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Pharmacopsychiatry 2004; 37(1): 26-31
DOI: 10.1055/s-2004-815471
Original Paper
© Georg Thieme Verlag Stuttgart · New York

Combination of Clozapine and Amisulpride in Treatment-Resistant Schizophrenia - Case Reports and Review of the Literature

Mathias Zink1 , Udo Knopf1 , Fritz A. Henn1 , Johannes Thome1
  • 1Central Institute of Mental Health, Mannheim, Germany
Weitere Informationen

Publikationsverlauf

Received: 16. 8. 2002 Revised: 6. 11. 2002

Accepted: 4. 12. 2002

Publikationsdatum:
29. Januar 2004 (online)

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Background: The clinical outcome of patients suffering from schizophrenic psychoses has been considerably improved by atypical antipsychotics like clozapine and amisulpride. In patients whose symptomatology cannot be ameliorated by monotherapy, it might be necessary to combine two atypical antipsychotics.

While clozapine interacts with a variety of neurotransmitter receptors, amisulpride predominantly binds with high affinity to D3/D2-dopamine receptors. Combination can be considered if a supplementary dopamine-receptor blockade is desired.

Methods: We report on the therapy of 15 patients using a combination regimen of amisulpride and clozapine. Data were collected from patient records. The case reports document previous treatment attempts, describe the reason for the combination therapy, and determine its effect.

Results: Major (six cases) or at least marked (eight cases) improvement of previously treatment-resistant positive and negative symptoms could be achieved by using a mean clozapine dose of 375 mg/day (serum level 0.38 mg/l) and an amisulpride dose of 527 mg/day. Additionally, by reducing the clozapine dose compared to monotherapy by 24 %, a significant reduction of side effects was observed.

Conclusions: The combination of amisulpride with clozapine considerably enriches the therapeutic arsenal in cases of severe schizophrenic psychoses. Additional prospective studies are needed in order to systematically evaluate this new treatment strategy.

References

  • 1 Adler G, Grieshaber S, Faude V, Thebaldi B, Dressing H. Clozapine in patients with chronic schizophrenia: Serum level, EEG and memory performance.  Pharmacopsychiatry. 2002;  35 190-194
    Thieme ConnectPubMedSuche in Google Scholar
  • 2 Barnes T R, McEvedy C J, Nelson H E. Management of treatment resistant schizophrenia unresponsive to clozapine.  Br J Psychiat - Suppl. 1996;  31 31-40
    PubMedSuche in Google Scholar
  • 3 Bennett M R. Monoaminergic synapses and schizophrenia: 45 years of neuroleptics.  J Psychopharmacol. 1998;  12(3) 289-304
    PubMedSuche in Google Scholar
  • 4 Bleuler E. Handbuch der Psychiatrie. Spezieller Teil. 4. Abteilung. 1911: Dementia praecox oder die Gruppe der Schizophrenien. 
    Suche in Google Scholar
  • 5 Bottlender R, Jager M, Hofschuster E, Dobmeier P, Moller H J. Neuroleptic malignant syndrome due to atypical neuroleptics: three episodes in one patient.  Pharmacopsychiatry. 2002;  35(3) 119-121
    Thieme ConnectPubMedSuche in Google Scholar
  • 6 Buchanan R W. Clozapine: efficacy and safety.  Schizophr Bull. 1995;  21(4) 579-591
    CrossrefPubMedSuche in Google Scholar
  • 7 Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications.  Clin Pharmacokinet. 2000;  38(5) 393-414
    PubMedSuche in Google Scholar
  • 8 Chong S A, Remington G. Clozapine augmentation: safety and efficacy.  Schizophr Bull. 2000;  26(2) 421-440
    PubMedSuche in Google Scholar
  • 9 Chue P, Welch R, Snaterse M. Combination risperidone and quetiapine therapy in refractory schizophrenia.  Can J Psychiatry - Revue Canadienne de Psychiatrie. 2001;  46(1) 86-87
    PubMedSuche in Google Scholar
  • 10 Cooke C, de Leon J. Adding other antipsychotics to clozapine.  J Clin Psychiat. 1999;  60(10) 710
    PubMedSuche in Google Scholar
  • 11 Croissant B, Hermann D, Olbrich R. Saving potential of clozapine due to combination with amisulpride.  Psychopharmakotherapie. 2002;  8(3) 128-130
    PubMedSuche in Google Scholar
  • 12 de Groot I W, Heck A H, van Harten P N. Addition of risperidone to clozapine therapy in chronically psychotic inpatients.  J Clin Psychiat. 2001;  62(2) 129-130
    PubMedSuche in Google Scholar
  • 13 Delcker A, Schoon M L, Oczkowski B, Gaertner H J. Amisulpride versus haloperidol in treatment of schizophrenic patients-results of a double-blind study.  Pharmacopsychiatry. 1990;  23(2) 125-130
    PubMedSuche in Google Scholar
  • 14 Deniker P. The neuroleptics: a historical survey.  Acta Psychiat Scand Suppl. 1990;  358 83-87
    PubMedSuche in Google Scholar
  • 15 Duval A M, Goldman D. The new drugs (chlorpromazine & reserpine): administrative aspects. 1956.  Psychiat Serv. 2000;  51(3) 327-331
    PubMedSuche in Google Scholar
  • 16 Freudenreich O, Goff D C. Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations.  Acta Psychiat Scand. 2002;  106 323-330
    CrossrefPubMedSuche in Google Scholar
  • 17 Friedman J, Ault K, Powchik P. Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine.  Biol Psychiat. 1997;  42(6) 522-523
    PubMedSuche in Google Scholar
  • 18 Green A I, Schildkraut J J. Should clozapine be a first-line treatment for schizophrenia? The rationale for a double-blind clinical trial in first-episode patients.  Harv Rev Psychiat. 1995;  3(1) 1-9
    PubMedSuche in Google Scholar
  • 19 Grohmann R, Koch R, Schmidt L G. Extrapyramidal symptoms in neuroleptic recipients.  Agents Actions - Suppl. 1990;  29 71-82
    PubMedSuche in Google Scholar
  • 20 Gupta S, Sonnenberg S J, Frank B. Olanzapine augmentation of clozapine.  Ann Clin Psychiat. 1998;  10(3) 113-115
    PubMedSuche in Google Scholar
  • 21 Hellewell J S. Treatment-resistant schizophrenia: reviewing the options and identifying the way forward.  J Clin Psychiat. 1999;  60 Suppl 23 14-19
    PubMedSuche in Google Scholar
  • 22 Henderson D C, Goff D C. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics.  J Clin Psychiat. 1996;  57(9) 395-397
    PubMedSuche in Google Scholar
  • 23 Horacek J. Novel antipsychotics and extrapyramidal side effects. Theory and reality.  Pharmacopsychiatry. 2000;  33 Suppl 1 34-42
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Koshino Y. Algorithm for treatment-refractory schizophrenia.  Psychiat Clin Neurosci. 1999;  53 Suppl S9S13
    PubMedSuche in Google Scholar
  • 25 Kraepelin E. Dementia precox and paraphrenia. 8. Edinburgh; E. and S. Livingstone 1919
    Suche in Google Scholar
  • 26 Lecrubier Y, Azorin M, Bottai T, Dalery J, Garreau G, Lemperiere T. et al . Consensus on the practical use of amisulpride, an atypical antipsychotic, in the treatment of schizophrenia.  Neuropsychobiology. 2001;  44(1) 41-46
    PubMedSuche in Google Scholar
  • 27 Leucht S, Pitschel-Walz G, Engel R R, Kissling W. Amisulpride, an unusual ”atypical” antipsychotic: A meta-Analysis of randomized controlled trials.  Am J Psychiat. 2002;  159 180-190
    CrossrefPubMedSuche in Google Scholar
  • 28 Mann K, Bartels M, Bauer H, Gaertner H J. Amisulpride - an open clinical study of a new benzamide in schizophrenic patients.  Pharmacopsychiatry. 1984;  17(4) 111-115
    PubMedSuche in Google Scholar
  • 29 Marsalek M. Tardive drug-induced extrapyramidal syndromes.  Pharmacopsychiatry. 2000;  33 Suppl 1 14-33
    Thieme ConnectPubMedSuche in Google Scholar
  • 30 Meltzer H Y. An overview of the mechanism of action of clozapine.  J Clin Psychiat. 1994;  55 Suppl B 7-52
    PubMedSuche in Google Scholar
  • 31 Meyer J M, Simpson G M. From chlorpromazine to olanzapine: a brief history of antipsychotics.  Psychiat Serv. 1997;  48(9) 1137-1139
    PubMedSuche in Google Scholar
  • 32 Miller D D. Review and management of clozapine side effects.  J Clin Psychiat. 2000;  61 Suppl 8 14 - 17; discussion 18 -17; discussion 18 - 19
    PubMedSuche in Google Scholar
  • 33 Moeller H J. Amisulpride: a review of its efficacy in schizophrenia.  Acta Psychiat Scand Suppl. 2000;  400 17-22
    PubMedSuche in Google Scholar
  • 34 Moore N A. Behavioural pharmacology of the new generation of antipsychotic agents.  Br J Psychiat Suppl. 1999;  38 5-11
    PubMedSuche in Google Scholar
  • 35 Pantelis C, Barnes T R. Drug strategies and treatment-resistant schizophrenia.  Aust N Z J Psychiat. 1996;  30(1) 20-37
    PubMedSuche in Google Scholar
  • 36 Pantelis C, Barnes T R. Drug strategies and treatment-resistant schizophrenia.  Aust N Z J Psychiat. 1996;  30(1) 20-37
    PubMedSuche in Google Scholar
  • 37 Prior T I, Chue P S, Tibbo P, Baker G B. Drug metabolism and atypical antipsychotics.  Eur Neuropsychopharmacol. 1999;  9(4) 301-309
    PubMedSuche in Google Scholar
  • 38 Raskin S, Katz G, Zislin Z, Knobler H Y, Durst R. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation.  Acta Psychiat Scand. 2000;  101(4) 334-336
    PubMedSuche in Google Scholar
  • 39 Rein W, Coulouvrat C, Dondey-Nouvel L. Safety profile of amisulpride in short- and long-term use.  Acta Psychiat Scand Suppl. 2000;  400 23-27
    PubMedSuche in Google Scholar
  • 40 Rein W, Turjanski S. Clinical update on amisulpride in deficit schizophrenia.  Int Clin Psychopharmacol. 1997;  12 Suppl 2 S19-27
    PubMedSuche in Google Scholar
  • 41 Scatton B, Claustre Y, Cudennec A, Oblin A, Perrault G, Sanger D J. et al . Amisulpride: from animal pharmacology to therapeutic action.  Int Clin Psychopharmacol. 1997;  12 Suppl 2 S29-36
    PubMedSuche in Google Scholar
  • 42 Sethi K D. Movement disorders induced by dopamine blocking agents.  Semin Neurol. 2001;  21(1) 59-68
    Thieme ConnectPubMedSuche in Google Scholar
  • 43 Shen W W. A history of antipsychotic drug development.  Compr Psychiat. 1999;  40(6) 407-414
    CrossrefPubMedSuche in Google Scholar
  • 44 Shiloh R, Zemishlany Z, Aizenberg D, Radwan M, Schwartz B, Dorfman-Etrog P. et al . Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study.  Br J Psychiat. 1997;  171 569-573
    Suche in Google Scholar
  • 45 Stahl S M. Antipsychotic polypharmacy, Part 1: Therapeutic option or dirty little secret?.  J Clin Psychiat. 1999;  60(7) 425-426
    PubMedSuche in Google Scholar
  • 46 Stahl S M. Antipsychotic polypharmacy: evidence based or eminence based?.  Acta Psychiat Scand. 2002;  106 321-322
    PubMedSuche in Google Scholar
  • 47 Stahl S M. Antipsychotic polypharmacy: squandering precious recources?.  J Clin Psychiat. 2002;  63(2) 93-94
    CrossrefPubMedSuche in Google Scholar
  • 48 Stephenson C M, Pilowsky L S. Psychopharmacology of olanzapine. A review.  Br J Psychiat Suppl. 1999;  (38) 52-58
    PubMedSuche in Google Scholar
  • 49 Stern R G, Schmeidler J, Davidson M. Limitations of controlled augmentation trials in schizophrenia.  Biol Psychiat. 1997;  42(2) 138-143
    PubMedSuche in Google Scholar
  • 50 Stubbs J H, Haw C M, Staley C J, Mountjoy C Q. Augmentation with sulpiride for a schizophrenic patient partially responsive to clozapine.  Acta Psychiat Scand. 2000;  102(5) 390 - 393; discussion 393 -393; discussion 393 - 394
    PubMedSuche in Google Scholar
  • 51 Taylor C G, Flynn S W, Altman S, Ehmann T, MacEwan G W, Honer W G. An open trial of risperidone augmentation of partial response to clozapine.  Schizophr Res. 2001;  48(1) 155-158
    CrossrefPubMedSuche in Google Scholar
  • 52 Wirshing D A. Adverse effects of atypical antipsychotics.  J Clin Psychiat. 2001;  62 Suppl 21 7-10
    PubMedSuche in Google Scholar
  • 53 Wirshing D A, Wirsshing W C, Kysar L, Berisford M A, Goldstein D, Pashdag J. et al . Novel antipsychotics: comparison of weight gain liabilities.  J Clin Psychiat. 1999;  60 358-363
    CrossrefPubMedSuche in Google Scholar
  • 54 Young C R, Bowers M B Jr, Mazure C M. Management of the adverse effects of clozapine.  Schizophr Bull. 1998;  24 381-390
    PubMedSuche in Google Scholar
  • 55 Young C R, Longhurst J G, Bowers M B Jr, Mazure C M. The expanding indications for clozapine.  Exp Clin Psychopharmacol. 1997;  5(3) 216-234
    CrossrefPubMedSuche in Google Scholar

Dr. med. Mathias Zink

Central Institute of Mental Health

P.O. Box: 12 21 20

D-68072 Mannheim

Germany

Fax: +49-621-23429

Telefon: +49-621-1703-0

eMail: zink@kv.zi-mannheim.de