A Double-Blind Study of Combination of Clozapine With Risperidone in Patients With Schizophrenia: Effects on Cognition

Berna Binnur Kıvırcık Akdede, M.D.; A. Elif Anıl Yağcıoğlu, M.D.;Köksal Alptekin, M.D.; Tolga I. Turgut, M.D.; Mevhibe Tümüklü, M.D.;M. Kâzım Yazıcı, M.D.; Karu Jayathilake, Ph.D.; Zeliha Tunca, M.D.; Ahmet Göğüs¸, M.D.; and Herbert Y. Meltzer, M.D.

Background: Atypical antipsychotic drugs produce improvement in some domains of cognition as well as psychopathology in patients with schizophrenia. However, the effect of combinations of atypical antipsychotic drugs on cognitive function is unknown. The aim of this study was to compare the effect of risperidone or placebo on cognitive function in patients with schizophrenia who were previously treated with clozapine monotherapy.

Method: This prospective, randomized, double-blind, placebo-controlled, 6-week study included 30 patients with DSM-IV schizophrenia. Patients whose psychopathology was no more than partially responsive to clozapine treatment were randomly assigned to receive adjunctive treatment with risperidone (N = 16) up to 6 mg/day or placebo (N = 14). Cognitive test scores for verbal learning and memory, verbal fluency, attention, executive function, verbal working memory, and motor function were the primary outcome measures. Secondary outcome measures included assessment of psychopathology, extrapyramidal side effects, and global functioning. Data were collected between November 2001 and July 2003.

Results: Significant improvement was found in both treatment groups in a variety of cognitive measures, but there was significantly greater improvement in the placebo-augmented group on measures of initial learning acquisition and attention. The improvement in cognition was not correlated with improvement in psychopathology. There were significant correlations between improvement in verbal working memory, verbal learning and memory, and attention and quality of life and global functioning in the placebo-augmented but not the risperidone-augmented group.

Conclusion: Adjunctive treatment with risperidone for 6 weeks in patients with schizophrenia who had received chronic treatment with clozapine does not significantly improve cognitive function.

(J Clin Psychiatry 2006;67:1912-1919)

Received Jan. 22, 2006; accepted May 1, 2006. From the Department of Psychiatry, Dokuz Eylül University School of Medicine, Izmir, Turkey (Drs. Akdede, Alptekin, Tümüklü, and Tunca); the Department of Psychiatry, Hacettepe University School of Medicine, Ankara, Turkey (Drs. An¹l Yagc¹oglu, Yaz¹c¹, and Gögüs¸); Medical and Human Sciences, Neuroscience and Psychiatry Unit, University of Manchester, Manchester, United Kingdom (Dr. Turgut); and the Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tenn. (Drs. Jayathilake and Meltzer).

Dr. Gögüs¸ passed away before the writing of this paper was completed. We acknowledge his contributions to this work and to the field of psychiatry in Turkey with respect.

Supported by grants from the Stanley Medical Research Institute (Drs. Akdede and Anıl Yagcıoglu), Janssen Pharmaceutical, the Ritter Foundation, and the William Warren Medical Research Foundation (Dr. Meltzer).

Presented at the 39th National Psychiatry Congress of Turkey, October 14-19, 2003, Antalya, Turkey.

Dr. Meltzer has received research grants or served as a consultant and lecturer for Acadia, AstraZeneca, Janssen, Novartis, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, Sanofi, Merck, and Solvay; has received honoraria from Janssen and Pfizer; and is a stock shareholder in Acadia. The other authors report no additional financial or other relationship relevant to the subject of this article.

Corresponding author and reprints: Berna Binnur Kıvırcık Akdede, M.D., Department of Psychiatry, Dokuz Eylül University School of Medicine, Balçova-35340, Izmir, Turkey (e-mail: binnur.kivircik@deu.edu.tr).