MOUNT SINAI JOURNAL OF MEDICINE 75:174–203, 2008 174 Experimental Therapeutics for Refractory Obsessive-Compulsive Disorder: Translational Approaches and New Somatic Developments Heather A. Berlin, PhD, MPH,1 Holly Hamilton, BA1 and Eric Hollander, MD1,2 1Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 2Seaver and NY Autism Center of Excellence, Mount Sinai School of Medicine, New York, NY ABSTRACT Key Words: caudate nucleus, cingulate gyrus, deep brain stimulation, internal capsule, neurosurgery, Significant advances over the past 20 years in our obsessive-compulsive disorder, prefrontal cortex, understanding of the phenomenology and patho- serotonin reuptake inhibitors, therapeutics, transcra- physiology of obsessive-compulsive disorder, made nial magnetic stimulation. in part from structural and functional neuroimag- ing and genetics research, can guide treatments that target brain regions, circuits, and neurotransmitter Obsessive-compulsive disorder (OCD) is a relatively systems specific to obsessive-compulsive disorder, common, chronic illness associated with consider- the disruption of which may alleviate obsessive- able morbidity and economic and social burden.1–5 compulsive disorder symptoms. We discuss here our OCD is characterized by intense anxiety caused current understanding of the underlying neurobiol- by unwanted, intrusive, persistent thoughts, images, ogy and heritability of obsessive-compulsive disor- or impulses (obsessions), which lead to repetitive der and integrate that understanding with a review behaviors or mental acts (compulsions) that the per- of the current pharmacological, neurosurgical, and brain stimulation treatments of refractory obsessive- son feels driven to perform to prevent or reduce 6 compulsive disorder. Expanding on these studies, his or her distress or anxiety. Obsessions and com- we hope that new pharmacological and psycholog- pulsions are time-consuming and cause significant ical treatment strategies and research-driven targets functional impairment and/or distress.7 OCD has a for lesioning, stimulation, or other types of focal mean lifetime prevalence of approximately 2% to neuromodulation can be identified that could lead 3% in the general population,5,8– 11 more than twice to future research directions. Cross-species transla- that of schizophrenia,6 and is the fourth most com- tional research and neuroimaging of the physiological mon mental disorder after depression, alcohol and and anatomical pathways implicated in the patho- 12 physiology and treatment response in obsessive- substance misuse, and social phobia. Lifetime and compulsive disorder will advance our understanding annual prevalence rates of OCD are remarkably sim- of the neural basis of obsessive-compulsive disorder ilar across cultures.6,9 andleadtomoretargetedandeffectivetreatment OCD onset may begin in childhood, adoles- options. Mt Sinai J Med 75:174–203, 2008. 2008 cence, or early adulthood.13 The mean age of onset Mount Sinai School of Medicine is in late adolescence for men and in the early twen- ties for women, for whom the incidence is slightly higher.6,9 Onset is gradual for most, but acute onset Address Correspondence to: has been noted in some cases. OCD may follow an acute, episodic, or chronic course.14 Most people Heather A. Berlin Department of Psychiatry have a chronic waxing and waning course, with exac- Mount Sinai School of Medicine erbation of symptoms that may be stress-related. OCD 5 New York, NY is highly comorbid with a variety of disorders, espe- Email: heather.berlin@mssm. cially anxiety disorders,14– 18 depression,19– 21 alcohol edu or substance misuse,22– 24 eating disorders,25 and body dysmorphic disorder.26 This article contains supplementary materials available at http://www3.interscience.wiley.com/journal/112736813/issueyear?year=2008 Published online in Wiley InterScience (www.interscience.wiley.com). DOI:10.1002/msj.20045 2008 Mount Sinai School of Medicine MOUNT SINAI JOURNAL OF MEDICINE 175 The most common treatments for OCD are phar- most relevant to the development of new treatment macological and cognitive behavioral interventions. approaches for OCD. We then describe standard According to the American Psychiatric Association first-line treatments for OCD and the treatments treatment practice guidelines for OCD,27 selective used for patients who are incomplete responders serotonin reuptake inhibitors (SSRIs) are considered or nonresponders to serotonin reuptake inhibitors first-line treatments for OCD. However, SSRIs are (SRIs). Finally, we discuss treatments for patients often associated with delayed onset of therapeutic who are still treatment-resistant, namely, ECT, TMS, effect (8–12 weeks), only partial symptom reduction, ablative neurosurgical procedures, and DBS, and and response failure or intolerability in 40% to 60% conclude with a discussion of possible directions of patients. Pharmacological options for SSRI refrac- for future research. tory cases include increasing drug dose, changing to another SSRI or clomipramine, combining SSRIs, or changing the mode of drug delivery. Augmentation ETIOLOGY with second-generation antipsychotics has demon- strated efficacy as a second-line treatment. Neurobiology Despite this, some patients still remain refractory Although the cause of OCD is unknown, there is to all standard pharmacological and psychological increasing evidence for the involvement of biological treatments. This review primarily focuses on several factors.4,5 For any individual, a range of factors are alternative medical interventions that have been likely to contribute to the expression of the disorder. considered for these severe cases, such as ablative OCD is heterogeneous in terms of the types of obses- neurosurgery, and brain stimulation techniques, sions and compulsions, heritability, and comorbid such as electroconvulsive therapy (ECT), transcranial conditions, and this probably reflects heterogeneity magnetic stimulation (TMS), and the nonablative in the underlying pathology.28 In accordance, there neurosurgical procedure deep brain stimulation are many disorders known as obsessive-compulsive (DBS). The study of translational approaches, spectrum disorders that share features with OCD, including underlying endophenotypes (mediating such as trichotillomania, Tourette’s syndrome (TS), factors based on the study of neurochemistry, and body dysmorphic disorder.26 neurobiology, and cognition) and predictive animal Although the neurobiological basis of OCD models used to investigate genetic factors and (symptoms and related cognitive impairments) is drugs with anticompulsivity effects, is crucial to unclear, lesion, functional neuroimaging, and neu- the development of appropriate psychological and ropsychological studies have implied that struc- somatic treatment methods for refractory OCD and tural and functional dysfunction of limbic or to our understanding of the pathogenesis of the affective corticostriatothalamocortical circuitry, which disorder. includes the orbitofrontal cortex (OFC), plays a key To review the relevant original research studies, role.28– 31 These circuits, first identified in nonhu- we conducted a computerized literature search of man primates,32,33 have been also been identified recent articles (PubMed, 2000 to February 2008, any in human lesion and imaging studies of OCD language) and also included older articles (before patients.34– 36 Reduced gray matter volume of OFC 2000) that we deemed relevant. Various combinations in OCD patients compared to healthy controls has of keywords were used. We also considered sources been the most consistent finding from structural mag- cited in the reports identified by our original search netic resonance imaging (MRI) studies. The OFC is and some key reviews. Given the limited number of involved in behavioral adaptation to change and available studies in certain areas, particularly DBS, motivational aspects of decision making,37 both of we applied no methodological exclusion criteria. which have implications for OCD. Similarities in neu- However, given the breadth of these topics and in rocognitive deficits of OFC lesion38 and OCD patients order to keep the article concise and focused, we in a range of cognitive and behavioral tasks involv- report only those publications that we consider most ing executive control further implicate the OFC in the pertinent to and as a framework for the alternative pathophysiology of OCD.39 Although studies suggest somatic treatments and those publications that were that OCD patients have increased activity in frontos- considered by the authors to meet rigorous research triatal circuitry, both hypoactivity and hyperactivity standards. of the prefrontal cortex (PFC) may produce deficits After briefly describing the proposed etiology in perceptual and cognitive flexibility, but for dif- of OCD in terms of the underlying neurobiology, ferent reasons.40 There is also imaging evidence, genetics, and environmental and psychological although less consistent, of volume changes in cau- factors, we go on to discuss animal models that seem date nucleus, anterior cingulate cortex, and medial DOI:10.1002/MSJ 176 BERLIN ET AL:OBSESSIVE-COMPULSIVE DISORDER THERAPEUTICS temporal lobe structures.36,41– 54 The inconsistencies published to date,49,72,73 and consistent with findings in the structural imaging literature may be related from ROI studies, they provide some evidence for to methodological issues (eg, medication effects and orbitofrontostriatal structural abnormalities.