Editors' ChoiceDepression

A glimmer of hope for depression

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ec62
DOI: 10.1126/scitranslmed.aaf7821

Depression is a common and frequently disabling illness, but treatment has not progressed substantively, and many patients remain treatment-resistant. A small but exciting body of work has used deep brain stimulation, a method developed for treating neurological disorders by modulating small structures deep in the brain using implanted electrodes to test whether targeting brain systems implicated by brain imaging can treat depression. Despite promising early exploratory results, subsequent well-powered controlled studies of deep brain stimulation for treating depression have been stopped prematurely for lack of efficacy. This has raised questions about the basic premise behind this approach— that is, using brain circuitry abnormalities revealed by imaging to guide the location of deep brain stimulation in the brain. In a new study, Bergfeld and colleagues have investigated a previously described stimulation target, the reward-related brain circuitry disrupted in depression that is located in and around the ventral striatum. Depressed patients received non-blinded deep brain stimulation of the ventral striatum for up to a year during an optimization phase followed by randomized sham discontinuation or continued stimulation in a double blind crossover trial design. Symptomatic improvement was seen during non-blinded stimulation, but quickly (i.e., often within a day) disappeared during the sham stimulation discontinuation phase. Thus, active stimulation did have a beneficial effect relative to the sham condition, but discovering this required a long treatment course and may reflect a rebound or discontinuation effect due to sudden stopping of stimulation rather than a direct therapeutic effect. Most concerning is the lack of a clear idea of which neural and behavioral/physiological processes are being modulated by stimulation, resulting in the reliance on a complicated endpoint (symptom relief), without knowing the mechanistic intermediate target. The study by Bergfeld and colleagues does provide a glimmer of hope for the utility of deep brain stimulation in depression, but also illustrates the many challenges ahead. Ultimately, deep brain stimulation may have its greatest impact as an intellectual milestone for the concept that information from brain imaging can inform treatment development.

I. O. Bergfeld et al., Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: A randomized clinical trial. JAMA Psych. 10.1001/jamapsychiatry.2016.0152 (2016). [Abstract]

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