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