Pharmacological augmentation strategies in treatment resistant obsessive-compulsive disorder: a double-blind placebo-controlled trial

Author(s)

Juliana Belo Diniz

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD)
• Defense date: 2011-02-21

Examining board members

Euripedes Constantino Miguel Filho; Helio Elkis; Antonio Egidio Nardi; Guilherme Vanoni Polanczyk; Albina Rodrigues Torres

• Advisor: Euripedes Constantino Miguel Filho

Abstract

Obsessive-compulsive disorder (OCD) manifests often as a chronic illness and is characterized by the presence of obsessions and compulsions. Firstline treatment options, which include selective serotonin reuptake inhibitors (SSRI) and cognitive-behavior therapy with exposure and response prevention techniques, fail to achieve a satisfactory response in up to 40% of patients. Current evidence supports the augmentation of SSRI with antipsychotics, such as quetiapine. However, anti-psychotics are effective for only one-third of the patients and have been associated with severe long term side effects. This study aimed to compare clomipramine and quetiapine augmentation of the SSRI fluoxetine. Previously to the beginning of this trial all patients had to: report OCD as they primary diagnosis, be taking the highest tolerated or recommended dose of fluoxetine for at least eight weeks, have a current Yale Brown Obsessive-Compulsive Scale (YBOCS) total of at least 16, and have had a reduction of less than 35% of the initial total YBOCS score with fluoxetine treatment. Fifty-four patients were allocated trough a minimization procedure in one of three arms: quetiapine (up to 200 mg/day) plus fluoxetine (up to 40 mg/day) (QTP/FLX) (N=18), clomipramine (up to 75 mg/day) plus fluoxetine (up to 40 mg/day) (CMI/FLX) (N=18) and 18 placebo plus sustained maximum dose fluoxetine (up to 80 mg/day) (PLC/FLX) (N=18). Blinded raters collected YBOCS scores at weeks 0 and 12. Analyses were made with intention-to-treat and hot-deck imputation of missing data. Wald statistics from non-parametric ANCOVA for ordinal categorical repeated measures were used to evaluate group, time and interaction effects for YBOCS scores and secondary outcome measures considering initial measures as covariates. Clinical Global Impression scores of improvement (CGI-I) were used to classify individuals in responders or non-responders. Chi-square was used to evaluate frequency of responders in each group. Percentile-plots were built and sensitivity analyses were performed. Completion rate was 74% (N=40). No severe adverse events occurred during the trial. Patients from the PLC/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=49%, SD=0.49) and CMI/FLX (final YBOCS score: mean=10, SD=4; reduction from initial YBOCS score: mean=46%, SD=0.51) groups improved significantly and also had a significantly better response than the ones from the QTP/FLX group (final YBOCS score: mean=13, SD=3; reduction from initial YBOCS score: mean=18%, SD=0.20; p=0.001). No significant differences were evident for secondary outcome measures. Percentile plots confirmed that patients in the QTP/FLX group got worse more often or improved less than in the other two groups. Sensitivity analyses showed that other analytical methods did not significantly change results. This is the first double-blind placebo-controlled trial of clomipramine augmentation and the first to compare quetiapine augmentation with another active augmenter. Limitations of our trial include the use of low dose of augmenters, differential drop-out rates for each treatment arm and short period of follow-up. Despite these limitations, our results support the use of clomipramine as an augmentation strategy (mainly for those who do not tolerate higher doses of fluoxetine) and the prorogation of the period of maximum dose of fluoxetine before an augmentation is tried (AU)

• FAPESP's process: 06/50273-0 - Pharmacological augmentation strategies in treatment of resistant obsessive-compulsive disorder: a double-blind placebo-controlled trial
• Grantee: Juliana Belo Diniz
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)