Review of: Naderi S, Psychiatry Clin Neurosci 2019;73(4):169–174 and Zheng H et al, Eur Neuropsychopharmacol 2019;29(3):397–404
Study types: Positive RCTs
Serotonergic agents—both SSRIs and clomipramine—have historically been the cornerstone of pharmacotherapy for OCD. However, response rates are notoriously low, and few patients achieve full remission. Atypical antipsychotics have so far failed to distinguish themselves as viable augmentation agents. Two novel augmentation strategies—amantadine and methylphenidate—recently underwent placebo-controlled trials in OCD, and we’ll review those results here.
Amantadine is a glutamatergic and dopaminergic agent that was originally approved in 1966 for the influenza virus and, more recently, in an extended-release form for Parkinson’s disease. Several other glutamatergic agents have demonstrated benefits for OCD in small (sample sizes of 15–50), double-blind, placebo-controlled augmentation trials: memantine, riluzole, N-acetylcysteine, and ketamine. Amantadine has also been found to enhance energy and cognition in Alzheimer’s dementia, multiple sclerosis, depression, and ADHD; and reduce irritability in autism and traumatic brain injury.
The most recent amantadine study randomized 100 subjects with moderate to severe OCD in a double-blind manner to receive fluvoxamine (Luvox; titrated up to 200 mg/day by week 4) plus either amantadine 100 mg/day or placebo over 12 weeks. Improvement was assessed at weeks, 4, 10, and 12 using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Y-BOCS scores were significantly lower in the subjects receiving amantadine augmentation compared to those receiving placebo augmentation at week 4 (reduction of 8.4 vs 5.6; p < 0.01) and at the 12-week endpoint (reduction of 12.4 vs 9.7; p < 0.05), though the difference fell just short of significance at week 10 (reduction of 11.9 vs 9.4; p = 0.08). The number needed to treat to see response was 2.5. As has historically been the case, amantadine was very well tolerated, with no side effects that were reported at a statistically significant higher rate than placebo.
Stimulants have been used to augment SSRIs in OCD since the early 1980s, but they can also induce compulsive behaviors. As the first placebo-controlled trial of a stimulant in OCD, this new study brings needed clarity.
The methylphenidate trial enrolled 44 patients with significant OCD who failed to respond to an effective dose of fluvoxamine. They were randomized for 8 weeks to 250 mg fluvoxamine and placebo, or 250 mg of fluvoxamine and extended-release methylphenidate. Subjects in the treatment arm blindly received 18 mg of methylphenidate for the first 4 weeks and 36 mg for the remainder of the study. The primary outcome was the total score on the Y-BOCS.
Patients given methylphenidate in combination with fluvoxamine showed robust improvement compared to those who received fluvoxamine alone. The treatment group had a significant reduction in their total OCD symptoms as measured by the Y-BOCS (reduction of 6.7 vs 1.9). Additionally, the treatment group showed a reduction in the obsessive subscale of the Y-BOCS (reduction of 5.5 vs -0.2). The number needed to treat to see response was 1.8. Secondary measures of depression and anxiety also showed significant improvement. Side effects were minimal (palpitations and headache). Dropout rates were similar in the treatment and placebo arms, and no subjects dropped out due to adverse effects.
Notably, the two studies differed in the types of patients enrolled. In the stimulant study, the patients had failed a trial of fluvoxamine; in the amantadine study, the patients began fluvoxamine along with amantadine.
These studies were well designed and build on previous findings as well as plausible biological pathways in OCD. The number needed to treat translates to an impressive 50% response rate, but with the small sample sizes, that estimate is very rough. Amantadine and methylphenidate have been used for a long time, so we have a good sense of their risks. Both are reasonable options when OCD persists after standard treatments.
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