Acta Psychiatr Scand 2011: 124: 495–496
All rights reserved
DOI: 10.1111/j.1600-0447.2011.01744.x
Debate section
Discussion paper
The heterogeneity of the depressive
syndrome: when numbers get serious
The current criteria for major depression (1) have been
criticized for the heterogeneity of the clinical syndrome they
define. This has led to suggestions of alternative classifications,
most recently by G. Parker in this journal (2). According to the
critics, the polymorphic syndrome is partly to blame for the
fact that the treatment of depression still has not moved
beyond the trial and error approach and that the genetics and
neurobiology underlying the depressive disorder still remain
largely unknown and without practical significance (3). Two of
the most interesting studies on major depression, conducted
within recent years, reflect this problem:
i) In the STAR*D study, which included more than 4000
subjects with major depression, only 30% of the patients
remitted on treatment with a current first-line antide-
pressant drug (Citalopram) and other 30% did not remit
after four consecutive treatment trials with antidepres-
sants from different pharmacological classes - despite a
formalized and aggressive dosing strategy (4).
ii) The hypothesis of increased risk for depression caused by
an interaction between the serotonin transporter pro-
moter gene polymorphism (5-HTTLPR) and Ôadverse life
eventsÕ, such as childhood maltreatment and medical
conditions, has been subjected to intense debate over the
past decade. Does the interaction take place or not? This
discussion may come to an end after the publication of a
recent meta-analysis by Karg et al. (5), which is based on
more than 40 000 subjects. The results of the meta-
analysis suggest that the 5-HTTLPR - adverse life event -
interaction does increase the risk of depression.
What can be learned from these two large-scale studies?
The fact that only 30% of patients remitted on a second-
generation antidepressant is probably not because the drug
does not work. Likewise, the fact that it took more than
40 000 subjects to ÔproveÕ the interaction between the seroto-
nin transporter gene and adverse life events is probably not
because such interaction does not have an impact on the risk
of developing depression. The underlying reason for these
rather disappointing results is likely to lie in the heterogeneity
of the depressive syndrome. The subjects included in the two
studies are probably so dissimilar that any relevant causal
effect of risk factors and clinical benefit of treatments are lost
in the flood.
But exactly how heterogeneous is the depressive syndrome?
To give a theoretical answer to this question, we applied simple
combinatorics to the nine symptoms considered in the DSM-IV
criteria (1):
i) Depressed mood
ii) Markedly diminished interest or pleasure
 2011 John Wiley & Sons A/S
ACTA PSYCHIATRICA
SCANDINAVICA
iii) Significant weight loss or weight gain
iv) Insomnia or hypersomnia
v) Psychomotor agitation or retardation
vi) Fatigue or loss of energy
vii) Feelings of worthlessness or excessive or inappropriate
guilt
viii) Diminished ability to think or concentrate or indecisive-
ness
ix) Recurrent thoughts of death or recurrent suicidal
ideation
A diagnosis of major depressive episode is assigned when five
or more symptoms, of which at least one is either Ôdepressed
moodÕ or Ôdiminished interest or pleasureÕ, are present for more
than 2 weeks. We used the following approach to calculate the
number of different symptom combinations fulfilling the DSM-
IV diagnostic criteria:
 
n n!
¼
k ðn  kÞ!k!
The binomial coefficient calculates the number of subsets of k
draws from n distinguishable objects without replacement and
without regard to order. The result is 227 different combinations
with ‡5 symptoms, but this is not the full picture. At least four of
the DSM-IV symptoms actually cover two distinct symptoms
each: Ôweight loss or weight gainÕ, Ôinsomnia or hypersomniaÕ,
Ôpsychomotor agitation or retardationÕ and Ôfeelings of worth-
lessness or inappropriate guiltÕ. When these, quite different,
individual symptoms are taken into account, the resulting
number of combinations is 1497, without considering the
psychotic subtype of depression (delusions, hallucinations, or
both) or the fact that depressive episodes can occur in both
unipolar and bipolar courses of illness. Furthermore, it can be
argued that the core symptom Ôdiminished interest or pleasureÕ
also covers two different symptoms. Thus, the 1497 combina-
tions are actually a conservative estimate.
These calculations may be considered as mere academic
exercise, but they also prove a point, namely that the current
depressive syndrome is at least very, if not too, heteroge-
neous. Obviously, some of the 1497 combinations have a
considerable overlap, but on the other hand, patients fulfilling
the diagnostic criteria do not necessarily share any symptoms
at all:
John, a former successful CEO of a large company,
developed depression after the bankruptcy of his company,
which led to his firing and subsequent divorce. John has no
relatives with depression or other mental disorders. Alice,
graduate student in psychology, developed depression without
any external stressors. There is a strong family history of
depression and bipolar disorder in her family.
495
Discussion paper

was a speaker ⁄ member of advisory boards for Astra-Zeneca,

John Alice Lilly, H Lundbeck A ⁄ S, and Organon. Signe Olrik Wallenstein
Depressed mood Diminished pleasure
Jensen declares no conflicts of interest.
Insomnia Hypersomnia
Weight loss Weight gain S. D. Østergaard1, S. O. W. Jensen1, P. Bech2
1
Psychomotor agitation Psychomotor retardation Unit For Psychiatric Research, Aalborg Psychiatric Hospital,
Inappropriate guilt Loss of energy Aarhus University Hospital, Mølleparkvej, Aalborg,
2
Psychiatric Research Unit, Psychiatric Center Nordsjælland,
Copenhagen University Hospital, Dyrehavevej, Hillerød,
Denmark
The clinical pictures of John and Alice are quite different, yet E-mail: sdo@rn.dk
both patients may have been included as subjects in the
STAR*D (4) and the gene-environment study by Karg et al.
(5). With this degree of heterogeneity among participants in References
depression-trials, it is not a major surprise that researchers are
1. American Psychiatric Association. Diagnostic and Statisti-
struggling to tease out clinically relevant effects of treatments
cal Manual of Mental Disorders, 4th Edn. Text Revision.
and significant interactions between genetic and environmental
Washington, DC: American Psychiatric Association, 2000.
risk factors.
The 1497 combinations suggest that a redefinition of the 2. Parker G. Classifying clinical depression: an operational
proposal. Acta Psychiatr Scand 2011;123:314–316.
depressive syndrome may be warranted (2). The new syndrome
3. Holtzheimer PE, Mayberg HS. Stuck in a rut: rethinking
should be more narrowly defined and ideally include a number
of relevant subtypes, to spur research into the etiology and depression and its treatment. Trends Neurosci 2011;34:1–9.
treatment of the depressive disorders. 4. Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M,
Rush AJ. What did STAR*D teach us? Results from a large-
scale, practical, clinical trial for patients with depression.
Acknowledgements Psychiatr Serv 2009;60:1439–1445.
5. Karg K, Burmeister M, Shedden K, Sen S. The serotonin
The authors thank Christian Winther Topp for mathematical transporter promoter variant (5-HTTLPR), stress, and
assistance. A detailed description of the calculation behind the depression meta-analysis revisited: evidence of genetic
resulting 1497 combinations will be provided upon request moderation. Arch Gen Psychiatry 2011;68:444–454.
(email: sdo@rn.dk).

Declaration of interest
S. D. Østergaard has received minor honoraria from Janssen-
Cilag. P. Bech has until August 2008 received funding from or

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