Deep Brain Stimulation for Depression: Keeping an Eye on a Moving Target

The article by Bergfeld et al1 in this issue of JAMA Psychiatry reports the resultsofan investigator-initiated trialofdeepbrain stimulation (DBS) to the ventral anterior limb of the internal capsule (vALIC) for treatment-resistantdepression (TRD).Deep brain stimulation for TRD is an evolving experimental therapy with a range of different gray and white matter targets currently under study.2 Although this is not the first report of vALIC DBS for TRD, it used a robust but underutilized trial design: an open-label, extended optimization period followed by a blinded, randomized, discontinuation experiment once a stable response was achieved. This design is incontrast to themore typicalblindedrandomizationat stimulationonsetused inmostpsychiatry treatment trials. The40% open-label response rate demonstrated by Bergfeld et al1 is similar to that reported in the first open-label study of vALIC DBS for TRD.3 However, it is the second phase of this study— discriminating effects of active vs sham stimulation—that is most compelling. This critical differential effect was not demonstrated in the recent industry-sponsored randomized clinical trial4 that used the more traditional, up-front active vs sham design. With increasing interest in targeted circuit modulation for depression and other psychiatric disorders, the Bergfeld et al1 study further highlights the need to seriously consider customized trial designs in planning any invasive device trials, be it DBS, vagus nerve stimulation, or a future novel technology. The Bergfeld et al1 study also tacitly reveals the risk of a rigidly fixed optimization period evenwhen unblinded treatment is delivered. The team modified the protocol and increased the duration of the optimization period to accommodate experimental observations of variability in the time needed to reach a stable response. These modifications provide new insights into intersubject variability with vALIC stimulation. Specifically, the implicit instability of theDBS response reported in this study provides new evidence that experimental studiesusing invasivedevicesmight best be structured so that they are not prematurely terminated at an arbitrary timepoint. Suchanapproachwill enableamorecomplete characterizationof the trajectory and timeline of behavioral changes in individualparticipantsprior to initiating largescale, industry-sponsored trials.Anopen-label adaptivedesign may be the most prudent approach for a high-risk procedure performed in avulnerable population. PatientswithTRDwho are enrolled in such studies have, by definition, already exhausted available approved options. Unlike studies of medication, psychotherapy, electroconvulsive therapy, or repetitive transcranialmagnetic stimulation,patientswith implanted devices continue to receive the experimental therapy beyond theprotocol-definedendpoint.Therefore, continueddata collection aspart of ongoing clinicalmanagement shouldbe considered both an opportunity and an ethical mandate, since it provides needed information on the course and long-termeffect of the intervention needed to fully evaluate its clinical viability.5 Beyond issues of trial design, sources of patient variability that might predict the likelihood of DBS response are also critical andremainunclear.Matchingapatient to thebest treatment as well as avoiding therapies that are unlikely to be effective are the goals for treatment selection for patients at all stages of depression.6 Patient heterogeneity in TRD, specifically, remainsanunexploredvariable in theBergfeldetal1 study aswell as otherDBS studies. At present, TRD is definednot by illness features, but by treatment failures. Published studies have yet to identify any clinical clues on demographic or behavioralvariables thatmightcharacterize responders toagiven target or support implantation in one brain region over another. Given that attempts to identify these variables may be hindered by the relatively few patients enrolled in any individual trial, it would be beneficial for the field to develop databases or registries that might enable such examination. Independent ofwhichDBS target is being investigated in a given trial, surgical accuracyandcontact selectionarenotonly potential contributors to response,butarevariables that canbe systematicallyevaluatedandrectified.Specificfiberbundlesand effects in remote targets canbedetermined.7Asourgroup8has learned fromstudiesof subcallosal cingulatewhitematterDBS for TRD, such characterization reliably distinguished responders from nonresponders at 6 months and 2 years of ongoing stimulation.Suchanalyses forvALICDBSmightsimilarlydifferentiatepatientswhoachievedastableresponserelativelyquickly comparedwithnonresponders ormorebrittle patients leading torefinedmethods in futurestudies. If theoptimalcombination of white matter bundles is defined for vALIC DBS, the more perplexingproblemof instability of response canbe examined without this confounding factor. As the field considers the potential use of a flexible trial design as used in the Bergfeld et al1 vALIC DBS study, it is important to avoid a one-size-fits-all approach for other targets. Some DBS studies9 show a rapid onset of antidepressant effects and require relatively fewadjustments.Others, as in this case, appear to have more difficulty achieving a stable response state and, in theabsenceof flexibility todetermine that Related article page 456 Opinion