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Role of Newer Atypical Antipsychotics in the Management of Treatment-Resistant Schizophrenia

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Abstract

This article reviews the evidence of the effects of atypical antipsychotics other than clozapine in patients with schizophrenia that is resistant to treatment with conventional agents. Clozapine remains the one drug with proven efficacy in patients with severely refractory symptoms. However, while the drug is modestly effective in 30 to 70% of these patients, there are many who are either intolerant of, or unresponsive to, it.

The initial hope that the new atypical antipsychotics would play a major role in treatment-resistant schizophrenia has not really materialised. Nevertheless, it is increasingly recognised that perhaps the majority of patients with schizophrenia have milder degrees of refractoriness — so-called ‘partial responders’ — and considerable evidence is emerging for an important role for risperidone, olanzapine and quetiapine in these patients. These drugs appear to have advantages over the conventional antipsychotics in terms of both efficacy and tolerability in these patients.

More studies are required to establish optimal dosages of the atypical antipsychotics in patients with refractory symptoms, as well as whether some individuals respond differentially to a particular drug.

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References

  1. Thomas CS, Lewis S. Which atypical antipsychotic? Br J Psychiatry1998; 172: 106–9

    Article  PubMed  CAS  Google Scholar 

  2. Carman J, Peuskens J, Vangeneugden A. Risperidone in thetreatment of negative symptoms of schizophrenia: a meta-analysis.Int J Psychopharmacol 1995; 10: 207–13

    Article  CAS  Google Scholar 

  3. Tollefson GD, Sanger TM, Lu Y, et al. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry 1998; 55(3): 250–8

    Article  PubMed  CAS  Google Scholar 

  4. Meltzer H, Okayli G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact onrisk-benefit assessment. Am J Psychiatry 1995; 152: 183–90

    PubMed  CAS  Google Scholar 

  5. Rossi A, Mancini F, Stratta P, et al. Risperidone, negative symptomsand cognitive deficit in schizophrenia: an open study. Acta Psychiatr Scand 1997; 95: 40–3

    Article  PubMed  CAS  Google Scholar 

  6. Franz M, Lis S, Pluddemann K, et al. Conventional versus atypical neuroleptics: subjective quality of life in schizophrenic patients. Br J Psychiatry 1997; 170: 422–5

    Article  PubMed  CAS  Google Scholar 

  7. Beasley CM, Dellva MA, Tamura RN, et al. Randomised doubleblind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment witholanzapine or haloperidol. Br J Psychiatry 1999; 174: 23–30

    Article  PubMed  CAS  Google Scholar 

  8. Weiden P, Aquila R, Standard J. Atypical antipsychotic drugs and long-term outcome in schizophrenia. J Clin Psychiatry 1996; 57 Suppl. 11: 53–60

    Google Scholar 

  9. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996; 14(2): 87–96

    Article  PubMed  CAS  Google Scholar 

  10. Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl.) 1996; 124(1–2): 57–73

    Article  CAS  Google Scholar 

  11. Kumar V. Use of atypical agents in geriatric patients: a review. Int J Geriatr Psychopharmacology 1997; 1: 15–23

    CAS  Google Scholar 

  12. Pickar D. Prospects for pharmacotherapy of schizophrenia. Lancet 1995; 345(8949): 557–62

    Article  PubMed  CAS  Google Scholar 

  13. Madhusoodanan S, Brenner R, Cohen CI. Role of atypical antipsychotics in the treatment of psychosis and agitation associated with dementia. CNS Drugs 1999; 12(2): 135–50

    Article  Google Scholar 

  14. Wirshing WC, Marder SR, Van Putten T, et al. Acute treatment of schizophrenia. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York (NY): Raven Press, 1994

    Google Scholar 

  15. Crow TJ, MacMillan JF, Johnson AL, et al. Northwick Park study of first episodes of schizophrenia II. A randomised controlled trial of prophylactic neuroleptic treatment. Br J Psychiatry 1986; 148: 120–7

    Article  PubMed  CAS  Google Scholar 

  16. Loebel AD, Lieberman JA, Alvir JMJ, et al. Duration of psychosis and outcome in first-episode schizophrenia. Am J Psychiatry 1992; 149: 1183–8

    PubMed  CAS  Google Scholar 

  17. Lieberman JA. Prediction of outcome in first-episode schizophrenia. J Clin Psychiatry 1993; 54 Suppl. 3: 13–7

    Google Scholar 

  18. Marder SR. An approach to treatment resistance in schizophrenia. Br J Psychiatry 1999; Suppl. 37: 19–22

    Google Scholar 

  19. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Press, 1994

    Google Scholar 

  20. Meltzer H. Commentary: defining treatment refractoriness in schizophrenia. Schizophr Bull 1990; 16(4): 563–5

    Article  PubMed  CAS  Google Scholar 

  21. Marder SR. Management of treatment-resistant patients with schizophrenia. J Clin Psychiatry 1996; 57 Suppl. 11: 26–30

    Google Scholar 

  22. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45(9): 789–96

    CAS  Google Scholar 

  23. Wahlbeck K, Cheine M, Essali A, et al. Clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomised trials. Am J Psychiatry 1999; 156: 990–9

    PubMed  CAS  Google Scholar 

  24. Lieberman JA, Safferman AZ, Pollack S, et al. Clinical effectsof clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994; 151(12): 1744–52

    PubMed  CAS  Google Scholar 

  25. Essock SM, Hargreaves WA, Covell NH, et al. Clozapine’s effectiveness for patients in state hospitals: results from a randomized trial. Psychopharmacol Bull 1996; 32(4): 683–97

    PubMed  CAS  Google Scholar 

  26. Conley RR, Carpenter Jr WT, Tamminga CA. Time to clozapine response in a standardized trial. Am J Psychiatry 1997; 154(9): 1243–7

    PubMed  CAS  Google Scholar 

  27. Song F. Risperidone in the treatment of schizophrenia: a meta-analysis of randomised controlled trials. J Psychopharmacol 1997; 11: 65–71

    Article  PubMed  CAS  Google Scholar 

  28. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151(6): 825–35

    PubMed  CAS  Google Scholar 

  29. Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group. Am J Psychiatry 1998; 155(4): 499–504

    CAS  Google Scholar 

  30. Green MF, Marshall Jr BD, Wirshing WC, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997; 154(6): 799–804

    PubMed  CAS  Google Scholar 

  31. Kern RS, Green MF, Marshall Jr BD, et al. Risperidone vs.haloperidol on reaction time, manual dexterity, and motorlearning in treatment-resistant schizophrenia patients. BiolPsychiatry 1998; 44(8): 726–32

    CAS  Google Scholar 

  32. Kern RS, Green MF, Marshall BD, et al. Risperidone versus haloperidol on secondary memory: can newer medications aid learning? Schizophr Bull 1999; 25: 223–32

    Article  PubMed  CAS  Google Scholar 

  33. Kee KS, Kern RS, Marshall BD, et al. Risperidone versus haloperidolfor perception of emotion in treatment-resistant schizophrenia:preliminary findings. Schizophr Res 1998; 31: 159–65

    Article  PubMed  CAS  Google Scholar 

  34. Wirshing DA, Marshall Jr BD, Green MF, et al. Risperidone intreatment-refractory schizophrenia. Am J Psychiatry 1999;156(9): 1374–9

    PubMed  CAS  Google Scholar 

  35. Flynn SW, MacEwan GW, Altman S, et al. An open comparisonof clozapine and risperidone in treatment-resistant schizophrenia. Pharmacopsychiatry. 1998; 31(1): 25–9

    Article  PubMed  CAS  Google Scholar 

  36. Still DJ, Dorson PG, Crismon ML, et al. Effects of switchinginpatients with treatment-resistant schizophrenia from clozapine to risperidone. Psychiatr Serv 1996; 47(12): 1382–4

    PubMed  CAS  Google Scholar 

  37. Conley RR, Tamminga CA, Bartko JJ, et al. Olanzapine comparedwith chlorpromazine in treatment-resistant schizophrenia. Am J Psychiatry 1998; 155(7): 914–20

    PubMed  CAS  Google Scholar 

  38. Breier A, Hamilton SH. Comparative efficacy of olanzapineand haloperidol for patients with treatment-resistant schizophrenia. Biol Psychiatry 1999; 45(4): 403–11

    Article  PubMed  CAS  Google Scholar 

  39. Martin J, Gomez JC, Garcia BE, et al. Olanzapine in treatment-refractoryschizophrenia: results of an open-label study. J ClinPsychiatry 1997; 58(11): 479–83

    Article  CAS  Google Scholar 

  40. Conley RR, Tamminga CA, Kelly DL, et al. Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response. Biol Psychiatry 1999; 46: 73–7

    Article  PubMed  CAS  Google Scholar 

  41. Dursun SM, Gardner DM, Bird DC, et al. Olanzapine for patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. Can J Psychiatry 1999; 44: 701–4

    PubMed  CAS  Google Scholar 

  42. Conley RR, Kelly DL, Gale EA. Olanzapine response in treatment-refractory schizophrenic patients with a history of substanceabuse. Schizophr Res 1998; 33: 95–101

    Article  PubMed  CAS  Google Scholar 

  43. Sanders RD, Mossman D. An open trial of olanzapine in patients with treatment-refractory psychoses. J Clin Psychopharmacol 1999; 19: 62–6

    Article  PubMed  CAS  Google Scholar 

  44. Kumra A, Jacobsen LK, Lenane M, et al. Childhood-onset schizophrenia:an open-label study of olanzapine in adolescents. J Am Acad Child Adolesc Psychiatry 1998; 37: 377–85

    Article  PubMed  CAS  Google Scholar 

  45. Emsley RA, Raniwalla J, Bailey PJ, et al. A comparison of the effects of quetiapine and haloperidol in schizophrenic patients with a history of, and a demonstrated, partial response to conventional antipsychotic treatment. Int J Psychopharmacol. In press

  46. Meltzer HY Risperidone and clozapine for treatment-resistantschizophrenia [letter]. Am J Psychiatry 1999; 156(7): 1126–7

    PubMed  CAS  Google Scholar 

  47. Rubin E. Risperidone and clozapine for treatment-resistant schizophrenia [letter]. Am J Psychiatry 1999; 156(7): 1127

    PubMed  CAS  Google Scholar 

  48. Dunayevich E, Chatterjee A. Risperidone and clozapine for treatment-resistantschizophrenia [letter]. Am J Psychiatry 1999;156(7): 1127

    PubMed  CAS  Google Scholar 

  49. Meltzer HY. Duration of a clozapine trial in neuroleptic-resistant schizophrenia [letter]. Arch Gen Psychiatry 1989; 46(7): 672

    Article  PubMed  CAS  Google Scholar 

  50. May PS, Dencker J, Hubbard K, et al. A systematic approach to treatment resistance in schizophrenic disorders. In: Dencker SJ, Kulhanek F, editors. Treatment resistance in schizophrenia. Wiesbaden: Vieweg, Branschweig, 1988: 22–3

    Google Scholar 

  51. Stanilla JK, de Leon J, Simpson GM. Clozapine withdrawalresulting in delirium with psychosis: a report of three cases. J Clin Psychiatry 1997; 58: 252–5

    Article  PubMed  CAS  Google Scholar 

  52. Klieser E, Lehman E, Kinzler E, et al. Randomised, double blind controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol 1995; 15 Suppl. 1: 45S–51S

    Article  PubMed  CAS  Google Scholar 

  53. Small JG, Miller MJ, Klapper MH. Risperidone versus clozapine in chronic schizophrenia [abstract no. NR724]. Poster presented at the annual meeting of the American Psychiatric Association: 1994 May; Philadelphia (PA)

  54. Daniel DG, Weinberger DR, Kleinman JE, et al. Risperidone versus clozapine in psychosis [abstract no. NR356]. Poster presented at the annual meeting of the American Psychiatric Association: 1994 May; Philadelphia (PA)

  55. Tollefson GD, Beasley-CM J, Tran PV, et al. Olanzapine versushaloperidol in the treatment of schizophrenia and schizoaffectiveand schizophreniform disorders: results of an internationalcollaborative trial. Am J Psychiatry 1997; 154(4): 457–65

    PubMed  CAS  Google Scholar 

  56. Pickar D, Owen RR, Litman RE, et al. Clinical and biologicresponse to clozapine in patients with schizophrenia. Crossovercomparison with fluphenazine. Arch Gen Psychiatry 1992;49(5): 345–53

    Article  CAS  Google Scholar 

  57. Frazier JA, Gordon CT, McKenna K, et al. An open trial ofclozapine in 11 adolescents with childhood-onset schizophrenia.J Am Acad Child Adolesc Psychiatry 1994; 33: 658–63

    Article  PubMed  CAS  Google Scholar 

  58. Szigethy E, Brent S, Findling RL. Quetiapine for refractoryschizophrenia. J Am Acad Child Adolesc Psychiatry 1998; 37: 1127–8

    Article  PubMed  CAS  Google Scholar 

  59. Chincilla A, Vega M, Cebollada A, et al. A long term treatmentwith seroquel (quetiapine) in a severe schizophrenia patient.Eur Neuropsychopharmacol 1997; 7 Suppl. 2: S198–S199

    Article  Google Scholar 

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Acknowledgements

The author is partially supported by the Medical Research Council of South Africa.

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  1. Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa

    Robin A. Emsley

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Correspondence to Robin A. Emsley.

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Emsley, R.A. Role of Newer Atypical Antipsychotics in the Management of Treatment-Resistant Schizophrenia. Mol Diag Ther 13, 409–420 (2000). https://doi.org/10.2165/00023210-200013060-00003

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