Psychiatric Annals

CME Article 

Overview of the Current Use of Deep Brain Stimulation in Psychiatric Disorders

Daniel P. Witter, MD, PhD; Herbert E. Ward, MD

Abstract

Stemming from its use in movement disorders, deep brain stimulation (DBS) has emerged as an experimental therapy for treatment-resistant cases of major depressive disorder, obsessive-compulsive disorder, and Tourette's syndrome. Early, positive results from case studies have led to controlled trials evaluating the use of DBS in each of these conditions. Results have been varied but suggest moderate benefit in many cases and remain encouraging. As the relative safety and potential efficacy of DBS has become more widely accepted, its use has expanded to include the treatment of other psychiatric disorders and symptoms including anorexia nervosa, substance use disorder, aggression, and Alzheimer's disease. Case studies using DBS for each of these have reported benefits. [Psychiatr Ann. 2016;46(11):631–636.]

Abstract

Stemming from its use in movement disorders, deep brain stimulation (DBS) has emerged as an experimental therapy for treatment-resistant cases of major depressive disorder, obsessive-compulsive disorder, and Tourette's syndrome. Early, positive results from case studies have led to controlled trials evaluating the use of DBS in each of these conditions. Results have been varied but suggest moderate benefit in many cases and remain encouraging. As the relative safety and potential efficacy of DBS has become more widely accepted, its use has expanded to include the treatment of other psychiatric disorders and symptoms including anorexia nervosa, substance use disorder, aggression, and Alzheimer's disease. Case studies using DBS for each of these have reported benefits. [Psychiatr Ann. 2016;46(11):631–636.]

Deep brain stimulation (DBS) has been used in treatment-resistant movement disorders since the late 1980s. Although it remains unclear exactly how DBS works to relieve symptoms, it is considered to play a modulatory role in abnormal neurocircuits. Its emergence for use in psychiatry grew from the suspected overlap between motor pathways being targeted by DBS in movement disorders and limbic pathways underlying many psychiatric disorders. Sites within the cortico-striatal-thalamic-cortical neurocircuit are generally the targets for DBS in psychiatric disorders.1 Lead placement has been guided by the well-documented history of treatment of psychiatric conditions by the lesioning of various brain regions and further informed by neuroimaging studies that continue to improve our understanding of neuroanatomy and neurocircuitry. Research using DBS for psychiatric disorders began in the late 1990s and has primarily focused on treatment-resistant cases of major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). More recently, its experimental use has expanded to include anorexia nervosa (AN), substance use disorder, aggressiveness, and Alzheimer's disease (AD). Herein, we provide a brief overview of the current use of DBS in psychiatric disorders with an emphasis on controlled trials in depression, OCD, and TS. The scope of this review is limited to the current state of DBS in psychiatric disorders. For more exhaustive reviews that cover much of the pioneering work of the use of DBS in psychiatric disorders, we recommended those by Ward et al.2 and Cleary et al.3

DBS in Major Depressive Disorder

DBS has long been known to cause positive, mood-altering effects in many patients with Parkinson's disease. This evidence, along with a growing understanding of the neurocircuitry suspected in depression, has led to its experimental use for patients who are resistant to treatment (up to 30%).4 The first study to use DBS in MDD was in 2005.5 A number of case studies followed targeting a variety of sites implicated in depression, including the subcallosal cingulate (SCC), inferior thalamic peduncle (ITP), ventral caudate/ventral striatum (VC/VS), nucleus accumbens (NAc), lateral habenula, and medial forebrain bundle. These studies generally showed improvement in depressive symptoms over time in a number of patients.

Based on the apparent successes of these case studies, several controlled clinical trials have also been published using DBS to target the SCC, subgenual cingulate, VC/VS, and ITP.6–9 The results of these studies are outlined in Table 1. Although trends indicate improvement in MDD with stimulation lasting several months to years, these clinical trials failed to show significant improvement during blinded phases. Underpowered studies, small sample sizes, and insufficient DBS stimulation have been offered as possible reasons for the unsuccessful outcomes of the controlled phases of these studies. BROADEN (BROdmann Area 25 DEep brain Neuromodulation), an additional clinical industry-sponsored trial targeting the SCC, was shut down after futility analysis indicated a 17.2% chance of outcome success.10 The overall trend toward improvement in numerous reported studies remains encouraging despite these somewhat disappointing results.


            Results of Selected Controlled Trials Using Deep Brain Stimulation in Major Depressive Disorder

Table 1.

Results of Selected Controlled Trials Using Deep Brain Stimulation in Major Depressive Disorder

DBS in Obsessive-Compulsive Disorder

Both pharmacotherapy and cognitive-behavioral therapy have been proven effective for many patients with OCD; however, up to one-third of patients are considered to be treatment resistant.11 OCD is the first psychiatric disorder for which DBS has been used, as well as the only for which DBS has received a humanitarian device exemption from the US Food and Drug Administration. Its use for OCD grew out of the known benefit of ablation studies as well as the observation that DBS in patients with Parkinson's disease unexpectedly improved OCD symptoms.12 The first study piloting the use of DBS in OCD documented electrode placement in the anterior limb of the internal capsule (ALIC) in 1999.13 Several subsequent case studies have reported improved OCD symptoms with DBS lead placement in the ALIC, VC/VS, subthalamic nucleus, ventral caudate nucleus, ITP, and NAc. A recent meta-analysis of the use of DBS in OCD confirmed it to be a valid alternative to lesional surgery for treatment-resistant OCD patients.14

Controlled trials of DBS in OCD have targeted the ALIC, VC/VS, and subthalamic nucleus.15–19 Patients in each of the cases were considered to have treatment-resistant OCD. Results of these trials are presented in Table 2. Although blinded phases of these trials were not remarkable, there was a definite trend toward improvement in the open phase, and overall the results remain encouraging.


            Results of Selected Controlled Trials Using Deep Brain Stimulation in Obsessive-Compulsive Disorder

Table 2.

Results of Selected Controlled Trials Using Deep Brain Stimulation in Obsessive-Compulsive Disorder

DBS in Tourette's Syndrome

Although symptoms of TS usually subside by late adolescence, they can persist into adulthood and frequently become disabling. Even though a considerable number of patients are considered to be resistant to treatment, there is no reported consensus on the actual percentage. The first reported use of DBS for TS was in 2003 and targeted the bilateral thalamus.20 Since that time, many studies21 have been published, including both open cases and controlled trials, mostly targeting thalamic or pallidal structures and generally report a mild to substantial level of improvement. Of note, TS is the only psychiatric disorder with published guidelines for patient selection for DBS, as per the Tourette's Syndrome Association.22

Controlled trials of DBS in TS have targeted the bilateral thalamic subnuclei and bilateral globus pallidus.23–25 Results of these trials are presented in Table 3. The outcomes were generally positive and showed improvement in blinded and open phases across the studies.


            Results of Selected Controlled Trials Using Deep Brain Stimulation for Tourette's Syndrome

Table 3.

Results of Selected Controlled Trials Using Deep Brain Stimulation for Tourette's Syndrome

DBS for Other Psychiatric Disorders and Symptoms

With the perceived efficacy and safety of this procedure gaining wider acceptance, numerous studies have evaluated the usefulness of DBS in other psychiatric conditions that are considered difficult to treat. Highlights of those findings are discussed below.

Anorexia Nervosa

Although the pathogenesis of AN has yet to be determined, imaging studies indicate that functional abnormalities associated with AN appear similar to those in depression, and likely involve the reward system, which has guided lead placement in DBS studies for AN.26 A study of four adolescents treated with DBS targeting the NAc reported a normalization of body mass index (BMI) in all patients at the 3-year follow-up visit.26 A study of six patients with DBS targeting the SCC reported an improvement to normal BMI after 9 months in three patients.27

Substance Use Disorder

The neurobiology of addictive behavior is complex and involves the limbic system and reward pathway. The NAc is known to have roles in both of these neurocircuits and is therefore a key player in the neurobiology of substance dependence.28 A study of five patients with alcohol dependence treated with DBS placed in the bilateral NAc reported improvement in cravings. Two remained abstinent for 4 years.29 DBS stimulation in the NAc of a 21-year-old with heroin dependence resulted in cessation of use during the 2.5 years of active stimulation and no subsequent relapse at the 6-year follow-up visit.30

Aggression

Historical psychiatric literature has reported that ablation of the amygdala as well as the posterior hypothalamus has demonstrated success in treating aggression. A single case of DBS in the bilateral amygdala reported improvement in aggression in a 13-year-old with autism by 26 months.31 Two case reports of patients with developmental delay with severe aggression describe a clinically significant improvement with DBS stimulation in the bilateral posterior hypothalamic region.32,33 A case series of patients with developmental delay and severe aggression indicated cessation or significant clinical improvement in aggressive symptoms in 6 of 7 patients during stimulation in the bilateral posterior hypothalamic region.34

Alzheimer's Disease

Although a small number of case reports have been published, only a single-controlled trial has been performed evaluating DBS in AD. Six patients had devices implanted in the nucleus basalis of Meynert, which has been known to have a decreased production of acetylcholine in AD. Four were considered responders at 12 months postimplantation based on stability or improvement of the AD assessment scale—cognitive subscale measure.35

Conclusion

DBS remains a promising treatment tool for the widespread unmet medical need of certain treatment-resistant psychiatric cases. It possesses a reasonably favorable side-effect profile, and its reversible and adjustable quality offers an advantage over lesioning procedures. Even though our growing understanding of the biological and anatomical underpinnings of psychiatric disorders have helped guide its expanding experimental use, we should continue to recognize that we remain in the early stages and proceed cautiously, albeit hopefully.

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Results of Selected Controlled Trials Using Deep Brain Stimulation in Major Depressive Disorder

Study Number of Study Participants Location of Stimulation Outcome Measure Controlled Phase Open Phase
Dougherty et al.6 26 VC/VS Response = 50% improvement from baseline MADRS score Remission = MADRS score ≤10 No significant difference between sham and treatment arms 23% response with 20%remission
Holtzheimer et al.7 11 SCC Response = 50% improvement from baseline HDRS score Remission = HDRS score <8 No significant difference between sham and treatment arms 92% response with 58%remission
Merkl et al.8 6 SGC Response = 50% improvement from baseline HDRS score Remission = HDRS score <10 No significant difference between sham and treatment arms 33% remission; 67% no response
Puigdemont et al.9 5 SCC Participants were previous DBS patients in remission: outcome was continued Remission with HDRS<8 vs relapse with HDRS>14 80% remission in treatment phase 40% maintained remission and 40% relapsed in sham phase Not applicable

Results of Selected Controlled Trials Using Deep Brain Stimulation in Obsessive-Compulsive Disorder

Study Number of Study Participants Location of Stimulation Outcome Measure Controlled Phase Open Phase
Abelson et al.15 4 Bilateral ALIC Response = 35% improvement on YBOCS 25% response 50% response
Denys et al.16 16 Bilateral NAc Response = 35% improvement on YBOCS 25% mean improvement in YBOCS scores 56% response
Goodman et al.17 6 Bilateral ALIC/VS Response = 35% improvement on YBOCS No significant differences in treatment and sham arms 67% response
Huff et al.18 10 Right NAc Full response = 35% reduction in YBOCS Partial response = 25% reduction in YBOCS 10% partial response 10% full response 40% partial response 10% full response
Mallet et al.19 17 Subthalamic nucleus Response = 25% improvement on YBOCS 75% response in treatment arm vs 38% response in sham arm Not applicable

Results of Selected Controlled Trials Using Deep Brain Stimulation for Tourette's Syndrome

Study Number of Study Participants Location of Stimulation Outcome Measure Controlled Phase Open Phase
Ackermans et al.23 6 Bilateral thalamic subnuclei YGTSS 37% improvement in score 49% improvement in score
Kefalopoulou et al.24 13 Bilateral globus pallidus YGTSS 15% improvement in score 40% improvement in score
Maciunas et al.25 5 Bilateral thalamic subnuclei mRVRS 53% reduction in motor tics 70% reduction in sonic tics 40% reduction in motor tics 21% increase in sonic tics 44% improvement in YGTSS (secondary outcome)
Authors

Daniel P. Witter, MD, PhD, is a Fourth-Year Resident, Department of Psychiatry, University of Florida. Herbert E. Ward, MD, is the Kaine Professor and a Vice Chair for Clinical Affairs, Department of Psychiatry, University of Florida.

Address correspondence to Daniel P. Witter, MD, PhD, 4037 NW 86th Terrace, University of Florida Health Adult Psychiatry, Gainesville, FL 32606; email: dwitter@ufl.edu.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20161003-01

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