What is the best way to treat patients who have obsessive compulsive disorder?
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ADDRESS FOR CORRESPONDENCE: Vladimir Coric, MD, Yale OCD Research Clinic, Clinical Neuroscience Research Unit-3rd Floor, 34 Park Street, New Haven, CT 06510 Phone: (203) 974-7522; E-mail: [email protected] Copyright notice AbstractObsessive compulsive disorder (OCD) was once thought to be extremely rare, but recent epidemiological studies have shown it to be the fourth most common psychiatric disorder (after substance abuse, specific phobias, and major depression). OCD is often a chronic disorder that produces significant morbidity when not properly diagnosed and treated. The mainstay of treatment includes cognitive behavioral therapy and medication management. The use of clomipramine in the 1960s and then the introduction of serotonin reuptake inhibitors in the 1980s represented important advances in the pharmacologic treatment of OCD. Despite effective treatment modalities, many patients demonstrate only a partial response or are resistant to available medications. SRI-resistant OCD is one of the few diagnoses in modern psychiatry for which invasive neurosurgical procedures remain part of the established treatment armamentarium. We review current treatment strategies used in the management of OCD symptoms. IntroductionObsessive compulsive disorder (OCD) is a debilitating neuropsychiatric disorder with a lifetime prevalence of 2 to 3 percent and is estimated to be the 10th leading cause of disability in the world.1 Patients with OCD experience recurrent, intrusive thoughts (obsessions) and/or repetitive, stereotyped behaviors (compulsions) that last for at least one hour per day and significantly interfere with the individual's normal level of functioning (see Table 1 for DSM-IV diagnostic criteria). The intrusive obsessional thoughts cause marked anxiety, and patients often describe their compulsions as efforts to reduce or neutralize these disturbing thoughts. Time-consuming obsessions and compulsions often distract from tasks at hand and significantly impair an individual's attention and concentration. Common obsessions include fear of contamination, fear of harming self or others, intrusive violent images, recurrent forbidden or perverse sexual thoughts, a need to save items of perceived value, concern with sacrilege or morality, a need for symmetry, and excessive concern about appearance. Examples of compulsions performed in response to obsessions include excessive hand washing, ritualized bathing or grooming, checking behaviors, mental rituals, need to repeat activities, re-reading text, hoarding behaviors, and superstitious behaviors. Although the intrusive thoughts seen in OCD are often described as being ego-dystonic, many individuals struggle to determine whether or not their time-consuming behaviors are excessive. Table 1DSM-IV-TR diagnostic criteria for obsessive-compulsive disorder Obsessions as defined by:
Open in a separate window Although OCD can begin in childhood, most cases first present in adolescence and early adulthood; the average age of onset is 22 to 36 years.2 Men typically have an earlier onset than women. Susceptibility to OCD is at least partly genetic;3–5 concordance rates are higher among monozygotic twins than dizygotic twins.4 In addition, first-degree relatives of patients suffering from OCD have an increased risk of developing the disorder.6 Recent studies have emphasized that different OCD symptom types (e.g., contamination obsessions with cleaning compulsions as opposed to hoarding obsessions and compulsions) may represent dissociable, though overlapping, syndromes, and may reflect different underlying genetics.7,8 A recent multicenter study by Mataix-Cols and colleagues9 documented the chronic course of OCD and waxing and waning of these distinct symptom clusters over time. Neuroimaging studies have consistently identified increased blood flow and energy use in the orbitofrontal cortex, striatum, and thalamus of individuals with OCD.10–20 These brain regions are components of the cortico-striato-thalamo-cortical (CSTC) circuitry. The CSTC circuitry consists of parallel pathways that receive cortical information, process it, and project it back to the cortex by way of the thalamus. The direct pathway through the CSTC circuitry has a net excitatory effect and is thought to modulate the initiation and sustainability of behavioral routines, while the indirect pathway modulates the cessation of these behaviors. A leading explanatory model for OCD proposes that increased activity in the direct pathway relative to the indirect pathway results in a disinhibited thalamus, creating a self-perpetuating hyperactive circuit between the thalamus and the orbital cortex that drives OCD symptoms.12,13 Interestingly, studies have demonstrated that individuals who respond to standard treatments show a correction of hyperactivity in the CSTC circuitry. Several studies have demonstrated decreased orbitofrontal, caudate, cingulate, and thalamic metabolism in treatment responders.12,13,21–24 Moreover, increased pre-treatment activity in the CST pathways has been shown to actually predict treatment response in a few studies.24,25 Treatment for OCD includes cognitive behavioral therapy (CBT) and medication management. Many clinincians regard the combination of the two treatments as more effective than either alone.26 Greater efficacy of combined treatment is supported by some controlled studies,27,28 though large, rigorous controlled studies examining the efficacy of the CBT, pharmacotherapy, and their combination in the treatment of OCD are lacking.29 Notably, there is little evidence in the literature that individuals who fail treatment with SRIs significantly respond to CBT alone. Behavioral Treatment of OCDThe efficacy of behavioral and cognitive-behavioral therapies in the treatment of OCD has been validated in more than 30 studies. Exposure and response prevention (ERP) therapy is the best-proven behavioral strategy. During ERP, anxiety and obsession-inducing stimuli are systematically presented in a controlled environment and patients are prevented from engaging in their usual compulsions.30,31 Because ERP is problematic in some patients (especially those who are reluctant to engage in the anxiety-provoking exercise associated with exposure to the feared stimuli or those with pure mental obsessions or compulsions that render response prevention exercises difficult), more purely cognitive therapies have also been established and show efficacy in some studies.32 When properly administered, CBT/ERP is an efficacious treatment modality and can be considered a first-line treatment for some patients.33 Pharmacotherapy of OCDClomipramine, the tricyclic antidepressant that is the most specific inhibitor of serotonin reuptake, was first shown to be efficacious in the treatment of obsessive compulsive symptoms in uncontrolled trials in the 1960s.34,35 Controlled trials later clearly established the efficacy of clomipramine.36,37 The introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s represented the next important pharmacotherapeutic advance in the treatment of OCD. Beginning with the demonstration that fluvoxamine can reduce symptoms in a substantial fraction of patients38,39 and is superior to tricyclic antidepressants other than clomipramine,40 numerous studies have shown that SSRIs are effective pharmacotherapy for many patients. Because of their more benign side effect profile, SSRIs are now considered first-line pharmacotherapy for OCD in most contexts, though clomipramine continues to be widely used. The use of SSRIs and clomipramine in the treatment of OCD differs from the treatment of depression and other anxiety disorders in two important ways: First, higher doses of SRI medications are typically required before clinical improvement is seen. Second, improvement in OCD tends to be gradual, and an adequate medication trial is considered to be at least 10 to 12 weeks in duration.41 Treatment-resistant OCDAlthough CBT and pharmacotherapy with SRIs are effective treatments for many patients, a subset experience minimal relief from their symptoms with these standard treatments. When severe, OCD is incapacitating and has devastating consequences for patients and their families. Despite the introduction of SRIs and CBT, treatment-resistant OCD remains a relatively common and debilitating problem.26,42 Although a consensus regarding the definition of “treatment-resistant” and “treatment-refractory” OCD has not been reached, treatment-resistant OCD generally refers to individuals who have failed at least two adequate trials of SRIs, while treatment-refractory refers to a greater degree of treatment failure.36 Treatment failure is generally defined in OCD research studies as failing to achieve the following: 1) a decline in Y-BOCS score of 25 or 35 percent; 2) an overall Y-BOCS score of less than 16; and 3) a Clinical Global Improvement rating of “much improved” or “very much improved” after at least two months of SSRI monotherapy.43 A number of therapeutic strategies have been attempted in the treatment-resistant population36,43,44 and can be conceptualized as failing in the following three categories: alternative monotherapies, augmentation strategies, and invasive procedures. While evidence exists for efficacy of several different modes of treatment in the treatment-resistant OCD population, there is currently no clear consensus on how to best treat patients once SRIs and CBT have proven inadequate. Alternative MonotherapiesEarly studies with tricyclic antidepressants, which act on both serotonin and norepinephrine, suggested that blockade of serotonin reuptake was required for anti-obsessional effect.45 The importance of the serotonin system in the standard treatment of OCD was reinforced by the improved efficacy of clomipramine and SRIs. Nevertheless, some investigators have hypothesized that a dual-acting agent might be more effective in treatment-resistant patients. This hypothesis is supported by the fact that clomipramine, which retains some norepinephrine reuptake inhibitory (NRI) effect relative to the SSRIs and whose metabolite desmethylclomipramine has significant NRI activity, appears to be more effective than the more selective agents in meta-analyses, though not in head-to-head comparisons.46 For example, in a meta-analysis of studies including over 1,000 adolescents with OCD performed by Geller et al.,47 clomipramine was shown to have greater efficacy than fluoxetine, fluvoxamine, paroxetine, and sertraline. SSRIs remain more widely prescribed as first-line pharmacotherapy despite such results because of their more benign side-effect profile. The possible contribution of NRI properties to the efficacy of clomipramine has motivated several trials of the serotonin-norepinephrine dual-acting reuptake inhibitor venlafaxine, both in treatment-naïve patients and in patients refractory to treatment with SRIs alone. An open-label trial of venlafaxine, both in treatment-naïve and treatment-resistant OCD, suggested superior efficacy to SSRIs,48 and a head-to-head comparison suggested comparable efficacy to clomipramine.49 However, a more recent head-to-head crossover comparison with paroxetine actually showed venlafaxine to be less effective than the SSRI.50 At present, it seems clear that venlafaxine is an effective agent in the treatment of OCD, but the evidence that it provides benefit in the treatment of symptoms refractory to SRI treatment is equivocal.51 Another strategy based on the efficacy of the SRIs is to use other agents that target the serotonin system. A single study suggests that mirtazapine, a 5HT2A agonist, can accelerate the effect of paroxetine on OCD symptoms,43 though the long-term benefit is unclear.52 Mirtazapine has also been shown to be efficacious as monotherapy.53 As is the case with venlafaxine, the limited evidence suggests that mirtazapine is an effective agent in OCD, but its benefit in treatment-resistant cases is unclear. Finally, a few studies suggest that higher effective doses of SRIs, such as can be achieved through intravenous infusion, can be efficacious treatment when standard oral dosing of SRIs has failed. Both intravenous clomipramine54 and intravenous citalopram55 have been shown to lead to a substantial improvement in symptoms in some treatment-resistant patients. Augmentation TherapyA number of different agents have been used as augmentation strategies for standard SRI therapy in treatment-refractory OCD with some success. In particular, agents with modes of action beyond the serotonin system have shown the capacity to significantly improve symptoms in patients with limited response to SRI therapy alone (Table 2).56–72 Table 2Antipsychotic augmentation of SRI-resistant OCD MedicationStudy DesignNumber of SubjectsDosageOutcomeCommentsTypical AntipsychoticsHaloperidol augmentation vs placebo56Double-blind, placebo-controlled augmentation study (4 weeks)n=34 (17 in each study group)Mean study dose of Haldol=6.2±3.0mg/dayHaldol tx grp: 65% (11 of 17 patients) >35% reduction in Y-BOCSHaloperidol significantly better than placebo beginning at week 4 of treatment (P<0.008)Haloperidol or risperidone augmentation vs placebo57Double-blind, placebo-controlled, cross-over design (9 weeks)n=12Risperidone dose=1mg/day; Haloperidol dose=2mg/dayBaseline Y-BOCS for entire group=24.33±4.27 Risperidone tx group final Y-BOCS=15.09±1.81, Haloperidol tx grp final Y-BOCS=13.45±1.83, Placebo grp final Y-BOCS=17.85±1.81.Risperidone did not reach statistical significance (p=0.065) vs. placebo; haloperidol showed a significant reduction (p=0.0065) vs. placebo. Study results are from the first 2 weeks of treatmentAtypical AntipsychoticsRisperidone vs placebo augmentation of fluvoxamine treatment58Double-blind placebo-controlled augmentation study (6 weeks)n=39 (20 risperidone and 19 placebo)Risperidone dose=0.5mg/dayRisperidone tx grp: 50% (n=5) of nonresponders to fluvoxamine had >35% reduction in Y-BOCS; Placebo grp: 20% (n=2) of fluvoxamine nonreponders had >35% reduction in Y-BOCSThe response rate was defined as reduction of >35% on Y-BOCSRisperidone augmentation vs placebo59Double-blind placebo-controlled augmentation study (8 weeks)n=16 (10 risperidone, 6 placebo)Risperidone dose=0.5–3.0mg/dayRisperidone tx grp: 40% (4 of 10) with >25% reduction in Y-BOCS; Placebo: 0% with >25% reduction in Y-BOCS.Among nonresponders to fluvoxamine, low-dose risperidone addition yielded a significant improvement in Y–BOCS; however, responders to fluvoxamine didn't show any significant improvement to risperidone additionRisperidone augmentation vs placebo60Double-blind, placebo-controlled augmentation study (6 weeks)n=33 (18 risperidone, 15 placebo)mean risperidone dose=2.2±0.7mg/dayRisperidone: 50% (9 of 18) >35% improvement in Y-BOCS; Placebo: 0% (0 of 15) >35% reduction in Y-BOCS (P<0.005)Olanzapine augmentation vs placebo61Double-blind, placebo-controlled augmentation study (6 weeks)n=44 (22 in each group)mean olanzapine dose=6.1±2.1mg/dayOlanzapine: 23% (5 of 22) with >35% improvement in Y-BOCS; Placebo: 18% (4 of 22) with >35% improvement of Y-BOCS.Olanzapine augmentation vs placebo62,63Double-blind, placebo-controlled augmentation study (6 weeks)n=26 (13 each group)mean olanzapine dose=11.2mg/dayOlanzapine: 46% (6 of 13) were responders; 0% responders in placebo group.Response rate was defined as >25% improvement in Y-BOCSQuetiapine vs placebo64Double-blind, placebo-controlled augmentation study (8 weeks)n=40 (20 in each group)Quetiapine titrated up to 300mg/dayQuetiapine: 40% (8 of 20) were responsers; 10% (2 of 20) responded in placebo group.The response rate was defined as reduction of >35% on Y-BOCSQuetiapine augmentation vs placebo37Double-blind, palcebo controlled study 16 weeksn=21 (11 quetipine, 10 placebo)mean quetiapine dose=215mg/dayQuetiapine: 27% (3 of 11) with >25% reduction in Y-BOCS (mean reduction=35%); Placebo: 10% (1 of 10) with >25% reduction in Y-BOCS.Quetiapine augmentation vs placebo65Single-blind, randomized, placebo-controlled augmentation 8 weeksn=27 (14 olanzapine, 13 placebo)mean quetiapine dose=91±41mg/dayQuetiapine tx grp: 64.4% (9 of 14) with ≥60% improvement on the Y-BOCS and 7.1% (1 of 14) with ≥30% improvement on the Y-BOCSThere were no responders in the placebo groupOlanzapine augmentation66Open label augmentation study (8 weeks)n=10mean olanzapine dose=7.3±7.3mg/dayOlanzapine+SSRI: 70% (7 of 10) with >30% reduction in Y-BOCSOlanzapine augmentation67Open label augmentation study (8 weeks)n=9Olanzapine dose=2.5–10mg/day33% (3 of 9) responders; Y-BOCS scores of responders decreased by 68%, 30%, and 29% respectively.Olanzapine augmentation68Open label augmentation study (12 weeks)n=18Olanzapine=10mg/day38.9% (7 of 18) rated as respondersResponders achieved a score of Y-BOCS of 16 or lessRisperidone augmentation69Open label augmentation study (3 weeks)n=16mean risperidone dose=2.75 mg/day87% (14 of 16) with >35% reduction in Y-BOCS after 3 weeksRisperidone augmentation70Open label augmentation study (8 weeks)n=14mean risperidone dose=3.0 mg/day50% (7 of 14) with >35% reduction in Y-BOCSThe response rate was defined as reduction of >35% on Y-BOCSQuetiapine augmentation71Open label augmentation study (8 weeks)n=10mean quetiapine dose=200mg/day70% (7 of 10) with >35% reduction in Y-BOCSThe response rate was defined as reduction of >35% on Y-BOCSRisperidone augmentation72Open label augmentation study (4 weeks)n=8Risperidone dose=1–2mg/day37.5% (3 of 8) characterized as respondersResponders defined by response in CGI of “much improvement” to “very much improvement” in OCD symptoms Open in a separate window OCD is highly comorbid with Tourette syndrome in the pediatric population,8 and potentially overlapping pathological changes in the basal ganglia are implicated in the two disorders.73,74 The clear efficacy of both typical and atypical antipsychotic agents in Tourette syndrome,75,76 therefore, motivates trials of dopamine antagonists as augmentation therapy in OCD. Indeed, augmentation with typical77 or atypical antipsychotics59,62,65,71,77–80 improves symptoms in a substantial fraction of patients whose symptoms are refractory to SRI treatment alone (Table 2). Early studies suggested that the benefit of antipsychotic medications was most pronounced in patients with OCD and comorbid tics,77 but more recent studies78 show benefit in treatment-resistant patients with and without tics. The evidence for efficacy of augmentation with atypical antipsychotic agents in SRI-resistant OCD continues to grow.81 In fact, eight double-blind, randomized, placebo-control trials have demonstrated statistically significant efficacy of antipsychotic agents compared to placebo control for treatment-resistant OCD patients taking concurrent SRI monotherapy.37,50,57,59,60,62,77,82 Only one randomized, double-blind, placebo-controlled trial has failed to demonstrate statistically significant efficacy of these agents.61 This negative result, as astutely acknowledged by the authors, was likely attributable to a high placebo response rate in their control population due to insufficient SRI treatment prior to antipsychotic augmentation. A smaller number of studies have examined augmentation therapy with opioid agents. Morphine given once weekly has shown efficacy in treatment-resistant OCD in a single double-blind study,82 and administration of the opioid agonist tramadol hydrochloride has also been show to diminish OCD symptoms.83,84 The mechanism of this interesting effect is unknown, but opioids may inhibit glutamate release in cortex via disinhibition of serotonergic neurons. A number of other augmentation agents have been tried in treatment-resistant OCD, generally in small case series, and with more equivocal results. Medications that have been tried either as monotherapy or as augmentation agents include clonazepam, inositol, clonidine, monoamine oxidase inhibitors, and antiandrogens.63 Finally, we conducted a small, open-label study of augmentation with the antiglutamatergic agent riluzole in SRI-resistant OCD patients and demonstrated significant efficacy.85 Agents manipulating glutamate neurotransmission are particularly exciting candidates for the pharmacotherapy of treatment-resistant OCD because they represent a new perspective on its pathophysiology, distinct from the focus on the monoaminergic modulatory systems that has characterized most pharmacological treatment strategies for the past two decades. Invasive Treatment OptionsSRI-resistant OCD is one of the few diagnoses in modern psychiatry for which invasive neurosurgical procedures remain part of the established treatment armamentarium. This underscores the clinical challenges posed by treatment-resistant OCD and the level of distress experienced by severely affected patients. Neurosurgical approaches to treatment-refractory OCD have recently been reviewed.36,86 Briefly, several different neurosurgical lesion approaches, using a variety of techniques (including standard craniotomy, implantation of radioactive seeds for local ablation, and gamma knife coagulative lesions), have shown some efficacy in open trials of limited numbers of patients with treatment-resistant OCD. The efficacy of neurosurgical ablative techniques is further emphasized by a few case reports of reduced obsessive-compulsive symptoms after neurosurgical removal of epileptic foci.87,88 All ablative neurosurgical techniques target the CSTC circuits that are believed to be hyperactive in OCD. Several specific procedures have been described. Anterior cingulotomy involves a lesion targeting the anterior cingulate cortex and cingulum. Anterior capsulotomy targets the subcaudate white matter, interrupting frontothalamic fibers. Limbic leucotomy combines these two, lesioning both cingulum and subcaudate white matter. Because of the technical and ethical issues involved, existing studies describe small numbers of patients and are not blinded or well controlled. There is some evidence that patients' improvement correlates with the extent of the lesion interrupting the CSTC circuitry: patients undergoing limbic leucotomy after unsuccessful cingulotomy showed a higher response rate in one study than those in whom limbic leucotomy was the first ablative procedure.89 The development of deep brain stimulation (DBS) techniques that can reversibly manipulate the activity of specific brain circuitry has garnered increasing recent interest as a possible treatment modality for OCD and other intractable neuropsychiatric conditions.90,91 The efficacy of such an approach was first suggested by case reports of the amelioration of obsessive-compulsive symptoms with DBS in Parkinson's disease; several small case series have since demonstrated that amelioration of symptoms is possible in at least some cases of severe, treatment-resistant OCD.92 Further, prospective, blinded studies with larger number of patients are needed before such techniques can be brought to bear on the large treatment-resistant OCD population. Finally, the uses of electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS),93 and vagal nerve stimulation (VNS) have been explored as less invasive methods of treatment than neurosurgical intervention. None of these therapies have demonstrated marked efficacy in the limited studies done to date.94 ConclusionsOCD is a chronic and severe psychiatric disorder that is often incapacitating when left untreated. Patients suffering from OCD often attempt to hide their symptoms due to the embarrassing or disturbing content of their thoughts. Many individuals isolate themselves as a consequence of their symptoms and avoid their exposure to potentially anxiety-provoking situations. Unfortunately, there is often a long delay between the time when an individual develops OCD symptoms and when they first obtain treatment. Early diagnosis and treatment minimizes symptom severity and level of disability. Effective first-line treatment with SRI medications and CBT are readily available, well tolerated, and typically provide at least partial relief of symptoms. Reasons for treatment failure often include inadequate dosage of SRI medication, less than a 12-week period of treatment on SRIs, inappropriately applied CBT/ERP techniques, and failure to use SRI and CBT treatments together. Few patients experience complete remission of symptoms despite available treatments. In severely refractory cases, neurosurgical interventions remain a treatment option. Clinical research has mainly focused on serotonergic and dopaminergic treatment interventions. There is an urgent need for conceptually novel pharmacological strategies to improve treatment outcomes for those patients who demonstrate only a partial response to therapy or prove to be highly treatment refractory. AcknowledgmentsThe authors acknowledge the NIMH support for the Yale Neuroscience Research Training Program (C.P.), the support from the State of Connecticut for the Abraham Ribicoff Research Facilities, the National Alliance for Research on Schizophrenia and Depression Young Investigator Award (NARSAD 2003, 2005, V.C.), the NIH Loan Repayment Program (V.C.), the U.S. Department of Veterans Affairs (J.K.), and the National Institute on Alcohol Abuse and Alcoholism (KO5 AA 14906-01, J.K.). We also would like to acknowledge the support of the Obsessive-Compulsive Foundation and the staff of the Clinical Neuroscience Research Unit. References1. Murray CJ, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Morbidity from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020.
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