Drug Safety

, Volume 22, Issue 3, pp 195–214 | Cite as

Tolerability of Atypical Antipsychotics

Review Article


Atypical antipsychotics are expected to be better tolerated than older antipsychotics because of their lower propensity to cause certain adverse effects. All atypical drugs have been shown to cause fewer acute extrapyramidal symptoms (EPS) than a standard typical agent (usually haloperidol) and some (clozapine, sertindole and quetiapine) appear to cause these effects no more often than placebo. In the longer term, clozapine, olanzapine and (less robustly) other atypical antipsychotics are thought to cause less tardive dyskinesia than typical antipsychotics. Problems caused by hyperprolactinaemia occur less often with some atypical antipsychotics than with typical drugs although risperidone and amisulpride appear to have no advantages in this respect.

Other adverse effects may occur as frequently with some atypical antipsychotics as with some typical drugs. Clozapine, risperidone and quetiapine are known to cause postural hypotension; clozapine, olanzapine and quetiapine are clearly sedative; and anticholinergic effects are commonly seen with clozapine, and, much less frequently, with olanzapine. Some adverse effects are more frequent with atypical drugs. Idiosyncratic effects seem particularly troublesome with clozapine and, to a lesser extent, sertindole, olanzapine and zotepine. Bodyweight gain is probably more problematic with atypical antipsychotics than with typical drugs.

Overall tolerability, as judged by withdrawals from therapy, is not clearly proven to be better with atypical drugs, although some individual trials do indicate an advantage with atypical agents. Differences in tolerability between individual atypical antipsychotics have not been clearly shown.

The tolerability profile of atypical drugs certainly benefits from a lower incidence of acute EPS effects, along with less certain or less uniform benefits in symptomatic hyperprolactinaemia or tardive dyskinesia. Other, perhaps more trivial, adverse effects militate against their good tolerability, and effects such as bodyweight gain may severely reduce tolerability. Without clear advantages in tolerability in patient groups used in trials, drug choice in regard to adverse effects should continue to be on a patient to patient basis.


Haloperidol Clozapine Risperidone Olanzapine Quetiapine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Day JC, Kinderman P, Bentall R. A comparison of patients’and prescribers’ beliefs about neuroleptic side-effects: prevalence, distress and causation. Acta Psychiatr Scand 1998; 97: 93–7PubMedCrossRefGoogle Scholar
  2. 2.
    Kane J, Honigfield G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic — a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–96PubMedCrossRefGoogle Scholar
  3. 3.
    Naber D, Hippius H. The European experience with use of clozapine. Hosp Community Psychiatry 1990; 41 (8): 886–91PubMedGoogle Scholar
  4. 4.
    Clozapine Study Group. The safety and efficacy of clozapine in severe treatment-resistant schizophrenic patients in the UK. Br J Psychiatry 1993; 163: 150–4CrossRefGoogle Scholar
  5. 5.
    Lieberman JA, Safferman AZ, Pollack S, et al. Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994; 151: 1744–52PubMedGoogle Scholar
  6. 6.
    Klieser E, Lehmann E, Kinzler E, et al. Randomised, doubleblind, controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol 1995; 15 Suppl. 1: 45S–51SPubMedCrossRefGoogle Scholar
  7. 7.
    Rosenheck R, Cramer J, XuW, et al. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997; 337: 809–15Google Scholar
  8. 8.
    Hong CJ, Chen JY, Chiu HJ, et al. A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia. Int Clin Psychopharmacol 1997; 12: 123–30PubMedCrossRefGoogle Scholar
  9. 9.
    Blin O, Azorin JM, Bouhours P. Antipsychotic and anxiolytic properties of risperidone, haloperidol and methotrimeprazine in schizophrenic patients. J Clin Psychopharmacol 1996; 16 (1): 38–44PubMedCrossRefGoogle Scholar
  10. 10.
    Chouinard G, Jones B, Remington G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13 (1): 25–40PubMedCrossRefGoogle Scholar
  11. 11.
    Huttunen MO, Piepponen T, Rantanen H, et al. Risperidone versus zuclopenthixol in the treatment of acute schizophrenic episodes: a double-blind parallel-group trial. Acta Psychiatr Scand 1995; 91: 271–7PubMedCrossRefGoogle Scholar
  12. 12.
    Claus A, Bollen J, De Cuyper H, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study. Acta Psychiatr Scand 1992; 85: 295–305PubMedCrossRefGoogle Scholar
  13. 13.
    Peuskens J and the Risperidone Study Group. Risperidone in the treatment of patients with chronic schizophrenia: a multinational, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995; 166: 712–26CrossRefGoogle Scholar
  14. 14.
    Zimbroff DL, Kane JM, Tamminga CA, et al. Controlled, doseresponse study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 1997; 154: 782–91PubMedGoogle Scholar
  15. 15.
    Tran PV, Hamilton SH, Kuntz AJ, et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997 Oct; 17 (5): 407–18PubMedCrossRefGoogle Scholar
  16. 16.
    Conley RR, Brecher M, and the Risperidone/Olanzapine Study Group. Risperidone versus olanzapine in patientswith schizophrenia or schizoaffective disorder [poster]. 11th Congress of the European College of Neuropsychopharmacology, Sept, Paris, 1998Google Scholar
  17. 17.
    Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol — acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14: 111–23PubMedCrossRefGoogle Scholar
  18. 18.
    Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997; 154: 457–6PubMedGoogle Scholar
  19. 19.
    Borison RL, Arvanitis LA, Miller BG, et al. ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996; 16 (2): 158–69PubMedCrossRefGoogle Scholar
  20. 20.
    Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia — a high- and low-dose double-blind comparison with placebo. Arch Gen Psychiatry 1997; 54: 549–57PubMedCrossRefGoogle Scholar
  21. 21.
    Peuskens J, Link CGG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96: 265–73PubMedCrossRefGoogle Scholar
  22. 22.
    Arvanitis LA, Miller BG, the Seroquel Trial 13 Study Group. Multiple fixed doses of ‘Seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997; 42: 233–46PubMedCrossRefGoogle Scholar
  23. 23.
    Loo H, Poirier-Littre M-F, Theron M, et al. Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 1997; 170: 18–22PubMedCrossRefGoogle Scholar
  24. 24.
    Freeman HL. Amisulpride compared with standard neuroleptics in acute exacerbations of schizophrenia: three efficacy studies. Int Clin Psychopharmacol 1997; 12 Suppl. 2: S11–7CrossRefGoogle Scholar
  25. 25.
    Puech A, Fleurot O, Rein W, and the Amisulpride Study Group. Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose ranging study vs haloperidol. Acta Psychiatr Scand 1998; 98: 65–72PubMedCrossRefGoogle Scholar
  26. 26.
    Daniel D, Reeves K, Harringan EP. The efficacy and safety of ziprasidone 80 mg/day and 160 mg/day in schizophrenia and schizoaffective disorder (poster presented at the 35th ACNP 1996 and the 6th ICSR 1997). Schizophr Res 1997; 24 (1,2): 77Google Scholar
  27. 27.
    Goff DC, Posever T, Herz L. An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 1998; 18 (4): 296–304PubMedCrossRefGoogle Scholar
  28. 28.
    Keck Jr P, Buffenstein A, Ferguson J, et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial. Psychopharmacology 1998; 140: 173–84PubMedCrossRefGoogle Scholar
  29. 29.
    Barnas C, Stuppäck CH, Miller C, et al. Zotepine in the treatment of schizophrenic patients with prevailingly negative symptoms: a double-blind trial vs haloperidol. Int Clin Psychopharmacol 1992; 7: 23–7PubMedCrossRefGoogle Scholar
  30. 30.
    Petit M, Raniwalla J, Tweed J. A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial. Psychopharmacol Bull 1996; 3 (1): 81–7Google Scholar
  31. 31.
    Breier A, Buchanan RW, Kirkpatrick B, et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994; 151: 20–6PubMedGoogle Scholar
  32. 32.
    Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–35PubMedGoogle Scholar
  33. 33.
    Sramek JJ, Mack RJ, Awni W, et al. Two rapid-dose titrations of sertindole in patients with schizophrenia. J Clin Psychopharmacol 1997; 17 (5): 419–22PubMedCrossRefGoogle Scholar
  34. 34.
    Speller JC, Barnes TRE, Curson DA, et al. One-year, low-dose neuroleptic study of in-patients with chronic schizophrenia characterised by persistent negative symptoms — amisulpride v haloperidol. Br J Psychiatry 1997; 171: 564–8PubMedCrossRefGoogle Scholar
  35. 35.
    Gunn KP, Harringan EP, Heym J. The safety and tolerability of ziprasidone treatment. In: Brunello N, Racagni G, Langer SZ, et al., editors. Critical issues in the treatment of schizophrenia. Basel: Karger, 1995; Vol. 10: 172–7Google Scholar
  36. 36.
    Casey DE. Side effect profiles of new antipsychotic agents. J Clin Psychiatry 1996; 57 Suppl. 11: 40–5PubMedGoogle Scholar
  37. 37.
    Casey DE. The relationship of pharmacology to side effects. J Clin Psychiatry 1997; 58 Suppl. 10: 55–62PubMedGoogle Scholar
  38. 38.
    Crawford AMK, Beasley Jr, CM, Tollefson GD. The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations. Schizophr Res 1997; 26: 41–54PubMedCrossRefGoogle Scholar
  39. 39.
    Olesen OV, Thomsen K, Jensen PN. Clozapine serumlevels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study. Psychopharmacology 1995; 117: 371–8PubMedCrossRefGoogle Scholar
  40. 40.
    Tandon R, Harrigan E, Zorn SH. Ziprasidone: a novel antipsychotic with unique pharmacology and therapeutic potential. J Serotonin Res 1997; 4: 159–77Google Scholar
  41. 41.
    Umbricht DSG, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994; 55 (9 Suppl. B): 157–60PubMedGoogle Scholar
  42. 42.
    Frankenburg FR, Zanarini MC, Kando J, et al. Clozapine and body mass change. Biol Psychiatry 1998; 43: 520–4PubMedCrossRefGoogle Scholar
  43. 43.
    Lee AM, Knoll IV, JL, Suppes T. The atypical antipsychotic sertindole: a case series. J Clin Psychiatry 1997; 58 (9): 410–6PubMedCrossRefGoogle Scholar
  44. 44.
    Allison DB, Mentore JL, Heo M, et al. Weight gain associated with conventional and newer antipsychotics [poster 30]. The American Psychiatric Association Conference, 1998Google Scholar
  45. 45.
    Alphs LD, Meltzer HY, Bastani B, et al. Side effects of clozapine and their management. In: Meltzer HY, Hippius H, editors. Symposiumatypical antipsychotics: clinical advantages. Pharmacopsychiatry 1991; 24 (2): 46Google Scholar
  46. 46.
    Gerlach J, Peacock L. Motor and mental side effects of clozapine. J Clin Psychiatry 1994; 55 (9 Suppl. B): 107–9PubMedGoogle Scholar
  47. 47.
    Daniel DG, Goldberg TE,Weinberger DR. Different side effect profiles of risperidone and clozapine in 20 outpatients with schizophrenia or schizoaffective disorder: a pilot study. Am J Psychiatry 1996; 153 (3): 417–9PubMedGoogle Scholar
  48. 48.
    Hinze-Selch D,Mullington J,Orth A, et al. Effects of clozapine on sleep: a longitudinal study. Biol Psychiatry 1997; 42: 260–6PubMedCrossRefGoogle Scholar
  49. 49.
    Grohmann R, Rüther E, Sassim N, et al. Adverse effects of clozapine. Psychopharmacology 1989; 99: S101–4CrossRefGoogle Scholar
  50. 50.
    Davis R, Markham A. Ziprasidone. CNS Drugs 1997; 8 (2): 153–9PubMedCrossRefGoogle Scholar
  51. 51.
    Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone and olanzapine in schizophrenia. Am J Psychiatry 1999; 156: 286–93PubMedGoogle Scholar
  52. 52.
    Miller CH, Mohr F, Umbricht D, et al. The prevalence of acute extrapyramidal signs and symptoms in patients treated with clozapine, risperidone, and conventional antipsychotics. J Clin Psychiatry 1998; 59: 69–75PubMedCrossRefGoogle Scholar
  53. 53.
    Simpson G, Lindenmayer J-P. Extrapyramidal symptoms in patients treated with risperidone. J Clin Psychopharmacol 1997; 17: 194–201PubMedCrossRefGoogle Scholar
  54. 54.
    Lindström E, Eriksson B, Hellgren A. Efficacy and safety of risperidone in the long-term treatment of patientswith schizophrenia. Clin Ther 1995; 17 (3): 402–12PubMedCrossRefGoogle Scholar
  55. 55.
    Boyer P, Lecrubier A, Puech J, et al. Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 1995; 166: 68–72PubMedCrossRefGoogle Scholar
  56. 56.
    Tamminga CA, Thaker GK, Moran M, et al. Clozapine in tardive dyskinesia: observations from human and animal model studies. J Clin Psychiatry 1994; 55 (9 Suppl. B): 102–6PubMedGoogle Scholar
  57. 57.
    Spivak B, Mester R, Abesgaus J, et al. Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry 1997; 58: 318–22PubMedCrossRefGoogle Scholar
  58. 58.
    Brecher M, Burks E. Long-term safety of risperidone: results of seven 1-year trials [poster]. The Annual Meeting of the American College of Clinical Pharmacy; 1996 Aug 4–7; Nashville, (TN)Google Scholar
  59. 59.
    Lemmens P, BrecherM, Van Baelen B. Acombined analysis of double-blind studies with risperidone vs placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms. Acta Psychiatr Scand 1999; 99: 160–70Google Scholar
  60. 60.
    Jeste DV, Lacro JP, Palmer B, et al. Incidence of tardive dyskinesia with atypical neuroleptics in older patients. Am J psychiatry 1999; 156: 309–11PubMedGoogle Scholar
  61. 61.
    Lieberman JA, Saltz BL, Johns CA, et al. The effects of clozapine on tardive dyskinesia. Br J Psychiatry 1991; 158: 503–10PubMedCrossRefGoogle Scholar
  62. 62.
    Casey DE. Effects of clozapine therapy in schizophrenic individuals at risk for tardive dyskinesia. J Clin Psychiatry 1998; 59 Suppl. 3: 31–7PubMedGoogle Scholar
  63. 63.
    Tollefson GD, Beasley CM, Tamura RN, et al. Blind, controlled, long-term study of the comparative incidence of treatment- emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997; 154 (9): 1248–54PubMedGoogle Scholar
  64. 64.
    Almeida OP. Olanzapine for the treatment of tardive dyskinesia [letter]. J Clin Psychiatry 1998; 59 (7): 380–1PubMedCrossRefGoogle Scholar
  65. 65.
    Aronowitz JS, Safferman AZ, Lieberman JA. Management of clozapine-induced enuresis [letter]. Am J Psychiatry 1995; 152 (3): 472PubMedGoogle Scholar
  66. 66.
    Fuller MA, Borovicka MC, Jaskiw GE, et al. Clozapine-induced urinary incontinence: incidence and treatment with ephedrine. J Clin Psychiatry 1996; 57: 514–8PubMedCrossRefGoogle Scholar
  67. 67.
    Fritze J, Elliger T. Pirenzepine for clozapine-induced hypersalivation [letter]. Lancet 1995; 346: 1034PubMedCrossRefGoogle Scholar
  68. 68.
    Haring C, Neudorfer C, Schwitzer J, et al. EEG alterations in the patients treatedwith clozapine in relation to plasma levels. Psychopharmacology 1994; 114: 97–100PubMedCrossRefGoogle Scholar
  69. 69.
    Chatterjee A, Safferman AZ. Cellulitis, eosinophilia and unilateral pleural effusion associated with clozapine treatment [letter]. J Clin Psychopharmacol 1997 June; 17 (3): 232–3PubMedCrossRefGoogle Scholar
  70. 70.
    Hummer M, Kurz M, Kurzthaler I, et al. Hepatotoxicity of clozapine. J Clin Psychoparmacol 1997; 17 (4): 314–7CrossRefGoogle Scholar
  71. 71.
    Popli AP, Konicki E, Jurjus GJ, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58 (3): 108–11PubMedCrossRefGoogle Scholar
  72. 72.
    Shammi CM, Remington G. Clozapine-induced necrotizing colitis [letter]. J Clin Psychopharmacol 1997 June; 17 (3): 230–2PubMedCrossRefGoogle Scholar
  73. 73.
    Leo RJ, Kreeger JL, Kim KY. Cardiomyopathy associated with clozapine. Ann Pharmacother 1996; 30: 603–5PubMedGoogle Scholar
  74. 74.
    Ravin DS, Levenson JW. Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother 1997; 31: 867–70PubMedGoogle Scholar
  75. 75.
    Bennett JA, Keck Jr, PE, Wallhausser LJ. Desmopressin for risperidone-induced enuresis. Ann Clin Psychiatry 1994; 6 (2): 139–40PubMedCrossRefGoogle Scholar
  76. 76.
    Deirmenjian JM, Erhart SM, Wirshing DA, et al. Olanzapineinduced reversible priapism: a case report [letter]. J Clin Psychopharmacol 1998; 18 (4): 351–2PubMedCrossRefGoogle Scholar
  77. 77.
    Landry P, Cournoyer J. Acute dystonia with olanzapine [letter]. J Clin Psychiatry 1998; 59 (7): 384PubMedCrossRefGoogle Scholar
  78. 78.
    Jauss M, Schröder J, Pantel J. Severe akathisia during olanzapine treatment of acute schizophrenia [case report]. Pharmacopsychiatry 1998; 31: 146–8PubMedCrossRefGoogle Scholar
  79. 79.
    Atkin K, Kendall F, Gould D, et al. Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland. Br J Psychiatry 1996; 169: 483–8PubMedCrossRefGoogle Scholar
  80. 80.
    Miller DD, Sharafuddin MJA, Kathol RG. Acase of clozapineinduced neuroleptic malignant syndrome. J Clin Psychiatry 1991; 52: 99–101PubMedGoogle Scholar
  81. 81.
    DasGupta K, Young A. Clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry 1991; 52: 105–7PubMedGoogle Scholar
  82. 82.
    Nopoulos P, Flaum M, Miller DD. Atypical neuroleptic malignant syndrome (NMS) with an atypical neuroleptic: clozapine- induced NMS without rigidity. Ann Clin Psychiatry 1990; 3: 251–3CrossRefGoogle Scholar
  83. 83.
    Sharma R, Trappler B, Ng YK, et al. Risperidone-induced neuroleptic malignant syndrome. Ann Pharmacother 1996; 30: 775–8PubMedGoogle Scholar
  84. 84.
    Meterissan GB. Risperidone-induced neuroleptic malignant syndrome: a case report and review. Can J Psychiatry 1996; 41: 52–4Google Scholar
  85. 85.
    Day J. Adherence to antipsychotic medication. In: Taylor D, Paton C, editors. Case studies in psychopharmacology: the use of drugs in psychiatry. London: Martin Dunitz, 1998; 54–9Google Scholar
  86. 86.
    Wolfson PM, Paton C. Clozapine audit: what do patients and relatives think? J Ment Health 1996; 5 (3): 267–73CrossRefGoogle Scholar

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Pharmacy DepartmentMaudsley HospitalLondonEngland

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