Deep Brain Stimulation for the Treatment of Severe, Medically Refractory Obsessive-Compulsive Disorder
Suketu Khandhar, MD; Conrad Pappas, MD, PhD; Gary Heit, MD, PhD, Aimee Lee, MD; Kuo-Wei Lee, MD;
Peter Khang, MD, MPH, FAAFP
Perm J 2013 Fall;17(4):47-51
Deep brain stimulation is a rapidly expanding therapy initially designed for the treatment of movement disorders and pain syndromes. The therapy includes implantation of electrodes in specific targets of the brain, delivering programmable small and safe electric impulses, like a pacemaker, that modulates both local and broad neurologic networks. The effects are thought to primarily involve a focus in the brain, probably inhibitory, which then restores a network of neural circuitry. Psychiatric diseases can be refractory and severe, leading to high medical costs, significant morbidity, and even death. Whereas surgery for psychiatric disease used to include destructive procedures, deep brain stimulation allows safe, reversible, and adjustable treatment that can be tailored for each patient. Deep brain stimulation offers new hope for these unfortunate patients, and the preliminary results are promising.
Historic Review of Psychiatric Surgery
Surgical interventions for the treatment of psychiatric illness began in 1932, when Antonio Egas Moniz observed that an extensive bilateral frontal lobe lesioning in a monkey produced a tame, calm animal.1 He then extended this result to humans in 1936 and developed the first somatic therapy of the modern era for psychiatric conditions—the frontal lobotomy. He was corecipient of the 1949 Nobel Prize for this work. James Papez formulated the so-called Papez Circuit at about the same time based on his work involving feline rabies infections. The Papez Circuit defined a core circuit of neuroanatomical connections that were thought to underlie emotional behaviors.2 Many of these structures have been studied since those times, in vast detail, and found to be excellent targets for surgical therapy.
From the beginning, psychiatric surgery has been exalted and celebrated but also mired in ethical, moral, and scientific controversy. These swings reflect not only the complex social currents of the time but also the evolving scientific milieu and the personalities of the prominent advocates of psychiatric surgery. In Moniz's time, the bilateral frontal lobotomy promised "salvation" and stood in contrast to bleak alternatives, which included lifetime institutionalization under inhumane conditions. Less attention, therefore, was focused on the obvious adverse sequelae of loss of frontal initiative and personality changes caused by these nonspecific ablative procedures. These procedures reached their pinnacle with Freeman's cavalier application of orbital frontal leucotomies in the mid-1960s.3 The emergence of successful pharmacologic agents for the treatment of psychiatric illnesses was the final force driving orbital frontal leucotomies from favor.
A subsequent somatic therapy, electroconvulsive therapy, did little to increase enthusiasm for nonpharmacologic somatic therapies.4 Despite the loss of interest in ablative surgical interventions for psychiatric diseases, centers in Europe and in the US continued to refine indications, techniques, and targets for psychosurgery. Ultimately, these centers helped define criteria for surgical intervention and localize targets of ablation. The Massachusetts General Hospital group refined cingulotomy for refractory obsessive-compulsive disorder (OCD), and a group at the Catholic University of Leuven in Belgium refined capsulotomy for the same indications.5,6 Remarkably, both groups independently defined similar indications for surgery. They both discovered that the interventions improved OCD. Appropriate surgical candidates were defined as those who had failed all somatic therapies, inclusive of multiple trials of pharmacologic agents and appropriate behavioral therapies.
The use of these approaches, particularly in the US, was hampered by a vigorous debate about the potential misuse of psychiatric somatic therapies as an instrument of social control, based on fears of mind control by the government amidst the prevailing social climate. These fears were reinforced with the publishing of Ervin and Marks' Violence and the Brain,7 which proposed the use of these therapies for control of what was then perceived as sociopathic behaviors arising from aberrant neural processes.8-10 These concerns led to the State of California adopting legislation to regulate somatic therapies for psychiatric diagnosis, inclusive of psychiatric surgery.11
As technology evolved, stereotactic radiosurgery, an incisionless technique, first came into significant use in the 1970s and involved ablating either the anterior limb of the internal capsule (capsulotomy) or the posterodorsal cingulum bundle (cingulotomy), which connects the cingulate cortex with orbitofrontal and dorsolateral convexities (Figure 1).12,13 This procedure has had a response rate of up to 64% in individuals with OCD. Enlargement of the initial ablative zone in a second procedure, however, is often required to achieve the 64% response rate and can lead to major complications including altered frontal lobe functioning (disinhibition and abulia) as well as radiation necrosis.14 Although outcomes reflected an impressive long-term response in an otherwise intractable disease and desperate population, the irreversible nature of the intervention and the historic misapplication of other ablative psychiatric surgeries limited the adoption of stereotactic radiosurgery for psychiatric indications.
Psychiatric surgery, however, has taken on new vigor with the introduction of a minimally invasive, reversible somatic therapy: deep brain stimulation (DBS). DBS has evolved and gained in popularity through its safe application in the treatment of Parkinson disease, essential tremor, and dystonia.15,16 Both the efficacy and complication rate for the DBS implantation procedure are now well defined, derived from outcomes of tens of thousands of DBS implantations performed worldwide for movement disorders.17 Serious complications with long-lasting, severe neurologic sequelae or death occur at a rate between 0.5% and 1%. Remaining complications, such as stroke or intracranial hemorrhage without lasting symptoms, skin erosions, seizures, device failure, and infection, have been reported to occur at rates of 3% to 15%.18
The relative safety of DBS coupled with identification of potential efficacious therapeutic targets has led to trials of its effectiveness in treatment-refractory OCD.6,19,20 The results of these trials led to the US Federal Drug Administration's Humanitarian Device Exemption approval of DBS for treatment-refractory OCD in 2009.21
Obsessive-Compulsive Disorder and Deep Brain Stimulation
OCD is categorized as an anxiety disorder and is marked by recurrent obsessive thoughts and compulsive behaviors.22 Affecting about 1% to 3% of the adult population, it is one of the most common anxiety disorders.23 In 50.6% of these patients, OCD is classified as severe.24 OCD can be extremely disabling because of the time the affected individual spends performing compulsive behaviors and the mental energy required to distract oneself from obsessive thoughts. In a 2000 World Health Organization mental health report,25 OCD was estimated to be the 11th leading cause of nonfatal burden in the world, accounting for 2.5% of total global years lost to disability. Moreover, many other research reports cite OCD as the fourth-most common mental illness, after phobias, substance abuse, and major depression.
Conventional treatments for OCD are well established.26 Cognitive-behavioral therapy, including exposure and ritual prevention, and medications, particularly serotonin reuptake inhibitors, are first-line treatments. In a naturalistic clinical study, over one-third of participants receiving recommended doses of serotonin reuptake inhibitors did not perceive substantial long-term benefit from pharmacotherapy.27 Treatment of OCD rarely results in complete remission.
OCD exacts a huge toll on patients and is a heavy economic burden. Between 10% and 27% of OCD patients attempt suicide at least once in their lifetime.28 Total annual cost of OCD was estimated to be $8.4 billion, constituting 5.7% of the total mental health care cost in 1990. This includes both direct and indirect costs. Direct costs are for outpatient services by physicians and other professionals, hospital care, supported housing and administrative costs, and private health insurance. These accumulate to $2.1 billion. Indirect costs, reflecting lost productivity of individuals dying from or otherwise suffering from the disorder, were estimated at $6.2 billion, or 73.8% of the total cost of OCD.29 According to one survey, 21.8% of severe OCD patients undergo psychiatric hospitalization during a year of treatment.30 Of these, more than 50% are hospitalized more than once, and more than 10% experience 5 or more hospitalizations. The average cost per hospitalization is approximately $12,500. Approximately 28% of OCD patients receive inappropriate treatment (no serotonin reuptake inhibitors or behavior therapy), such that for each of them about $4000 per year is spent on nonproductive outpatient provider costs and $1500 per year is spent on ineffective medication. This amounts to approximately $2 billion per year for ineffective treatment.31 In a retrospective analysis of claims data from a large, prepaid health plan, Koran et al found that OCD patients had 63% higher mean annual costs for nonpsychiatric (ie, medical) visits, and 56% higher costs for laboratory and radiology services compared with patients with no psychiatric visits.32
Abnormalities in so-called cortico-striatal-thalamic-cortical loops seem to be involved in the pathophysiology of OCD.33 Recent diffusion tensor magnetic resonance imaging tractography data demonstrate rich interconnections between these systems in the anterior limb of the internal capsule target area.34,35 Connections between the orbitofrontal cortex, medial prefrontal cortex (anterior and rostral cingulate gyrus), caudate, ventral striatum, anterior cingulate nucleus accumbens, bed nucleus of the stria terminalis, and thalamus are central to OCD (Figure 2). Numerous studies have demonstrated associated abnormal metabolic activity in these regions, with normalization following successful somatic therapies inclusive of DBS.20,34,36,37 Acute DBS has been shown to increase perfusion to the orbitofrontal cortex, anterior cingulate, striatum, pallidum, and thalamus.19 Interestingly, normalization of subsystems in this network is seen with any effective treatment for OCD, be it behavioral or pharmacologic intervention or the aforementioned somatic intervention.36
Results of DBS for the treatment of severe OCD have been published for at least 9 studies (Table 1). Six of these studies were double-blind. In the double-blind studies, improvement rates ranged from 25% to 100%. Pooled together, 22 out of 43 (51%) study participants responded.38
More specifically, Abelson et al reported on 4 patients with medically intractable OCD who participated in a double-blind crossover stimulation paradigm in the anterior limb of the internal capsule, the site of prior ablative brain targeting and interventions.20 Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, used to measure OCD symptom severity in all active-stimulation patients, decreased from 30 to 10 (a decrease from severe to mild symptom intensity) during each of the ON-STIM testing periods; researchers and patients were blinded to ON and OFF stimulation status. Greenberg et al19 reported 3-year follow-up data for 9 OCD patients with stimulating leads implanted in the anterior limb of the internal capsule. Eight patients had been followed up for at least 36 months. Mean Y-BOCS score decreased from 34 (severe) at baseline to 22 (moderate) at 36 months (p < 0.001). Four of 8 patients had a 35% decrease in Y-BOCS at 36 months; in 2 patients, scores declined between 25% and 35%. Depression and anxiety improved, as did functioning in self-care, independent living, work, school, and social domains.
These data led to a multicenter DBS trial conducted by Medtronic.6 Deep brain stimulating leads were implanted in a total of 29 patients, with a 38.7% decrease in Y-BOCS scores at 12 months. This level of symptom reduction is equivalent to full response as defined by the Expert Consensus Panel on OCD. A responder is a subject with a 25% reduction in Y-BOCS score. These data were used to obtain a Humanitarian Device Exemption from the Federal Drug Administration that was approved in 2009.39 Since then, a number of small studies have been done using DBS in a variety of targets.38,40 Stronger research designs using blind or crossover protocols are problematic because stimulation produces rapid and marked clinical effects.41 Patients feel the dramatic effects of stimulation immediately, breaking the on and off blinding spontaneously and making crossover studies impractical—a testament to the dramatic effects of DBS.
DBS is established as a safe, reversible, adjustable, efficacious, evidence-based treatment for severe, refractory OCD. Patients with severe, refractory OCD suffer from high morbidity, and the illness exacts an enormous toll on their well-being. Considerable resources are devoted to reducing their suffering. The emergence of DBS as a highly effective treatment for this population offers them hope of a much higher quality of life as well as more effective and efficient use of their financial resources. The Permanente Medical Group is uniquely situated to define and develop the appropriate scope of application of this promising intervention.
The author(s) have no conflicts of interest to disclose.
Leslie Parker, ELS, provided editorial assistance.
1. Tierney AJ. Egas Moniz and the origins of psychosurgery: a review commemorating the 50th anniversary of Moniz's Nobel Prize. J Hist Neurosci 2000 Apr;9(1):22-36. DOI: https://doi.org/10.1076/0964-704X(200004)9:1;1-2;FT022
2. Papez JW. A proposed mechanism of emotion. Arch Neurol Psychiatry 1937 Oct;38(4):725-43. DOI: https://doi.org/10.1001/archneurpsyc.1937.02260220069003
3. Fusar-Poli P, Allen P, McGuire P. Egas Moniz (1875-1955), the father of psychosurgery. Br J Psychiatry 2008 Jul;193(1):50. DOI: https://doi.org/10.1192/bjp.193.1.50
4. Zwil AS, Pelchat RJ. ECT in the treatment of patients with neurological and somatic disease. Int J Psychiatry Med 1994;24(1):1-29. DOI: https://doi.org/10.2190/5HXY-ACM5-Q6PK-04H5
5. Jenike MA, Baer L, Ballantine T, et al. Cingulotomy for refractory obsessive-compulsive disorder. A long-term follow-up of 33 patients. Arch Gen Psychiatry 1991 Jun;48(6):548-55. DOI: https://doi.org/10.1001/archpsyc.1991.01810300060009
6. Greenberg BD, Gabriels LA, Malone DA Jr, et al. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 2010 Jan;15(1):64-79. DOI: https://doi.org/10.1038/mp.2008.55
7. Mark VH, Ervin FR. Violence and the brain. New York, NY: Harper & Row; 1970
8. Mark VH, Sweet WH, Ervin FR. Role of brain disease in riots and urban violence. JAMA 1967 Sep 11;201(11):895. DOI: https://doi.org/10.1001/jama.1967.03130110121050
9. Mashour GA, Walker EE, Martuza RL. Psychosurgery: past, present, and future. Brain Res Brain Res Rev 2005 Jun;48(3):409-19. DOI: https://doi.org/10.1016/j.brainresrev.2004.09.002
10. Fins JJ. Neuromodulation, free will and determinism: lessons from the psychosurgery debate. Clin Neurosci Res 2004 Jul;4(1-2):113-8. DOI: https://doi.org/10.1016/j.cnr.2004.06.011
11. Rudin E, Zimmerman R. Psychiatric treatment. General implications and lessons from recent court decisions in California. West J Med 1978 May;128(5):459-66.
12. Lippitz BE, Mindus P, Meyerson BA, Kihlström L, Lindquist C. Lesion topography and outcome after thermocapsulotomy or gamma knife capsulotomy for obsessive-compulsive disorder: relevance of the right hemisphere. Neurosurgery 1999 Mar;44(3):452-60. DOI: https://doi.org/10.1097/00006123-199903000-00005
13. Kim MC, Lee TK. Stereotactic lesioning for mental illness. Acta Neurochir Suppl 2008;101:39-43. DOI: https://doi.org/10.1007/978-3-211-78205-7_7
14. Friehs GM, Park MC, Goldman MA, Zerris VA, Norén G, Sampath P. Stereotactic radiosurgery for functional disorders. Neurosurg Focus 2007;23(6):E3. DOI: https://doi.org/10.3171/FOC-07/12/E3
15. Umemura A, Jaggi JL, Hurtig HI, et al. Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients. J Neurosurg 2003 Apr;98(4):779-84. DOI: https://doi.org/10.3171/jns.2003.98.4.0779
16. Deuschl G, Schade-Brittinger C, Krack P, et al; German Parkinson Study Group, Neurostimulation Section. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006 Aug 31;355(9):896-908. DOI: https://doi.org/10.1056/NEJMoa060281
17. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 2002 Jun;50(6):1268-76. DOI: https://doi.org/10.1097/00006123-200206000-00017
18. Hamani C, Lozano AM. Hardware-related complications of deep brain stimulation: a review of the published literature. Stereotact Funct Neurosurg 2006;84(5-6):248-51. DOI: https://doi.org/10.1159/000096499
19. Greenberg BD, Malone DA, Friehs GM, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006 Nov;31(11):2384-93. DOI: https://doi.org/10.1038/sj.npp.1301165
20. Abelson JL, Curtis GC, Sagher O, et al. Deep brain stimulation for refractory obsessive-compulsive disorder. Biol Psychiatry 2005 Mar 1;57(5):510-6. DOI: https://doi.org/10.1016/j.biopsych.2004.11.042
21. Medical devices: Reclaim DBS therapy for OCD - H050003 [monograph on the Internet]. Silver Spring, MD: US Food and Drug Administration; last updated 2012 Nov 29 [cited 2013 Aug 21]. Available from: www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm125520.htm.
22. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992 Apr;53 Suppl:4-10.
23. Ozaki N, Goldman D, Kaye WH, et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 2003 Nov;8(11):933-6. DOI: https://doi.org/10.1038/sj.mp.4001365
24. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005 Jun;62(6):617-27. DOI: https://doi.org/10.1001/archpsyc.62.6.617
25. Ayuso-Mateos JL. Global burden of obsessive-compulsive disorder in the year 2000 [monograph on the Internet]. Geneva, Switzerland: World Health Organization; 2006 Aug 21 [cited 2013 Aug 21]. Available from: www.who.int/healthinfo/statistics/bod_obsessivecompulsive.pdf.
26. Bandelow B, Zohar J, Hollander E, Kasper S, Möller HJ; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders—first revision. World J Biol Psychiatry 2008;9(4):248-312. DOI: https://doi.org/10.1080/15622970802465807
27. Mancebo MC, Eisen JL, Pinto A, Greenberg BD, Dyck IR, Rasmussen SA. The Brown Longitudinal Obsessive Compulsive Study: treatments received and patient impressions of improvement. J Clin Psychiatry 2006 Nov;67(11):1713-20. DOI: https://doi.org/10.4088/JCP.v67n1107
28. Kamath P, Reddy YC, Kandavel T. Suicidal behavior in obsessive-compulsive disorder. J Clin Psychiatry 2007 Nov;68(11):1741-50. DOI: https://doi.org/10.4088/JCP.v68n1114
29. DuPont RL, Rice DP, Shiraki S, Rowland CR. Economic costs of obsessive-compulsive disorder. Med Interface 1995 Apr;8(4):102-9.
30. Ruscio AM. Stein DJ, Chiu WR, Kessler RC. The epidemiology of obsessive-compulsive behavior in the National Comorbidity Survey Replication. Mol Psychiatry 2010 Jan;15(1):53-63. DOI: https://doi.org/10.1038/mp.2008.94
31. Hollander E. Obsessive-compulsive disorder: the hidden epidemic [introduction]. J Clin Psychiatry 1997;58 Suppl 12:3-6.
32. Koran LM, Leventhal J, Fireman B, Jacobsen A. Recognition and treatment of obsessive compulsive disorder in a pre-paid health plan: does adequate treatment reduce costs? Eur Neuropsychopharmacol 1997 Sep;7 Suppl 2:S243. DOI: https://doi.org/10.1016/S0924-977X(97)88803-7
33. Cavedini P, Gorini A, Bellodi L. Understanding obsessive-compulsive disorder: focus on decision making. Neuropsychol Rev 2006 Mar;16(1):3-15. DOI: https://doi.org/10.1007/s11065-006-9001-y
34. Haber SN, Greenberg BD. Neural circuits affected by deep brain stimulation for the treatment of psychiatric disorders. In: Denys D, Feenstra M, Schuurman R, editors. Deep brain stimulation: a new frontier in psychiatry. Heidelberg, Germany: Springer; 2012. p 11-20. DOI: https://doi.org/10.1007/978-3-642-30991-5_2
35. Cannistraro PA, Makris N, Howard JD, et al. A diffusion tensor imaging study of white matter in obsessive-compulsive disorder. Depress Anxiety 2007;24(6):440-6. DOI: https://doi.org/10.1002/da.20246
36. Rauch SL, Dougherty DD, Malone D, et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg 2006 Apr;104(4):558-65. DOI: https://doi.org/10.3171/jns.2006.104.4.558
37. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am 2000 Sep;23(3):563-86. DOI: https://doi.org/10.1016/S0193-953X(05)70181-7
38. Lakhan SE, Callaway E. Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review. BMC Res Notes 2010 Mar 4;3:60. DOI: https://doi.org/10.1186/1756-0500-3-60
39. Fins JJ, Mayberg HS, Nuttin B, et al. Misuse of the FDA's humanitarian device exemption in deep brain stimulation for obsessive-compulsive disorder. Health Aff (Millwood) 2011 Feb;30(2):302-11. DOI: https://doi.org/10.1377/hlthaff.2010.0157
40. Goodman WK, Foote KD, Greenberg BD, et al. Deep brain stimulation for intractable obsessive compulsive disorder: pilot study using a blinded, staggered-onset design. Biol Psychiatry 2010 Mar 15;67(6):535-42. DOI: https://doi.org/10.1016/j.biopsych.2009.11.028
41. Okun MS, Mann G, Foote KD, et al. Deep brain stimulation in the internal capsule and nucleus accumbens region: responses observed during active and sham programming. J Neurol Neurosurg Psychiatry 2007 Mar;78(3):310-4. DOI: https://doi.org/10.1136/jnnp.2006.095315