Deep brain stimulation for obsessive-compulsive disorder: A systematic review of randomised controlled trials

https://doi.org/10.1016/j.neubiorev.2020.01.007Get rights and content

Highlights

  • Deep brain stimulation is an effective treatment for obsessive-compulsive disorder.

  • Effects of deep brain stimulation on affective state are ambiguous.

  • Impact of deep brain stimulation on quality of life and cognition needs further investigation.

  • There is a need for clinical trials and standardisation of study methodology to address further questions.

Abstract

Deep brain stimulation (DBS) is considered a promising intervention for treatment-resistant obsessive-compulsive disorder (trOCD). We conducted a systematic search to investigate the efficacy and safety of DBS for OCD. Primary outcomes included the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), adverse events (AE), and quality of life. We assessed affective state, global functioning, cognition, and tolerability as secondary outcomes. Eight studies comprising 80 patients with trOCD were analysed both individually and collectively. We found a pooled mean reduction in Y-BOCS of 38.68 %, indicating DBS could be considered an effective therapy for trOCD. Most AE were mild and transient, however there were five severe surgery-related AE: intracerebral haemorrhage in three patients and infection in two. Mood-related serious AE were one completed suicide, three suicide attempts in two patients, and suicidal thoughts and depression in four. Despite this, affective state improved following stimulation. Despite being limited by significant heterogeneity across studies, our review has shown DBS to be an effective treatment in otherwise trOCD. There is a need to standardise study methodology in future research.

Introduction

Human stereotactic surgery was introduced in 1947 by Ernest A. Spiegel and Henry T. Wycis with the aim of avoiding the side effects of frontal leucotomy for psychiatric patients. The first operation was performed on a patient suffering from obsessive-compulsive disorder (OCD) and depression (Rzesnitzek et al., 2019). Later on, likely due to substantial ethical issues related to psychosurgery, stereotactic neurosurgery found its major applications not in psychiatric patients, but in pain and movement disorders. Deep brain stimulation (DBS) represents an evolution of this technique.

DBS is a neurosurgical procedure which involves precisely implanting microelectrodes in targeted brain areas through a combination of stereotactic and neuroimaging techniques. A subcutaneous external battery device is connected to these electrodes, and electrical current is used to modulate pathological neuronal network activity.

Besides neurological diseases, in recent years, indications for therapeutic use of DBS have been extended to other neuropsychiatric disorders, including OCD (Wichmann and Delong, 2006). In 2009, the U.S. Food and Drug Administration approved a Medtronic humanitarian device exemption for DBS for OCD as an adjunct to medications, and as an alternative to more invasive procedures such as capsulotomy for treatment of severe, treatment-resistant OCD patients defined as having failed to respond to at least three selective serotonin reuptake inhibitors (SSRIs; see https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=H050003). Despite this, a sizable number of patients still opt for ablative procedures, preferring the single procedure to hardware implantation and longer-term follow-up (e.g. for parameter changes). DBS for OCD remains strictly experimental and is reserved only for carefully selected patients. Therefore, comprehensive assessments of the current state of evidence and well-controlled randomised clinical trials, taking the latest findings into account, are essential to improve patients’ outcomes as well as benefits from the procedure.

OCD is a chronic neuropsychiatric disorder affecting around 2–3 % of the general population (Ruscio et al., 2010). Currently, it is considered the fourth most common mental disorder after depression, alcohol/substance misuse, and social phobia (Torres et al., 2017). OCD is characterized by symptoms such as uncontrollable recurring thoughts (obsessions) which cause significant anxiety. Some patients might also spend hours engaging in repetitive behaviours (compulsions), which are considered an attempt to reduce or neutralise the anxiety. OCD is often found to occur alongside other comorbidities like depression, social phobia and Tourette’s disorder (Ruscio et al., 2010), and is associated with a significant disability and poor quality of life (Rodriguez-Salgado et al., 2006; Bobes et al., 2001). First-line treatments for OCD include selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT), but unfortunately there remains severe treatment-resistant or treatment-refractory cases. For this non-responsive group, DBS has been investigated as an alternative treatment option.

A variety of methods have been applied to obtain a better understanding of the mechanisms underlying OCD. The cortico–striato–thalamo–cortical (CSTC) model was proposed in the latter part of the 20th century and has guided research in OCD ever since (Milad and Rauch, 2012). According to this model, abnormalities in connectivity between cortical and striatal structures, their subsequent modulating inputs to the thalamus, and recurrent projections to the cortex, might explain the OCD symptoms (Rauch et al., 2002). The CSTC circuits each emerge from specific frontal cortical areas and have been associated with cognitive, emotional, and motor functions. The exact mechanisms underlying the therapeutic effect of DBS for OCD remain unclear; however, it is postulated that DBS might cause a disruption into the CSTC circuit, thus regulating hyperconnectivity and hypoconnectivity within and between circuits back to a normal state (Veerakumar and Berton, 2015; Mian et al., 2010). A comprehensive review of DBS mechanisms of action in view of the OCD pathology is available elsewhere (Bourne et al., 2012).

Several anatomical sites for DBS have been investigated in OCD. Those include the ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAcc), subthalamic nucleus (STN), bed nucleus of the stria terminalis (BST), anterior limb of the internal capsule (ALIC), anteromedial globus pallidus interna (AMGPi), inferior thalamic peduncle (ITP), superolateral branch of the median forebrain bundle (SLMFB), medial dorsal and ventral anterior nucleus of the thalamus (MD/VANT), and basolateral amygdala (BLA; Borders et al., 2018). The dorsal striatum and its cortical inputs have been linked to behavioural automaticity, and changes in the activity of cells in these brain regions have been associated with the formation of automatic behaviours (Lipton et al., 2019). The VC/VS is the most common anatomical target for OCD, depression, and addiction (Zhang et al., 2017). The nucleus accumbens (NAcc) is a prominent stimulation target for neuropsychiatric disorders due to its significance for emotional and motivational processes as well as its limbic-motor interface. The subthalamic nucleus (STN) has proven effective for treatment of movement disorders. Non-motor effects following STN DBS in Parkinson’s Disease (PD), such as impulse control disorders, (hypo)mania, acute depression, and improvement in co-morbid OCD as well as its pronounced connectivity with limbic structures has provided a rationale for the investigation of STN DBS for OCD (Mulders et al., 2016). The ALIC has been linked to the processing of emotion, cognition, decision making, and motivation, and abnormalities in ALIC white matter and integrity have been associated with OCD, schizophrenia, addiction, bipolar disorder, and depression (Safadi et al., 2018). The BST is situated anteriorly at the level of the anterior commissure and joins the ventral region more posteriorly (Lebow and Chen, 2016). Its role in anxiety and stress related behaviours has been established (Lebow and Chen, 2016; Miles and Maren, 2019). The anteromedial part of the globus pallidus internus (AMGPi) adjacent to the amygdala is thought to be the limbic region of the GPi. This, as well as additional clinical, pathological and experimental observations resulted in one study investigating AMGPi DBS for OCD (Nair et al., 2014). Similarly, the remaining four anatomical targets have also been associated with disturbances in the CSTC model, however so far those have not been investigated intensively in OCD (Borders et al., 2018).

One meta-analysis addressing the question of efficacy of DBS for OCD was published in 2015 (Alonso et al., 2015). In their analysis, Alonso et al. found a 45.1 % (95 % CI = 29.4–60.8 %) improvement from baseline on the Y-BOCS scale as assessed at the last available follow-up (2015). Clinically, a 35 % reduction from baseline has been accepted as a full response (Farris et al., 2013). Since then, several systematic and narrative reviews have been published (Kohl et al., 2014; Kisely et al., 2014).

In this article, we assessed the efficacy and safety of DBS for OCD using RCTs alone, focussing on the results from double-blind phase, in order to make a complete use of its methodological advantages. We aim to provide clinicians and researchers with an up-to-date systematic review of the topic.

Section snippets

Method

Methods of the analysis and inclusion criteria were specified in advance, documented in a protocol and registered on PROSPERO (International prospective register of systematic reviews, registration number: CRD42019127650). The systematic review adhered to the items of preferential reports for systematic reviews and meta-analyses (PRISMA, Moher et al., 2009), the PRISMA harms checklist (Zorzela et al., 2016) and the Cochrane Handbook of Systematic Reviews of Interventions (Higgins and Green, 2011

Search results

In the initial search, 1866 records were identified. After adjusting for duplicates, 1367 remained, including two studies that were found through additional sources. Of these, 1330 were discarded because they did not meet the criteria. The full texts of 37 articles were examined thoroughly and 27 did not satisfy the inclusion criteria either in terms of the study design or the outcomes of interest. Additionally, we excluded two studies (Nuttin et al., 1999, 2003) because the cases the authors

Discussion

The aim of this article was to assess the efficacy and safety of DBS for OCD by summarising the existing evidence reported from randomised controlled trials. Overall, eight studies encompassing 80 patients were included. We found a mean Y-BOCS score reduction at the end of each double-blind phase from baseline of 38.68 %, indicating that DBS could be considered an effective therapy for treatment-resistant OCD. A full-response is defined as a 35 % or more reduction of Y-BOCS score from baseline (

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None.

References (51)

  • T. Wichmann et al.

    Deep brain stimulation for neurologic and neuropsychiatric disorders

    Neuron

    (2006)
  • P. Alonso et al.

    Deep brain stimulation for obsessive-compulsive disorder: a meta-analysis of treatment outcome and predictors of response

    PLoS One

    (2015)
  • J.A. Barcia et al.

    Personalized striatal targets for deep brain stimulation in obsessive-compulsive disorder

    Brain Stimul.

    (2019)
  • A. Berney et al.

    Effect on mood of subthalamic DBS for Parkinson’s disease A consecutive series of 24 patients

    Neurology

    (2002)
  • C. Borders et al.

    Deep brain stimulation for obsessive compulsive disorder: a review of results by anatomical target

    Ment. Illn.

    (2018)
  • S.K. Bourne et al.

    Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits

    Front. Integr. Neurosci.

    (2012)
  • L. Castelli et al.

    Chronic deep brain stimulation of the subthalamic nucleus for Parkinson’s disease: effects on cognition, mood, anxiety and personality traits

    Eur. Neurol.

    (2006)
  • M.C. Campbell et al.

    Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson’s disease

    J. Neuropsychiatry Clin. Neurosci.

    (2012)
  • D. Denys et al.

    Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder

    Arch. Gen. Psychiatry

    (2010)
  • L.R. Derogatis

    Symptom Checklist-90-R: Administration, Scoring & Procedure Manual for the Revised Version of the SCL-90

    (1994)
  • J. Endicott et al.

    The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance

    Arch. Gen. Psychiatry

    (1976)
  • S.G. Farris et al.

    Treatment response, symptom remission and wellness in obsessive-compulsive disorder

    J. Clin. Psychiatry

    (2013)
  • Food and drug administration

    Humanitarian Device Exemption

    (2009)
  • W. Guy

    ECDEU Assessment Manual for Psychopharmacology

    (1976)
  • M. Hamilton

    A rating scale for depression

    J. Neurol. Neurosurg. Psychiatry

    (1960)
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