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Obsessive-compulsive disorder is a prevalent, disabling and chronic illness. Serotonin reuptake inhibitors are the first-line of treatment; however a large proportion of patients will have either a partial or nonresponse. This review outlines the strategies for treatment-resistant OCD, including augmentation agents, alternative monotherapies, intravenous strategies and newer nonpharmacologic somatic treatments under development.
Obsessive-compulsive disorder is a severe, chronic condition that affects 2% to 3% of the U.S. population, or 4 million to 7 million people (Weissman et al., 1994). It is characterized by recurrent thoughts, images, feelings or behaviors that persist against the patient's wishes and is usually accompanied by severe anxiety and marked impairment of function.
Obsessive-compulsive disorder was listed as the 10th leading cause of disability worldwide by a World Health Organization study. The total cost of the disorder in the United States is estimated to be over $8 billion (Murray and Lopez, 1996).
Serotonin reuptake inhibitors are the first line of pharmacological treatment for OCD. Approximately 40% to 60% of patients treated with SRIs alone will have a response. This is conventionally defined as at least a 25% reduction on the widely used Yale-Brown Obsessive-Compulsive Scale (YBOCS), with an average of 23% to 43% reduction in symptoms (Greist et al., 1995; Pallanti et al., 2002a). Due to the often incomplete reduction of symptoms in patients who respond to SRIs and those patients who do not show a response, additional treatment strategies are often necessary in OCD.
The focus of this review will be primarily on somatic treatments. In this article, treatment-resistant will be defined as less than a 35% reduction of symptoms as measured by the YBOCS after two SRI trials, with or without cognitive-behavioral therapy (CBT) (Pallanti et al., 2002a).
An adequate trial of an SRI or clomipramine (Anafranil) consists of at least 12 weeks to reach a full therapeutic dose (Table). If CBT has not already been tried, it should be combined with pharmacotherapy at this point, either by a psychiatrist or by referral to a therapist with experience treating OCD.
The treatments described below are listed approximately in the recommended sequence. The Figure outlines the stepwise approach suggested for treatment-resistant OCD. Although some evidence exists for the following strategies, relatively few have been validated in controlled trials.
Atypical antipsychotics. Within the last decade, it has become increasingly evident that medications with both D2 receptor and 5-HT2 receptor antagonism can be effective for treatment-resistant OCD (Jenike and Rauch, 1994). Typical antipsychotics have been demonstrated to be particularly efficacious with comorbid tic disorders (McDougle et al., 1994). More recently, atypical antipsychotics have been demonstrated to have efficacy for augmentation in OCD, with lower risks for extrapyramidal side effects and tardive dyskinesia.
Risperidone (Risperdal) has shown to be effective in open trials and in case series (Saxena et al., 1996). A randomized, controlled trial conducted on 36 patients with SRI-refractory OCD demonstrated that 50% of those taking risperidone, but none of those taking placebo, were "much" or "very much" improved on the Clinical Global Impression (CGI) scale (Hollander et al., 2003a; McDougle et al., 2000).
Two open trials have been conducted using olanzapine (Zyprexa) in patients showing partial response to an SRI (Bogetto et al., 2000; Weiss et al., 1999).
Quetiapine (Seroquel) has also been studied in two open-label trials, one showing a 70% response rate, compared to only 25% in the other study (Denys et al., 2002; Sevincok and Topuz, 2003). In a single-blind, placebo-controlled study, nine of 14 patients showed a 60% or greater improvement on the YBOCS (and one with a 30% improvement), while none in the placebo group responded (Atmaca et al., 2002). Another double-blind, placebo-controlled study showed that 40% of 20 patients were responders versus 10% with placebo, with an average of 31% decrease in YBOCS scores (Denys et al., 2004).
Atypical antipsychotics in combination with an SRI are often efficacious in the management of nonresponders to SRI treatment. In addition, the combination is generally well tolerated. The response tends to occur at lower doses (Bogetto et al., 2000; Hollander et al., 2003a), and a four-week therapeutic trial at the maximum tolerated dose is considered sufficient.
Clomipramine. Clomipramine may be added to an SRI as augmentation. This was demonstrated in a study in which the combination of clomipramine with citalopram (Celexa) was more effective than citalopram alone in treatment-resistant OCD (Pallanti et al., 1999). This strategy should be used with caution, as there is potential for drug-drug interactions (although with cytochrome P450 3A4 inhibitors such as fluvoxamine [Luvox], this may be advantageous in order to increase the parent-to-metabolite ratio).
Clonazepam. Clonazepam (Klonopin) has been studied in two controlled trials. One showed equal efficacy to clomipramine, while the other showed no difference from placebo (Hewlett et al., 1992; Hollander et al., 2003c). Clonazepam may have a role in patients with extreme anxiety and/or insomnia but should not be used "as needed," especially if the patient is also undergoing CBT.
Buspirone. Buspirone (BuSpar), a partial 5-HT1A receptor agonist, appeared promising from case reports and open trials. One early controlled trial showed equal efficacy to clomipramine (Pato et al., 1991). However, three controlled trials have since yielded disappointing results (Grady et al., 1993; McDougle et al., 1993; Pigott et al., 1992).
Lithium. Despite promising case reports, lithium (Eskalith, Lithobid) did not prove to be efficacious in two double-blind, placebo-controlled trials (McDougle et al., 1991; Pigott et al., 1991). However, lithium and other mood stabilizers have a role in patients with comorbid bipolar disorder and/or who experience mood instability or hypomania as a result of SRI treatment.
Other Augmenting Agents
Oral morphine. Preliminary results from a once-a-week, double-blind trial of this opioid receptor agonist showed modest but significant improvement in symptoms over lorazepam (Ativan) and placebo in eight patients (Franz et al., 2001).
Other augmentation strategies with medication or dietary supplements have been tried, including stimulants, L-tryptophan, pindolol (Visken), oxytocin and androgen antagonists. None of these has shown sufficient promise (Altemus et al., 1999; Mundo et al., 1998; Owley et al., 2002).
If the patient has shown no response to SRIs or clomipramine, a different medication in the antidepressant class may be tried.
Venlafaxine. Several case reports and open-label studies suggest that venlafaxine (Effexor) (a serotonin and norepinephrine reuptake inhibitor), alone or in combination with SRIs, may be helpful (Hollander et al., 2003b; Sevincok and Uygur, 2002). A single-blind comparison with clomipramine showed venlafaxine to be nearly as effective and more tolerable (Albert et al., 2002). A double-blind comparison with paroxetine (Paxil) showed both to be equally effective, with a 40% response rate (Denys et al., 2003). Venlafaxine may be a good option after failed SRI trials or as augmentation. It is relatively well-tolerated.
Monoamine oxidase inhibitors. A randomized, controlled trial comparing phenelzine (Nardil) with clomipramine found the two to be equally efficacious (Vallejo et al., 1992). However, a placebo-controlled comparison of phenelzine with fluoxetine (Prozac) found fluoxetine to be significantly superior except for obsessions regarding symmetry, which responded well to phenelzine (Jenike et al., 1997).
For severely treatment-resistant cases, there is some evidence for the efficacy and safety of intravenous clomipramine. In a double-blind, randomized, controlled trial in treatment-refractory patients, Fallon and colleagues (1998) found that nine of 21 patients treated with 14 days of clomipramine infusions followed by seven days of oral treatment were responders, compared with none of 18 in the placebo group. Improvement was maintained by the end of blind ratings at three weeks, and the regimen was well tolerated.
Citalopram has been tested intravenously in an open trial of 39 outpatients, in which 59% achieved a response by day 21 (Pallanti et al., 2002b). In both trials, the intravenous administration appeared to produce a relatively rapid effect (two to three weeks).
After pharmacologic and CBT strategies have been exhausted, nonpharmacologic somatic treatments may be considered.
Deep brain stimulation. A group of investigators treated eight patients with severe treatment-resistant OCD with stereotactically implanted quadripolar electrodes in the bilateral anterior limbs of the internal capsule (using the same targets as in capsulotomy) (Cosyns et al., 2003). Their initial report showed beneficial effects in three of the first four patients.
Vagus nerve stimulation. In theory, direct stimulation of the vagus afferent fibers could affect sensory input to limbic, brain stem and cortical areas known to be involved in mood and anxiety disorders. There are currently seven patients with OCD, two patients with posttraumatic stress disorder and one with panic disorder implanted with the device. Acute and long-term data are not yet available on these patients.
Repetitive transcranial magnetic stimulation. Greenberg et al. (1997) treated 12 patients with OCD and found that a single session of right prefrontal repetitive transcranial magnetic stimulation (rTMS) decreased compulsive urges for eight hours, although there was no effect on obsessions. Alonso and colleagues (2001) randomly assigned 18 patients with OCD to real or sham rTMS and did not find any difference between the treatment groups.
Neurosurgery. For treatment-refractory patients with extreme physical and psychological distress including suicidality and significant disability, psychosurgery may be a treatment option. Different procedures including cingulotomy, subcaudate tractotomy, capsulotomy and limbic leucotomy have been employed, with reported response rates of 35% to 65% (Cosgrove, 2000).
It is hypothesized that such lesions disrupt dysfunctional neural circuits by severing connections between the orbitomedial frontal lobes and limbic or thalamic structures. However, the observation that most patients take weeks or months to improve suggests that secondary effects such as nerve degeneration may be important. No conclusive data exist on comparative efficacy or safety of each approach, and there have been no controlled comparisons with sham surgery. The potential long-term side effects, including lethargy and personality changes, should be weighed against the risks of nonintervention.
Effective management of treatment-resistant OCD should employ a stepwise treatment strategy (Figure). Treatment-resistant cases may benefit from consultation with specialized centers where expertise is available for diagnostic reevaluation, as well as intensive CBT and pharmacotherapy. Identifying and tracking the treatment of refractory cases should be an important focus of future research. It is important for a clinician to be persistent, inventive and thorough in the treatment of patients with this prevalent and disabling condition.
Dr. Feusner is a research fellow at the University of California, Los Angeles, Neuropsychiatric Institute. He has experience treating patients in the UCLA OCD Intensive Treatment Program and the Anxiety Disorders Clinic.
Dr. Bystritsky is professor of psychiatry and behavioral sciences at UCLA and director of the Anxiety Disorders Treatment Program and the OCD Treatment-Resistant Program.
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