likely to prove superior to placebo in pa- sant therapies need to be considered in the context
tients with low pretreatment scores.20,21 Clinical im- of treatment adherence, distinct patient profiles in-
pression that moclobemide is less effective in severe cluding personality differences, and illness severi-
depression was initially supported in a global re- ty. One or more of these variables often contribute
view of moclobemide trials, in which imipramine to poor treatment outcome.
was superior to moclobemide in the group with
baseline HRSD scores of 28 or higher,22 but not con- Unmet needs with current
firmed in a subsequent analysis using the same therapeutic choices
drug.23 Greater efficacy in more severely depressed
patients is a desirable characteristic of any antide- The widespread use of SSRIs to treat patients with
pressant. Khan and colleagues24 have also examined depression in primary care and specialist settings
the relationship between severity of depressive represents a significant advance in managing one
symptoms and response to a range of selective sero- of the most functionally disabling and frequently
tonin reuptake inhibitor (SSRI) antidepressants, comorbid medical conditions.35,36 With greater safe-
venlafaxine, nefazodone, and placebo. Pretreatment ty and tolerability compared with TCA and MAOI
severity was assessed using the 17-item HRSD, and agents, compliance with SSRI and newer antide-
patients were categorized into 4 groups according pressants during acute and maintenance phases has
to baseline scores. The drug-placebo difference from improved, and the percentage of depressed patients
baseline to end of treatment (effect size) was pro- who are hospitalized for treatment continues to
gressively greater as baseline severity increased. decline.37 Even so, there are still considerable lim-
itations to SSRI and dual action (duloxetine, ven-
◆ Melancholic and psychotic features lafaxine, bupropion, milnacipran, and mirtazapine)
Other considerations that likely overlap, but are not antidepressant agents.
synonymous with severity, include inpatient status The “therapeutic lag” between initiating treat-
and the presence of psychotic or melancholic fea- ment and achieving clinically meaningful effects

242 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Shortcomings of current antidepressant therapies – Kennedy

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-
Based on understanding of 5-HT1A
neurophysiology, pindolol, a 5-HT1A Incidence of side effects
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
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

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 agents have been observed most often when parox-
a plateau after the first few months of treatment. etine or venlafaxine are stopped abruptly.57,58
Nevertheless, for many depressed patients, the pros- In a double-blind, treatment interruption trial,
pect of substantial weight gain during antidepres- patients who abruptly discontinued paroxetine and
sant treatment represents an unacceptable health sertraline experienced significantly more discon-
burden. tinuation emergent signs and symptoms (DESS)
compared with those who discontinued fluoxetine.57
◆ Antidepressant discontinuation emergent The authors attributed differences in pharmacoki-
effects netic profiles among SSRIs for the different rates of
Since the mechanisms of action of reuptake inhib- DESS. Similarly, high rates of DESS have been re-
itor antidepressants (SSRIs, SNRIs [serotonin and ported with venlafaxine compared with escitalo-
norepinephrine reuptake inhibitors], and others) in- pram 1 week after discontinuation.58 The effects of
volve adaptive downregulation early in the treat- abrupt interruption of agomelatine, a new antide-
ment process, it is not surprising that drug discon- pressant with a unique melatonin agonist profile,
tinuation, particularly abrupt discontinuation, were compared with interruption of paroxetine. De-
would result in unpleasant rebound effects. In gen- spite its short half-life of 2 hours or less,59 patients
eral, the shorter the half-life of the drug, the greater who discontinued agomelatine experienced signif-
the likelihood of discontinuation emergent symp- icantly fewer DESS compared with those who dis-
toms. Such occurrences are not limited to SSRIs or continued paroxetine.60
dual action antidepressants. Cholinergic rebound
was often observed following rapid discontinuation Conclusion
of amitriptyline or other TCAs with significant an-
ticholinergic effects. Patients reported urinary fre- Advances in neurogenetic and neuroimaging tech-
quency, headaches, hypersalivation, and diarrhea. niques have contributed to understanding the com-
Benzodiazepine withdrawal phenomena have also plex etiopathology of depression. Future challenges
been recognized for many decades and include in drug development involve better matches be-
symptoms of insomnia, nausea, appetite loss, sweat- tween patient profiles and therapeutic targets, with
ing, and dysphoria.56 Emergent symptoms associat- an increased attention to drug tolerability and long-
ed with drug discontinuation of SSRIs or dual action term safety. ❒

1. Demyttenaere K, Enzlin P, Dewe W, et al. Compliance with an- ality disorders to treatment outcome in depressed outpatients.
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43. Blier P, de Montigny C. Current advances and trends in the latine and occurrence of discontinuation symptoms with parox-
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732-739. sion Effectively: Applying Clinical Guidelines. London, UK: Mar-
45. Segrave R, Nathan PJ. Pindolol augmentation of selective tin Dunitz; 2004.
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major depression. Hum Psychopharmacol. 2005, Jan 12. (Epub
46. Rabiner EA, Bhagwagar Z, Gunn RN, et al. Pindolol augmen-
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efficacité du traitement d’un Épisode Dépressif Majeur (Major Depres-
that the dose used in clinical trials is too low. Am J Psychiatry.
2001;158:2080-2082. sive Episode, MDE) est soumise à de nombreuses influences au-delà des
47. Behnke K, Sogaard J, Martin S, et al. Mirtazapine orally dis- propriétés intrinsèques de tel ou tel médicament. Ces influences com-
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study. J Clin Psychopharmacol. 2003;23:358-364.
48. Sanchez C, Bogeso KP, Ebert B, Reines EH, Braestrup C. Es- sécurité d’emploi/tolérance/efficacité du médicament, ainsi que l’interaction
citalopram versus citalopram: the surprising role of the R-enan- entre les patients et les soignants. Alors que les antidépresseurs récents ont
tiomer. Psychopharmacology (Berl). 2004;174:163-176. 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-
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rêt du traitement soulignent les limites des antidépresseurs actuels.

246 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Shortcomings of current antidepressant therapies – Kennedy

▲ ▲
Siegfried KASPER, MD
O Univ Prof Dr Dr hc
Department of General Psychiatry
Medical University of Vienna

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 tients in spring and in fall. However, this finding was

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
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
environment affect humans’ physical and mental first systematic study on seasonal affective disorder
health: Hippocrates of Kos (460-377 BC) and Are- (SAD) by Rosenthal et al.4 Scientific research has
taeus the Cappadocian (about 150 AD) proposed the been encouraged ever since and has led to the pub-
healing powers of sunlight for a range of somatic lication of more than one thousand studies on SAD
illnesses, but also for the state of melancholia.1 The and BLT, not only because SAD is clinically impor-
majority of humans seem to experience seasonal tant, but also because it represents an important
variations of psychopathological symptoms to some chronobiological paradigm.
extent.2 These seasonal changes are of clinical inter-
est if their intensity leads to subjective suffering Epidemiology
and a reduction in psychosocial functioning. Emil
Kraepelin (1856-1926) was one of the first modern Numerous epidemiological studies have investi-
psychiatrists to become aware of a rise in the inci- gated the prevalence of SAD and of its subsyndro-
dence of affective episodes in manic-depressive pa- 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

easonal affective disorder (SAD, fall-winter depression) is a subtype of the rate of individuals with minor problems dur-
major depressive or bipolar disorder, and has been a subject of psychi- ing the fall-winter period indicating s-SAD is even
atric research for over two decades. The prevalence in the general pop- higher. A number of reports have documented an
ulation ranges between 2% and 5% in temperate climates, females are much increase in SAD prevalence with northerly lati-
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- 5-HTTLPR serotonin transporter promoter
riod. Bright light therapy (BLT) is generally accepted for depression in SAD, but repeat length polymorphism
psychopharmacological treatment with antidepressants has likewise been found BLT bright light therapy
to be effective and well tolerated. This article reviews the most important patho- GSS Global Seasonality Score
physiological concepts and gives an overview of current diagnostic procedures HDRS Hamilton Depression Rating Scale
and treatment options for SAD. PMDD premenstrual dysphoric disorder
Medicographia. 2005;27:247-253. (see French abstract on page 253) SAD seasonal affective disorder
SIGH-SAD Structured Interview Guide for the
Keywords: seasonal affective disorder (SAD); winter depression; light therapy; HDRS SAD version
SPAQ Seasonal Pattern Assessment
Address for correspondence: Prof Siegfried Kasper, Department of General Psychiatry, S-SAD subsyndromal seasonal affective
Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Wien, Austria disorder
(e-mail: sci-genpsy@meduniwien.ac.at)

Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper MEDICOGRAPHIA, VOL 27, No. 3, 2005 247

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
The prevalence of SAD is higher in female than in
male patients.24 In most clinical samples, women
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
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.
According to most clinical and epidemiological stud-
ies, the majority of patients experience their first
affective episode in their late twenties or early thir-
ties. The symptom pattern found in a clinical sam-
ple of 610 SAD patients is shown in Figure 2.29 Sea-
sonal depressive episodes share the core symptoms
with nonseasonal major depression. Depressed mood












and reduced drive (subjectively experienced as loss















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














ever, most SAD patients display a reversed vegeta-






tive symptom pattern and fulfill the criteria of the

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

Table I. Diagnostic criteria for a major depressive episode

◆ A. At least five of the following symptoms have been present during the same
according to DSM-IV-TR.30
Reproduced from reference 30: American Psychiatric Association.
two-week period, nearly every day, and represent a change from previous Diagnostic and Statistical Manual of Mental Disorders, 4th edition,
functioning. At least one of the symptoms is either (1) depressed mood text revision (DSM-IV-TR). Washington, DC: American Psychiatric
or (2) loss of interest or pleasure. Press; 2000. Copyright © 2000, American Pychiatric Press.
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 ◆ A. Regular temporal relationship between the
and adolescents) onset of major depressive episodes and a
(2) Markedly diminished interest or pleasure in all, or almost all, activities particular time of the year (unrelated to ob-
(3) Significant weight loss when not dieting or weight gain or decrease vious season-related psychosocial stressors)
or increase in appetite
(4) Insomnia or hypersomnia ◆ B. Full remissions (or a change from depression
to mania or hypomania) also occur at a
(5) Psychomotor agitation or retardation
characteristic time of the year
(6) Fatigue or loss of energy
(7) Feelings of worthlessness or excessive or inappropriate guilt ◆ C. Two major depressive episodes meeting crite-
(8) Diminished ability to think or concentrate, or indecisiveness ria A and B in last 2 years and no nonsea-
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal sonal episodes in the same period
ideation without a specific plan, or a suicide attempt or a specific
plan for committing suicide ◆ D. Seasonal major depressive episodes substan-
tially outnumber the nonseasonal episodes
◆ B. The symptoms are not better accounted for by a mood disorder due to a over the individual’s lifetime
general medical condition, a substance-induced mood disorder, or bereave-
ment (normal reaction to the death of a loved one) Table II. Diagnostic criteria of the seasonal pattern
specifier according to DSM-IV-TR.30
◆ C. The symptoms are not better accounted for by a psychotic disorder like Reproduced from reference 30: American Psychiatric Association.
schizoaffective disorder 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 ◆ 1. A history of some difficulty during the winter months that had
female SAD patients suffer from premenstrual dys- occurred on a regular basis (at least two consecutive winters)
phoric disorder (PMDD).32 The severity of seasonal and had lasted for a sustained period of time (at least 4 weeks).
Examples of these difficulties are decreased energy, decreased
depressive episodes ranges mostly between mild and efficiency at work (eg, concentration, completing tasks), de-
moderate. However, severe depression, occasional- creased creativity or interest in socializing, and change in
ly with suicidal ideations requiring inpatient treat- eating habits (eg, eating more carbohydrates), weight (gaining
ment, is possible. About one quarter of SAD patients weight), or sleep patterns (more sleep)
suffer from bipolar affective disorder with hypoman-
◆ 2. Subjects have to regard themselves as normal, ie, not suffering
ic or (rather seldom) manic episodes during spring from an illness or disorder
or summer in addition to depressive symptoms dur-
ing the fall-winter period. ◆ 3. They have not sought medical or psychological help specifically
for the above difficulties, nor has anyone else suggested that
they do so
Diagnostic procedure
◆ 4. People who do not know them well do not recognize that they
As SAD is either a form of recurrent major depres- have a problem, or if they do, easily attribute it to circum-
sive or bipolar disorder with onset and remission stances such as “flu” or “overwork”
of the affective episodes at a specific time of the year, ◆ 5. The symptoms experienced by the subjects have not disrupted
patients have to fulfill the diagnostic criteria of these their functioning to a major degree, eg, calling in sick several
disorders (see Table I 30 for the diagnostic criteria times per winter, or severe marital discord
for major depression). According to the Diagnostic
◆ 6. No history of major affective disorder in wintertime
and Statistical Manual of Mental Disorders, Fourth
Edition, Revised (DSM-IV-TR), it is possible to ap- ◆ 7. No serious medical illness
ply a seasonal pattern specifier to diagnose SAD
(Table II).30 Table III. Diagnostic criteria for subsyndromal seasonal affective disorder
The Global Seasonality Score (GSS), which is (s-SAD) according to Kasper et al.35
calculated from the Seasonal Pattern Assessment 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-
Questionnaire (SPAQ),33,34 has frequently been used tive disorder. Arch Gen Psychiatry. 1989;46:837-844. Copyright ©, 1989 JAMA & Archives.
to assess the degree of seasonal change in psycho-
pathology in the past. According to the Rosenthal difficulties during fall and winter. The diagnostic
criteria, patients have to obtain a GSS of at least 10 criteria for s-SAD are presented in Table III.35 To ex-
to qualify for SAD. Furthermore, the overall degree amine the severity of seasonal depression, a mod-
of impairment during the worst time of the year ified version of the Hamilton Depression Rating
has to be at least “moderate” to establish the diag- Scale (HDRS) has been recommended: the Struc-
nosis. This is the most important difference between tured Interview Guide for the HDRS–SAD version
SAD and s-SAD.35,36 Patients with the subsyndromal (SIGH-SAD), which contains 29 items and covers
form report differences in several psychopatholog- not only melancholic symptomatology of depres-
ical items, however they experience no or only mild sion, but also contains 8 items for atypical depres-

Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper MEDICOGRAPHIA, VOL 27, No. 3, 2005 249

sive symptoms, which are frequently found in SAD. mus.47 A further study was likewise able to show
For many patients it takes years until the correct reductions in the availability of striatal dopamine
diagnosis is made: the mean diagnostic latency in transporter binding sites in untreated depressed
a German-speaking sample was approximately 10 SAD patients.48 This study provides evidence that
years after the first depressive episode.37 This is still the dopaminergic systems may also be involved in
unacceptably long. However, since the early 1990s, the pathogenesis of SAD. However, these findings do
the diagnostic latency has decreased by about 3 not explain whether lowered availability of mono-
years, probably due to education of medical profes- amine transporters in the synaptic cleft represents
sionals and increased awareness of patients. a primary defect or an attempt to overcome a state
of possible lowered dopamine/serotonin availability
Pathogenesis of SAD during a depressive episode.
There is evidence that specific genetic factors may
It is supposed that the shorter photoperiod during lead to increased vulnerability for developing SAD.
fall and winter triggers the onset of depressive symp- Genetic association studies have examined the role
toms in predisposed individuals. Light is one of the of several candidate genes: a number of surveys have
most important zeitgebers and is able to reliably al- investigated the serotonin transporter promoter re-
ter the length and phase of the human circadian peat length polymorphism (5-HTTLPR), but the re-
rhythm by affecting the main circadian pacemaker sults of these studies are inconsistent.49,50 One study
in the diencephalon, the suprachiasmatic nucleus. examined the relationship between SAD and PMDD
Scientific research has focused especially on the and found an association between the presence of
hormone melatonin (5-methoxy-N-acetyltrypt- PMDD and family history and 5-HTTLPR long/short
amine), which is produced in the pineal gland and allele-heterozygosity in females with SAD.51 PMDD
thought to mediate the photoperiod signal by the and SAD may thus share some genetic vulnerabil-
onset and duration of nocturnal secretion. Studies ity factors such as the 5-HTTLPR. A higher rate of
measuring dim light melatonin onset have found a affective disorders in relatives of patients with SAD
phase delay in SAD patients that was successfully and PMDD may be indicative of higher genetic vul-
reversed with BLT.38-40 However, there is a subset of nerability in this subgroup when compared with pa-
SAD patients who do not display any circadian ab- tients with SAD alone. A further interest-deserving
normalities, so other mechanisms may also be in- study investigated the association of the 5-HTTLPR
volved in the pathogenesis of SAD.41 with the DSM-IV clinical subtypes of depression:
There is converging evidence that alteration of Willeit et al52 were able to demonstrate that melan-
monoaminergic neurotransmitters, such as sero- cholic depression is associated with the 5-HTTLPR
tonin, norepinephrine, or even dopamine, may be long allele and atypical depression with the short
involved in the pathophysiology of SAD. Tryptophan allele.
depletion has been used to selectively reduce the Apart from the 5-HTTLPR several other candidate
plasma tryptophan concentration by administration genes have been investigated: guanine nucleotide-
of a mixture of amino acids free of tryptophan, which binding proteins (G-proteins) have been implicated
is a precursor of serotonin. Studies using neuro- in affective disorders, with reports of altered signal
imaging techniques have been able to show that transduction and G-protein levels.53 The higher ac-
serotonin synthesis is reduced for a few hours in tivity T-allele of the G-protein beta-3-subunit C825T
the human brain after this procedure.42 Additional- polymorphism has been found to be associated with
ly, two further studies have demonstrated that SAD SAD54; however, other authors have failed to repli-
patients in stable remission during summer time43 cate these findings.55 The investigation of genetic
and after successful BLT44 experience a temporary variations in clock-genes deserves specific attention
depressive relapse after tryptophan depletion. To as SAD is thought to be a circadian rhythm disor-
investigate the role of norepinephrine in SAD, Neu- der: indeed, Johansson et al56 were able to demon-
meister et al45 conducted a study comparing the ef- strate a significant association between the NPAS2
fects of tryptophan depletion with catecholamine 471 Leu/Ser polymorphism and SAD, and with the
depletion and sham depletion in SAD patients in Period3 647 Val/Gly polymorphism and diurnal pref-
remission with BLT: Both active depletion protocols erences (morningness-eveningness tendencies). In
resulted in temporary depressive relapses provid- conclusion, the results of these genetic association
ing evidence that brain catecholaminergic systems studies have been most promising so far. However,
may also be involved in the mechanism of action of each of these studies has to be considered prelim-
BLT. Interestingly, another study in SAD was able inary and replicated in larger samples before defi-
to demonstrate that monoamine depletion led to nite conclusions may be drawn.
alterations in several humoral and cellular immuno-
logic parameters, suggesting a potential role of the Treatment of SAD
immune system in the pathogenesis of the disorder.46
Several neuroimaging studies have investigat- Even one of the oldest written resources of man-
ed the importance of specific molecular targets in kind, the Bible, mentions the beneficial effects of
the pathophysiology of SAD. Binding studies using light: “Truly the light is sweet, and a pleasant thing
123I-β-CIT and single photon emission computed it is for the eyes to behold the sun.” (Ecclesiastes
tomography (SPECT) have found that depression in 11:7). From the first reports of SAD,4,57 bright arti-
SAD is associated with reduced serotonin trans- ficial light has been proposed as a most promising
porter availability in the thalamus and hypothala- therapeutic method. Further studies58,59 have ac-

250 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper

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
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

reduce patients’ performance at work.84 SAD, in its tion as well as an underlying genetic predisposition
most frequent manifestation, fall-winter depression, have been implicated in the pathogenesis of SAD.
is characterized in most cases by reverse vegetative Antidepressant psychopharmacotherapy is used for
symptoms such as increased appetite, carbohydrate the treatment of SAD depression similar to other
craving, hypersomnia, daytime fatigue, and loss of forms of depression; however, BLT is now recog-
energy. However, the most important clinical feature nized as the treatment option of choice. Future re-
is that patients feel worst in the fall-winter months, search should aim at investigating specific treat-
ie, in the time of light deficiency. Changes in hor- ment options for SAD patients with a bipolar course
monal and monoaminergic neurotransmitter func- of illness. ❒

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62. Kogan AO, Guilford PM. Side effects of short-term 10,000-lux

e trouble affectif saisonnier (TAS, ou « blues de l’hiver ») est un sous-
light therapy. Am J Psychiatry. 1998;155:293-294.
63. Labbate LA, Lafer B, Thibault A, Sachs GS. Side effects in- type de la dépression majeure ou du trouble bipolaire qui fait l’objet de
duced by bright light treatment for seasonal affective disorder. recherches en psychiatrie depuis plus de 20 ans. La prévalence dans la
J Clin Psychiatry. 1994;55:189-191. population générale varie entre 2 % et 5 % dans les pays à climat tempéré, les
64. Swiecicki L. Phototherapy for winter depression: report of
three cases. Psychiatr Pol. 1993;27:667-672. femmes étant beaucoup plus souvent touchées par le syndrome. Des symptômes
65. Praschak-Rieder N, Neumeister A, Hesselmann B, Willeit M, dépressifs atypiques accompagnés d’une symptomatologie végétative inversée
Barnas C, Kasper S. Suicidal tendencies as a complication of light prédominent pendant les épisodes dépressifs au cours de la période obscure de
therapy for seasonal affective disorder: a report of three cases.
J Clin Psychiatry. 1997;58:389-392. 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.

Seasonal affective disorder: from diagnosis to treatment – Winkler and Kasper MEDICOGRAPHIA, VOL 27, No. 3, 2005 253

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-

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

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

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
reported problems are cardiovascular disease, dia-
betes, obesity, and thyroid disease. The accumula-
tion of key medical risk factors related to excessive
nicotine use, alcohol and drug use, concomitant
anxiety, and eating disorders, lead to the early onset

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 10
and motivation required to reduce such medical
risk factors. Katon12 has established the clear rela- 5
tionship between depression and a host of negative
health behaviors including smoking, poor diet, over- 0
0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45+
eating, and sedentary lifestyle and has shown that
depression has a maladaptive effect on adherence Age of first onset (y)
to medical regimens and direct adverse physiolog-
ic effects including decreased heart rate variability Figure 2. Distribution of bipolar symptom onset by age.
and increased adhesiveness of platelets.
Bipolar I disorder is almost always treated in men- cific chromosomal regions have been identified, but
tal health settings, with patients viewing their psy- only 5 out of 16 chromosomal regions currently
chiatric care as their most important form of med- meet criteria for significant linkage.13 Complement-
ical care. This has led to a relative underrecognition ing this work on genetics, anatomical and MRI neu-
of and inattention to the many physical diseases roimaging studies have demonstrated functional
from which these patients suffer. Only recently has abnormalities of the medial prefrontal cortex.16 Neu-
a greater awareness of medical burden and medi- ropsychological dysfunction, including abnormal-
cal risk factors, stimulated by the introduction of ities in cognitive and memory activity,17,18 but par-
atypical antipsychotic medication for bipolar I dis- ticularly in social cognition,19 have been found in
order with its attendant medical problems, led clin- individuals with bipolar disorder. This is consistent
icians and investigators to focus on these issues. To- with work of others, including Phillips,20 who has
day there is broad recognition that advances in the been particularly interested in alterations in emo-
treatment of bipolar disorder must go together with tional perception. Neurocognitive deficits and, per-
increased medical risk factor assessment, ongoing haps, deficits in social cognition may represent, if
laboratory surveillance, and integrated treatment 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

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- in bipolar disorder
icits represents a potential cascade of processes deal-
ing with gene-environmental interaction, similar Once thought of as our “good prognosis” illness in
to the research ongoing in the area of schizophre- psychiatry, bipolar disorder has emerged in the last
nia.21 decade as one of our most significant treatment
A second area of interest in bipolar disorder has challenges. Thinking back to what it must have
emerged from the long-standing research in bio- been like to try to manage this condition in the pre-
logical rhythms and bipolar disorder. Ehlers and lithium era, it is easy to understand how, once lithi-
colleagues22 hypothesized that biological dysregu- um was introduced, the field was lulled into a false
lation, both at the level of neurobiology and also at sense of complacency. In the late 1980s and early
the level of social rhythms, may be responsible for a 1990s, however, both naturalistic data27,28 and data
cascade of events leading to episodes of mania and from controlled trials (eg, Prien et al,29 1984) made
depression and proposed a “social zeitgeber theo- it clear that bipolar disorder was not a problem
ry,” to explain the onset of bipolar disorder.23 In sup- solved. This led a relatively small group of investi-
port of this concept, Malkoff-Schwartz and others24 gators in the US and abroad to take a renewed in-
demonstrated that events associated with changes terest in developing treatment strategies for bipolar
in social routines were common prior to the onset disorder, both psychopharmacologic and psycho-
of a manic episode. The social rhythm disruption therapeutic.30 As we have entered the 21st century,
concept led to the design and implementation of a we have come to recognize the multiple factors that
psychosocial intervention specifically tailored for complicate the process of achieving ideal outcomes
the treatment of bipolar disorder that has been de- for those that suffer from bipolar disorder.
veloped both from interpersonal psychotherapy 25 Our model for understanding these complexities
and social rhythm theory.26 Consistent with this bi- is illustrated in Figure 3. According to our model,
ological rhythms perspective, a host of biological the early age of onset typical of bipolar disorder
clock genes has been studied in both families and means that early years spent in coping with the ill-
patients with bipolar disorder, suggesting a vulner- ness often lead to social developmental/matura-
ability in certain patient groups or groups at risk for tional deficits. Future experience of the illness often,
bipolar disorder. 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 less ill manic patients, lithium, valproate, or carba-
with difficult challenges more difficult for the in- mazepine can be administered; for more severe ma-
dividual even during euthymic periods. The com- nia, atypical antipsychotics or valproate are rec-
plexity of the disorder itself (as discussed earlier), ommended. For mania associated with psychosis,
involving as it does an ever-changing mix of psy- atypical antipsychotics are preferred.
chotic symptoms, dysphoric or negative mood and Monotherapy is initially recommended to address
behavior, manic mood and behavior, and cognitive manic features. The use of lithium, valproate, as well
symptoms makes treatment decision-making a con- as of a number of atypical antipsychotics, including
stantly ongoing process in which no sooner is a olanzapine, risperidone, quetiapine, nefazodone, and
symptom or group of symptoms effectively ad- aripiprazole is recommended. If patients do not im-
dressed than others appear which require new treat- prove on any of these drugs, a number of clinical
ment decisions. Further complicating the picture specialists have suggested that the addition of olan-
are the psychiatric and medical comorbidities com- zapine, risperidone, or quetiapine to lithium or val-
monly encountered in bipolar disorder: panic, al- proate confers an additional effect, as does the addi-
cohol abuse, substance abuse, and personality dis- tion of valproate. The avoidance of major depressive
orders (particularly Cluster B disorders) as well as symptomatology as an outcome in the successful
obesity, thyroid disease, diabetes, and cardiovascu-
lar disease. Each of these comorbidities can have
important impact on treatment decisions. For ex-
0.0 Depressed
ample, we have observed that patients with panic
comorbidity are much more sensitive to medica-
tion side effects, often necessitating lower starting
Cumulative proportion of patients remitted

doses and slower titration of new treatments.8 In 0.2

the area of medical comorbidity, those patients with
thyroid disease or diabetes also warrant special clin-
ical attention if their bipolar disorder treatment is 0.4
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 0.8

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 1.0
0 10 20 30 40 50
in this population. Thought of in this way, there are,
then, a series of potential targets for improving Weeks of preliminary phase treatment
treatment paradigms for bipolar disorder.
*P<0.0001 vs manic; **P<0.001 vs manic; and P<0.05 vs depressive
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 Figure 4. Bipolar depressive and mixed episodes are difficult to treat.
of acute depression, and the treatment for the pre- 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,
vention or prophylaxis of both mania and depres- Blackwell Publishing.
sion in the future (maintenance treatment). The
treatment of acute mania involves the following resolution of manic symptoms could be helped by
aims: the improvement of manic symptoms, possi- use of antipsychotics, which may have antidepres-
bly requiring rapid tranquillization; the resolution sant effects of their own. It is further recommend-
of manic symptomatology avoiding both the onset ed that after acute treatment, on the way to stabi-
of new depressive symptomatology or the unmask- lization and maintenance treatment, patients and
ing of depressive symptomatology; and finally, the family members receive psychoeducation, with par-
consideration of mood stabilization and subsequent ticular emphasis on recognition of early symptoms
treatment. With respect to rapid tranquillization, of mania. Many clinicians also further recommend
Cookson and others have demonstrated that hal- the availability of rescue medication, such as small
doperidol, as well as the new atypical antipsychotics, doses of an atypical antipsychotic.
have immediate antimanic effects independent of The treatment of acute depression is longer and
sedation.31 Other drugs often used in the treatment more difficult than that of mania, as shown in Fig-
of acute mania may not act as quickly and there- ure 4.34 Many expert clinicians have recommended
fore have delayed antimanic effects. The American the initial optimization of a mood stabilizer and, if
Psychiatric Association (APA) Guidelines suggest this strategy is ineffective, adding an antidepressant
that for mild mania, lithium or valproate or an atyp- to the mood stabilizer. If this second step does not
ical antipsychotic can be utilized.32 For severe ma- work, then there are a variety of recommendations
nia, they recommend the immediate combination including adding a second mood stabilizer.35 Re-
of a mood stabilizer and an atypical antipsychotic. cently, it has been shown that an atypical antipsy-
The recent British Guidelines33 conclude that for chotic plus an selective serotonin reuptake inhib-

Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank MEDICOGRAPHIA, VOL 27, No. 3, 2005 257

itor (SSRI) is effective in acute bipolar depression,36 but not necessarily depressive episodes39; the data
leading to Food and Drug Administration (FDA) ap- for valproate for long-term treatment are minimal
proval of this combination for treatment of bipolar despite its wide use40; the data for lamotrigine for
depression. In considering alternatives involving long-term treatment support a specific indication
mood stabilizers, various controlled trials have sug- for the prevention of depressive as compared with
gested that lithium may have antidepressant effica- manic episodes.41,42 Recently, attention has been de-
cy. Similarly, lamotrigine may possess antidepres- voted to the conduct of controlled trials of atypical
sant efficacy in acute bipolar depression. Recent antipsychotics in the maintenance phase. The ma-
reviews of controlled trials of antidepressants versus jority of such controlled studies have been carried
placebo37 have demonstrated a mild positive effect out with olanzapine, with one recent trial of aripi-
for antidepressants, accompanied by a relatively low prazole.43 Studies of olanzapine demonstrate supe-
switch rate from depression to mania with antide- rior efficacy to valproate; and comparisons of olan-
pressants (except for the tricyclics). Two clinical tri- zapine to lithium show an advantage of olanzapine
als with quetiapine have shown efficacy in acute with respect to study completion.44,45 An olanzapine
bipolar depression (J. R. Calabrese, personal com- versus placebo study for relapse prevention demon-
munication). The failure to respond to a mood sta- strated efficacy for olanzapine in preventing relapse
bilizer (or an atypical antipsychotic) with or with- into mania as well as into depression.46 Finally, a
out an antidepressant leads the clinician to consider study comparing olanzapine plus lithium or val-
substituting another antidepressant or mood sta- proate versus placebo plus lithium or valproate
bilizer, as well as the use of electroconvulsive ther- showed the advantage of the addition of olanzapine
apy (ECT) and/or adjunctive psychological interven- as compared with placebo, suggesting the possibil-
tions. Finally, a key unanswered question is how ity of combined long-term treatment.47 Recently, a
long one should continue an antidepressant follow- 26-week trial comparing aripiprazole to placebo has
ing resolution of a bipolar depressive episode. No been reported demonstrating a significant advan-
guidelines, similar to those available for the treat- tage for this atypical antipsychotic.43
ment of acute unipolar depression, exist. Maintenance treatment should include, at the
When we review options for long-term treatment, minimum, patient management strategies33 con-
one important issue is that we need to deal with the sisting of five specific areas: establishment and
prevention of both manic and depressive episodes. maintenance of a therapeutic alliance; education of
Indeed, one could list the therapeutic objectives in patients and their families about the disorder; ef-
the following manner: to achieve symptom control forts to enhance treatment adherence; promotion
of all four domains that have been mentioned pre- of awareness of stresses, sleep disturbance, and ear-
viously; to prevent syndromal recurrence; and to ly signs of relapse and regular patterns of activity;
reduce or oblate all subsyndromal symptomatology and finally, evaluation and management of func-
because this is often related to significant function- tional impairment. Furthermore, targeted psycho-
al impairment. Finally, it is important to minimize social interventions are now being studied in the
the risk of cycling, which, when it occurs, makes it treatment of bipolar disorder that may be very ap-
more difficult to treat both the acute manic or de- plicable to larger groups of patients suffering from
pressive state and to manage the illness over the this illness.26,48 Interestingly, these approaches gen-
long term. erally include strong emphasis on improving treat-
Complicating the treatment of bipolar disorder, ment adherence.
both acutely and long term, is the presence of con-
siderable psychiatric and medical comorbidity. Future trends
Therefore, a successful long-term treatment ap-
proach will also assist in treating the psychiatric In considering future trends, the increased use of
and medical comorbidities. Underscoring the im- atypical antipsychotics and their possible utility,
portance of complete symptomatic relief is the asso- not only for stabilization of mania, but for depres-
ciated functional recovery as manifested by return sive symptomatology, is an important area of fur-
to work, family, and schooling for younger people. ther investigation. That monotherapy may not be
Another important consideration in maintenance the optimal way to proceed with patients with bipo-
treatment is a reduction in overall mortality. While lar disorder is becoming clearer, making it very like-
a great deal of appropriate attention has been de- ly that an increased emphasis will be placed on com-
voted to suicide prevention, bipolar patients also die bination treatments in the next 5 years. It is hoped
of other causes, especially medical disease.38 Con- that controlled clinical trials will be available to
sequently, a major goal of maintenance treatment guide the clinician. With respect to the treatments
is to reduce overall mortality. This goal is compli- specifically for bipolar depression, it is likely that
cated by the fact that adherence to treatments for a novel serotonin receptor agonist or antagonist
both medical and psychiatric disorders for patients will be used to treat bipolar depression. Some of the
with bipolar disorder is very poor and, therefore, other novel treatments being suggested for unipo-
we must pay specific attention to treatment adher- lar depression may also be useful for bipolar depres-
ence principles. sion. In assessing the risk-benefit ratio of the use
In reviewing the possibilities of long-term treat- of any medication in bipolar disorder, it is important
ment in bipolar disorder, at the present time we to consider the level of medical risk factors that may
have the following information: lithium appears to make patients more vulnerable to the adverse effects
be effective for the prevention of manic episodes, of certain atypical antipsychotics and to the devel-

258 MEDICOGRAPHIA, VOL 27, No. 3, 2005 Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank

opment of medical diseases. Consequently, patients neuroimaging techniques, the application of social
with bipolar disorder should receive careful medi- rhythm and social cognition strategies, as well as
cal monitoring throughout the period of treatment. further examinations of temperament. Only by de-
While we have considered the need for new drug fining better phenotypes and endophenotypes, will
treatment targets, it is also clear that our under- we be able to understand the pathogenesis of bipo-
standing of bipolar disorder will also be facilitated lar disorder. ❏
by paying more careful attention to a better defini-
Funding/Support: National Institute of Mental Health
tion of behavioral phenotypes as well as to identify- grants MH-30915 and MH-29618; and The Common-
ing markers for intermediate endophenotypes. This wealth of Pennsylvania Department of Health grant ME-
will require the use of pharmacogenomic strategies, 02385.

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20. Phillips ML. Understanding the neurobiology of emotion per- 18-month trial of lamotrigine and lithium maintenance treat-
ception: implications for psychiatry. Am J Psychiatry. 2003;182: ment in recently depressed patients with bipolar I disorder. J Clin
190-192. Psychiatry. 2003;64:1013-1024.
21. Weinberger DR. Biological phenotypes and genetic research 42. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled
on schizophrenia. World Psychiatry. 2002;1:2-6. 18-month trial of lamotrigine and lithium maintenance treat-
22. Ehlers CL, Frank E, Kupfer DJ. Social zeitgebers and bio- ment in recently manic or hypomanic patients with bipolar I dis-
logical rhythms: a unified approach to understanding the eti- order. Arch Gen Psychiatry. 2003;60:392-400.

Trends in diagnosis and treatment of bipolar disorders – Kupfer and Frank MEDICOGRAPHIA, VOL 27, No. 3, 2005 259

43. Keck PE, Sanchez R, Marcus RN, et al. Aripiprazole for re- 46. Tohen M, Bowden C, Calabrese J, et al. Olanzapine’s efficacy
lapse prevention in a 26-week placebo-controlled trial. Present- for relapse prevention in bipolar disorder: a randomized double-
ed at: 157th American Psychiatric Association Annual Meeting; blind placebo-controlled 12-month clinical trial. Bipolar Disord.
May 1-6, 2004; New York, NY. Abstract NR746. 2003;5(S1):89(p200).
44. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus dival- 47. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention
proex sodium for the treatment of acute mania and maintenance in bipolar I disorder: 18-month comparison of olanzapine plus
of remission: a 47-week study. Am J Psychiatry. 2003;160:1263- mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004;
1271. 184:337-345.
45. Tohen M, Marneros A, Bowden C, et al. Olanzapine versus 48. Miklowitz DJ, George EL, Richards JA, Simoneau TL, Sud-
lithium in relapse prevention in bipolar disorder: a randomized, dath RL. A randomized study of family-focused psychoeducation
double-blind, controlled, 12-month clinical trial. Am J Psychia- and pharmacotherapy in the outpatient management of bipolar
try. In press. disorder. Arch Gen Psychiatry. 2003;60:904-912.



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
he problem with core symptoms is the Core symptoms of depressive illnesses

T availability of acceptable guidelines and

classifications of depressive illnesses. Many
nonpsychiatrist doctors consider any patient who
Depression is characterized by the following
symptoms, whether in developing countries or
in other countries.
is distressed as depressed, especially if the patient ◆ Lowering of mood, volition and outlook. The
is crying! Suicide attempts or parasuicides are patient has a negative outlook, a low mood, a
always equated by nonpsychiatrists as depression. feeling of loss, of despondency. Everything is col-
Persons who are irritable and angry and easily orless, negative, gray, and gloomy.
provoked are often seen as either normal or psy- ◆ Inability to deal with normal work, play, and
chotic, but seldom considered to be depressed. social obligations satisfactorily.
M. Parameshvara DEVA, MD Such looseness in diagnosis leads to injudicious ◆ Preoccupation with bodily functions and phys-
FRCPsych, FRANZCP, FAMM use and noneffectiveness of antidepressant medi- ical symptoms. Patients often want their doctor
Hon Professor of Psychiatry cines. Thus, a review of the current concepts in to prove they have a physical disease that is not
UPNG, SSB Hospital
Kuala Belait, KA 1131 recognizing depressive illnesses and treating them there.
BRUNEI is needed. The answer lies in a good history taking ◆ Sleep disturbances. Patients usually report
(e-mail: devaparameshvara@ through a good interview of the patient. The core early morning awakening, but many experience
symptoms include a history of at least 3 weeks difficulty in falling asleep.
(but usually 6 weeks) of low mood and negative ◆ Disturbances in eating. Patients show a lack
thoughts, gloomy outlook on everyday topics, of interest in food and therefore usually lose
sleep patterns disturbed without reason, lack of weight; occasionally, they eat too much and put
interest in eating, some loss of weight, poor inter- on weight.
est in work, recreation, sexual function. To pa- ◆ In severe and prolonged depressive illnesses
tients, everything looks gray, hopeless, useless, there may be suicidal ideas, a stuporous state. ❒
they have vague thoughts of leaving their job,
going somewhere else, or even “ending it all.”

2 ◆ T. Partonen, Finland
epression is heterogeneous in terms of put forward in favor of this. For instance, depres-

D etiology and phenotype. Depressions are

many; they vary according to profile and
intensity of symptoms, and course and cause of
sive disorders and generalized anxiety disorder
tend to be related to the same genetic factors and
may be interpreted as different manifestations of
illness. Symptoms may be melancholic, atyp- the same predisposition.1 This predisposition could
ical, psychotic, or mild; there may be one or nu- involve mutations in the so-called circadian clock
merous episodes; the course may be recurrent genes and result in errors in regulation of the cir-
or chronic; the depression may be reactive or en- cadian pacemaker.2 This would lead to abnormal
dogenous in nature. Thus, trying to pin down the circadian rhythms and alteration of the sleep-
core of depression is like peeling an onion. The wake cycle, resulting in changes in core body
Timo PARTONEN, MD essential characteristic of depression is the feel- temperature and short latencies to rapid eye
Associate Professor of ing of loss: the core symptoms of depressive dis- movement (REM) sleep,3-6 the outcome of which
Psychiatry at the University
of Helsinki, and
order are therefore lack of pleasure and sadness, is compromised mood regulation and ultimately,
Academy Research Fellow in other words, anhedonia and depressed mood. feelings of depression and anxiety. One way to
at the National Public Health These constitute the key criteria for a major de- look at the question is to analyze the individual
Institute pressive episode, not only in terms of diagnosis, domains that may show differing trajectories rath-
Department of Mental Health
and Alcohol Research but also of evolution. However, this point of view er than the overall severity of depression reflecting
Helsinki, FINLAND has been challenged by recent findings suggesting a summation of these domains.7 Severe depres-
(e-mail: a need to focus on core pathways in the patho- sions are characterized by two symptoms only
genesis of illness rather than on manifestations that commonly occur in both typical and atypi-
of individual disorders. Several arguments can be cal depressive disorders. These key symptoms—

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 261

feelings of depression and loss of interest— are flating scores on the routinely administered rating
reported by 9 patients out of 10.8 Are these the scales.11-13 For example, depressive elderly persons
core symptoms of depression? Not necessarily, with mild cognitive impairment tend to report
since in addition to these two symptoms, severe sadness, anhedonia, and pessimistic thoughts.14
typical depression is characterized by difficulty Self-reports of depression may be of benefit in
in concentrating, insomnia, and loss of pleasure. terms of both expense and time, and a valuable
Moreover, major depressive episodes with a sea- substitute for clinician-based ratings in treatment
sonal pattern (seasonal affective disorder) are trials of outpatients with major depressive disor-
frequently accompanied by atypical symptoms of der, but no psychotic symptoms or cognitive im-
depression such as prolonged sleep, weight gain, pairment.15 Global ratings, however, seem to pro-
carbohydrate craving, and increased appetite.9 duce less valid findings than specific item-based
Nevertheless, a simple two-question screening tool ratings. To ensure optimal control of the core
inquiring about the presence of depressed mood symptoms of depression, an antidepressant should
and anhedonia may be just as effective as a more have mood-lifting and energizing effects, in other
complex questionnaire.10 Despite its limitations, words it needs to achieve elation and activation.
such a screening tool is certainly a useful, more Rapid relief from anxiety and insomnia are nat-
pragmatic, and less time-consuming method for urally of great help for a good outcome. In the
detecting depression in the primary care setting. long run, the patient will recover feelings of plea-
Specific groups of individuals with depressive dis- sure and optimistic thoughts. However, it is neces-
order, including children and adolescents, wom- sary to realize that no treatment—not even the
en after delivery, and the elderly, need specific most potent one—stands a true chance of success
attention in clinical practice, since their clinical if resources in terms of health-care professionals
picture may differ, and therefore can be missed by are insufficient to ensure an adequate follow-up
the usual case-finding instruments, thereby de- of patients suffering from depression.16 ❒

1. Vollebergh WA, Iedema J, Bijl RV, de Graaf R, Smit F, Ormel J. 9. Partonen T, Lönnqvist J. Seasonal affective disorder. Lancet.
The structure and stability of common mental disorders: the 1998;352:1369-1374.
NEMESIS study. Arch Gen Psychiatry. 2001;58:597-603. 10. Whooley MA, Avins AL, Miranda J, Browner WS. Case-find-
2. Johansson C, Willeit M, Smedh C, et al. Circadian clock-re- ing instruments for depression: two questions are as good as
lated polymorphisms in seasonal affective disorder and their many. J Gen Intern Med. 1997;12:439-445.
relevance to diurnal preference. Neuropsychopharmacology. 11. Timbremont B, Braet C, Dreessen L. Assessing depression
2003;28:734-739. in youth: relation between the Children’s Depression Inventory
3. Schulz H, Lund R. Sleep onset REM episodes are associated and a structured interview. J Clin Child Adolesc Psychol.
with circadian parameters of body temperature: a study in de- 2004;33:149-157.
pressed patients and normal controls. Biol Psychiatry. 1983;18: 12. Teissedre F, Chabrol H. Detecting women at risk for post-
1411-1426. natal depression using the Edinburgh Postnatal Depression Scale
4. Avery DH, Wildschiodtz G, Smallwood RG, Martin D, Rafael- at 2 to 3 days postpartum. Can J Psychiatry. 2004;49:51-54.
sen OJ. REM latency and core temperature relationships in 13. Watson LC, Pignone MP. Screening accuracy for late-life
primary depression. Acta Psychiatr Scand. 1986;74:269-280. depression in primary care: a systematic review. J Fam Pract.
5. Czeisler CA, Kronauer RE, Mooney JJ, Anderson JL, Allan JS. 2003;52:956-964.
Biologic rhythm disorders, depression, and phototherapy: a 14. Gabryelewicz T, Styczynska M, Pfeffer A, et al. Prevalence
new hypothesis. Psychiatr Clin North Am. 1987;10:687-709. of major and minor depression in elderly persons with mild
6. Schwartz PJ, Rosenthal NE, Kajimura N, et al. Ultradian cognitive impairment—MADRS factor analysis. Int J Geriatr
oscillations in cranial thermoregulation and electroencephalo- Psychiatry. 2004;19:1168-1172.
graphic slow-wave activity during sleep are abnormal in humans 15. Rush AJ, Trivedi MH, Carmody TJ, et al. Self-reported de-
with annual winter depression. Brain Res. 2000;866:152-167. pressive symptom measures: sensitivity to detecting change
7. Parker G, Roy K. The development of a six-item daily self- in a randomized, controlled trial of chronically depressed,
report measure assessing identified depressive domains. J Affect nonpsychotic outpatients. Neuropsychopharmacology.
Disord. 2003;73:289-294. 2005;30:105-116.
8. Sullivan PF, Kessler RC, Kendler KS. Latent class analysis 16. Scott J, Thorne A, Horn P. Quality improvement report:
of lifetime depressive symptoms in the national comorbidity Effect of a multifaceted approach to detecting and managing
survey. Am J Psychiatry. 1998;155:1398-1406. depression in primary care. BMJ. 2002;325:951-954.

262 MEDICOGRAPHIA, VOL 27, No.3, 2005 What are the core symptoms of depression?

3 ◆ A. Soykan, Turkey
epression has been a long-standing focus disorders, thus decreasing the possibility of de-

D of attention for writers, poets, philoso-

phers, artists, and, eventually, scientists.
The theories proposed to explain depression have
tecting differences in underlying etiopathology.
In all, the drawbacks of the DSM system restrict
the number and power of the studies investigat-
shed light on the many facets of the disease and ing the heterogeneity of depressive disorders. All
contributed to increase our awareness, under- symptoms are the end-product or by-product of
standing, and conceptualization of it. Thus, Freud pathological or functional changes in organs. The
stressed the importance of grieving in depression, brain is an organ with highly specialized functions
in the absence of any obvious loss. Beck, a psy- assigned to different areas of the hemispheres.
choanalyst and the father of the Depression In- Unlike most other organs, expansion or a slight
Attila SOYKAN, MD ventory that bears his name, started investigating change in the location of pathology can result in
Associate Professor the role of aggression directed toward self in de- very different clinical presentations. In regard to
Division of Consultation
Liaison Psychiatry
pression, and ended up by formulating a cognitive depression, great variability of symptoms and
Department of Psychiatry theory of depression. Interestingly, almost all high frequency of comorbid diseases could well
Ankara University theories have emphasized two symptoms of de- be related to the extent of the areas affected. To
School of Medicine pression; depressed mood and anhedonia/loss of date, although much remains to be learned, we do
TURKEY interest. These symptoms are also included in the have some clues about the possible brain loca-
core of Hamilton’s conceptualization of depres- tions that control some of functions that are af-
sion as presented in the Hamilton Depression Rat- fected in depression. For example, depressed mood
ing Scale.1 Eventually, the Diagnostic and Statis- possibly originates in increased activity of the
tical Manual of Mental Disorders (DSM) approach limbic cortex, specifically, the anterior cingulate
highlighted depressed mood and anhedonia/loss cortex and the limbic orbital cortex. Abnormal
of interest as the cardinal features of depression.2 neuronal activity in the hypothalamus and other
Since the third edition of the DSM in 1980, the limbic areas could lead to anhedonia/loss of in-
differences among cultures have gradually sub- terest, decreased libido, and dysregulation of ap-
sided, mainly due to the widespread acceptance petite and sleep. We also know some of the areas
of the conceptual framework enshrined in the involved in other psychiatric disorders as well.
DSM classification system. Recent studies indicate For example, the hippocampal region is affected
that, although culture can affect the expression in dementia, and mesolimbocortical dopaminer-
of depressive mood and symptoms, there appears gic pathways and the prefrontal cortex are af-
to be a “core syndrome” of depression, regardless fected in schizophrenia. I fully expect that, in
of sociocultural context.3 Current classification future, new syndromes will be defined according
systems consider depressed mood and anhedonia/ to the affected brain areas and circuits, and that
loss of interest as the “core” symptoms of depres- this will lead to a thorough overhaul of current
sion. Classification systems relying on clinical diagnostic criteria for psychiatric disorders. In
presentation need to identify “core” symptoms to conclusion, although we still need to rely on
differentiate individual “disorders,” which are “core” and other symptoms for the differential
accordingly defined. However, major drawbacks diagnosis of depression, we should also bear in
are associated with the DSM approach regarding mind that the current conceptualization of de-
the conceptualization of depression, and, as the pression limits our understanding of depression
etiopathology of depressive disorders is increas- and how to treat it. Once the diagnosis of depres-
ingly elucidated, the concept of “core” symptoms sion has been established, all the symptoms and
tends to be replaced with etiologically relevant signs presented by the patient should be consid-
symptom profiles. First of all, the DSM approach ered as “core” symptoms. Every single symptom
relies heavily on “clinical” observations, and in should receive clinical attention regardless of
terms of etiology—the ultimate goal of any clas- severity. We should rethink our current partially
sification—this hardly allows to go beyond syn- successful concept of medical treatment that con-
drome level. Secondly, the description of depres- siders depression as a whole. Instead, we should
sion is best adapted to middle-aged patients focus on individual symptoms and new thera-
without comorbid psychiatric or physical disor- peutic strategies to address them. ❒
ders. Even when only anxiety disorders are taken
into account, at least 50% of depressive patients 1. Hamilton M. Development of a rating scale for primary
present with symptoms of anxiety that interact depressive illness. Br J Soc Clin Psychol. 1967;6:278-296.
with the symptomatology produced by depression. 2. American Psychiatric Association. Diagnostic and Statisti-
cal Manual of Mental Disorders. 4th ed. Washington, DC:
Last but not least, in describing a common “ma- American Psychiatric Association; 1994.
jor depressive episode” syndrome, the DSM em- 3. Douki S, Tabbane K, Taktak MJ. Cross-cultural aspects of
phasizes similarities more than differences among depressive disorders. Eur Psychiatry. 1997;12(suppl 2):124s.

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 263

4 ◆ A. C. Altamura, Italy
t is well known that the word depression refers in the same patient (this is more likely to happen

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
in the most severe forms), but more often some
aspects (besides depressed mood or loss of inter-
est or pleasure) are predominant, particularly in
clinical context, the term depression refers not the early phase, where some patients can be “pau-
simply to a state of depressed mood, but to a syn- cisymptomatic,” with a more prominent psychic
drome comprising mood disorders, psychomotor or somatic or cognitive expression.2,3 However,
changes, and various types of somatic (neuroveg- along with the development of a full-blown major
etative) dysfunction and cognitive impairment.1 depressive syndrome, all core or nuclear symp-
According to the 4th edition of the Diagnostic and toms tend to occur. Thus, depression is like the
A. Carlo ALTAMURA, MD Statistical Manual of Mental Disorders (DSM-IV), rings that a pebble makes in a pond, which en-
Chairman Department of all these changes may occur (they should be pre- large progressively from the center (depressed
Center for Diagnosis and
sent for at least 2 weeks), but none except “de- mood and loss of interest), to progressively include
Treatment of Mood Disorders pressed mood” and “loss of interest or pleasure in more and more symptoms (psychic, somatic, and
University of Milan nearly all activities,” are essential for the diagno- cognitive). In other words, depression evolves from
Hospital Luigi Sacco sis of Major Depression. DSM-IV and the Inter- an initial “paucisymptomatological” presentation
Milan, ITALY
(e-mail: national Statistical Classification of Diseases and to the full-blown, multisymptomatic form usu-
c.altamura@hsacco.it) Health-Related Problems, 10th Revision (ICD-10) ally seen by the GP. Psychiatrists usually see pa-
show some degree of divergence in their criteria tients at a later stage, after weeks of suffering, if
for depression, regarding type and number of they are not adequately diagnosed and treated by
symptoms. ICD-10 contains 10 items, in contrast GPs.4 It is of paramount importance that GPs be
to the 9 DSM-IV items (loss of self-esteem is in a aware that patients with a monosymptomatic
separate category from inappropriate guilt in presentation (depressed mood/anxiety and reduced
ICD-10). Also, in ICD-10, the severity of Major interest or anhedonia), even though the 2-week
Depressive Episodes is rated according to an in- criterion is not fulfilled or other symptoms are not
cremental number of criteria: mild depression present, may present subclinical signs that can
starts from 4 out of 10 symptoms, moderate de- quickly develop into the core or nuclear symp-
pression from 6 out of 10 symptoms, and severe toms of a major depressive episode. The final point
depression from 8 out of 10 symptoms. Finally, in we must address is whether an antidepressant
ICD-10, the diagnostic algorithm differs by re- should be active on the core symptoms of depres-
quiring the presence of at least 2 out of the follow- sion.5,6 We favor a “holistic” approach to the psy-
ing 3 symptoms: depressed mood, loss of interest, chobiology of depression taking into account
and decreased energy for mild and moderate de- dysfunctions of the serotonergic (5-HT) or nora-
pressive episodes, and all 3 for severe depressive drenergic (NA) pathways, as well as the fine reg-
episodes. ICD-10 episodes with psychotic features ulation of disturbed biological rhythms involved
exclude first-rank symptoms and bizarre delu- in the pathogenesis of depression (such as the
sions. In terms of core or nuclear symptoms, both hypothalamopituitary axis [HPA], melatonin,
DSM-IV and ICD-10 include the following symp- etc), which are responsible for diurnal variations
toms: (i) psychic (eg, mood or anxiety or suicidal in mood, sleep disorders, anxiety, neurovegetative
ideation and guilt feelings); (ii) psychomotor (eg, symptoms, etc.7 Future approaches should ad-
retardation or agitation); (iii) somatic/neuroveg- dress not only the classic monoaminergic path-
etative (eg, sweating, tachycardia, dryness of ways, but also other neurotransmitters and/or
mouth); (iv) diurnal variation; (v) insomnia/hy- neuromodulators involved in the dysregulation of
persomnia; (vi) loss of energy; and (vii) cognitive biological rhythms, which influence, at least in
symptoms (eg, difficulty concentrating and loss part, the pathophysiology and outcome of major
of memory). All these components can be present depression.8,9 ❒

1. Altamura AC, Montresor C, Salvadori D, Mundo E. Does long term treatment of recurrent depression: rationale, cur-
comorbid subthreshold anxiety affect clinical presentation and rent methodologies and future directions. J Clin Psychiatry.
treatment response in depression? A preliminary 12-month 1993;54(suppl 8):29-37.
naturalistic study. Int J Neuropsychopharmacol. 2004;7:1-7. 6. Paykel ES. Treatment of depression: the relevance of research
2. Altamura AC. Anxious-depressive syndromes in the elderly. for clinical practice. Br J Psychiatry. 1989;155:754-763.
Assessment, clinical course and treatment. In: Racagni G, 7. Maes M, Meltzer HY. The serotonin hypothesis of major de-
Smeraldi E, eds. Anxious Depression: Assessment and Treat- pression. In: Maes M, Meltzer HY, eds. Psychopharmacology:
ment. New York, NY: Raven Press; 1987:209-216. The Fourth Generation of Progress. New York, NY: Raven
3. Lepine JP, Altamura AC, Ansseau M et al. Tianeptine and Press; 1994:933-944.
paroxetine in major depressive disorder, with a special focus 8. Altamura AC, Carta MG, Carpiniello B, Piras A, Maccio MV,
on the anxious component in depression: an international, Marcia M. Lifetime prevalence of brief recurrent depression
6-week double-blind study. Hum Psychopharmacol Clin Exp. (results from a community survey). Eur Neuropsychophar-
2001;16:219-227. macol. 1995;5(suppl):99-102.
4. Judd LL, Akiskal HS, Paulus MP. The role and clinical sig- 9. Frank E, Prien RF, Jarret RB, et al. Conceptualization and
nificance of subsyndromal depressive symptoms (SSD) in uni- rationale for consensus definitions of terms in major depres-
polar major depressive disorder. J Affect Disord. 1997;45:5-17. sive disorder: remission, recovery, relapse, and recurrence.
5. Altamura AC, Percudani M. The use of antidepressants for Arch Gen Psychiatry. 1991;48:851-855.

264 MEDICOGRAPHIA, VOL 27, No.3, 2005 What are the core symptoms of depression?

5 ◆ A. B. Smulevitch, Russia
he concept of “depression” embraces a wide neurasthenic, autonomic and somatoform dis-

T range of states of pathologically changed

affects (from typical melancholic forms to
atypical, masked, and seasonal, depressions). The
orders, algias, sleep disturbances, mainly in the
form of insomnia/hypersomnia), while the basic
affect manifestations (melancholy, psychomotor
core symptoms of depression determine the patho- disturbances, ideas of guilt) are moderate. In
logical course and the type of response to thera- these cases, the diagnosis of depression is made
py, and form the basis of the psychopathological easier by evidence of a circadian rhythm, pes-
structure of depression. These manifestations of simistic thoughts about the persons’ own health
depression are also the main measures of compli- and future, passive suicidal thoughts (desirability
ance used to evaluate the action of psychotropic of an accident, sudden death, etc). The diagnos-
Anatoly B. SMULEVITCH, drugs (target symptoms). The basic symptoms of tic criteria for seasonal depressions are based on
MD typical depression include positive affectivity man- chronobiological characteristics, as these types
National Mental Health
Research Center
ifestations (mentally oppressive depressive hyper- of affective disorders manifest during the autumn
Kachirskoe Shosse 34 esthesia (eg, heartache, suffering) or somatic dis- and winter period. During spring and summer,
115522 Moscow orders, which determine the clinical presentation depressions can be followed by a remission or
RUSSIA of typical (vital) depressions. These core diagnos- hypomania. The peculiarities of the psychopatho-
tic features include: (i) melancholy, ie, an uncer- logical structure of seasonal depressions should
tain (protopathic) feeling of intolerable pressure be taken into account. Two types of somatovege-
in the chest or epigastrium (precardiac or epi- tative symptom complex can be distinguished in
gastric melancholy) accompanied by low spirits, seasonal depressions: hyperesthetic (increase in
despondency, despair, hopelessness; (ii) intellec- appetite, including appetency for carbohydrate-
tual and motor retardation, ie, difficulties in con- rich meals, increase in weight, hypersomnia) and
centration and attention, delayed responses, slow- anesthetic (reduction in appetite and taste, ac-
ness of movements, loss of spontaneous activity; com-panied by a nutrition deficit and consider-
(iii) pathological circadian rhythm, ie, mood able loss of weight, insomnia with absence of
swings during the day with maximum symptom feeling of sleep and reduction of sleep duration).
severity early in the morning; (iv) ideas of self- The choice of antidepressants is based on the
inferiority, ie, persisting thoughts of self-useless- psychopathological manifestations of depressions
ness and self-accusation, depreciation of personal as describe above. Effective control of typical de-
successes in the past, pessimistic thoughts about pression with basic symptomatology is achieved
the future; and (v) suicidal thoughts, ie, psycho- with the majority of current thymoanaleptics.
logically not derivable wish to die, thoughts that Severe depression with agitation or marked psy-
life is not worth living, suicidal ideation, occasion- chomotor retardation requires use of potent psy-
ally an irresistible urge to commit suicide). The chotropic medications: injectable tricyclic anti-
diagnosis of atypical depressions is based on neg- depressants are preferable. In mild or moderate
ative affectivity manifestations, involving mental depressions, as well as atypical depressions, with
alienation (persisting feeling of impoverished predominance of negative affectivity, the recent
and altered mental life, loss of motivation to any antidepressants are the drugs of choice. Com-
activity). The symptom complexes of negative af- pared with tricyclic antidepressants these are
fectivity include: (i) anaesthesia psychica dolorosa, much more neurochemically selective and pro-
ie, a painful feeling of loss of emotions, inability duce fewer side effects (selective stimulators and
to feel love, hatred, empathy, anger; (ii) depres- inhibitors of serotonin reuptake, fluoxetine,
sive devitalization, ie, loss of life instinct, instinct paroxetine, etc; dual action antidepressants, in-
of self-preservation, vital inclinations (sleep, ap- cluding venlafaxine, mirtazapine, etc; selective,
petite, libido); (iii) apathy, ie, appetency deficit reversible monoamine oxidase A–type inhibitors
accompanied by a loss of zest for life, lack of en- like pirlindole, or other antidepressants like tia-
ergy, indifference to everything; (iv) dysphoria, neptine). Finally, the acute treatment and pre-
gloominess, “anger attacks,” querulousness; and vention of seasonal affective disorder, which is
(v) anhedonia, ie, inability to experience plea- associated with dysfunction of the serotonergic
sure, joy, and delight. The difficulty of detecting system and pineal gland, as well as of other de-
masked depressions (or “latent,” “alexithymic”), pressions characterized by abnormal biological
which are prevalent in general medical practice, rhythms, relies on new therapeutic strategies
is related to the predominance of neurotic symp- interacting with circadian rhythms and other
tom complexes (anxiety, phobic, hypochondriac, targets. ❒

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 265

6 ◆ B. Millet, France
hat is the epidemiologic and historical Statistical Manual of Mental Disorders (DSM-IV)

W background to a modern definition of

Given its huge epidemiologic variation, with point
required at least either depressed mood or loss of
interest to meet the criteria for Major Depressive
Episode.7 Cognitive symptoms (diminished ability
prevalences of Major Depressive Episode in the to think, concentrate, or take decisions) were also
general population over 1 year ranging from 0.6% given a major role. It was specified that depres-
in Taiwan through 5% in France to 10% in the sive symptoms vary with the branch of medicine
United States, it is essential to define the core concerned (in general medicine patients with de-
symptoms of depression if we are to identify a nu- pressive disorder report more pain and somatic
cleus of depression for use as a model in clinical illness than others) and age (predilections for ir-
Bruno MILLET, MD psychiatric research and operating criteria for ritability and social withdrawal in children, im-
Service Universitaire de appropriate antidepressant treatment. The defini- pulsiveness and toxic substance use in adoles-
CHS Guillaume Régnier
tion of depression is grounded in Ey’s description cents, and cognitive impairment in the elderly).
108 avenue du Général of melancholia as a state of “intense depression Disruption of circadian rhythm as a major symp-
Leclerc experienced with psychic pain and characterized tom of depression appears only in the form of
35011 Rennes Cedex by psychomotor inhibition.”1 The concepts of sleep disturbance (maintenance insomnia, early
(e-mail: b.millet@ch-guillau- neurasthenia, neurotic depression, and anxiety morning awakening insomnia, or, conversely,
meregnier.fr) and depression were then coined to characterize hypersomnia).
syndromes falling outside this definition. Since
these comprised symptoms such as insomnia, Response to antidepressants and clinical
functional somatic complaints and anxiety, clin- profile
icians were led to differentiate between “endoge- Antidepressant response profiles appear to differ
nous” and “psychogenic” depression—only for with the clinical characteristics of the depression:
this distinction to be swept aside after 1960 by the monoamine oxidase inhibitors in atypical de-
arrival of the first antidepressants that proved pression (mood reactivity, increased appetite or
active against all forms of depression, irrespec- body weight, hypersomnia, impression of limb
tive of their cause. International classification anesthesia, oversensitivity to rejection); tricyclics
systems subsequently jettisoned the concept of and electroconvulsive therapy in melancholic
endogenicity so dear to Kraepelin.2 depression; selective serotonin reuptake inhibitors
in nonmelancholic depression.8 Depression with
Core symptoms of depression anxiety and sleep disturbance appears sensitive
However, a number of psychiatric manuals differ- to the more sedative antidepressants.
entiate between endogenous depression (whether
unipolar or manic-depressive bipolar) and a much Neuroimaging and understanding of the patho-
more mixed presentation extending from reac- physiology of depressive symptoms
tive depression to neurotic depression.3 Clinical The key to future breakthroughs could lie in the
studies have identified the following core symp- ability to identify specific symptoms with certain
toms across a multiplicity of presentations 4,5: neuronal circuits and develop substances to target
◆ Depressed mood (expressed in its most severe those circuits.9 The demonstration of structures
form as convictions of unworthiness, incurability, mediating the self-referential processing of emo-
and guilt). tional stimuli10 and of corticosubcortical circuits
◆ Inhibition or loss of élan vital (asthenia, global involved in depression justifies further research
disinterest, loss of initiative, impaired intellectual into the connections between clinical symptoms
performance and motor function). and functional neurology.11,12 Depressive symp-
◆ Somatic symptoms (anorexia, weight loss, con- toms may thus be divided into spheres:
stipation, sleep disturbance). ◆ Emotion: depressed mood, self-depreciation,
◆ Anxiety and personality disturbances (irritabil- guilt.
ity, impulsiveness, social withdrawal). ◆ Motivation: loss of interest, loss of affect, psy-
◆ Ideas of death and suicidal thoughts (often as- chomotor retardation.
sociated with depressed mood). ◆ Association: abnormal executor function, with
◆ Delusional ideas (in the most severe forms of each sphere being concerned by a neighboring,
depression): mood-congruent (guilt, ruin, mourn- but different, neuronal circuit.
ing, misfortune, hypochondria) or mood-incon- A pathophysiologic approach to depression brings
gruent (ideas of influence and possession).6 the clinical targets of antidepressants into sharper
The introduction of international criteria advanced focus. Depression is a clinically mixed syndrome
the understanding of depression by assembling with core characteristics that are recognized by
experts who reanalyzed the literature data and all clinicians. The next step is to establish clini-
drew on new studies. It was thus no surprise when, coneurophysiologic correlates that optimize the
in 1994, the 4th edition of the Diagnostic and deployment of our therapeutic arsenal. ❒

266 MEDICOGRAPHIA, VOL 27, No.3, 2005 What are the core symptoms of depression?

1. Ey H, Bernard P, Brisset C. Manuel de Psychiatrie. Paris, 7. American Psychiatric Association. Diagnostic and Statistical
France: Masson; 1963. Manual of Mental Disorders (DSM-IV). 4th ed. Washington, DC:
2. Sartorius N. Classification: an international perspective. American Psychiatric Association; 1994.
Psychiatr Ann. 1976;6:22-35. 8. Esposito K, Goodnick P. Predictors of response in depres-
3. Lempérière T , Féline A, Gutman A, Adès J, Pilate C. sion. Psychiatr Clin N Am. 2003;26:353-365.
Abrégé de Psychiatrie de l’Adulte. Paris, France: Masson; 9. LeDoux JE. Synaptic Self. New York, NY: Viking; 2001.
1977. 10. Fossati P, Hevenor SJ, Graham SJ, et al. In search of the
4. Guelfi JD. Psychiatrie de l’Adulte. Paris, France: Editions emotional self: an fMRI study using positive and negative
Ellipses; 1985. emotional words. Am J Psychiatry. 2003;160:1938-1945.
5. Gelder M, Gath D, Mayou R. Oxford Textbook of Psychiatry. 11. Seminowicz DA, Mayberg HS, McIntosh AR, et al. Limbic-
2nd ed. Oxford, UK: Oxford University Press; 1989. frontal circuitry in major depression: a path modeling meta-
6. De Carvalho W, Cohen D. États dépressifs chez l’adulte. In: nalysis. Neuroimage. 2004;22:409-418.
Olié JP, Poirier MF, Lôo H, eds. Les Maladies Dépressives. 2nd 12. Mayberg HS. Positron emission tomography imaging in
ed. Paris, France: Éditions Médecine Sciences Flammarion; depression: a neural systems perspective. Neuroimaging Clin
2003:3-19. 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:
◆ Presence of one symptom (or a group of
symptoms) pathognomonic for depression, which
disorders, pains, psychomotor retardation, etc.
From a practical perspective, the high incidence
of depression has resulted in its being treated es-
leads to an immediate diagnosis of depression; or sentially at primary health care level. This patient
◆ Absence of characteristic symptoms, in which population has a lesser prevalence of dysphoria
case it is the ensemble of a more or less variable or ideas of guilt, but a high incidence of fatigue,5
clinical picture that leads to diagnosis of the which has been proposed as the primordial symp-
disorder. tom of major depression.6 We need to improve the
The first presentation is the classic one in psychi- early diagnosis and recognition of depression in
Jerónimo SAIZ-RUIZ, atry. Since Kurt Schneider,1 “vital sadness” has this setting, for example, by using certain simple
MD, PhD been considered as a fundamental symptom of epidemiological screening tools and evaluation
Hospital Ramón y Cajal
Head, Psychiatric
depression. Depressed mood is described as hav- scales (Primary Care Evaluation of Mental Disor-
Department, and ing a “different quality” than “normal sadness.” ders [PRIME-MD], Mini-Mental Status Examina-
University of Alcalá It is sadness that is nonreactive, internal, “cor- tion [MMSE], Zung Self-rating Depression Scale
Vice-Dean and Professor poralized,” persistent, not voluntarily changeable. [SDS], etc).7,8 Physicians need to carry out appro-
of Psychiatry
Ca Colmenar, km 9,1 For these authors, this symptom is the very core priately detailed clinical interviews that cover the
28034 Madrid of depression, it is depression itself. This type of full psychopathological gamut of symptoms in
SPAIN depression is described as endogenous,2,3 and is order to improve the detection rates of depression.
characterized by inhibition, lack of emotional re- Another factor that adds to the difficulties is the
activity, and loss of interest and pleasure in things. lack of stability in symptoms throughout the
The second presentation is increasingly at the course of the depression. This was clearly shown
forefront in current practice. Modern operating in a recent study,9 with respect to both the con-
classifications have switched from the former en- tinuity of symptoms in successive recurrences and
dogenous (melancholy)/reactive (neurotic) dis- the subtypes of depression. Variations based on
tinction to that between major depression and gender have also been reported.10 Likewise, trans-
dysthymia. They postulate a sequential develop- cultural divergences have been pointed out when
ment of the different subtypes of depression studying samples in different populations.11 How-
throughout the subject’s evolution. These classifi- ever, all of these studies suffer from having been
cations do not take into account the subtle phe- performed on samples of severe patients, frequent-
nomenological distinction of the “different quali- ly in hospital, which may not be very representa-
ty” of the depressive mood, which is so difficult to tive of the usual setting in which depression oc-
detect.4 It has been claimed that this devaluates curs. One field of interest over recent years is that
the symptom, and blurs the limits between the of the importance of residual symptoms (fatigue,
syndrome and the pathological entity and the dif- anxiety, sexual dysfunction, sleep disorders, etc),12
ferent types of mood disorder. However, the basic which may persist after partial relief from symp-
diagnostic criteria continue to include an alter- toms following treatment of the episode. These
ation of mood and a lack of pleasure, with various residual symptoms multiply the risk of relapse by
combinations of the following symptomatic com- three, worsen social and occupational function-
plexes later completing the picture: ing, favor chronic depression, and increase the
◆ Psychic: sadness, demoralization, lack of inter- risk of suicide. Although it is debated whether
est, negative thoughts, low self-esteem, decreased these residual symptoms are caused by comorbid-
attention and memory, etc, and ity with personality or anxiety disorders, they are

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 267

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

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

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

Screening Questionnaires5 facilitate the diagno- ◆ Achieve complete remission, promote function-
sis of depression. Ultimately, the combination of al recovery, prevent relapse.
clinical awareness, vigilance, and diagnostic ori- ◆ Safe in overdose, pregnancy, lactation, and in
entation of the primary care physician is critical cardiac, respiratory, autoimmune, skin, hepatic,
to early recognition of a depressive disorder. 2,5 renal, and other systemic disorders.
Once the presence of a depressive disorder is di- ◆ Minimal drug interactions.
agnosed, a finer analysis is required to subtype ◆ Established safety for long-term use in all age
the disorder.4,10 Age, education, race, income, and groups.
marital status are related to the outcome more ◆ Absent or minimal adverse and emergent ef-
than the presentation.4 Psychosocial events may fects on weight, hair growth, appetite, libido,
influence the first few episodes, but do not have and others.
much relevance in subsequent episodes.4 An ideal ◆ No diurnal sedation.
antidepressant drug is definitely on any clini- ◆ Easy to administer, preferably once daily
cian’s wish list.11 The ten tenets for an ideal an- standard dose, no dose titration.
tidepressant drug should be: ◆ Cost-effective, easily available.
◆ Rapid onset, broad spectrum of action in all ◆ Low risk of breakthrough mania. ❒

1. Ustun TB. The world-wide burden of depression in the 21st cal Manual of Mental Disorders. 4th Edition, Text Revision.
century. In: Weissman MM, ed. Treatment of Depression. Bridg- Washington DC; American Psychiatric Association; 2000.
ing the 21st Century. Bombay, India: First Indian Edition; 7. Akiskal HS. Mood disorders: clinical features. In: Sadock BJ,
2003:35. Sadock VA, eds. Comprehensive Textbook of Psychiatry. 7th
2. Murthy RS, Bertolote JM, Eppig Jordan J, eds. World Health Edition, Vol 1. Philadelphia, Pa: Lippincott Williams & Wilkins;
Report 2001. Geneva, Switzerland: World Health Organization; 2000:1341.
2001. 8. Depression Research at National Institute of Mental Health.
3. Chisholm D, Sanderson K, Ayuso-Mateos JL, Saxena S. Re- Depression Fact Sheet 1999. Available at http://www.loren-
ducing the global burden of depression population–level analy- bennett.org/depfactsheet.htm. Accessed on 04/20/2005.
sis of intervention cost-effectiveness in 14 regions. Br J Psy- 9. Greunberg AM, Goldstein RD. Mood Disorders: Depression.
chiatry. 2004;184:393-403. In: Tasman A, Kay J, Lieberman JA, eds. Psychiatry. Vol 2, 2nd
4. Depression Guidelines Panel. Depression in Primary Care. edition. Indian Reprint. Bangalore, India: Panther Publishers
Vol 1. Detection and Diagnosis. Clinical Practice Guideline, Private Ltd; 2004:1217-1218.
Number 5. Rockville, MD. U.S. Department of Health and Hu- 10. Greunberg AM, Goldstein RD. Mood Disorders: Depression.
man Service, Agency for Health Care Policy and Research. In Tasman A, Kay J, Lieberman JA, eds. Psychiatry. Vol 2, 2nd
AHCPR Publication No. 93-0550. April 1993. edition. Indian Reprint. Bangalore, India: Panther Publishers
5. Wittchen HU, Beesdo K, Bittner A. Depression, an under- Private Ltd; 2004:1210-1213.
diagnosed disease. Medicographia. 2003;25:9-18. 11. Lôo H. Antidepressants of the future: a clinician’s wish list.
6. American Psychiatric Association. Diagnostic and Statisti- Medicographia. 2003;25:3-8. Editorial.

What are the core symptoms of depression? MEDICOGRAPHIA, VOL 27, No.3, 2005 269


Interview with N. Sartorius

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

o. Needs for mental health ser-

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

ental health needs should no longer be expressed in form. Governmental policies contain the solution to some, but
terms of prevalence of mental disorders as such, but in certainly not all, health issues. Although the development of new
terms of demands for which an adequate response is and better medications is unquestionably useful, it is by no means
available to mental health services. Therefore, assessment of needs the only solution to the needs for better mental health services.
should take into account not only what the patient wants, but Knowledge about mental illnesses and ways of dealing with men-
also the needs of families, doctors, and society. The main diffi- tally ill people should also be improved. Therapeutic advances
culty in the application of this definition is that the needs and must be accompanied by an adjustment of the health system and
demands of each party may be conflicting or show only partial an active commitment of society to deal with mental disorders
overlap. What patients want, for example, is to be treated with in the best way known.
dignity, to be free of symptoms, and to retain their source of in- Medicographia. 2005;27:270-272. (see French abstract on page 272)
come (jobs). Family needs include the preservation of their rep-
utation and financial situation. Doctors want to be effective, avoid Keywords: depression; mental disorder; patient; family; society;
litigation, be confident that the risk of suicide is low, and that government; health service; cultural setting
treatment will have a rapid onset of action and not be unduly
Address for correspondence: Prof Norman Sartorius, 14 Chemin Colladon,
long. Governments (voicing society’s demands) want to reduce 1209 Geneva, Switzerland
the cost of care, while remaining in tune with their election plat- (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 their treatment; that they demand easy And society’s needs?
focusing on certain groups of disorders access—whenever necessary—to the
and providing the least expensive service. service providers; that they wish to be n democratic societies, govern-
All three would like to see the illness dis-
appear, but in its presence will demand
freed from symptoms that are severely
disturbing (some symptoms of mental
I ments are “spokespersons” for so-
ciety as a whole (or at least 51% of it).
or do different things to resolve the disorders are not experienced as too Governments, however, rarely have the
problems. much of a nuisance by the patient); that luxury of fulfilling long-range plans and
their disease—if it cannot be eliminat- usually have to change them for political
Can you give us another example illus- ed—does not affect functions that they reasons. This also changes governments’
trating the relevance of this approach consider most important (for example, demands on the health sector. Still, it
to the assessment of needs? their thinking or their sexual function- seems that some demands are becoming
ing); that they do not remain for ever universal. Governments want health ser-
nother example is the often marked by the disease; and that their vices to help them contain disruptions of
A quoted desideratum that treat-
ment must be simple. The argument is
sources of income — eg, their job — is
not affected by the illness.
communities that they fear might arise if
patients with mental illnesses were to be
that this will allow less well-trained per- These examples of patients’ wishes and allowed to go about unattended; they want
sonnel to apply the treatment and that expectations were found in a major pro- to reduce the cost of care and keep it low
compliance with the instructions of the ject against stigma started a decade ago in all sectors with the exception of those
service provider to the patient will be and currently under way in some 18 that are politically very important and
better. The requirement that treatment countries. These findings may not be therefore often very visible; they want to
be simple stems from priorities of the valid everywhere, and it is therefore ex- build and retain their image in harmony
health service, which aims to simplify tremely useful to carry out local studies with their election platform, which often
training and to delegate treatment re- to find out what the patients’ needs are. contains the solution of some, but certain-
sponsibility to less expensive staff. Pa- ly not all, health problems; and they want
tients do not express that need. In fact, What about families’ needs? to avoid scandals which involve them.
both the experience of traditional prac-
titioners and of medical practice seem to ere, even more than with pa- What about unmet needs concerning
indicate that patients are prepared to
follow very complex treatment regimens
H tients’ needs, it is important
to carry out assessments in the cultural

provided that they have received instruc- setting in which the service is provided oday’s array of medications
tions about the treatment and that they
believe that, if taken in the specified way,
because the needs of families tend to be
profoundly affected by traditions and
T and techniques that have been
shown to be effective and safe is consid-
the treatment will help. other cultural markers of a community. erable, certainly larger than ever before.
Another common example is the fami- In many countries, families are reported The main challenge therefore does not lie
ly’s demand to the health worker to find to go to extreme lengths to protect their in the development of better treatments,
a treatment that will make the patient’s good reputation; they try to avoid finan- but in the equitable use of those available.
sleep/wake rhythm predictable and co- cial crises because of one of its members’ Stigma of mental illness reduces the pri-
inciding with theirs. While a patient may sickness; they will often have only a lim- ority given to the development of effec-
not feel the need to take sleeping pills ited amount of patience in waiting for tive mental health services. Burnout of
and might even prefer being awake for a their sick member to reassume his/her personnel in institutions dealing with
great part of the night, the family finds role in the family; and they will insist on mental illness is on the increase, fueled
this difficult to tolerate because of their having a decisive word in decisions about by an excessive amount of work (with
obligations during the day. Recognizing the patient’s treatment. They will also continuous reduction of personnel and
the difference between what patients and often refuse to take on—forever—the other resources) and unrealistic expecta-
families need and taking it into account burden that a sick member imposes; for tions. Ignorance about mental illness and
will require that doctors use their nego- the family as well as for the patient it is ways of dealing with people who have it
tiating skills with both parties in order incomparably easier to fight if the end is monumental. Also, the disintegration
to find a compromise solution. If they do of the disease is in sight, even if very of families and communities reduces their
not, they will lose the good will and con- distant. capacity to deal with their ill members.
fidence of one or both of the crucial par- These are challenges that have to be
ties involved in the treatment process— And what about the doctors’s needs? addressed if the currently available treat-
the patients and/or their families. ment techniques are to give maximum
octors want to help their pa- benefit and satisfy the mental health ser-
Tell us more about the needs that
patients express?
D tients, but also want to avoid
litigation; they want to be reassured that
vice needs of the population.

the risk of suicide in a patient they have Does this mean that we do not need to
esearch on expressed needs to treat is low; they want to see a rapid improve treatment techniques?
R and demands has only recently
begun to take on more serious dimen-
onset of treatment—not only because
they want to help the patient, but also o, improvement of therapy is
sions. Until now, such studies were not
seen as a priority and it was difficult to
because they want to see the good results
of their work; they want to learn about
N very useful, but it will not be
sufficient. Advances must go hand in
find funding for them. What we do know techniques that can shorten the duration hand with an adjustment of the health
is that patients wish to be treated with of their intervention; and they want to be system and an active commitment of
due respect to their dignity; that they able to refer away patients whose treat- society to deal with mental disorders in
want to be involved in decisions about ment is beyond their competence. the best way known. ❒

Unmet needs in depression (and other mental disorders) – Sartorius MEDICOGRAPHIA, VOL 27, No.3, 2005 271


es besoins dans le domaine des maladies mentales ne de- de maintenir leur réputation et leur situation financière. Les mé-
vraient plus être exprimés en termes de prévalence des decins veulent être efficaces, éviter litiges et procès, être assurés
troubles mentaux en tant que tels, mais en termes de de- que le risque de suicide est bas, que le traitement agira rapide-
mandes pour lesquelles il existe une réponse adéquate sur le plan ment et ne s’étendra pas sur une durée trop longue. Les gouver-
des services de santé mentale. L’évaluation des besoins doit prendre nements (représentant la société) cherchent à réduire les coûts
en compte non seulement les souhaits du patient, mais égale- de santé, tout en restant à l’unisson de leurs plates-formes élec-
ment ceux exprimés par les familles, les médecins et la société. torales. Si nul ne nie l’utilité de développer des médicaments
La difficulté principale liée à l’application de cette définition est nouveaux et plus efficaces, ceci ne peut en aucun cas constituer
que les besoins et les demandes de chaque partie peuvent être en la seule solution aux besoins des services de santé mentale. La
conflit ou ne se recouvrir que de façon partielle. Ce que deman- connaissance des maladies mentales et la manière de soigner les
dent les patients, par exemple, c’est d’être traités avec dignité, patients qui en souffrent doivent également être améliorées. Les
d’être soulagés de leurs symptômes, et d’être sûrs que leurs sources avancées thérapeutiques doivent s’accompagner des révisions
de revenus (emplois) ne soient pas affectées par leur maladie. nécessaires des systèmes de santé et d’une implication active de
L’évaluation des besoins des familles comprennent entre autres la société dans la prise en charge des troubles mentaux.

272 MEDICOGRAPHIA, VOL 27, No.3, 2005 Unmet needs in depression (and other mental disorders) – Sartorius


by R. Emsley, South Africa

his article looks at the pivotal importance of sleep physiological processes may be intimately in-

T depression-associated sleep abnormalities

throughout their course: from diagnosis at
the early stage of depression to initial treatment,
volved in the pathophysiological and recovery pro-
cesses of major depression.2 Insomnia associated
with depression can be categorized as follows: diffi-
and to their long-term outcome. culty initiating sleep, difficulty maintaining sleep
The quality of life of depressed patients is dimin- (or continuity disturbances), and early morning
ished by a variety of factors, sleep disturbances be- awakening. Difficulty initiating sleep is the least
ing one of the most prominent among these. Very specific, and early morning awakening the most
few patients with depression do not experience dis- Robin EMSLEY, MB ChB, specific to major depression. Factors such as age,
turbance of sleep pattern in one form of another. MMed, FCPsych, MD sex, severity of the episode, and comorbid anxiety
Department of Psychiatry
Sleep disturbances in depression comprise insom- Faculty of Health Sciences
play a role in determining the incidence, severity,
nia and, less commonly, hypersomnolence. Some University of Stellenbosch and nature of sleep disturbances associated with
patients actually fluctuate between these two pat- Cape Town, SOUTH AFRICA major depression.
terns of sleep disturbance during the course of an
episode of depression, reflecting the psychobiolog- Time course
ical heterogeneity of major depressive episodes.1
Whether as insomnia or hypersomnia, it has be- Sleep abnormalities in depression are seen across
come clear that sleep dysregulation is more than the age spectrum, from an early age, ie, in adoles-
just an epiphenomenon of depression. Thus, not cence,3 to the elderly. The bidirectional risk rela-
only is disturbed sleep one of the most common
concomitants of a persistent depressed mood—ad-
ditional associations include the following: (i) the SELECTED ABBREVIATIONS AND ACRONYMS
presence of sleep abnormality in depressed patients
HPA hypothalamic-pituitary-adrenal (axis)
has prognostic and outcome implications; (ii) the
MAOI monoamine oxidase inhibitor
majority of antidepressants cause substantial chang-
es in polysomnographic measures as well as in sub- N-REM non–rapid eye movement (sleep)
jective and objective aspects of sleep; and (iii) var- REM rapid eye movement (sleep)
ious sleep manipulations can alleviate or exacerbate SSRI selective serotonin reuptake inhibitor
symptoms of depression in a subset of patients. For TCA tricyclic antidepressant
these reasons it has been suggested that changes in

lmost all patients with major depression experience a dis- suppress rapid eye movement (REM) sleep to varying degrees.
turbance of sleep pattern. Sleep disturbance is a core fea- Selective serotonin reuptake inhibitors (SSRIs) generally sup-
ture of major depression, and is associated with important press REM sleep, but are often associated with subjective reports
prognostic and outcome implications. While sleep abnormalities of insomnia. Insomnia in patients with major depression requires
with major depression are seen across the age spectrum, aging is careful assessment. Exclusion of primary insomnia, as well as of
associated with more prominent insomnia. Disordered sleep pre- general medical and substance-related causes, is important. Treat-
cedes the onset of a depressive episode, and the reemergence of ment strategies involve pharmacological and nonpharmacolog-
insomnia may herald the onset of a new episode of recurrent ical interventions. Some clinicians prescribe an antidepressant
depression. While insomnia often resolves with successful treat- with sedative properties. Alternatively, a hypnotic can be copre-
ment of the depressive episode, most polysomnographic sleep ab- scribed. Neither of these approaches is without problems. Sleep
normalities persist after recovery, suggesting that they are more hygiene and other behavioral treatments may be helpful adjuncts.
trait-like than state-like. Excessive daytime sleepiness and fa- Medicographia. 2005;27:273-278. (see French abstract on page 278)
tigue are consequences of insomnia, and can result in decreased
productivity and an increased risk of accidents. Persistent sleep Keywords: sleep; insomnia; depression; major depression;
disturbance is associated with significant risk of recurrence, an antidepressant
increased risk of suicide, and poorer overall outcome. Most anti-
depressants cause substantial changes in subjective aspects of
Address for correspondence: Prof Robin Emsley, Department of Pyschiatry, Faculty
sleep as well as in polysomnographic measures. Tricyclic antide- of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505
pressants and the conventional monoamine oxidase inhibitors South Africa (e-mail: rae@sun.ac.za)

The impact of sleep disorders on the course of depression – Emsley MEDICOGRAPHIA, VOL 27, No. 3, 2005 273

tionship between sleep and depression may be par- mentation during the night, early morning wak-
ticularly strong in older adults.4 Aging is associated ening with an inability to return to sleep, reduced
with more prominent insomnia in depression, while sleep efficiency, and decreased total sleep time.
hypersomnolence is relatively more common ear- ◆ Regarding abnormal sleep architecture, abnor-
lier in life and may even be nearly as prevalent as in- malities have been reported in the amounts and
somnia among younger depressed women.1 There distribution of non-rapid eye movement (N-REM)
is considerable evidence to suggest that disordered sleep stages throughout the night, including an
sleep actually precedes the onset of a depressive increase in the amount of light stage 1 sleep and
episode. In a longitudinal epidemiological study reduction of deep, slow-wave (stages 3 and 4) sleep.
investigating the association between sleep distur- ◆ REM sleep disturbances in patients include a
bance and psychiatric disorders in young adults, shortening of REM latency (<65 minutes), a pro-
prior insomnia was a significant predictor of subse- longation of the first REM sleep period, and in-
quent major depression. On the basis of their find- creased REM density (ie, increased total REM sleep
ings, the authors suggested that complaints of 2 time), particularly in the first half of the night.14,15
weeks or more of insomnia nearly every night might Sleep disturbances can be verified with polysom-
be a useful marker of subsequent onset of a major nography in 90% of patients with major depression.
depressive episode.5 In the National Institute of Men- They are most pronounced in melancholic depres-
tal Health Epidemiologic Catchment Area study, sion16 and in bipolar and psychotic depression.17
10.2% and 3.2% of a community sample noted in- The underlying mechanisms involved in the
somnia and hypersomnia, respectively. The risk of pathogenesis of sleep abnormalities in major de-
developing new major depression was significantly pression are not known. In cases of early morning
higher in those who had insomnia compared with wakening and decreased REM latency there may be
those without insomnia, but this risk was much re- a phase advance of the sleep-wake cycle.18 Although
duced if the insomnia had resolved at a follow-up not fully elucidated, a recent study involving EEG
visit.6 In subjects with preexisting major depression sleep and regional metabolism assessments with
the reemergence of insomnia can similarly herald positron emission tomography reported interest-
the onset of a new episode of recurrent depression.7 ing findings regarding the underlying neurobiology
Considerable research attention has focused on of disturbed REM sleep in depression. Depressed pa-
whether sleep changes occurring in major depres- tients showed signs of altered function of limbic/
sion are state-related (ie, emerge during the episode anterior paralimbic, and prefrontal circuits during
only) or trait-related (ie, whether they persist after the REM sleep state, possibly reflecting an imbal-
full remission of the episode). Research to date has ance in monoaminergic/cholinergic function af-
produced mixed results. On the one hand, improve- fecting not only the brainstem generation of REM
ment in subjective insomnia was found to be close- sleep, but also the manner in which the forebrain
ly related to global improvement in depression,8 and responds to the stimuli of REM sleep.19
it was originally thought to be a state marker. This Sleep disturbances seem to be more prominent in
is also supported by findings that hypothalamic- patients with more severe depression, as suggested
pituitary-adrenal (HPA) axis changes appear to be by the finding that they were reported in 80% in-
specifically state-related.3 On the other hand, lon- patients with depression (presumably more severe)
gitudinal studies in fact indicate that most EEG compared with only 40% to 60% depressed outpa-
sleep measures persist after episode recovery, sug- tients. About 30% depressed patients actually have
gesting that they are more trait-like.3,9,10 There are hypersomnia.13 When EEG sleep profiles were com-
indications that the type of treatment may have an pared in the first 6 weeks of a depressive episode in
effect on sleep in the postrecovery phase of depres- a group of subjects with recurrent depression and
sion. A study reported quantitative differences in compared with their sleep profiles as measured
EEG sleep measures in subjects who had recovered during their previous episode at a later stage, it was
from a major depressive episode after treatment found that REM sleep abnormalities were more pro-
with interpersonal therapy and those who recov- nounced earlier in the course of a depressive epi-
ered after treatment with interpersonal therapy plus sode.20 Deficiencies in sleep efficiency may explain
fluoxetine.11 why depressed patients often feel fatigued even
when they appear to sleep excessively. However, the
Classification diagnostic specificity of the sleep disturbances is
poor. It has been reported that no single sleep vari-
Sleep EEG changes, together with HPA axis changes able reliably distinguishes patients with major de-
associated with major depressive disorder are among pression from healthy controls or from patients
the best replicated biological findings in psychia- with other psychiatric disorders.21
try.12 Sleep disturbances in patients with major de-
pressive disorders can be classified according to Clinical implications
polysomnographic studies as: (i) difficulties initiat-
ing and maintaining sleep; (ii) abnormal sleep ar- Excessive daytime sleepiness and fatigue are un-
chitecture; and (iii) disruptions in the timing of avoidable consequences of insomnia, and are there-
rapid eye movement (REM) sleep13: fore common features of patients suffering from
◆ Difficulties with sleep initiation and maintenance depression.22 This in turn can result in impaired oc-
include prolonged sleep latency (ie, sleep-onset in- cupational and social functioning, with decreased
somnia), intermittent wakefulness and sleep frag- productivity and an increased risk of accidents.23

274 MEDICOGRAPHIA, VOL 27, No. 3, 2005 The impact of sleep disorders on the course of depression – Emsley

There are other important clinical implications has the most prominent alerting effect on sleep.28
for sleep disturbances in depression. Persistent sleep The clinical response to amitriptyline34 and clo-
disturbance is associated with significant risk of re- mipramine35 may be related to the degree of REM
currence.6 Also, recurrent depression is associated sleep suppression, with better outcome being as-
with a more severe neurophysiologic substrate than sociated with a greater degree of REM suppression.
phenotypically similar single-episode cases.24 Two One curious TCA is trimipramine. Although a clas-
studies have reported an association between sleep sic TCA, trimipramine shows unusual pharmaco-
disturbance and suicide. The first found that both logical properties. Rather than reducing, it increas-
insomnia and hypersomnia are associated with sui- es, REM sleep. This property has important clinical
cidal behavior in patients with major depression,25 implications. Clinicians have for many years found
and the second reported an association between trimipramine particularly useful in depressed pa-
poor subjective sleep quality and suicidal behavior tients with prominent insomnia, and in addition
in patients with major depressive disorder.26 Poly- it has been shown to be effective in treating non-
somnographic sleep changes such as REM latency depressed patients with primary insomnia.36
have also been reported to predict treatment re-
sponse and the clinical course of illness.27 ◆ Monoamine oxidase inhibitors
Monoamine oxidase inhibitors (MAOIs) have been
Effects of antidepressants on sleep found to also suppress REM sleep in patients with
major depression.28 The onset of the suppressant ef-
All antidepressants have some effects on sleep ar- fect is delayed, however, and there is considerable
chitecture.28 In fact, in early studies, suppression of associated REM rebound upon withdrawal.37 Unlike
REM sleep was regarded as necessary for the anti- in the case of TCAs, the antidepressant response to
depressant action, based on a finding of a correla- phenelzine treatment is not correlated with the de-
tion between clinical response and REM suppres- gree of suppression of REM sleep.38 MAOIs also re-
sion as well as a temporal relationship between the duce total sleep time and may decrease sleep effi-
onset of clinical response and REM suppression. ciency.39 Different findings to the classic MAOIs have
However, this was later found not to be the case.1 been reported with the reversible MAOI moclobe-
Clinical trials investigating the effects of antide- mide. One study reported improved sleep continu-
pressants in patients with major depressive disor- ity in depressed subjects, particularly during the in-
der have reported varying effects of these agents on termediate and late stages of drug administration
sleep latency and sleep efficiency, as well as on day- in a 4-week trial. This was accompanied by signif-
time somnolence.29 Some antidepressants have pro- icant improvements in the symptoms of depres-
found effects on sleep regulation, and others min- sion.40 A second study found an activating effect
imal. Specific antidepressants also vary in their with moclobemide, most marked during the early
effects from individual to individual. An antidepres- phase of treatment. The most noticeable effects were
sant may produce a strong sedative effect in one on REM sleep, affecting polysomnographic and spec-
individual, and no effect or even an activating effect tral sleep EEG parameters. A REM sleep habituation
in another. Clinicians have traditionally selected phenomenon was observed, and a slight REM sleep
an antidepressant with a more sedative profile for rebound effect occurred early during withdrawal.41
depressed subjects with prominent insomnia, while
a more activating antidepressant may be prescribed ◆ Selective serotonin reuptake inhibitors
in cases where hypersomnia is a significant prob- Serotonergic neurons play a critical role in modu-
lem. It has also been suggested that the nature of lating the onset and maintenance of sleep, and it is
the sleep disturbance at initial clinical presenta- thought that insomnia in depression is linked to
tion may be relevant to the choice of antidepres- dysfunction of central nervous system serotonergic
sant medications and the likelihood of experiencing systems.31 Selective serotonin reuptake inhibitors
treatment-emergent side effects.30 (SSRIs) generally suppress REM sleep. However,
they have variable effects on subjective reports of
◆ Tricyclics effects on sleep. Between 10% and 15% of patients
The tricyclic antidepressants (TCAs) primarily in- treated with an SSRI complain of insomnia during
hibit the reuptake of the neurotransmitter nore- the early stages of treatment. As a consequence,
pinephrine, and to a lesser extent serotonin.31 They clinicians often coprescribe concomitant hypnotic
have additional effects on a variety of other recep- medication. One source found that 35% patients
tors. Most of the TCAs are potent suppressors of prescribed an SSRI also received a sedative/hypnot-
REM sleep, although some do so only moderately.32 ic.42 Studies have highlighted increased wakeful-
Clomipramine and desipramine are the most po- ness with SSRIs, particularly on fluoxetine. A study
tent in this regard. REM suppression is usually more investigating the longer-term effects of fluoxetine in
pronounced during the first few hours of sleep and patients with major depression who were treatment
there is some accommodation to these effects with responders reported significantly reduced sleep ef-
continuation therapy.1 TCAs also prolong REM la- ficiency, decreased stage 2 sleep, increased stage 1
tency and decrease the total amount of REM sleep sleep, prolonged REM latency, and a 3.4% reduction
time.13 Clomipramine, desipramine, and amitripty- in REM time at 10 weeks of treatment. This study
line increase stage 1 sleep and decrease sleep effi- showed that these effects persist, as even after 30
ciency over baseline levels.33 Clomipramine, with weeks of treatment there were still alerting effects
the strongest serotonergic effects of all of the TCAs, on sleep.43 Paroxetine is also associated with an

The impact of sleep disorders on the course of depression – Emsley MEDICOGRAPHIA, VOL 27, No. 3, 2005 275

alerting effect44 as well as a significant REM rebound than depression (eg, anxiety disorder, mania, psy-
with discontinuation.44 Fluvoxamine also appears to chosis). There are various strategies for treating pa-
have an alerting effect in patients with major de- tients with insomnia in major depression. First, an
pression. This effect was found to have a fast onset, antidepressant with sedative properties can be pre-
being evident even after the first day or two of treat- scribed. Mirtazapine is commonly used these days,
ment.45 Citalopram did not appear to have any dele- although sedative TCAs such as amitriptyline and
terious effects on sleep continuity or wakefulness trimipramine, trazodone, and nefazodone have also
during the night in a study of patients over 6 weeks been used. Patients successfully treated with an
of treatment.46 Escitalopram is reported to cause in- SSRI, but who experience persistent insomnia, may
somnia at a greater rate than placebo.47 be treated with a hypnotic such as zolpidem or zopi-
clone. Alternatively, they may be switched to a se-
◆ Other antidepressants dating antidepressant. Finally, combinations of an-
Mirtazapine is a potent blocker of 5-HT2 , 5-HT3 and tidepressants (ie, adding a sedative antidepressant
histamine receptors, and it has the strongest ini- at night to a patient being treated with an SSRI) can
tial sedative effects among the newer antidepres- be considered as a last resort in patients responding
sants. These effects cause daytime sedation in about inadequately to the above strategies.1 However, cau-
half of patients during the first 2 weeks of treat- tion is necessary with the TCAs because of poten-
ment,48 but they may be very useful for depressed tially toxic effects due to drug-drug interactions,
patients with prominent insomnia. In a study em- and combination of an SSRI with mirtazapine is
ploying low doses of venlafaxine, the effects on sleep likely to be safer.
architecture were similar to those of the SSRIs.49 In addition to pharmacologic management, sleep-
Bupropion is generally considered to be an activat- hygiene and other behavioral strategies can be help-
ing antidepressant, and has been reported to short- ful in treating insomnia associated with major de-
en REM latency and increase REM sleep.50 Rebox- pression. Activities that may be detrimental to op-
etine, a selective norepinephrine reuptake inhibitor, timal nighttime sleep should be eliminated. These
has been reported to induce sleep-EEG changes include things such as daytime napping, excessive
similar to those after SSRIs by increasing intermit- alcohol consumption and brisk exercise in the
tent wakefulness and decreasing REM time.51 evening, and excessive daytime caffeine intake.22
Other behavioral treatments include stimulus con-
Treatment options for insomnia trol therapy (aimed at breaking the cycle of prob-
associated with depression lems commonly associated with initiating sleep),
sleep restriction therapy, relaxation and biofeedback
Insomnia is a symptom with many possible under- therapy, and chronotherapy (resetting the biolog-
lying causes. Careful assessment and establishment ical clock by progressively phase-delaying sleep).
of a differential diagnosis is necessary. It is impor-
tant to rule out a primary sleep disorder as the Conclusion
cause of the insomnia as one of the first steps. A sig-
nificant association has been reported between pri- Since insomnia associated with major depression
mary sleep disorder and major depression. There is causes subjective distress and is associated with
an increased risk of depression in patients with rest- many risks, its optimal management must be an
less legs syndrome52 as well as sleep apnea,53 and ef- important clinical goal. Clinicians have for a long
fective treatment of sleep apnea appears to improve time been aware of the importance of the effects of
depression in these patients. A further important antidepressants on sleep when choosing a drug to
reason for ruling out primary sleep disorders is be- treat major depression. Previously, such decisions
cause some of the medications used to treat insom- were based largely on clinical experience. Today,
nia associated with depression can actually exacer- much research has been conducted, and we have a
bate the primary sleep disorders.1 Once identified, better understanding of the specific effects of indi-
primary sleep disorders should be referred to a sleep vidual antidepressants on sleep regulation. Howev-
specialist. There are numerous other possible caus- er, there is still a lack of consensus on the manage-
es of insomnia. Insomnia may also be related to a ment of insomnia associated with major depression.
general medical condition, whether due to pain, Consequently, long-term treatment of insomnia is
discomfort, or a more direct physiological mecha- driven primarily by the individual choices of patients
nism. Examples of the latter include hyperthyroid- and their clinicians.54 Clinicians are frequently faced
ism and pheochromocytoma. Insomnia may be re- with a difficult choice when dealing with depressed
lated to a side effect of medication, or to the use of patients with prominent insomnia. Prescribing an
some other substance. Both substance (eg, alcohol) antidepressant with an activating effect may exac-
intoxication and withdrawal may cause insomnia. erbate the sleep disturbance, and coprescription of
In attempting to improve sleep patterns, patients a hypnotic goes against the basic principle of avoid-
with insomnia may sometimes use medications in- ing polypharmacy where possible, as well as intro-
appropriately. This may include the use of hypnotics ducing the inherent risks of hypnotic therapy. Us-
or alcohol to help them sleep at night, as well as caf- ing a sedative antidepressant is therefore often re-
feine or other stimulants to combat excessive day- garded as a better option. However, this may result
time fatigue. Alcohol dependence is often associat- in a spillover of daytime sedation, and also com-
ed with prominent, persistent insomnia. Insomnia plicate the return of normal sleep-cycle in recover-
may also be related to a psychiatric disorder other ing patients. ❒

276 MEDICOGRAPHIA, VOL 27, No. 3, 2005 The impact of sleep disorders on the course of depression – Emsley

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cology:The Fourth Generation of Progrress.New York, 31. Thase ME. Treatment issues related to sleep and al. A double-blind, placebo-controlled evaluation of
NY: Raven Press; 1995:957-969. depression. J Clin Psychiatry.2000;61(suppl 11):46-50. the effects of orally administered venlafaxine on sleep
13. Armitage R. The effects of antidepressants on sleep 32. Vogel GW, Buffenstein A, Minter K, et al. Drug ef- in inpatients with major depression. Psychopharma-
in patients with depression. Can J Psychiatry. 2000; fects on REM sleep and on endogenous depression. col Bull. 1996;32:637-646.
45:803-809. Neurosci Biobehav Rev. 1990;14:49-63. 50. Nofzinger EA, Reynolds CF 3rd, Thase ME, et al.
14. Armitage R. Microarchitectural findings in sleep 33. Shipley JE, Kupfer DJ, Griffin SJ, et al. Compar- REM sleep enhancement by bupropion in depressed
EEG in depression: diagnostic implications. Biol Psy- ison of effects of desipramine and amitriptyline on men. Am J Psychiatry. 1995;152: 274-276.
chiatry. 1995;37:72-84. EEG sleep of depressed patients. Psychopharmacolo- 51. Kuenzel HE, Murck H, Held K, et al. Reboxetine
15. Bahro M, Riemann D, Stadtmuller G, et al. REM gy (Berl). 1985;85:14-22. induces similar sleep-EEG changes like SSRIs in pa-
sleep parameters in the discrimination of probable 34. Gillin JC, Wyatt RJ, Fram D, et al. The relationship tients with depression. Pharmacopsychiatry. 2004;37:
Alzheimer’s disease from old-age depression. Biol Psy- between changes in REM sleep and clinical improve- 193-195.
chiatry. 1993;34:482-486. ment in depressed patients treated with amitriptyline. 52. Saletu B, Anderer P, Saletu M, et al. EEG mapping,
16. Thase ME, Kupfer DJ, Fasiczka A, et al. Identify- Psychopharmacology (Berl). 1978;59:267-272. psychometric, and polysomnographic studies in rest-
ing an abnormal electroencephalographic sleep pro- 35. Hochli D, Riemann D, Zulley J, et al. Is there a re- less legs syndrome (RLS) and periodic limb movement
file to characterize major depressive disorder. Biol lationship between response to total sleep deprivation disorder (PLMD) patients as compared with normal
Psychiatry. 1997;1:964-973. and efficacy of clomipramine treatment in depressed controls. Sleep Med. 2002;3(suppl):S35-S42.
17. Dubovsky SL, Thomas M. Psychotic depression: patients? Acta Psychiatr Scand. 1986;74:190-192. 53. Millman RP, Fogel BS, McNamara ME, et al. De-
advances in conceptualization and treatment. Hosp 36. Berger M, Gastpar M. Trimipramine: a challenge pression as a manifestation of obstructive sleep ap-
Community Psychiatry. 1992;43:1189-1198. to current concepts on antidepressives. Eur Arch Psy- nea: reversal with nasal continuous positive airway
18. Poland RE, McCracken JT, Lutchmansingh P, et chiatry Clin Neurosci. 1996;246:235-239. pressure. J Clin Psychiatry. 1989;50:348-351.
al. Differential response of rapid eye movement sleep 37. Dunleavy DL, Oswald I. Phenelzine, mood response, 54. Jindal RD, Buysse DJ, Thase ME. Maintenance
to cholinergic blockade by scopolamine in current- and sleep. Arch Gen Psychiatry. 1973;28:353-356. treatment of insomnia: what can we learn from the de-
ly depressed, remitted, and normal control subjects. 38. Landolt HP, Raimo EB, Schnierow BJ, et al. Sleep pression literature? Am J Psychiatry. 2004;161:19-24.

The impact of sleep disorders on the course of depression – Emsley MEDICOGRAPHIA, VOL 27, No. 3, 2005 277


a plupart des patients atteints de dépression majeure ont bale plus mauvaise. La plupart des antidépresseurs provoquent

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
des changements substantiels des aspects subjectifs du sommeil
ainsi que des paramètres polysomnographiques. Les antidépres-
seurs tricycliques et les inhibiteurs de la monoamine-oxydase
et évolutives. Alors que les anomalies du sommeil accompagnant classiques suppriment à des degrés divers le sommeil paradoxal
une dépression majeure sont retrouvées à tout âge, le vieillisse- (REM sleep). Les inhibiteurs sélectifs de la recapture de la séro-
ment est associé à une insomnie plus marquée. Les troubles du tonine (ISRS) suppriment généralement le sommeil paradoxal,
sommeil précèdent l’installation de l’épisode dépressif et la réap- mais sont souvent accompagnés de plaintes subjectives d’insom-
parition de l’insomnie peut annoncer le début d’un nouvel épi- nies. L’insomnie chez les patients atteints de dépression majeure
sode de dépression récurrente. Alors qu’un traitement efficace de requiert une évaluation rigoureuse. Il est important d’exclure une
l’épisode dépressif résout souvent l’insomnie, la plupart des ano- insomnie primaire, ainsi que les causes médicales générales et
malies polysomnographiques du sommeil persistent après la gué- celles liées à une substance. Les interventions pharmacologiques
rison, suggérant qu’elles seraient plus liées au profil du malade et non pharmacologiques font partie des stratégies thérapeu-
qu’à l’épisode lui-même. Une fatigue et une somnolence diurnes tiques. Certains praticiens prescrivent un antidépresseur ayant
excessives sont les conséquences de l’insomnie, et peuvent provo- des propriétés sédatives. Autrement, un hypnotique peut être as-
quer une baisse de productivité et un risque accru d’accidents. Un socié. Aucune de ces approches n’est dépourvue d’inconvénient.
trouble du sommeil persistant est associé à un risque significa- Une bonne hygiène du sommeil et d’autres traitements compor-
tif de récurrence, un risque accru de suicide et une évolution glo- tementaux peuvent être des auxiliaires utiles.

278 MEDICOGRAPHIA, VOL 27, No. 3, 2005 The impact of sleep disorders on the course of depression – Emsley

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

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.

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)

Hygeia versus Polymnia: some French painters and their diseases – Régnier MEDICOGRAPHIA, VOL 27, No.3, 2005 279

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).
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

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

Hygeia versus Polymnia: some French painters and their diseases – Régnier MEDICOGRAPHIA, VOL 27, No.3, 2005 281

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 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
In the movie Ceux
same enjoyment.16 Renoir was treated with antipyrine, an analgesic
de Chez Nous (1917), much in fashion at the start of the 19th century. He also took the waters at the spa towns of Bourbonne-
Sacha Guitry filmed les-Bains and Aix-les-Bains. He consulted the famous Doctor Gachet, physician and “protector” of Honoré
Pierre-Auguste Renoir,
whose fingers, deformed Daumier, Vincent van Gogh, Édouard Manet, Armand Guillaumin, Paul Cézanne, Gustave Courbet, Claude
by polyarthritis, can be Monet, Alfred Sisley, and Camille Pissaro.17
clearly seen. © Ciné- When his art dealer, Vollard, visited him in Cagnes, Renoir declared, “As you can see, hands are not need-
mathèque Française.
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

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


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,
◆ 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.

Hygeia versus Polymnia: some French painters and their diseases – Régnier MEDICOGRAPHIA, VOL 27, No.3, 2005 283

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

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

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

Hygeia versus Polymnia: some French painters and their diseases – Régnier MEDICOGRAPHIA, VOL 27, No.3, 2005 285

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


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

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. ❒

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


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

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

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.

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

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

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

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

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

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

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

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

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.” ❒


◆ 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

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


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


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
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