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Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review

Published online by Cambridge University Press:  16 April 2020

Vassilis P. Kontaxakis ,
Panayotis P. Ferentinos ,
Beata J. Havaki-Kontaxaki  and
Dimitris K. Roukas
Panayotis P. Ferentinos
Affiliation:
Department of Psychiatry, Eginition Hospital, University of Athens, 74 Vas. Sophias Avenue, 11528Athens, Greece
Beata J. Havaki-Kontaxaki
Affiliation:
Department of Psychiatry, Eginition Hospital, University of Athens, 74 Vas. Sophias Avenue, 11528Athens, Greece
Dimitris K. Roukas
Affiliation:
Department of Psychiatry, Eginition Hospital, University of Athens, 74 Vas. Sophias Avenue, 11528Athens, Greece
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Abstract

Approximately 40–70% of treatment-resistant schizophrenic patients fail to benefit from clozapine monotherapy or are partial responders. During the last years several clozapine adjunctive agents have come into clinical practice. This study aims to critically review all published randomized, double-blind, placebo-controlled clinical trials (RCTs) regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. A MEDLINE search for RCTs on clozapine adjunctive agents published from January 1980 to February 2004 was conducted. All identified papers were critically reviewed and examined against several methodological features as well as clinical and pharmacological parameters. Eleven trials including 270 patients, partial or non-responders to clozapine, assessed the efficacy of sulpiride, lithium, lamotrigine, fluoxetine, glycine, d-serine, d-cycloserine and ethyl-eicosapentanoate (E-EPA) as clozapine adjuncts. There were eight parallel-group and three crossover trials. The inclusion criteria varied widely. The duration as well as the dosage of clozapine monotherapy were reported adequate in only one trial. Plasma clozapine levels were assessed in only three trials. Main side-effects reported were hypersalivation, sedation, diarrhea, nausea, hyperprolactinaemia. The outcome favored clozapine augmentation with sulpiride, lamotrigine and E-EPA. Lithium was shown to benefit only schizoaffective patients. However, the methodological shortcomings of trials analyzed limit the impact of evidence provided.

Keywords

SchizophreniaClozapine-resistantDouble-blindControlledAugmentationAdjunctive
Type
Review
Information
European Psychiatry , Volume 20 , Issue 5-6 , August 2005 , pp. 409 - 415
Copyright
Copyright ©Elsevier SAS 2005

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References

al-Semaan, Y.Bromocriptine as adjunctive therapy to clozapine in treatment-resistant schizophrenia. Can J Psychiatry 1996; 41: 484–485Google ScholarPubMed
American Psychiatric Association Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 1997; 154Suppl 41–63CrossRefGoogle Scholar
Baethge, C., Gruschka, P., Berghofer, A., Bauer, M., Muller-Oerlinghausen, B., Bschor, T., et al.Prophylaxis of schizoaffective disorder with lithium or carbamazepine: outcome after long-term follow-up. J Affect Disord 2004; 79: 43–50CrossRefGoogle ScholarPubMed
Boyer, P.Sense and non-sense of polypharmacy: increasing efficacy, decreasing compliance? Eur Psychiatry 2003; 18: 54S–61SCrossRefGoogle Scholar
Breier, A., Buchanan, R.W., Irish, D., Carpenter, W.T. Jr.Clozapine treatment of outpatients with schizophrenia: outcome and long-term response patterns. Hosp Community Psychiatry 1993; 44: 1145–1149Google ScholarPubMed
Buchanan, R.W., Kirkpatrick, B., Bryant, N., Ball, P., Breier, A.Fluoxetine augmentation of clozapine treatment in patients with schizophrenia. Am J Psychiatry 1996; 153: 1625–1627Google ScholarPubMed
Buckley, P., Miller, A., Olsen, J., Garver, D., Miller, D.D., Csernansky, J.When symptoms persist: clozapine augmentation strategies. Schizophr Bull 2001; 27: 615–628CrossRefGoogle ScholarPubMed
Carpenter, W.T. Jr., Breier, A., Buchanan, R.W., Kirkpatrick, B., Shepard, P., Weiner, E.Mazindol treatment of negative symptoms. Neuropsychopharmacology 2000; 23: 365–374CrossRefGoogle ScholarPubMed
Chong, S.A., Remington, G.Clozapine augmentation: safety and efficacy. Schizophr Bull 2000; 26: 421–440CrossRefGoogle ScholarPubMed
Conley, R.R., Carpenter, W.T. Jr., Tamminga, C.A.Time to clozapine response in a standardized trial. Am J Psychiatry 1997; 154: 1243–1247Google Scholar
Conley, R.R., Kelly, D.L.Management of treatment resistance in schizophrenia. Biol Psychiatry 2001; 50: 898–911CrossRefGoogle Scholar
Dettling, M., Sachse, C., Brockmoller, J., Schley, J., Muller-Oerlinghausen, B., Pickersgill, I., et al.Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric in- and outpatients. Psychopharmacology (Berlin) 2000; 152: 80–86CrossRefGoogle ScholarPubMed
Dursun, S.M., McIntosh, D., Milliken, H.Clozapine plus lamotrigine in treatment resistant schizophrenia. Arch Gen Psychiatry 1999; 56 950CrossRefGoogle ScholarPubMed
Emsley, R., Myburgh, C., Oosthuizen, P., Van Rensburg, S.J.Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 2002; 159: 1596–1598CrossRefGoogle Scholar
Evins, A.E., Fitzgerald, S.M., Wine, L., Rosselli, R., Goff, D.C.Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry 2000; 157: 826–828CrossRefGoogle Scholar
Fenton, W.S., Dickerson, F., Boronow, J., Hibbeln, J.R., Knable, M.A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001; 158: 2071–2074CrossRefGoogle Scholar
Freudenreich, O., Goff, D.C.Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002; 106: 323–330CrossRefGoogle ScholarPubMed
Goff, D.C., Brotman, A.W., Waites, M., McCormick, S.Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients. Am J Psychiatry 1990; 147: 492–494Google ScholarPubMed
Goff, D.C., Henderson, D.C., Evins, A.E., Amico, E.A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia. Biol Psychiatry 1999; 45: 512–514CrossRefGoogle ScholarPubMed
Goff, D.C., Middha, K.K., Sarid-Segal, O., Hubbard, J.W., Amico, E.A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia. Psychopharmacology (Berlin) 1995; 117: 417–423CrossRefGoogle ScholarPubMed
Goff, D.C., Tsai, G., Levitt, J., Amico, E., Manoach, D., Schoenfeld, D.A., et al.A placebo-controlled trial of d-cycloserine added to conventional neuroleptics in patients with schizophrenia. Arch Gen Psychiatry 1999; 56: 21–27CrossRefGoogle ScholarPubMed
Henderson, D.C., Goff, D.C.Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry 1996; 57: 395–397Google ScholarPubMed
Heresco-Levy, U., Javitt, D.C., Ermilov, M., Mordel, C., Silipo, G., Lichtenstein, M.Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry 1999; 56: 29–36CrossRefGoogle ScholarPubMed
Kane, J., Honigfeld, G., Singer, J.Meltzer H and the Clozaril Collaborative Study Group Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796CrossRefGoogle ScholarPubMed
Kronig, M.H., Munne, R.A., Szymanski, S., Safferman, A.Z., Pollack, S., Cooper, T., et al.Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995; 152: 179–182Google ScholarPubMed
Lieberman, J.A., Safferman, A.Z., Pollack, S., et al.Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994; 151: 1744–1752Google ScholarPubMed
Llorca, P.M., Lancon, C., Disdier, B., Farisse, J., Sapin, C., Auquier, P.Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations. J Psychiatry Neurosci 2002; 27: 30–37Google ScholarPubMed
Mauri, M.C., Volonteri, L.S., Dell'Osso, B., Regispani, F., Papa, P., Baldi, M., et al.Predictors of clinical outcome in schizophrenic patients responding to clozapine. J Clin Psychopharmacol 2003; 23: 660–664CrossRefGoogle ScholarPubMed
Meltzer, H.Y., Burnett, S., Bastani, B., Ramirez, L.F.Effects of 6 months of clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Community Psychiatry 1990; 41: 892–897Google Scholar
Peet, M., Brind, J., Ramchand, C.N., Shah, S., Vankar, G.K.Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 2001; 49: 243–251CrossRefGoogle ScholarPubMed
Peet, M., Horrobin, D.F.E-E Multicentre Study Group. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 2002; 36: 7–18CrossRefGoogle Scholar
Perry, P.J., Miller, D.D., Arndt, S.V., Cadoret, R.J.Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148: 231–235Google ScholarPubMed
Potkin, S.G., Bera, R., Gulasekaram, B., Costa, J., Hayes, S., Jin, Y., et al.Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 55Suppl B1994 133–136Google ScholarPubMed
Potkin, S.G., Jin, Y., Bunney, B.G., Costa, J., Gulasekaram, B.Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Am J Psychiatry 1999; 156: 145–147CrossRefGoogle ScholarPubMed
Rosenheck, R., Cramer, J., Xu, W., Thomas, J., Henderson, W., Frisman, L., et al.for The Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. New Engl J Med 1997; 337: 809–815CrossRefGoogle Scholar
Saba, G., Dumortier, G., Kalalou, K., Benadhira, R., Degrassat, K., Glikman, J., et al.Lamotrigine- clozapine combination in refractory schizophrenia: three cases. J Neuropsychiatry Clin Neurosci 2002; 14: 86CrossRefGoogle ScholarPubMed
Shiloh, R., Zemishlany, Z., Aizenberg, D., Radwan, M., Schwartz, B., et al.Sulpiride augmentation in people with schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled study. Br J Psychiatry 1997; 171: 569–573CrossRefGoogle ScholarPubMed
Shiloh, R., Zemishlany, Z., Aizenberg, D., Weizman, A.Sulpiride adjunction to clozapine in treatment-resistant schizophrenic patients: a preliminary case-series study. Eur Psychiatry 1997; 12: 152–155CrossRefGoogle ScholarPubMed
Silver, H., Kushnir, M., Kaplan, A.Fluvoxamine augmentation in clozapine-resistant schizophrenia: an open pilot study. Biol. Psychiatry 1996; 40: 671–674CrossRefGoogle Scholar
Small, J.G., Klapper, M.H., Malloy, F.W., Steadman, T.M.Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder. J Clin Psychopharmacol 2003; 23: 223–228CrossRefGoogle ScholarPubMed
Spina, E., Avenoso, A., Facciola, G., Scordo, M.G., Ancione, M., Madia, A.G., et al.Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology (Berlin) 2000; 148: 83–89CrossRefGoogle ScholarPubMed
Spina, E., Scordo, M.G.Newer antipsychotics: Comparative review of drug interactions. Expert Rev Neurotherapeutics 2001; 1: 171–182CrossRefGoogle ScholarPubMed
Stahl, S.M., Grady, M.M.A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem 2004; 11: 313–327CrossRefGoogle ScholarPubMed
Tiihonen, J., Hallikainen, T., Ryynanen, O.P., Repo-Tiihonen, E., Kotilainen, I., Eronen, M., et al.Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry 2003; 54: 1241–1248CrossRefGoogle ScholarPubMed
Tsai, G., Yang, P., Chung, L.C., Lange, N., Coyle, J.T.d-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 1998; 44: 1081–1089CrossRefGoogle ScholarPubMed
Tsai, G.E., Yang, P., Chung, L.C., Tsai, I.C., Tsai, C.W., Coyle, J.T.d-serine added to clozapine for the treatment of schizophrenia. Am J Psychiatry 1999; 156: 1822–1825Google ScholarPubMed
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