A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression

Highlights

• This is a systematic meta-analysis of DBS targeting all four reported brain regions including SCG, VC/VS, MFB, and NAcc in TRD.

• DBS significantly alleviates depressive symptoms in TRD patients.

• Adverse effects of DBS during TRD therapy were statistically analyzed and reported in this work.

Abstract

Background

Deep brain stimulation (DBS) has been applied in treatment-resistant depression (TRD) as a putative intervention targeting different brain regions. However, the antidepressant effects of DBS for TRD in recent clinical trials remain controversial.

Methods

We searched Scopus, EMBASE, the Cochrane Library, PubMed, and PsycINFO for all published studies investigating the efficacy of DBS in TRD up to Feb 2017. Hamilton depression rating scale (HDRS) scores and Montgomery–Asberg depression rating scale (MARDS) scores were compared between baseline levels and those after DBS using the standardized mean difference (SMD) with 95% confidence intervals (CIs). The pooled response and remission rates were described using Risk Difference with 95% CIs.

Results

We identified 14 studies of DBS in TRD targeting the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS), medial forebrain bundle (MFB), and nucleus accumbens (NAcc). The overall effect sizes showed a significant reduction in HDRS after DBS stimulation in these four regions, with a standardized mean difference of − 3.02 (95% CI = − 4.28 to − 1.77, p < 0.00001) for SCG, − 1.64 (95% CI = − 2.80 to − 0.49, p = 0.005) for VC/VS, − 2.43 (95% CI = − 3.66 to − 1.19, p = 0.0001) for MFB, and − 1.30 (95% CI = − 2.16 to − 0.44, p = 0.003) for NAcc. DBS was effective, with high response rates at 1, 3, 6, and 12 months. Some adverse events (AEs), especially some specific AEs related to targeting regions, occurred during the DBS treatment.

Conclusions

DBS significantly alleviates depressive symptoms in TRD patients by targeting the SCG, VC/VS, MFB, and NAcc. Several adverse events might occur during DBS therapy, although it is uncertain whether some AEs can be linked to DBS treatment. Further confirmatory trials are required involving larger sample sizes.

Introduction

Depression is the most common of all mental disorders, affecting > 300 million people of all ages globally, and ranks among the top causes of disability (WHO, 2017). Although depression can be effectively treated in the majority of patients by pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin noradrenaline reuptake inhibitors (SNRIs), psychotherapy such as cognitive-behavior therapy (CBT) or interpersonal psychotherapy (IPT) and electroconvulsive therapy (Lisanby, 2007, Grunhaus et al., 2000, Chen et al., 2017), almost 30% of patients fail to respond to adequate interventions (Keller et al., 1992, Fava, 2003). For this subpopulation diagnosed with treatment-resistant depression (TRD), it is important to explore alternative treatment for them (Fava and Davidson, 1996, Zhou et al., 2015).

Recently, deep brain stimulation (DBS) has been used as a potential neurosurgical treatment in cooperation with antidepressant medicine for TRD, because of its adjustable and reversible electrical stimulation. The first clinical trial proved the efficacy of DBS treatment in TRD patients by stimulating the subcallosal cingulate gyrus (SCG) (Mayberg et al., 2005). Later, DBS for TRD was studied in a number of open-label trials targeting different brain regions, including the SCG, ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAcc), and the medial forebrain bundle (MFB). And there were also data of DBS targeting VC/VS from randomized controlled trials (RCTs) in TRD patients (Dougherty et al., 2015, Bergfeld et al., 2016). Although some of these studies confirmed the treatment efficacy and safety of short- or long-term active DBS in TRD, there were inconsistent results. For instance, a RCT of DBS targeting the VC/VS in TRD reported no differences between the active and control groups at the end of the 16-week controlled phase (Dougherty et al., 2015). By contrast, a significant decrease in depressive symptoms was identified in TRD patients with active DBS in the ventral anterior limb of the internal capsule, compared with sham stimulation (Bergfeld et al., 2016). The contrasting antidepressant effects of DBS in TRD treatment may be due to the difference in clinical trial design, DBS treatment duration, the heterogeneity in disease pathology and limited sample size. Therefore, the optimal target brain regions and treatment stimulation for DBS remain undetermined. However, few specific meta-analyses focus on these impact factors for DBS in TRD patients. A review of clinical outcomes demonstrated that NAcc-DBS and VC/VS-DBS benefit patients with MDD (Morishita et al., 2014), and a previous meta-analysis only focused on SGC-DBS trials finding promising outcomes in TRD patients (Berlim et al., 2014). Owing to the lack of evidence and practical information on DBS treatment among TRD patients, we performed herein an updated systematic review and meta-analyses to detail the effects of DBS in TRD.