Molecular Psychiatry (2010) 15, 850–855 & 2010 Macmillan Publishers Limited All rights reserved 1359-4184/10 www.nature.com/mp ORIGINAL ARTICLE Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder MH Bloch1, J McGuire1, A Landeros-Weisenberger1, JF Leckman1 and C Pittenger2 1Yale Child Study Center, Yale University School of Medicine, New Haven, CT, USA and 2Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed- doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD. Molecular Psychiatry (2010) 15, 850–855; doi:10.1038/mp.2009.50; published online 26 May 2009 Keywords: serotonin reuptake inhibitors; obsessive-compulsive disorder; meta-analysis Introduction demonstrated to have superior efficacy to placebo.7 A recent meta-analysis suggested that SSRIs have a Obsessive-Compulsive Disorder (OCD) is characterized number needed to treat (NNT) to achieve treatment by obsessions (unwanted, intrusive thoughts, impulses response of 5.4 (95% CI: 3.9–8.2) when compared to or images) and compulsions (mental or physical acts placebo.7 Many OCD experts advocate the use of undertaken to relieve the anxiety of the obsession) that higher and quickly escalating doses of SSRI in the cause distress. OCD has several symptom dimensions, treatment of OCD, as compared to other conditions including hoarding, forbidden thoughts (aggression, where antidepressants are effective, such as other sexual and religious obsessions), symmetry (symmetry anxiety disorders and major depressive disorder.6,8 obsessions and counting, ordering, repeating and The American Psychiatric Association Practice arranging compulsions) and cleaning, that are stable Guidelines recommend higher target doses of SSRIs across the lifespan.1,2 OCD has a cross-sectional in the treatment of OCD than they do for depres- prevalence between 1 and 3% and is projected to sion.9,10 The clinical definitions of treatment resis- become one of the top 10 leading causes of disability tance and refractory OCD require patients to fail to worldwide within the next 20 years.3–5 experience improvement on multiple SSRI at the Cognitive behavioral therapy and pharmacotherapy maximum tolerated dose for an adequate duration (at with selective serotonin reuptake inhibitors (SSRIs) least 2 months).8 Thus OCD patients are treated with are the first-line treatments for OCD.6 SSRIs have been higher doses of SSRI compared to many other conditions before progressing to alternative or aug- Correspondence: Dr MH Bloch, Child Study Center, Yale mentation therapies However, controlled studies have University School of Medicine, PO Box 20709, New Haven, CT not consistently shown benefit from higher doses of 06520, USA. SSRIs, which may carry a higher side effect burden. E-mail: [email protected] Received 22 January 2009; accepted 13 April 2009; published Indeed, a meta-analysis of antidepressant agents in online 26 May 2009 the treatment of Major Depressive Disorder has Dose-response relationship of SSRIs in OCD MH Bloch et al 851 demonstrated a significantly increased side-effect randomized clinical trials comparing at least two burden but no improvement in efficacy with higher different fixed doses of a single selective serotonin doses.11 In OCD, some fixed-dose SSRI studies have reuptake inhibitor with each other and with placebo; demonstrated greater efficacy with higher doses (2) participants included were adults diagnosed with of SSRIs12,13 while most have not.14–19 No such Obsessive-Compulsive Disorder by explicit criteria meta-analyses have been conducted for the treatment i.e. DSM-IV or ICD-10 criteria and (3) Obsessive- of OCD. compulsive disorder symptom severity was measured The goal of this current meta-analysis was to better before and after medication treatment using the quantify the dose-response relationship of SSRI in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS).20 treatment of adults with OCD. We examined double- blind, placebo-controlled, fixed-dose trials of SSRIs Outcome measures that included multiple drug dosages, to determine (1) Our primary outcome measure was mean change in Y- if higher doses of SSRI are more effective in the BOCS severity during the course of treatment. treatment of OCD compared to lower doses and (2) the Secondary outcome measures included proportion relative side effect burden of higher doses of SSRI of treatment responders (assessed by the original compared to lower doses. manuscript criteria), proportion of dropouts, and proportion of dropouts due to side effects. The latter two measures served as a proxy for medication Materials and methods tolerability. The trade-off between improved efficacy and increased side effect burden is important when Search strategy for identification of studies considering dose increases of medication. Two reviewers (JM and MHB) searched PubMed on November 1, 2008 for relevant studies using the Meta-analytic procedure used search ((serotonin uptake inhibitors or fluoxetine or All statistical analysis was performed using RevMan sertraline or paroxetine or citalopram or escitalopram 4.2.8 and specially designed spreadsheets in Micro- or fluvoxamine) and obsessive-compulsive disorder) soft Excel. Our primary outcome (mean change in and limited the search to randomized clinical trials. Y-BOCS score) was analyzed using weighted mean There was no language limitation on our search. The difference. Secondary outcome measures (proportion references of relevant review articles, (identified of treatment responders, proportion of dropouts and using the same search strategy but limited to review proportion of dropouts due to side effects) were articles), were scanned for additional eligible trials. analyzed using pooled absolute risk difference Additionally, the Food and Drug Administration (ARD). Low, medium and high dose categories of website at http://www.accessdata.fda.gov/scripts/ SSRI of each available SSRI were calculated based on cder/drugsatfda/index.cfm?fuseaction = Search.Search_ fluoxetine equivalents of SSRI medications used in Drug_Name was searched for additional unpublished previous meta-analytic studies of antidepressants and fixed dose drug trials used for FDA approval of according to the APA dose recommendations for serotonin reuptake inhibitors for OCD, using the individual SSRI in OCD.9,11 Table 1 depicts dose generic names of the medications. stratification categories of all eligible SSRIs, which were determined prior to identification of studies. Selection of studies The initial test of significance for continuous data was The titles and abstracts of studies obtained by this a one-way ANOVA. The Chi-Square Test for Trend search strategy were scrutinized by two reviewers (JM was used for dichotomous outcomes. If this initial test and MHB) to determine if they were potentially was significant (P < 0.05) then each of the SSRI dose eligible for inclusion in this review. Eligibility for categories (Low, Medium, High and placebo) was the study was based upon scrutiny of the full articles compared to each other in RevMan 4.2.8 to detect for the following inclusion criteria (1) they were significant differences. For all outcome measures, Table 1 Dose classifications for selective-serotonin reuptake inhibitors Medication Minimum (mg) Maximum (mg) Low (mg) Medium (mg) High (mg) Fluoxetine 20 80 20–30 40–50 60–80 Sertraline 50 200 50–75 100–175 200 Paroxetine 20 60 20–30 40–50 60 Fluvoxamine 150 300 50–150 200–250 300–350 Citalopram 20 60–80 20–30 40–50 60–80 Escitralopram 10 40 10–15 20–25 30–40 These dose categories were defined a priori and were calculated based on fluoxetine equivalents of SSRIs used in previous meta-analytic studies of antidepressants and according to the American Psychiatric Association dose recommendations for individual SSRIs in Obsessive-Compulsive Disorder.9,11 Molecular Psychiatry Dose-response relationship of SSRIs in OCD MH Bloch et