Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: possibilities, limits and future perspectives

Abstract

The authors of this study (1), who have a strong tradition of well-designed studies treating mental disorders by deep brain stimulation (DBS) attempt to find out whether the beneficial effects of DBS of the ventral part of the anterior limb of the internal capsule (vALIC) for treatment resistant depression (TRD) are due to placebo or a real effect.The authors' approach was to start with an openlabel phase lasting one year during which the stimulation parameters (active contact, amplitude, stimulation frequency, and pulse width) were optimized, i.e., individually adjusted to the patient. After this period both responders (n=9) and non-responders (n=7) were randomized in a double blinded fashion to sham-real or real-sham stimulation, as to verify whether the effects obtained in the open label phase were due to placebo or not. The open label phase showed that DBS of the vALIC resulted in >50% improvement on HADS-17 in 40% of patients, and the double-blind placebo phase demonstrated that this effect was very likely a real effect due to the DBS and not due to placebo. Beyond the demonstration of the efficacy of DBS of the vALIC for TRD, the study illustrates the feasibility of appropriate placebo-controlled study designs for the evaluation of DBS in psychiatric disorders. Moreover, this study raises some interesting questions that go beyond the intent of the study and are relevant for DBS in general, irrespective of the indication.First of all, DBS or brain stimulation in general seems to be able to benefit patients with mental or brain disorders who cannot be helped with any other treatment, and this warrants its further use, albeit that it comes at a risk. The patients who enrol in brain implant studies are very sick and often very desperate people who commonly enrol as a last resort, which makes them extremely vulnerable to negative outcomes. This is clearly demonstrated by the fact that two patients who felt they did not benefit from the DBS ended their lives (one suicide, one euthanasia), but also that there were four more suicide attempts in the nonresponder group and two patients with suicide ideation. It is unclear whether this high rate of suicide/suicide attempt is due to the severity of the depression of these participants, the hopelessness of ever improving "if even brain surgery doesn't help", or whether it is DBS-induced. It might therefore be of interest to compare this suicide or suicide attempt rate to a clinically similar group of patients who are not treated by DBS.The 40% responder rate is similar to other DBS studies for TRD, as the authors mention, but interestingly and intriguingly, 30-50% response rates are also similar to outcomes in brain stimulation for other indications as shown by meta-analyses or case series for pain, tinnitus,