Biological research into depression: a clinician's commentary
Authors: JULES ANGST
Journal: World Psychiatry (2010)

This commentary presents a clinician's view of biological research into depression. It seeks to demonstrate the shortcomings of correlating highly sophisticated biological research with simple and questionable DSM diagnoses of depression. In his wide-ranging review of the patho- physiology of depression, G. Hasler repeatedly stresses that depression is heterogeneous. It is in fact striking how great is the discrepancy between the simplistic DSM-IV clinical diagnosis of major depressive disorder (applying a top-down approach), on the one hand, and the battery of highly sophisticated, expensive biological research techniques (bottom-up approach) which are used in order to study the disorder's pathophysiology, on the other. In view of this methodological incongruence, it is hardly surprising that biological research contributes very little to the early recognition, clinical application and treatment of depression. A clinical bottom-up approach would be more promising. It would consist of: a) a careful, exhaustive psychopathological description of all depressive, including somatic, symptoms; b) a syndromal diagnosis (e.g., retarded, agitated, hypochondriacal, somatic, atypical, neurasthenic, mood-congruent and mood-incongruent psychotic depression); and c) a more sophisticated subclassification of major depressive disorder, duly identifying the large subgroup with hidden subthreshold bipolarity, which is an important element of the diagnostic mood spectrum extending from depression, via several subgroups of bipolar disorder, to pure mania 1. As a first, and feasible, step in the right direction, all biological studies on depression should be checked for a diagnosis of subthreshold bipolarity of major depressive disorder, and the biological data re-analysed. There is convergent evidence from three epidemiological investigations 2,3,4 that 40% to 50% of subjects diagnosed as suffering from DSM-IV major depressive disorder are subthreshold bipolars. These epidemiological findings are confirmed by the international BRIDGE study on 5,635 patients with major depressive episodes 5. This study also demonstrates that the DSM exclusion criterion of an antidepressant-induced switch to hypomania is misleading: in fact, patients in whom switches are observed differ greatly from other major depressives in terms of a positive family history of mania and of course characteristics distinguishing bipolar from unipolar depression. Moreover, recent reviews found no sound evidence that patients who switch to hypomania under treatment with placebo differ from those who switch under antidepressants 6,7. Hasler also summarizes the evidence for important gender differences in the biological findings on depressive patients. The prevalence of major depressive disorder among women is about twice that among men, whereas in bipolar disorder there is only a slight female preponderance. The Zurich epidemiological data suggest that certain components or subtypes of major depression, namely somatic items of DSM-IV atypical depression 8 and somatic depression 9, may explain those differences. Clearly, biological research should take such findings into account. In addition, there are marked gender differences in childhood adversity which can create biological and psychological vulnerability to stressors in adolescence and adulthood 10. Hasler states that 60% to 70% of the variance in susceptibility to depression is non-genetic. This leaves promising space for epigenetic and environmental research, which should at the same time also consider gender differences. Findings from the prospective Zurich study confirmed childhood adversity as being associated in both women and men with an earlier onset of depression and bipolar disorder, but also with a more frequent chronicity of the disorders. The risk may be partially mediated by anxious personality traits, poor coping and low self-esteem. Sexual trauma in childhood/adolescence (mainly in females) and conduct problems (mainly in males) were not related to chronicity 10. As Hasler points out, depression is currently considered to be one of the most important causes of disability worldwide. But, would that conclusion still hold true if subthreshold bipolar depressives were correctly diagnosed and identified as bipolars? The review of Pini et al 11 suggests that bipolar disorder carries an equally high if not higher burden compared to major depressive disorder. The above-mentioned epidemiological studies 3,4,5 have shown that, when bipolars are properly identified, there is a major shift of comorbidity from the depressive to the bipolar group; for instance, alcohol use disorders and some anxiety disorders become much more strongly associated with bipolarity than with pure depression. The resulting reduced prevalence rates and comorbidity will probably show pure depression to be less of a burden than bipolar disorders, and the estimates of the World Health Organization 12 may need to be considerably revised.