Translating progress in depression research to the clinic: one step at a time on a very long road

In his article, G. Hasler reviews the strengths and limitations of major theories regarding the neurobiology of depression. A fundamental premise on which the paper is based, which certainly appears warranted by the extant data, is that a unified model is unlikely to explain the variable results across studies of depression or the variable responses to treatments characterized by disparate receptor pharmacologies among patients with mood disorders. Instead, Hasler argues, each prevailing theory of depression likely applies only to mood disordered subtypes. Consequently, antidepressant treatments, including psychological and biological approaches, will continue to require tailoring to individual patients.

Hasler provides examples of how several major models of depression’s pathophysiology have guided researchers to develop novel therapeutics for individuals suffering from major depressive disorder. Thus, research involving hypothalamic-pituitary-adrenal axis function, monoaminergic neurotransmitter function, and glutamatergic transmission recently led to reports that corticotropin releasing hormone antagonists, dopamine receptor agonists, and NMDA receptor antagonists/glutamate release inhibitors, respectively, exert antidepressant effects 1,2. In addition, neuroimaging findings implicating the neural circuits involving projections between the subgenual anterior cingulate cortex, amygdala, ventral striatum and medial thalamus have guided the development of deep brain stimulation therapies for treatment of refractory depression 3,4,5,6.

As Hasler indicates, the results of genetic association studies suggest that most cases of major depressive disorder are associated with some combination of numerous variants that individually exert small effects, which interact together with environmental influences to confer vulnerability to affective disease. Thus, each pedigree in which depression is overrepresented may be unique with respect to the combination of single nucleotide polymorphisms and/or copy number variants that interact to increase vulnerability to depression. This observation highlights the importance of research aimed at identifying the neural circuits or systems where dysfunction arising via diverse etiologies can give rise to affective disease.

Hasler concludes from these results that “the clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of major depressive disorder”. Nevertheless, the paper later reviews evidence that loss-of-function mutations in genes causing major functional effects may account for some cases of major depressive disorder, such as variation in the gene coding for the brain-specific enzyme tryptophan hydroxylase-2 that impairs serotonin synthesis 7. Such findings raise the possibility that genetic variants of large effect on risk for the disorder will be discovered that hold implications for pharmacotherapy which collectively will justify genetic testing in the management of depression.

Another theme within the paper which conveys optimism that psychiatric morbidity can be reduced is Hasler’s conclusion that the large proportion of major depressive disorder cases for whom pathogenesis involves gene-environment interactions implies that “huge potential [exists] in the prevention of major depressive disorder by means of psychosocial interventions”. Within this context, Hasler reviews evidence that psychosocial approaches ultimately will prove most effective in preventing and treating major depressive disorder if they are gender-sensitive. This theme was highlighted by evidence that neuroendocrine responses to stress are sex-specific and that life events that increase vulnerability to depression differ between men and women.

An integration of the data reviewed in Hasler’s manuscript illustrates how several seemingly unrelated pathological constructs may link together through interactions across brain systems to underlie the neurobiological bases of depression. Thus, accumulating evidence that increased pro-inflammatory cytokine expression plays a role in the pathophysiology of mood disorders also suggests mechanistic links to the abnormalities in stress-responsive neuroendocrine and monoaminergic neurotransmitter systems found in these disorders 8. This pathological construct also may confer susceptibility to the neuroplasticity effects evidenced by reductions in gray matter volume in neuroimaging studies and in glial cells and neuropil in neuropathological studies of mood disorders 4,9,10. The interactions across these systems are likely to illuminate the mechanisms underlying the medical comorbidities associated with depression, and elucidate targets for novel therapeutic interventions.