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Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial.

ABSTRACT: Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population and is associated with significant morbidity. Many patients receive little benefit from the best available treatments, and even those who do respond often suffer from significant residual symptoms. Convergent evidence suggests that abnormalities in glutamate homeostasis and neurotransmission may contribute to OCD and that glutamate-modulating medications may be of benefit in patients whose symptoms are refractory to standard interventions. Small open-label trials of augmentation of serotonin reuptake inhibitor (SRI) pharmacotherapy with the glutamate modulator riluzole have suggested benefit in adults with refractory symptoms. We report a pilot randomized placebo-controlled trial of riluzole augmentation of ongoing SRI treatment in SRI-refractory patients.Outpatients (n = 27) and inpatients (n = 11) with DSM-IV OCD on stable SRI pharmacotherapy were randomized between November 2006 and December 2012 to receive riluzole 50 mg or placebo twice a day and followed for 12 weeks after a 2-week placebo lead-in phase.Riluzole was well tolerated; 1 patient experienced moderate nausea, but none discontinued treatment due to side effects. While there was nominally greater Y-BOCS improvement in the riluzole group (our primary outcome) compared to placebo, it did not reach statistical significance. In the outpatient subsample, a trend suggesting benefit from riluzole augmentation for obsessions (P = .056, 2-tailed, uncorrected) was found in a secondary analysis. Among outpatients, more achieved at least a partial response (> 25% improvement) with riluzole than with placebo (P = .02 in a secondary analysis).Riluzole may be of benefit to a subset of patients. Larger samples would be required to detect effects of the order suggested by the nominal improvement in our outpatient subsample.ClinicalTrials.gov identifier: NCT00523718.

SUBMITTER: Pittenger C

PROVIDER: S-EPMC4560666 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial.

Pittenger Christopher C Bloch Michael H MH Wasylink Suzanne S Billingslea Eileen E Simpson Ryan R Jakubovski Ewgeni E Kelmendi Ben B Sanacora Gerard G Coric Vladimir V

The Journal of clinical psychiatry 20150801 8

<h4>Objective</h4>Obsessive-compulsive disorder (OCD) affects approximately 2.5% of the population and is associated with significant morbidity. Many patients receive little benefit from the best available treatments, and even those who do respond often suffer from significant residual symptoms. Convergent evidence suggests that abnormalities in glutamate homeostasis and neurotransmission may contribute to OCD and that glutamate-modulating medications may be of benefit in patients whose symptoms ...[more]

PMID: 26214725

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Project description:BackgroundMany patients with obsessive-compulsive disorder do not respond adequately to serotonin reuptake inhibitors. Augmentation with antipsychotic drugs can be beneficial in this regard. However, since new relevant randomized controlled trials evaluating new antipsychotics were conducted, a recalculation of the effect sizes appears necessary.MethodsWe meta-analyzed all double-blind, randomized, placebo-controlled trials comparing augmentation of serotonin reuptake inhibitors with antipsychotics to placebo supplementation in treatment-resistant obsessive-compulsive disorder. The primary outcome was mean change in the Yale-Brown Obsessive-Compulsive Scale total score. Secondary outcomes were obsessions, compulsions, response rates, and attrition rates. The data collection process was conducted independently by 2 authors. Hedges's g and risks ratios were calculated as effect sizes. In preplanned meta-regressions, subgroup analyses, and sensitivity analyses, we examined the robustness of the results and explored reasons for potential heterogeneity.ResultsAltogether, 14 double-blind, randomized, placebo-controlled trials (n=491) investigating quetiapine (N=4, n=142), risperidone (N=4, n=132), aripiprazole (N=2, n=79), olanzapine (N=2, n=70), paliperidone (N=1, n=34), and haloperidol (N=1, n=34) were incorporated. Augmentation with antipsychotics was significantly more efficacious than placebo in Yale-Brown Obsessive-Compulsive Scale total reduction (N=14, n=478; Hedges's g=-0.64, 95% CI: -0.87 to -0.41; P=<.01). Aripiprazole (Hedges's g=-1.35), haloperidol (Hedges's g=-0.82), and risperidone (Hedges's g=-0.59) significantly outperformed placebo. Antipsychotics were superior to placebo in treating obsessions, compulsions, and achieving response. There was no between-group difference concerning all-cause discontinuation. The nonsignificant meta-regressions suggest no influence of the antipsychotic dose or baseline symptom severity on the meta-analytic results.ConclusionsAccording to our findings, antipsychotic augmentation of serotonin reuptake inhibitors can be regarded as an evidence-based measure in treatment-resistant obsessive-compulsive disorder.

Project description:Cognitive behavior therapy (CBT) among youth with obsessive-compulsive disorder (OCD) is effective, but many patients remain symptomatic after intervention. d-cycloserine, a partial agonist at the N-methyl-d-aspartate receptor in the amygdala, has been associated with enhanced CBT outcome for OCD among adults but requires evaluation among youth.To examine the relative efficacy of weight-adjusted d-cycloserine (25 or 50 mg) vs placebo augmentation of CBT for youth with OCD and to assess if concomitant antidepressant medication moderated effects.In a placebo-controlled randomized clinical trial, 142 youths (age range, 7-17 years) enrolled between June 1, 2011, and January 30, 2015, at 2 academic health science centers (University of South Florida and Massachusetts General Hospital) with a primary diagnosis of OCD were randomized in a double-blind fashion to d-cycloserine plus CBT or placebo plus CBT. Intent-to-treat analysis was performed.Patients were randomly assigned in a 1:1 ratio to either 10 sessions of d-cycloserine plus CBT or placebo plus CBT. d-cycloserine (25 or 50 mg) or placebo was taken 1 hour before sessions 4 through 10.Children's Yale-Brown Obsessive Compulsive Scale at randomization, biweekly, midtreatment, and posttreatment. Secondary outcomes included the Clinical Global Impressions-Severity or Clinical Global Impressions-Improvement, remission status, Children's Depression Rating Scale, Multidimensional Anxiety Scale for Children, and Children's Obsessive-Compulsive Impact Scale-Parent Version.The study cohort comprised 142 participants. Their mean (SD) age was 12.7 (2.9) years, and 53.5% (76 of 142) were female. A mixed-effects model using all available data indicated significant declines in the Children's Yale-Brown Obsessive Compulsive Scale total score and Clinical Global Impressions-Severity. No significant interaction between treatment group and changes in the Children's Yale-Brown Obsessive Compulsive Scale and Clinical Global Impressions-Severity indicated that the d-cycloserine plus CBT group and the placebo plus CBT group declined at similar rates per assessment point on the Children's Yale-Brown Obsessive Compulsive Scale total score (estimate, -2.31, 95% CI, -2.79 to -1.83 and estimate, -2.03, 95% CI, -2.47 to -1.58, respectively) and Clinical Global Impressions-Severity (estimate, -0.29, 95% CI, -0.35 to -0.22 and estimate, -0.23, 95% CI, -0.29 to -0.17, respectively). No group differences in secondary outcomes were present. Antidepressant medication use at baseline did not moderate changes for either group.d-cycloserine augmentation of CBT did not confer additional benefit relative to placebo among youth with OCD. Other augmentation approaches should be examined to enhance outcome.clinicaltrials.gov Identifier: NCT00864123.

Project description:ContextThe extant literature on the treatment of pediatric obsessive-compulsive disorder (OCD) indicates that partial response to serotonin reuptake inhibitors (SRIs) is the norm and that augmentation with short-term OCD-specific cognitive behavior therapy (CBT) may provide additional benefit.ObjectiveTo examine the effects of augmenting SRIs with CBT or a brief form of CBT, instructions in CBT delivered in the context of medication management.Design, setting, and participantsA 12-week randomized controlled trial conducted at 3 academic medical centers between 2004 and 2009, involving 124 pediatric outpatients between the ages of 7 and 17 years with OCD as a primary diagnosis and a Children's Yale-Brown Obsessive Compulsive Scale score of 16 or higher despite an adequate SRI trial.InterventionsParticipants were randomly assigned to 1 of 3 treatment strategies that included 7 sessions over 12 weeks: 42 in the medication management only, 42 in the medication management plus instructions in CBT, and 42 in the medication management plus CBT; the last included 14 concurrent CBT sessions.Main outcome measuresWhether patients responded positively to treatment by improving their baseline obsessive-compulsive scale score by 30% or more and demonstrating a change in their continuous scores over 12 weeks.ResultsThe medication management plus CBT strategy was superior to the other 2 strategies on all outcome measures. In the primary intention-to-treat analysis, 68.6% (95% CI, 53.9%-83.3%) in the plus CBT group were considered responders, which was significantly better than the 34.0% (95% CI, 18.0%-50.0%) in the plus instructions in CBT group, and 30.0% (95% CI, 14.9%-45.1%) in the medication management only group. The results were similar in pairwise comparisons with the plus CBT strategy being superior to the other 2 strategies (P < .01 for both). The plus instructions in CBT strategy was not statistically superior to medication management only (P = .72). The number needed-to-treat analysis with the plus CBT vs medication management only in order to see 1 additional patient at week 12, on average, was estimated as 3; for the plus CBT vs the plus instructions in CBT strategy, the number needed to treat was also estimated as 3; for the plus instructions in CBT vs medication management only the number needed to treat was estimated as 25.ConclusionsAmong patients aged 7 to 17 years with OCD and partial response to SRI use, the addition of CBT to medication management compared with medication management alone resulted in a significantly greater response rate, whereas augmentation of medication management with the addition of instructions in CBT did not.Trial registrationclinicaltrials.gov Identifier: NCT00074815.

Dataset Information

Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial.

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Riluzole augmentation in treatment-refractory obsessive-compulsive disorder: a pilot randomized placebo-controlled trial.

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