Evidence-Based Reviews

Treatment-resistant OCD: Options beyond first-line medications

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Duloxetine also may be effective in treating OCD. One case series reported improvement in 3 of 4 SSRI nonresponders who were switched to this medication and rapidly titrated to 120 mg/d.12

Clomipramine/SSRI augmentation. For patients who have not responded to an SSRI, several open-label trials support adding clomipramine.13 Conversely, SSRI augmentation for patients who have not adequately responded to clomipramine may be effective.14 With any dual therapy with serotonergic agents, monitor patients for signs and symptoms of serotonin syndrome.

IV clomipramine. By bypassing first-pass metabolism, IV clomipramine rapidly achieves high plasma levels. In a double-blind, placebo-controlled study of 54 OCD patients who were nonresponsive to oral clomipramine, IV clomipramine was more effective than placebo.15 An additional study found IV clomipramine is more effective when pulse loaded than when titrated gradually.16

Pindolol. The beta blocker pindolol acts as an antagonist of presynaptic 5-HT1A autoreceptors, increasing serotonergic signaling. A small double-blind, placebo-controlled trial (N = 14) found a significant decrease in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score with pindolol augmentation, 2.5 mg, 3 times daily, among patients who did not respond to ≥3 serotonin reuptake inhibitor (SRI) trials.17 Pindolol augmentation showed modest effects in 2 open-label studies.18,19 However, another small double-blind, placebo-controlled study (N = 15) found no difference between placebo and fluvoxamine augmented with pindolol.20

Ondansetron. A 5-HT3 receptor antagonist, ondansetron is used primarily as an antiemetic but has been shown to have anxiolytic properties in animal studies. In an open-label study of 8 patients with non–treatment refractory OCD, 3 achieved clinical response (at least 35% reduction in Y-BOCS score) with ondansetron monotherapy dosed at 1 mg, 3 times daily.21 In a subsequent single-blind trial with 14 treatment-resistant patients, 9 responded (at least 25% reduction in Y-BOCS score).22

Other medications

Antipsychotics. Most studies examining antipsychotic monotherapy for OCD have been negative. One exception was a small, open-label trial of aripiprazole monotherapy (N = 8) that found modest efficacy among non–treatment refractory patients.23 Augmentation with antipsychotics, however, has been well studied and there is good evidence of efficacy for this approach. Double-blind, placebo-controlled studies have supported the efficacy of augmenting SRIs with haloperidol, risperidone, olanzapine, quetiapine, and aripiprazole.24-26 Several case reports suggest ziprasidone may be an effective SRI adjunct, but 1 retrospective study found it was inferior to quetiapine.27

Benzodiazepines. Case reports present positive effects of clonazepam and alprazolam for OCD, but double-blind, placebo-controlled trials for monotherapy or adjunctive clonazepam have been negative.28,29 Furthermore, cognitive impairment and potential for dependence associated with benzodiazepines weigh against their use in OCD.

Opioids. A double-blind, placebo controlled crossover study of 23 patients with treatment-refractory OCD found once-weekly oral morphine added to patients’ current regimen significantly reduced Y-BOCS score vs placebo. Patients received 30 mg the first week and 15 to 45 mg the next week, depending on response or side effects.30 A case report and a small open-label trial support the efficacy of tramadol, a weak agonist of the μ opioid receptor and an inhibitor of serotonin and norepinephrine transporters, as monotherapy and as an adjunct to fluoxetine.31,32 Because patients with OCD may be particularly vulnerable to dependence and intentional or accidental overdose via opioid/benzodiazepine combinations, evaluate the risks and benefits before initiating an opioid.

Psychostimulants. Sparse but good evidence supports the efficacy of dextroamphetamine monotherapy for OCD.33,34 There are no positive studies of methylphenidate and several case reports of methylphenidate-induced OCD symptoms.35

N-methyl-D-aspartate (NMDA) antagonists. Increased glutamatergic neurotransmission has been implicated in the pathophysiology of OCD, which suggests a possible role for glutamate receptor antagonists. In an open-label trial, memantine, an NMDA antagonist used primarily to treat dementia, was associated with clinical response (>25% reduction in Y-BOCS scores) in 6 of 14 patients with treatment-refractory OCD.36 Several case reports and an open-label trial support the efficacy of riluzole—which is indicated for treating amyotrophic lateral sclerosis—as an adjunct for treatment-refractory OCD.37 Although its exact mechanism of action is unclear, riluzole’s effects are thought to be mediated via reduction in glutamatergic neurotransmission. IV ketamine has reported anti-OCD effects in a case report of a woman with treatment-resistant OCD. These effects occurred almost immediately and persisted for several days.38

Hallucinogens. Psilocybin, psilocin, and lysergic acid diethylamide have reported anti-OCD properties.39 As schedule I substances, however, they are not available outside of sanctioned research protocols and may carry substantial risk. Nonetheless, their efficacy suggests that other compounds that share their mechanism of action—namely agonism of 5-HT2A and 5-HT2C receptors—may merit investigation as potential treatments for OCD.


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