Selective Serotonin Reuptake Inhibitor (SSRI) Add-On Therapy for the Negative Symptoms of Schizophrenia: A Meta-Analysis

Amir Ali Sepehry, B.A.; Stéphane Potvin, Ph.D.; Robert Élie, M.D., Ph.D.; and Emmanuel Stip, M.D., C.S.P.Q.

Background: Negative symptoms are among the most chronic symptoms of schizophrenia. Even with the advent of atypical antipsychotic drugs, negative symptoms remain mostly refractory to treatment. It has been proposed that selective serotonin reuptake inhibitor (SSRI) augmentation therapy in schizophrenia could provide a greater relief of these symptoms. Published studies, however promising, have produced conflicting results.

Objective: To overcome this discrepancy in results, we performed a meta-analysis of studies assessing SSRI add-on therapy for the negative symptoms of schizophrenia.

Data Sources and Study Selection: A search was performed using the computerized search engines PsycINFO, PubMed (MEDLINE), and Current Contents. Keywords used were schizophrenia and (for SSRI) sertraline, citalopram, paroxetine, fluoxetine, and fluvoxamine. Hand search of published review articles as well as cross-referencing were carried out, too. Pharmaceutical companies were also contacted. Studies were retained if (1) SSRI add-on therapy was compared with antipsychotic monotherapy among schizophrenia-spectrum disorder patients; (2) the clinical trial was randomized, double-blind, placebo-controlled with parallel-arm design; (3) negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms or the Positive and Negative Syndrome Scale-negative subscale.

Data Extraction: With a consensus, authors (A.A.S. and S.P.) extracted and checked the data independently on the basis of predetermined exclusion and inclusion criteria. Effect size estimates were calculated using Comprehensive Meta-Analysis software.

Data Synthesis: Eleven studies responded to our inclusion criteria. Within a random-effects model, a nonsignificant composite effect size estimate for (end point) negative symptoms was obtained (N = 393; adjusted Hedges' g = 0.178; p = .191). However, when studies were divided according to severity of illness, a moderate and significant effect size emerged for the studies involving so-called "chronic patients" (N = 274; adjusted Hedges' g = 0.386; p = .014).

Conclusion: The current meta-analysis provides no global support for an improvement in negative symptoms with SSRI augmentation therapy in schizophrenia.

(J Clin Psychiatry 2007;68:604-610)

Received Feb. 28, 2006; accepted Aug. 4, 2006. From the Fernand-Seguin Research Center, Louis-H Lafontaine Hospital (Drs. Potvin, Élie, and Stip and Mr. Sepehry), and the Departments of Psychiatry (Drs. Potvin and Stip and Mr. Sepehry) and Pharmacology (Dr. Élie), Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

The authors would like to thank Raimo K. R. Salokangas, M.D., Ph.D., and colleagues who generously provided additional data that allowed us to include their study in the meta-analysis.

Dr. Potvin is holder of a scholarship from the Canadian Institute in Health Research (CIHR). Dr. Stip is chairman of the Eli Lilly Chair of Schizophrenia from the University of Montreal. Mr. Sepehry and Dr. Élie report no financial affiliations or other relationships relevant to the subject of this article.

Corresponding author and reprints: Emmanuel Stip, M.D., Centre de recherche Fernand-Seguin, 7331 Hochelaga, Montreal, Quebec, Canada H1N 3V2 (e-mail: emmanuel.stip@umontreal.ca).