A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression

Published:December 12, 2014DOI:



      Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published.


      Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery–Åsberg Depression Rating Scale from baseline.


      There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery–Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.


      The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed.


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        • World Health Organization
        The Global Burden of Disease: 2004 Update.
        World Health Organization, Geneva, Switzerland2008
        • Rush A.J.
        • Trivedi M.H.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Stewart J.W.
        • Warden D.
        • et al.
        Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.
        Am J Psychiatry. 2006; 163: 1905-1917
        • Christmas D.
        • Eljamel M.S.
        • Butler S.
        • Hazari H.
        • MacVicar R.
        • Steele J.D.
        • et al.
        Long term outcome of thermal anterior capsulotomy for chronic, treatment refractory depression.
        J Neurol Neurosurg Psychiatry. 2011; 82: 594-600
        • Montoya A.
        • Weiss A.P.
        • Price B.H.
        • Cassem E.H.
        • Dougherty D.D.
        • Nierenberg A.A.
        • et al.
        Magnetic resonance imaging-guided stereotactic limbic leukotomy for treatment of intractable psychiatric disease.
        Neurosurgery. 2002; 50 (discussion 1049–1052): 1043-1049
        • Shields D.C.
        • Asaad W.
        • Eskandar E.N.
        • Jain F.A.
        • Cosgrove G.R.
        • Flaherty A.W.
        • et al.
        Prospective assessment of stereotactic ablative surgery for intractable major depression.
        Biol Psychiatry. 2008; 64: 449-454
        • Bewernick B.H.
        • Hurlemann R.
        • Matusch A.
        • Kayser S.
        • Grubert C.
        • Hadrysiewicz B.
        • et al.
        Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression.
        Biol Psychiatry. 2010; 67: 110-116
        • Bewernick B.H.
        • Kayser S.
        • Sturm V.
        • Schlaepfer T.E.
        Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy.
        Neuropsychopharmacology. 2012; 37: 1975-1985
        • Holtzheimer P.E.
        • Kelley M.E.
        • Gross R.E.
        • Filkowski M.M.
        • Garlow S.J.
        • Barrocas A.
        • et al.
        Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.
        Arch Gen Psychiatry. 2012; 69: 150-158
        • Kennedy S.H.
        • Giacobbe P.
        • Rizvi S.J.
        • Placenza F.M.
        • Nishikawa Y.
        • Mayberg H.S.
        • et al.
        Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years.
        Am J Psychiatry. 2011; 168: 502-510
        • Lozano A.M.
        • Giacobbe P.
        • Hamani C.
        • Rizvi S.J.
        • Kennedy S.H.
        • Kolivakis T.T.
        • et al.
        A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression.
        J Neurosurg. 2012; 116: 315-322
        • Malone Jr, D.A.
        • Dougherty D.D.
        • Rezai A.R.
        • Carpenter L.L.
        • Friehs G.M.
        • Eskandar E.N.
        • et al.
        Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression.
        Biol Psychiatry. 2009; 65: 267-275
        • Mayberg H.S.
        • Lozano A.M.
        • Voon V.
        • McNeely H.E.
        • Seminowicz D.
        • Hamani C.
        • et al.
        Deep brain stimulation for treatment-resistant depression.
        Neuron. 2005; 45: 651-660
        • Sartorius A.
        • Kiening K.L.
        • Kirsch P.
        • von Gall C.C.
        • Haberkorn U.
        • Unterberg A.W.
        • et al.
        Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient.
        Biol Psychiatry. 2010; 67: e9-e11
        • Schlaepfer T.E.
        Neuromodulation of reward circuits with deep brain stimulation in treatment resistant depression.
        Biol Psychiatry. 2013; 73: 143S
        • Schlaepfer T.E.
        • Bewernick B.H.
        • Kayser S.
        • Madler B.
        • Coenen V.A.
        Rapid effects of deep brain stimulation for treatment-resistant major depression.
        Biol Psychiatry. 2013; 73: 1204-1212
        • Dougherty D.D.
        • Greenberg B.D.
        Neurobiology and neurocircuitry of obsessive-compulsive disorder and relevance to its surgical treatment.
        in: Hudak R. Dougherty D.D. Clinical Obsessive-Compulsive Disorders in Adults and Children?>. Cambridge University Press, 2011: 20-29
        • Nuttin B.
        • Cosyns P.
        • Demeulemeester H.
        • Gybels J.
        • Meyerson B.
        Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder.
        Lancet. 1999; 354: 1526
        • Greenberg B.D.
        • Gabriels L.A.
        • Malone Jr, D.A.
        • Rezai A.R.
        • Friehs G.M.
        • Okun M.S.
        • et al.
        Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience.
        Mol Psychiatry. 2010; 15: 64-79
        • Kopell B.H.
        • Halverson J.
        • Butson C.R.
        • Dickinson M.
        • Bobholz J.
        • Harsch H.
        • et al.
        Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder.
        Neurosurgery. 2011; 69 (discussion 1029): 1015-1029
        • Riva-Posse P.
        • Choi K.S.
        • Holtzheimer P.E.
        • McIntyre C.C.
        • Gross R.E.
        • Chaturvedi A.
        • et al.
        Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression.
        Biol Psychiatry. 2014; (Epub ahead of print)

      Linked Article

      • Deep Brain Stimulation for Major Depression—Steps on a Long and Winding Road
        Biological PsychiatryVol. 78Issue 4
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          Most patients with psychiatric disorders respond to combinations of psychotherapy and psychopharmacotherapy; however, some patients experience little, if any, benefit even after many years of treatment (1). Over the past decade, different modalities of targeted neuromodulation—among them most prominently deep brain stimulation (DBS)—are being actively researched as putative approaches to very treatment-resistant forms of those disorders. The fact that patients included in all DBS studies so far had been treated unsuccessfully for many years with conventional treatment methods renders these findings remarkable.
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