Abstract
Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial “failures” are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this “valley of disillusionment,” DBS may be nearing a “slope of enlightenment.” Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care.
Highlights
CIRCUIT-DIRECTED TREATMENTS FOR CIRCUIT ILLNESSESThe past 20 years have been promising and frustrating for psychiatry
We review the results of those studies, with an emphasis on three major randomized, double-blind, sham-controlled clinical trials (RCTs) conducted for treatment resistant depression (TRD) to date
Those trials identified numerous barriers to wider use of deep brain stimulation (DBS) in MDD/TRD. Chief among these is the subjective, trial-and-error nature of DBS programming, especially when combined with the weeks to months needed to detect clinical effects. Recognition of those barriers has spurred efforts to understand the physiologic basis of DBS response
Summary
The past 20 years have been promising and frustrating for psychiatry. We have new insight into circuits that are conserved across species and involved in mental illness, but that research has not yielded a substantial change in the treatment of mental disorders. We review the results of those studies, with an emphasis on three major randomized, double-blind, sham-controlled clinical trials (RCTs) conducted for treatment resistant depression (TRD) to date. This is a qualitative review; at present, these trials are the entirety of RCT evidence for DBS in TRD. The clinical community has considered this evidence of DBS’ poor efficacy We argue that it represents a need for improvements in technology and clinical trial design. Improved implant and laboratorybased technologies allow direct measurement of DBS’ physiologic effects These new technologies are emerging in the context of a major change in psychiatric nosology, a change that is expected to yield more reliable physiologic markers of mental illness. We may soon see trials of closed-loop DBS systems, where the implant self-adjusts stimulation to bring a target biomarker to a pre-specified level associated with healthy function
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