Maintenance Treatment With Risperidone or Low-Dose Haloperidol in First-Episode Schizophrenia: 1-Year Results of a Randomized Controlled Trial Within the German Research Network on Schizophrenia

Wolfgang Gaebel, M.D.; Mathias Riesbeck; Wolfgang Wölwer, Ph.D.; Ansgar Klimke, M.D.; Matthias Eickhoff, M.D.; Martina von Wilmsdorff, M.D.; Maria C. Jockers-Scherübl, M.D.; Kai-Uwe Kühn, M.D.; Matthias Lemke, M.D.; Andreas Bechdolf, M.D.; Stefan Bender, M.D.; Detlef Degner, M.D.; Ralf Schlösser, M.D.; Lutz G. Schmidt, M.D.; Andrea Schmitt, M.D.; Markus Jäger, M.D.; Gerd Buchkremer, M.D.; Peter Falkai, M.D.; Stefan Klingberg, Ph.D.; Wolfgang Köpcke, Sc.D.; Wolfgang Maier, M.D.; Heinz Häfner, M.D.; Christian Ohmann, M.D.; Hans J. Salize, Ph.D.; Frank Schneider, M.D., Ph.D.; and Hans-Jürgen Möller, M.D.; for the German Study Group on First-Episode Schizophrenia

Objective: Second-generation antipsychotics (SGAs) have proven superior to first-generation antipsychotics regarding relapse prevention, mainly in multiple-episode patients. Practice guidelines recommend SGAs as first-line treatment particularly in first-episode patients, although evidence for this group is still limited. Accordingly, the hypothesis of whether 1-year relapse rate in first-episode schizophrenia under maintenance treatment with risperidone is lower compared to haloperidol in low dose was tested.

Method: Between November 2000 and May 2004, 1372 patients had been screened for eligibility in the inpatient facilities of 13 German psychiatric university hospitals. 159 remitted patients were enrolled after treatment of an acute first episode of schizophrenia according to ICD-10 F20 criteria. In the randomized controlled trial, double-blind antipsychotic treatment with risperidone or haloperidol was maintained in a targeted dose of 2 to 4 mg/day for 1 year. 151 patients were eligible for analysis. For 127 patients, this was a continuation trial after 8 weeks of randomized, double-blind, acute treatment with the same drugs; 24 patients were additionally randomly assigned after open acute treatment.

Results: With both antipsychotics (risperidone, N = 77; haloperidol, N = 74), no relapse evolved. Additionally, according to 2 post hoc defined measures of "marked clinical deterioration," significant differences occurred neither in the 2 respective deterioration rates (risperidone = 9%/23%; haloperidol = 8%/22%) nor in time until deterioration. Both antipsychotics were equally effective regarding significant symptom reduction and improvement in quality of life. Extrapyramidal symptoms were slightly higher with haloperidol. The overall dropout rate of 68%, however, was not significantly different between the 2 drug groups.

Conclusion: Against the background of an overall favorable outcome, the hypothesized difference between risperidone and low-dose haloperidol regarding relapse prevention could not be supported for this sample of patients with first-episode schizophrenia. Possible design-related reasons for this finding are discussed. With regard to the high dropout rate, special programs are needed to keep schizophrenia patients who are in their early acute and postacute illness course in effective and safe treatment.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT00159081.

(J Clin Psychiatry 2007;68:1763-1774)

Received Sept. 28, 2006; accepted Jan. 2, 2007. From the Department of Psychiatry and Psychotherapy, Heinrich-Heine-University of Düsseldorf, Rhineland State Clinics Düsseldorf, Düsseldorf (Drs. Gaebel, Wölwer, and von Wilmsdorff and Mr. Riesbeck); the Department of Psychiatry and Psychotherapy, Klinikum Offenbach, Offenbach (Dr. Klimke); the Department of Psychiatry, Westfalia Clinics, Warstein/Lippstadt (Dr. Eickhoff); the Department of Psychiatry and Psychotherapy, University of Berlin, Berlin (Dr. Jockers-Scherübl); the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn (Drs. Kühn and Maier); the Department of Psychiatry and Psychotherapy, Rhineland State Clinics Bonn, Bonn (Dr. Lemke); the Department of Psychiatry and Psychotherapy, University of Cologne, Cologne (Dr. Bechdolf); the Department of Psychiatry and Psychotherapy, University of Essen-Duisburg, Rhineland State Clinics Essen, Essen (Dr. Bender); the Department of Psychiatry and Psychotherapy, University of Goettingen, Goettingen (Dr. Degner); the Department of Psychiatry and Psychotherapy, University of Jena, Jena (Dr. Schlösser); the Department of Psychiatry and Psychotherapy, University of Mainz, Mainz (Dr. Schmidt); the Central Institute of Mental Health, Mannheim (Drs. Schmitt, Häfner, and Salize); the Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich (Drs. Jäger and Möller); the Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen (Drs. Buchkremer and Klingberg); the Department of Psychiatry and Psychotherapy, University of Saarland, Homburg/Saar (Dr. Falkai); the Department of Medical Informatics and Biomathematics, University of Muenster, Muenster (Dr. Köpcke); the Coordinating Centre for Clinical Trials, Heinrich Heine University of Düsseldorf, Düsseldorf (Dr. Ohmann); and the Department of Psychiatry, RWTH Aachen University, Aachen (Dr. Schneider), Germany.

This study was conducted within the framework of the German Research Network on Schizophrenia, which is funded by the German Federal Ministry for Education and Research (grants 01 GI 9932 and 01 GI 0232). Risperidone and haloperidol were provided by Janssen-Cilag, Germany.

The authors are much obliged to the members of the German Study Group on First-Episode Schizophrenia as well as to the members of the scientific advisory board of the German Research Network on Schizophrenia for all their contributions. The authors also thank Janssen-Cilag for providing the study drugs.

The German Study Group on First-Episode Schizophrenia: W.G.; W.W.; M.v.W.; Robert Krohmer, M.D.; Jürgen Brinkmeyer, Ph.D.; and M.R. (Düsseldorf, Germany); A.K. (Offenbach, Germany); M.E. (Warstein/Lippstadt, Germany); H.-J.M. and M.J. (Munich, Germany); G.B.; S.K.; and Michael Mayenberger, M.D. (Tuebingen, Germany); Paul Hoff, M.D., and F.S. (Aachen, Germany; recruitment until June 2002); W.M.; M.L.; Beate Johannwerner, M.D.; and K.-U.K. (Bonn, Germany); Isabella Heuser, M.D., and M.C.J.-S. (Berlin, Germany); Joachim Klosterkötter, M.D.; A.B.; and Wolfgang Huff, M.D. (Cologne, Germany); Markus Gastpar, M.D.; S.B.; and Volker Reissner, M.D. (Essen, Germany); Eckhart Rüther, M.D.; D.D.; and P.F. (Goettingen, Germany); Heinrich Sauer, M.D.; R.S.; and Gerd Wagner, M.D. (Jena, Germany); Fritz A. Henn, M.D., Ph.D.; H.H.; Kurt Maurer, Ph.D.; H.J.S.; and A.S. (Mannheim, Germany); and L.G.S. (Mainz, Germany; recruitment until February 2002).

The scientific advisory board of the German Research Network on Schizophrenia: A. George Awad, Ph.D. (Toronto, Ontario, Canada); Wolfgang Fleischhacker, M.D. (Innsbruck, Austria); Rolf Holle, D.Sc. (Neuherberg, Germany); Stephen R. Marder, M.D. (Los Angeles, Calif.); Patrick D. McGorry, M.D., Ph.D., F.R.C.P., F.R.A.N.Z.C.P. (Melbourne, Australia); Franz Müller-Spahn, M.D. (Basel, Switzerland); Wulf Rössler, M.D. (Zürich, Switzerland); and Hendrik van den Bussche, M.D. (Hamburg, Germany).