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Accepted by the Journal World Psychiatry

Pathophysiology of depression: do we have any solid evidence of interest to clinicians?
Gregor Hasler
Psychiatric University Hospital, University of Berne, Bolligenstrasse 111, 3000 Berne 60, Switzerland

Abstract Due to the clinical and etiological heterogeneity of major depressive disorder, it has been difficult to elucidate its pathophysiology.Current neurobiological theories with the most valid empirical foundation and the highest clinical relevance are reviewed with respect to their strengths and weaknesses. The selected theories are based on studies investigating psychosocial stress and stress hormones, neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA), neurocircuitry,neurotrophic factors, and circadian rhythms. Because all theories of depression apply to only some types of depressed patients but not others, and because depressive pathophysiology may vary considerably across the course of illness, the current extant knowledge argues against a unified hypothesis of depression. As a consequence, antidepressant treatments, including psychological and biologicalapproaches, should be tailored for individual patients and disease states. Individual depression hypotheses based on neurobiological knowledge are discussed in terms of their interest to both clinicians in daily practice and clinical researchers developing novel therapies.

Key words: Depression, pathophysiology, genetics, stress, serotonin, norepinephrine, dopamine, neuroimaging, glutamate, GABA

1 Major depressive disorder (MDD) is a common and costly disorder which is usually associated with severe and persistent symptoms leading to important social role impairment and increased mortality (1,2). It is one of the most important causes of disability worldwide (3). The high rate of inadequate treatment of the disorder remains a serious concern (1). This review is aimed at summarizing thesolid evidence on the etiology and pathophysiology of MDD that is likely relevant for clinical psychiatry. Neurobiological findings are regarded as solid when they are consistent and convergent, i.e., they have been confirmed by several studies using the same method and fit into results from studies using different methodological approaches. Genes and psychosocial stress Family, twin, and adoptionstudies provide very solid and consistent evidence that MDD is a familial disorder and that this familiality is mostly or entirely due to genetic factors (4). This important finding suggests that parental social behavior and other familial environmental risk factors are not as important in the pathogenesis of MDD as previously assumed and should not be the major focus of the treatment of thedisorder. The above-mentioned studies consistently show that the influence of genetic factors is around 30-40% (4). Non-genetic factors, explaining the remaining 60-70% of the variance in susceptibility to MDD, are individual-specific environmental effects (including measurement error effects and gene-environment interactions). These effects are mostly adverse events in childhood and ongoing or recentstress due to interpersonal adversities, including childhood sexual abuse, other lifetime trauma, low social support, marital problems, and divorce (5,6). These results suggest that there is a huge potential in the prevention of MDD by means of psychosocial interventions (e.g., in schools, at workplace). In addition, these results mirror the clinical practice of empirically validated psychotherapiesto treat depression (7-9), including interpersonal, psychodynamic and cognitive behavioral psychotherapies and cognitive behavioural analysis system of psychotherapy, which all focus directly or indirectly on interpersonal difficulties and skills. This does not exclude the fact that unidentified non-genetic, non-psychosocial risk factors may also play important roles in some patients (e.g.,...
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