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|Year : 2020 | Volume
| Issue : 8 | Page : 282-287
Deep Brain Stimulation for Refractory Depression, Obsessive-Compulsive Disorder and Addiction
Manish Ranjan1, Nutan Ranjan2, Milind Deogaonkar1, Ali Rezai1
1 Department of Neurosurgery, Rockefeller Neuroscience Institute, USA
2 Department of Behavioral Medicine and Psychiatry, West Virginia University, West Virginia, USA
|Date of Web Publication||5-Dec-2020|
Dr. Ali Rezai
Executive Chair, Rockefeller Neuroscience Institute, John D. Rockefeller IV Tenured Professor in Neuroscience, West Virginia University, 33 Medical Center Drive, Morgantown, WV
Source of Support: None, Conflict of Interest: None
Background: Depression, Obsessive-compulsive Disorder (OCD), and addiction are the leading disabling psychiatric conditions with huge health care and psychosocial burden besides increased morbidity and mortality. Deep brain stimulation (DBS) for depression, OCD, and addiction is increasingly explored and is quite challenging. We present a brief review of the pertinent literature of DBS for depression, OCD, and addiction and present the status and challenges.
Objective: The aim of this study was to review the current status and challenges with the DBS for Depression, Obsessive-compulsive Disorder (OCD), and addiction.
Method: The pertinent brief literature was reviewed in reference to the DBS for Depression, Obsessive-compulsive Disorder (OCD), and addiction.
Results: To date, OCD is the only psychiatric condition approved for DBS therapy (under humanitarian device exemption). Although the initial encouraging results of DBS in depression were encouraging but the two larger multicenter clinical trials failed to meet the primary objective. Further evaluation and studies are ongoing. Similarly, the initial results of DBS for addiction are encouraging; however, the experience is limited.
Conclusion: DBS for depression, OCD, and addiction seem challenging but promising. Further refinement of the target and evaluation in a larger and controlled setting is needed, specifically for depression and addiction.
Keywords: Addiction, deep brain stimulation (DBS), depression, neuromodulation, obsessive-compulsive disorder (OCD)
Key Message: DBS for depression, OCD, and addiction is promising, potentially feasible, however, needs more controlled study.
|How to cite this article:|
Ranjan M, Ranjan N, Deogaonkar M, Rezai A. Deep Brain Stimulation for Refractory Depression, Obsessive-Compulsive Disorder and Addiction. Neurol India 2020;68, Suppl S2:282-7
|How to cite this URL:|
Ranjan M, Ranjan N, Deogaonkar M, Rezai A. Deep Brain Stimulation for Refractory Depression, Obsessive-Compulsive Disorder and Addiction. Neurol India [serial online] 2020 [cited 2021 Mar 2];68, Suppl S2:282-7. Available from: https://www.neurologyindia.com/text.asp?2020/68/8/282/302459
Deep Brain Stimulation (DBS) is an effective and a cost-effective treatment in properly selected cases of movement disorders. It is standard of care for Parkinson's disease (PD), essential tremor (ET) and dystonia and recently approved for drug-resistant epilepsy. With increasing understanding of neural networks and dysfunction circuitry in neuropsychiatric disorders, DBS is increasingly considered for certain refractory neuro-psychiatric conditions. Among psychiatric conditions, Obsessive-compulsive disorder (OCD) is the only approved indication of DBS under humanitarian device exemption (HDE). There are increasing numbers of indications being explored but among the various indications, disorders of mood, cognition, and addiction is much explored and in fact much needed given the scale of prevalence and associated morbidity/mortality and health care burden. In this paper, we will review the pertinent literature, background and experiences of DBS therapy in depression, OCD and addiction.
| » Depression|| |
Depression is the leading cause of mental health-related disease burden globally not only affecting the quality of life and daily functioning of the individual but also associated with reduced life expectancy and suicide., The health care burden and direct/indirect cost are huge, especially given the caseload and the fact that up to 30% of the patients remain refractory to treatment.,
With a huge experience with the DBS in movement disorders, advancement in functional imaging and emerging understanding of network disorder in depression led to exploring DBS to modulate the neural network in depression.,,,,,
Subgenual cingulate cortex (SCC) was the first potential DBS target for depression based on the functional imaging. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. SCC DBS was associated with about 60-70% treatment response rates at 3-6 years follow up. Observations of improvement in depression with VC/VS DBS for OCD led to exploration of VC/VS as a DBS target for the treatment of depression. Significant improvements in depressive symptoms were observed with DBS treatment with a responder rates of 40% at 6 months (53.3% at last follow-up) and a remission rates were 20% at 6 months (40% at last follow-up). However, two industry-sponsored multicenter randomized sham-controlled trials of either SCC or ALIC DBS in depression failed in their primary outcome measure.,
Evolution in the brain imaging, especially diffusion tensor imaging (DTI) allows for personalized charting of the tract and allows personalized DBS targeting. The superolateral medial forebrain bundle (slMFB), a white matter tract was the first tractographically defined DBS target for depression, following observation that patients treated with Parkinson's Disease developed hypomania when the stimulation extended more medially than planned, into the slMFB. In an open-label, proof-of-concept study, rapid antidepressant effects were seen in six of seven treatment-refractory depression (TRD) patients with MFB DBS and benefits maintained for at least 12 to 33 weeks. The results of slMFB DBS seem promising as long-term data in over 30 patients from two centers reported a response rates of at least 70%. Further exploring DTI in SCC DBS, it was reported that compared with non-responders, responders shared a similar white matter tract blueprint – the convergence of four tract pathways – the forceps minor, cingulum, uncinate fasciculus, and frontal-striatal fibers. Based on these findings the same group explored placement of active electrodes at the convergence of these four white matter tracts in depression and noted an 82% response rate at 12 months. This study was an open-label trial; however, it provides a proof of concept of individualized targeting of DBS with a positive impact on the primary outcome based on neuroimaging adjunct. Other targets considered for DBS in TRD include the inferior thalamic peduncle, the lateral habenular complex; and the ventral caudate with promising results.
It appears that depression is a more heterogeneous condition consisting of multiple subtypes with possible neurobiological differences and different DBS targets address some symptoms better than others suggesting different mechanisms of action. It is also possible that futility of two industry-sponsored RCTs was due to fact that primary end was assessed too early to distinguish the DBS effect from that of placebo. Placebo effects were observed in the sham-stimulation groups, with 14% and 20% meeting response criteria, which could be because interventions of greater cost or invasiveness amplify placebo effects. Although there was no difference was found in response rates between the active and sham stimulation arms after 6 months in SCC DBS trial, which led to stopping of the trial after futility analysis but approximately one- half of the patients were deemed to have responded to treatment after 18 months to 2 years of open-label stimulation. This again reflects the complexity/heterogeneity of psychiatric disorders and challenges of large multicenter clinical trials.
DBS for depression is a complex and evolving process. Insights from the failures and sub-group analysis with better understanding of depression subtypes and novel neuroimaging adjunct allowing individualized circuit-based DBS interventions hold a promise for future study to investigate/validate role of DBS in depression.
| » Obsessive-Compulsive Disorder (OCD)|| |
Obsessive-compulsive disorder (OCD) is chronic debilitating disease and ranked among the top ten causes of disability worldwide affecting 2–3% of the population.,, Up to 25% of patients remain refractory to the best available therapy leading to significant morbidity and higher mortality.,, The basal ganglia − thalamocortical loop implicated in the pathophysiology of OCD and historically, there have been a good therapeutic response with capsulotomy. In 1999, Nuttin et al. proposed ALIC DBS as an alternative to capsulotomy following favorable results in three out of four patients. However, there were no assessment scores to quantify improvements. Subsequently, the same investigators reported bilateral ALIC-DBS in six patients with medically refractory OCD with significant improvement in the Y-BOCS score and Global Assessment of Functioning (GAF) scale after DBS. With initial encouraging results and greater understanding of abnormalities in the cortico-striato-thalamic-cortical (CSTC) circuitry in OCD, several DBS targets have been explored. DBS target areas were refined to target just ventral to the ALIC, the ventral capsule and ventral striatum (VC/VS) and/or the nucleus accumbens besides exploring subthalamic nucleus and inferior thalamic peduncle (ITP) with encouraging results.,,,,,,
A metacentric study of ALIC-VC/VS − DBS in 26 patients with refractory OCD reported a responder rate of 62% with an average of 13.1-point reduction in the Y-BOCS score after DBS. leading to FDA approval of DBS for severe treatment-resistant OCD. On further evaluation of DBS in the patients with OCD, a more posterior sites at the junction of the anterior capsule, anterior commissure and posterior ventral striatum produced additional therapeutic improvement, leading to implantation of DBS electrode posteriorly targeting the bed nucleus of the stria terminalis (BNST) with a favorable result.,
While various DBS targets were still being investigated for OCD, an extensive clinical experience was emerging from the clinical STN DBS in PD. It was observed that STN DBS in PD resulted a significant improvement in comorbid OCD symptoms., A randomized, double-blind, crossover, multicenter study investigated efficacy of bilateral STN-DBS in 16 patients with severe refractory OCD and reported a statistically significant reduction of OCD symptoms. To investigate further the effect of DBS in NAcc/ventral capsule and STN for OCD, electrode contact covering NAcc and ventral capsule – model 3387 and electrode in anteromedial STN (amSTN – model 3389) were placed in same 6 patients and assessed in a double-blinded fashion. There was a significant and equivalent reduction in OCD symptoms with DBS at each site. There was only little added improvement with combined stimulation of both targets. Few groups also explore DBS of Inferior Thalamic Peduncle with a favorable outcome, however, there is a limited experience ITP DBS in OCD but reports appear promising.
Overall, DBS is effective and safe in severe treatment-refractory OCD in carefully selected cases. Several brain targets have been tried and actively investigated. Currently there is no clear consensus about the best or optimum DBS target for OCD but the VC/VS DBS has the most explored with encouraging results.
| » Addiction|| |
Currently, we are amidst a public health crisis with drug abuse and addiction. Collectively, smoking, alcohol and illicit drug use kills 11.8 million people each year, which is more than the number of deaths from all cancers. Opioid addiction is a new epidemic and is the leading cause of the non-accidental death. Drug overdose is not the only contributor to mortality but chronic, relapsing nature of substance-use disorders also has indirect impacts on mortality. Current treatment of substance use disorder is far from ideal. About 85% of addicted individuals are known to relapse within 1 year of treatment., Individuals failing standard treatment have a substantial risk of death. As per CDC from 1999 to 2016, more than 630,000 people have died from a drug overdose, which is 5 times higher than in 1999 and opioid overdose itself was involved in around 66% of these deaths.
Novel treatment is much needed for addiction and as we understand more about the neurocircuitry of the various neurological disorders modulating such pathways seems a very promising approach. Nucleus accumbens is the key nodal center of the reward circuit and crucial for mediating motivated behavior via the corticobasal ganglia-thalamic loop.,, On functional brain imaging, NAcc activation was seen with drug expectancy, euphoria, and craving and has a key role together with the ventral tegmental area in the binge/intoxication. Various animal studies targeted neural targets to modulate the network in addiction which includes subthalamic nucleus (STN), dorsal striatum, lateral habenula, medial, prefrontal cortex (mPFC) and lateral hypothalamus; however, the NAcc was the most studied and promising target. Most of these studies have targeted either the NAcc core or shell and demonstrate that DBS of NAcc could be the effective and promising target to modulate the addiction network.,
The potential beneficial effect of DBS in addiction was observed from the STN DBS for PD and control of associated dopamine dysregulation syndrome (DDS), which is characterized by neuropsychiatric disturbances such as psychosis and pathological gambling. Furthermore, it was observed that NAcc DBS performed for OCD in a patient resulted in unintended but unaided alleviation of the patient's comorbid alcohol dependence, which was independent and not associated with any improvement in the patient's primary condition. Subsequently authors reviewed 10 patients who underwent NAcc DBS for psychiatric indication, such as Tourette's syndrome (TS), obsessive-compulsive disorders (OCD) or anxiety disorders (AD), among these patients, three patients could achieve cessation of cigarette smoking. Following these reports of NAcc DBS improving drug addiction in the setting of comorbid neuropsychiatric disease, Muller et al. reported NAcc DBS targeting specifically addiction. They performed bilateral NAcc DBS in three patients with chronic resistant alcoholism. Two patients achieved abstinence while one showed a remarkable reduction. However, this was an open-label study and had a short term follow up. Muller et al. subsequently reported a long term outcome of DBS in alcohol addiction in five patients, in which two patients remained abstinent for many years while three patients showed a marked reduction of alcohol consumption at a follow up extending up to 8 years.
A double-blinded trial of NAc DBS for cocaine addiction was initiated, where one patient received bilateral nucleus accumbens DBS. The clinical trial was structured to titrate and assess the DBS in different phases (single-blinded/double-blinded/contentious stimulation). At the conclusion of this 2.5-year trial, though there was an objective decline in cocaine craving and there were no major differences between the “off” and “on ‘’ stimulation state in the blinded phase. In another recent study, eight patients with heroin addiction DBS electrodes were implanted through the ALIC into the NAc using a costumed DBS electrode in China and followed for at least 24 months. Authors reported that five patients could achieve abstinence for more than three years, and two relapsed after abstaining for six months, while one patient lost to follow-up at three months. Authors also noted that the degree of cravings for drug use after DBS therapy was reduced, if the patients continued to remain abstinent. Furthermore, DBS of the NAcc and ALIC not only improved the quality of life and alleviated psychiatric symptoms in this cohort but was also associated with objective change in neuroimaging. Brain regions associated with addiction had increased glucose metabolism. Similarly, another study from Germany revealed H2[15O]-PET activation of paracingulate cortex, temporal poles, precuneus and hippocampus with NAcc DBS. Valencia-Alfonso reported an abstinent patient of chronic heroin addiction with NAcc DBS and associated concurrent EEG changes with effective contact stimulation. Various small series and case reports have been encouraging and were reported decrease in drug use.,,,,
There have been encouraging results both from the pre-clinical and the clinical series that DBS can modulate the brain network and positively influence addiction behavior. Among the potential targets, NAcc appears to be the most studied and promising clinical DBS target in addiction.,,,, However, a long term and a controlled study on a larger patient population is needed. In an effort to address this much-needed question, we initiated a clinical trial of NAcc/VC DBS for addiction. Result of this ongoing clinical trial may provide more insight and guide this innovative treatment strategy in clinical field of addiction.
| » Conclusion|| |
There have been several advancements to understand the pathological and dysfunctional neuronal circuits in psychiatric disorders, supporting DBS a potential therapeutic intervention in select treatment-refractory cases. Deep Brain stimulation for neuropsychiatric disorders is quite challenging but promising. It is of utmost important that DBS for psychiatric disorders should be done with the multidisciplinary team expert in dealing with neuromodulation with psychiatric disorders. Depression, OCD and addiction are viewed actively as a potential indication of DBS in psychiatric conditions. DBS is currently an approved therapeutic intervention in OCD under HDE while DBS for addiction is actively explored. DBS for depression is a complex and evolving process. Positive clinical experience but failed controlled clinic trials make DBS for depression quite challenging. Insights from the failures, better understanding of depression subtypes and novel neuroimaging adjunct could potentially allow an individualized circuit-based DBS intervention for depression in future and further enhance the field to investigate/validate role of DBS in depression.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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