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Topiramate Add-On in Treatment-Resistant Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Jari Tiihonen, M.D., Ph.D.; Pirjo Halonen, Ph.D.; Kristian Wahlbeck, M.D., Ph.D.; Eila Repo-Tiihonen, M.D., Ph.D.; Soile Hyvärinen, M.D.; Markku Eronen, M.D., Ph.D.; Hanna Putkonen, M.D., Ph.D.; Pirjo Takala, M.D.; Olli-Pekka Mehtonen, M.D.; Martin Puck, M.D.; Jorma Oksanen, M.D.; Pasi Koskelainen, M.D.; Grigori Joffe, M.D., Ph.D.; Juhani Aer, M.D., Ph.D.; Tero Hallikainen, M.D.; Olli-Pekka Ryynänen, M.D., Ph.D.; and Erkki Tupala, M.D., Ph.D.

Objective: We tested the hypothesis that topiramate is more effective than placebo in reducing symptoms in patients with treatment-resistant schizophrenia when combined with ongoing antipsychotic medication.

Method: Twenty-six hospitalized treatment-resistant patients with chronic DSM-IV-diagnosed schizophrenia participated in a randomized, double-blind, placebo-controlled trial in which 300 mg/day of topiramate was gradually added to their ongoing treatment (clozapine, olanzapine, risperidone, or quetiapine) over two 12-week crossover treatment periods. Data were collected from April 2003 to November 2003.

Results: In intention-to-treat analysis, topiramate was more effective than placebo in reducing Positive and Negative Syndrome Scale general psychopathologic symptoms (effect size = 0.7, p = .021), whereas no significant improvement was observed in positive or negative symptoms.

Conclusion: Glutamate antagonist topiramate may be an effective adjuvant treatment in reducing general psychopathologic symptoms in patients with schizophrenia resistant to treatment with second-generation antipsychotics.

(J Clin Psychiatry 2005;66:1012-1015)

Received Nov. 26, 2004; accepted Feb. 1, 2005. From the Department of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospital, Kuopio (Drs. Tiihonen, Repo-Tiihonen, Hyvärinen, Hallikainen, and Tupala); the Department of Clinical Physiology, Kuopio University Hospital, Kuopio (Dr. Tiihonen); the Department of Psychiatry, University of Helsinki, Helsinki (Dr. Tiihonen); the Information Technology Center, University of Kuopio, Kuopio (Dr. Halonen); the National Research and Development Center for Welfare and Health, Helsinki (Dr. Wahlbeck); Vanha Vaasa Hospital, Vaasa (Drs. Eronen, Putkonen, and Takala); Kaivanto Hospital, Kangasala (Drs. Mehtonen and Puck); Aurora Hospital, Helsinki (Drs. Oksanen and Koskelainen); Kellokoski Hospital, Kellokoski (Drs. Joffe and Aer); and the Department of Public Health and General Practice, University of Kuopio, Kuopio (Dr. Ryynänen), Finland.

The study was supported by funding from the Stanley Foundation, Bethesda, Md., and annual EVO, Helsinki, Finland, financing (special government subsidies). No support was provided by any pharmaceutical company.

Financial disclosure appears at the end of this article.

The authors thank Tarja Mehtonen, B.A., and Aija Räsänen, B.A., for secretarial assistance.

Corresponding author and reprints: Jari Tiihonen, M.D., Ph.D., University of Kuopio, Department of Forensic Psychiatry, FI-70240 Kuopio, Finland (e-mail: