Abstract
Short- and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/− 4) at baseline to 12.9 (SD +/− 9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.
Highlights
Most patients suffering from major depressive disorder (MDD)respond to a combination of psychotherapy and pharmacotherapy [1]; about 20–30% of MDD patients fail to respond to established treatments [2] and are classified as suffering from treatment-resistant major depression (TRD)
Deep brain stimulation (DBS) electrodes were implanted as to typically reach the deepest part of supero-lateral branch of the medial forebrain bundle (slMFB) with the electrode tip and on the same day were connected to an internal pulse generator (ACTIVA PC, Medtronic, USA; located subcutaneously in the abdominal region) in a separate session under general anesthesia
We argued that stimulation contacts correlated with response were all located inside the triangle between subthalamic nucleus (STN)/substantia nigra reticulata (SNR), red nucleus, and mammillothalamic tract
Summary
Most patients suffering from major depressive disorder (MDD). Respond to a combination of psychotherapy and pharmacotherapy [1]; about 20–30% of MDD patients fail to respond to established treatments [2] and are classified as suffering from treatment-resistant major depression (TRD). Deep brain stimulation (DBS) has provided therapeutic benefits for otherwise treatment-resistant disorders [3] and has emerged as a potential treatment option for severe TRD. Several open-label pilot studies have documented significant short- and long-term antidepressant effects of DBS of the subgenual cingulate gyrus (cg25) [4], the ventral capsule and ventral striatum (vc/vs) [5, 6], and the nucleus accumbens (NAC) [7,8,9]
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