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Pharmacopsychiatry 2010; 43(4): 122-129
DOI: 10.1055/s-0030-1249097
Review

© Georg Thieme Verlag KG Stuttgart · New York

Combination Therapy in the Treatment of Schizophrenia

C. Wolff-Menzler1 , A. Hasan1 , B. Malchow1 , P. Falkai1 , T. Wobrock1
  • 1Department of Psychiatry and Psychotherapy, Georg-August-University, Goettingen, Germany
Further Information

Publication History

received 03.09.2009 revised 25.01.2010

accepted 29.01.2010

Publication Date:
22 March 2010 (online)

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Abstract

Background: Although the international guidelines for the treatment of schizophrenia recommend antipsychotic monotherapy as the treatment of choice, many schizophrenia patients receive two or more antipsychotics in clinical practice, while co-treatment with antidepressants, mood stabilizers and benzodiazepines is also common.

Aim: The aim of the present review is to summarize the results of the randomized controlled trials of combination therapy versus monotherapy in schizophrenia and to discuss possible implications of these results.

Discussion: Altogether, recommendations  are based upon theoretical assumptions rather than upon evidence-based knowledge regarding the combination of different antipsychotics or antipsychotics with other psychotropic agents in schizophrenia treatment, since the available studies reveal conflicting results. The augmentation with antidepressants for the treatment of persisting negative symptoms and with mood stabilizers in patients with additional affective symptoms seems to be a successful strategy.

Conclusions: Further randomized controlled trials are warranted to provide substantial evidence and to suggest combination strategies for treatment-resistant schizophrenia.

References

  • 1 American Psychiatric Association . Practice guideline for the treatment of patients with schizophrenia. Second Edition.  Am J Psychiatry.  2004;  161 ((2 Suppl)) 1-114
    CrossrefPubMedGoogle Scholar
  • 2 Anil Yağcioğlu AE, Kivircik Akdede BB, Turgut TI. et al . A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety.  J Clin Psychiatry. 2005;  66 63-72
    CrossrefPubMedGoogle Scholar
  • 3 Arango C, Kirkpatrick B, Buchanan RW. Fluoxetine as an adjunct to conventional antipsychotic treatment of schizophrenia patients with residual symptoms.  J Nerv Ment Dis. 2000;  188 50-53
    CrossrefPubMedGoogle Scholar
  • 4 Basan A, Kissling W, Leucht S. Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials.  Schizophr Res. 2004;  70 33-37
    CrossrefPubMedGoogle Scholar
  • 5 Battaglia J, Moss S, Rush J. et al . Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study.  Am J Emerg Med. 1997;  15 335-340
    Google Scholar
  • 6 Berk M, Ichim C, Brook S. Efficacy of mirtazapine add on therapy to haloperidol in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study.  Int Clin Psychopharmacol. 2001;  16 87-92
    CrossrefPubMedGoogle Scholar
  • 7 Biederman J, Lerner Y, Belmaker RH. Combination of lithium carbonate and haloperidol in schizo-affective patients.  Arch Gen Psychiatry. 1979;  36 327-333
    PubMedGoogle Scholar
  • 8 Bieniek SA, Ownby RL, Penalver A. et al . A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation.  Pharmacotherapy. 1998;  18 57-62
    PubMedGoogle Scholar
  • 9 Binder RL, McNiel DE. Emergency psychiatry: contemporary practices in managing acutely violent patients in 20 psychiatric emergency rooms.  Psychiatr Serv. 1999;  50 1553-1554
    PubMedGoogle Scholar
  • 10 Buchanan RW, Kirkpatrick B, Bryant N. et al . Fluoxetine augmentation of clozapine treatment in patients with schizophrenia.  Am J Psychiatry. 1996;  153 1625-1627
    CrossrefPubMedGoogle Scholar
  • 11 Buchanan RW, Kreyenbuhl J, Zito JM. et al . Relationship of the use of adjunctive pharmacological agents to symptoms and level of function in schizophrenia.  Am J Psychiatry. 2002;  159 1035-1043
    CrossrefPubMedGoogle Scholar
  • 12 Carpenter Jr WT, Buchanan RW, Kirkpatrick B. et al . Diazepam treatment of early signs of exacerbation in schizophrenia.  Am J Psychiatry. 1999;  156 299-303
    PubMedGoogle Scholar
  • 13 Casey DE, Daniel DG, Wassef AA. et al . Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.  Neuropsychopharmacology. 2003;  28 2052-2053
    PubMedGoogle Scholar
  • 14 Citrome L, Casey DE, Daniel DG. et al . Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone.  Psychiatr Serv. 2004;  55 290-294
    CrossrefPubMedGoogle Scholar
  • 15 Collins PJ, Larkin EP, Shubsachs AP. Lithium carbonate in chronic schizophrenia − a brief trial of lithium carbonate added to antipsychotics for treatment of resistant schizophrenic patients.  Acta Psychiatr Scand. 1991;  84 150-154
    CrossrefPubMedGoogle Scholar
  • 16 Correll CU, Rummel-Kluge C, Corves C. et al . Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled studies.  Schizophr Bull. 2009;  35 443-457
    Google Scholar
  • 17 Decina P, Mukherjee S, Bocola V. et al . Adjunctive trazodone in the treatment of negative symptoms of schizophrenia.  Hosp Community Psychiatry. 1994;  45 1220-1223
    PubMedGoogle Scholar
  • 18 Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN) ., Hrsg S3 – Praxisleitlinien in Psychiatrie und Psychotherapie. Band 1, Behandlungsleitlinie Schizophrenie.. Leitlinienprojektgruppe: W. Gaebel (federführend), P. Falkai, S. Weinmann, T. Wobrock. Steinkopff-Verlag, Darmstadt; 2006
    Google Scholar
  • 19 Dose M, Apelt S, Emrich HM. Carbamazepine as an adjunct of antipsychotic therapy.  Psychiatry Res. 1987;  22 303-310
    CrossrefPubMedGoogle Scholar
  • 20 Dose M, Hellweg R, Yassouridis A. et al . Combined treatment of schizophrenic psychoses with haloperidol and valproate.  Pharmacopsychiatry. 1998;  31 122-125
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Falkai P, Wobrock T, Lieberman J. et al . WFSBP Task Force on Treatment Guidelines for Schizophrenia. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: acute treatment of schizophrenia.  World J Biol Psychiatry. 2005;  6 132-191
    Google Scholar
  • 22 Fisk GG, York SM. The effect of sodium valproate on tardive dyskinesia - revisited.  Br J Psychiatry. 1987;  150 542-546
    CrossrefPubMedGoogle Scholar
  • 23 Freudenreich O, Henderson DC, Walsh JP. et al . Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial.  Schizophr Res. 2007;  92 90-94
    CrossrefPubMedGoogle Scholar
  • 24 Ganguly R, Kotzan JA, Miller S. et al . Prevalence, trends, and factors associated with antipsychotic polypharmacy among medicaideligible schizophrenia patients, 1998-2000.  J Clin Psychiatry. 2004;  65 1377-1388
    CrossrefPubMedGoogle Scholar
  • 25 Genc Y, Taner E, Candansayar S. Comparison of clozapine-amisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine: a single-blind randomized study.  Adv Ther. 2007;  24 1-13
    CrossrefPubMedGoogle Scholar
  • 26 Goff DC, Midha KK, Sarid-Segal O. et al . A placebo-controlled trial of fluoxetine added to antipsychotic in patients with schizophrenia.  Psychopharmacology (Berl). 1995;  117 417-423
    CrossrefPubMedGoogle Scholar
  • 27 Hayashi T, Yokota N, Takahashi T. et al . Benefits of trazodone and mianserin for patients with late-life chronic schizophrenia and tardive dyskinesia: an add-on, double-blind, placebo-controlled study.  Int Clin Psychopharmacol. 1997;  12 199-205
    CrossrefPubMedGoogle Scholar
  • 28 Hesslinger B, Normann C, Langosch JM. et al . Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.  J Clin Psychopharmacol. 1999;  19 310-315
    CrossrefPubMedGoogle Scholar
  • 29 Hogarty GE, McEvoy JP, Ulrich RF. et al . Pharmacotherapy of impaired affect in recovering schizophrenic patients.  Arch Gen Psychiatry. 1995;  52 29-41
    PubMedGoogle Scholar
  • 30 Honer WG, Procyshyn RM, Chen EY. et al . A translational research approach to poor treatment response in patients with schizophrenia: clozapine-antipsychotic polypharmacy.  J Psychiatry Neurosci. 2009;  34 433-442
    PubMedGoogle Scholar
  • 31 Honer WG, Thornton AE, Chen EY. et al . Clozapine alone versus clozapine and risperidone with refractory schizophrenia.  N Engl J Med. 2006;  354 472-482
    Google Scholar
  • 32 Jockers-Scherübl MC, Bauer A, Godemann F. et al . Negative symptoms of schizophrenia are improved by the addition of paroxetine to antipsychotics: a double-blind placebo-controlled study.  Int Clin Psychopharmacol. 2005;  20 27-31
    CrossrefPubMedGoogle Scholar
  • 33 Johnstone EC, Crow TJ, Frith CD. et al . The Northwick Park “functional” psychosis study: diagnosis and treatment response.  Lancet. 1988;  2 119-125
    CrossrefPubMedGoogle Scholar
  • 34 Josiassen RC, Joseph A, Kohegyi E. et al . Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial.  Am J Psychiatry. 2005;  162 130-136
    Google Scholar
  • 35 Joukamaa M, Heliövaara M, Knekt P. et al . Schizophrenia, neuroleptic medication and mortality.  Br J Psychiatry. 2006;  188 122-127
    CrossrefPubMedGoogle Scholar
  • 36 Junghan U, Albers M, Woggon B. Increased risk of hematological side-effects in psychiatric patients treated with clozapine and carbamazepine?.  Pharmacopsychiatry. 1993;  26 262
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Kahn EM, Schulz SC, Perel JM. et al . Change in haloperidol level due to carbamazepine − a complicating factor in combined medication for schizophrenia.  J Clin Psychopharmacol. 1990;  10 54-57
    CrossrefPubMedGoogle Scholar
  • 38 Ko YH, Joe SH, Jung IK. et al . Topiramate as an adjuvant treatment with atypical antipsychotics in schizophrenic patients experiencing weight gain.  Clin Neuropharmacol. 2005;  28 169-175
    CrossrefPubMedGoogle Scholar
  • 39 Kotler M, Strous RD, Reznik I. et al . Sulpiride augmentation of olanzapine in the management of treatment-resistant chronic schizophrenia: evidence for improvement of mood symptomatology.  Int Clin Psychopharmacol. 2004;  19 23-26
    CrossrefPubMedGoogle Scholar
  • 40 Kremer I, Vass A, Gorelik I. et al . Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia.  Biol Psychiatry. 2004;  56 441-446
    CrossrefPubMedGoogle Scholar
  • 41 Lee MS, Kim YK, Lee SK. et al . A double-blind study of adjunctive sertraline in haloperidol-stabilized patients with chronic schizophrenia.  J Clin Psychopharmacol. 1998;  18 399-403
    CrossrefPubMedGoogle Scholar
  • 42 Leucht S, Kissling W, McGrath J. Lithium for schizophrenia revisited: a systematic review and meta-analysis of randomized controlled trials.  J Clin Psychiatry. 2004;  65 177-186
    CrossrefPubMedGoogle Scholar
  • 43 Leucht S, McGrath J, White P. et al . Carbamazepine augmentation for schizophrenia: how good is the evidence?.  J Clin Psychiatry. 2002;  63 218-224
    PubMedGoogle Scholar
  • 44 Llorca PM, Wolf MA, Lancon C. et al . Clinical efficacy of bromocriptine, carbamazepine, and cyproheptadine as adjuvant to antipsychotics in 24 chronic resistant schizophrenics.  Encephale. 1993;  19 565-571
    PubMedGoogle Scholar
  • 45 Martin-Munoz JC, Morinigo-Dominguez AV, Mateo-Martin I. et al . Carbamazepine: An effective adjunct treatment for schizophrenia.  Actas Luso Espanolas de Neurologia, Psiquiatria y Ciencias Afines. 1992;  20 11-16
    PubMedGoogle Scholar
  • 46 McGorry P, Killackey E, Elkins K. et al . for the RANZCP Clinical Practice Guideline Team for the treatment of schizophrenia. Summary Australian and New Zealand clinical practice guideline for the treatment of schizophrenia.  Australasian Psychiatry. 2003;  11 136-147
    CrossrefPubMedGoogle Scholar
  • 47 Nachshoni T, Levin Y, Levy A. et al . A double-blind trial of carbamazepine in negative symptom schizophrenia.  Biol Psychiatry. 1994;  35 22-26
    CrossrefPubMedGoogle Scholar
  • 48 National Institute for Clinical Excellence . Core Interventions in the Treatment of Schizophrenia.  NICE, London 2003;  http://www.nice.org.uk
    PubMedGoogle Scholar
  • 49 Neppe VM. Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities.  J Clin Psychiatry. 1983;  44 326-331
    PubMedGoogle Scholar
  • 50 Potter WZ, Ko GN, Zhang LD. et al . Clozapine in China: a review and preview of US/PRC collaboration.  Psychopharmacology (Berl). 1989;  99 ((Suppl)) S87-S91
    CrossrefPubMedGoogle Scholar
  • 51 Rummel C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia.  Cochrane Database Syst Rev. 2006;  3 CD005581
    PubMedGoogle Scholar
  • 52 Rupnow MF, Greenspan A, Gharabawi GM. et al . Incidence and costs of polypharmacy: data from a randomized, double-blind, placebo-controlled study of risperidone and quetiapine in patients with schizophrenia or schizoaffective disorder.  Curr Med Res Opin. 2007;  23 2815-2822
    CrossrefPubMedGoogle Scholar
  • 53 Schulz SC, Thompson PA, Jacobs M. et al . Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.  J Clin Psychiatry. 1999;  60 366-372
    PubMedGoogle Scholar
  • 54 Sepehry AA, Potvin S, Elie R. et al . Selective serotonin reuptake inhibitor (SSRI) add-on therapy for the negative symptoms of schizophrenia: a meta-analysis.  J Clin Psychiatry. 2007;  68 604-610
    CrossrefPubMedGoogle Scholar
  • 55 Shiloh R, Zemishlany Z, Aizenberg D. et al . Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study.  Br J Psychiatry. 1997;  171 569-573
    Google Scholar
  • 56 Shiloh R, Zemishlany Z, Aizenberg D. et al . Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia.  Int Clin Psychopharmacol. 2002;  17 59-64
    CrossrefPubMedGoogle Scholar
  • 57 Silver H, Barash I, Aharon N. et al . Fluvoxamine augmentation of antipsychotics improves negative symptoms in psychotic chronic schizophrenic patients: a placebo-controlled study.  Int Clin Psychopharmacol. 2000;  15 257-261
    CrossrefPubMedGoogle Scholar
  • 58 Silver H, Nassar A. Fluvoxamine improves negative symptoms in treated chronic schizophrenia: an add-on double-blind, placebo-controlled study.  Biol Psychiatry. 1992;  31 698-704
    CrossrefPubMedGoogle Scholar
  • 59 Silver H, Shmugliakov N. Augmentation with fluvoxamine but not maprotiline improves negative symptoms in treated schizophrenia: evidence for a specific serotonergic effect from a double-blind study.  J Clin Psychopharmacol. 1998;  18 208-211
    CrossrefPubMedGoogle Scholar
  • 60 Simhandl C, Meszaros K, Denk E. et al . Adjunctive carbamazepine or lithium carbonate in therapy-resistant chronic schizophrenia.  Can J Psychiatry. 1996;  41 317
    PubMedGoogle Scholar
  • 61 Small JG, Kellams JJ, Milstein V. et al . A placebo-controlled study of lithium combined with antipsychotics in chronic schizophrenic patients.  Am J Psychiatry. 1975;  132 1315-1317
    PubMedGoogle Scholar
  • 62 Small JG, Klapper MH, Malloy FW. et al . Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder.  J Clin Psychopharmacol. 2003;  23 223-228
    CrossrefPubMedGoogle Scholar
  • 63 Spina E, De DP, Ruello C. et al . Adjunctive fluoxetine in the treatment of negative symptoms in chronic schizophrenic patients.  Int Clin Psychopharmacol. 1994;  9 281-285
    CrossrefPubMedGoogle Scholar
  • 64 Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation.  Curr Med Chem. 2004;  11 313-327
    CrossrefPubMedGoogle Scholar
  • 65 Taiminen TJ, Syvälahti E, Saarijärvi S. et al . Citalopram as an adjuvant in schizophrenia: further evidence for a serotonergic dimension in schizophrenia.  Int Clin Psychopharmacol. 1997;  12 31-35
    CrossrefPubMedGoogle Scholar
  • 66 Terao T, Oga T, Nozaki S. et al . Lithium addition to antipsychotic treatment in chronic schizophrenia: a randomized, double-blind, placebo-controlled, cross-over study.  Acta Psychiatr Scand. 1995;  92 220-224
    CrossrefPubMedGoogle Scholar
  • 67 Tiihonen J, Hallikainen T, Ryynanen OP. et al . Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial.  Biol Psychiatry. 2003;  54 1241-1248
    CrossrefPubMedGoogle Scholar
  • 68 Tiihonen J, Halonen P, Wahlbeck K. et al . Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial.  J Clin Psychiatry. 2005;  66 1012-1015
    CrossrefPubMedGoogle Scholar
  • 69 Volz A, Khorsand V, Gillies D. et al . Benzodiazepines for schizophrenia.  Cochrane Database Syst Rev. 2007; Jan;  24 ((1)) CD006391
    PubMedGoogle Scholar
  • 70 Waehrens J, Gerlach J. Antidepressant drugs in anergic schizophrenia. A double-blind cross-over study with maprotiline and placebo.  Acta Psychiatr Scand. 1980;  61 438-444
    CrossrefPubMedGoogle Scholar
  • 71 Wassef AA, Dott SG, Harris A. et al . Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia.  J Clin Psychopharmacol. 2000;  20 357-361
    CrossrefPubMedGoogle Scholar
  • 72 Wilson WH. Addition of lithium to haloperidol in non-affective, antipsychotic non-responsive schizophrenia – A double blind, placebo controlled, parallel design clinical trial.  Psychopharmacology. 1993;  111 359-366
    CrossrefPubMedGoogle Scholar
  • 73 Zhu B, Ascher-Svanum H, Faries DE. et al . Cost of antipsychotic polypharmacy in the treatment of schizophrenia.  BMC Psychiatry. 2008;  8 19
    CrossrefPubMedGoogle Scholar
  • 74 Zoccali R, Muscatello MR, Bruno A. et al . The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study.  Schizophr Res. 2007;  93 109-116
    CrossrefPubMedGoogle Scholar
  • 75 Zoccali R, Muscatello MR, Cedro C. et al . The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study.  Int Clin Psychopharmacol. 2004;  19 71-76
    CrossrefPubMedGoogle Scholar

Correspondence

Dr. med. C. Wolff-Menzler

Department of Psychiatry and Psychotherapy

University of Goettingen

von-Siebold-Straße 5

37075 Goettingen

Germany

Phone: +49/551/39 6947

Fax: +49/551/39 14935

Email: cwolff@gwdg.de