Drug Safety

, Volume 24, Issue 1, pp 59–73 | Cite as

Bodyweight Gain with Atypical Antipsychotic

A Comparative Review
  • Tilman WetterlingEmail author
Review Article


The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs.

In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000.

Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight.

The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics.

Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.


Schizophrenia 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.
    Kane JM. What makes an antipsychotic ‘atypical’? CNS Drugs 1997; 7: 947–8CrossRefGoogle Scholar
  2. 2.
    Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999; 60Suppl. 10: S31–S41Google Scholar
  3. 3.
    Kinon BJ, Lieberman JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology 1996; 124: 2–34PubMedCrossRefGoogle Scholar
  4. 4.
    Schotte A, Janssen PFM, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology 1996; 124: 57–73PubMedCrossRefGoogle Scholar
  5. 5.
    Arnt J, Skarsfeldt T. Do novel antipsychotics have similar pharmacological characteristics. Neuropsychopharmacology 1998; 18: 63–101PubMedCrossRefGoogle Scholar
  6. 6.
    Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156(11): 1686–96PubMedGoogle Scholar
  7. 7.
    Bernstein JG. Induction of obesity by psychotropic drugs. Ann N Y Acad Sci 1985; 499: 203–15CrossRefGoogle Scholar
  8. 8.
    Stanton JM. Weight gain associated with neuroleptic medication: a review. Schizophr Bull 1995; 21: 463–72PubMedCrossRefGoogle Scholar
  9. 9.
    Wetterling T, Müssigbrodt HE. Weight gain: side effect of atypical neuroleptics? J Clin Psychopharmacol 1999; 19(4): 316–21PubMedCrossRefGoogle Scholar
  10. 10.
    Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60(6): 358–63PubMedCrossRefGoogle Scholar
  11. 11.
    Allison DB, Fontaine KR, Heo M, et al. The distribution of Body Mass Index among individuals with and without schizophrenia. J Clin Psychiatry 1999; 60(4): 215–20PubMedCrossRefGoogle Scholar
  12. 12.
    Lamperti JS, Bellnier T, Schwarzkopf SB. Weight gain among schizophrenic patients treated with clozapine. Am J Psychiatry 1992; 149(5): 689–90Google Scholar
  13. 13.
    Silverstone T, Smith G, Goodall E. Prevalence of obesity in patients receiving depot antipsychotics. Br J Psychiatry 1988; 153: 214–7PubMedCrossRefGoogle Scholar
  14. 14.
    Kraus T, Haack M, Schuld A, et al. Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 1999; 156(2): 312–4PubMedGoogle Scholar
  15. 15.
    Bondolfi G, Dufour H, Patris M, et al. Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. Am J Psychiatry 1998; 155(4): 499–504PubMedGoogle Scholar
  16. 16.
    Bustillo JR, Buchanan RW, Irish D, et al. Differential effect of clozapine on weight: a controlled study. Am J Psychiatry 1996; 153(6): 817–9PubMedGoogle Scholar
  17. 17.
    John JP, Chengappa KN, Baker RW, et al. Assessment of changes in both weight and frequency of use of medications for the treatment of gastrointestinal symptoms among clozapine-treated patients. Ann Clin Psychiatry 1995; 7(3): 119–25PubMedCrossRefGoogle Scholar
  18. 18.
    Leadbetter R, Shutty M, Pavalonis D, et al. Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 1992; 149(1): 68–72PubMedGoogle Scholar
  19. 19.
    Briffa D, Meehan T. Weight changes during clozapine treatment. Aust N Z J Psychiatry 1998; 32(5): 718–21PubMedCrossRefGoogle Scholar
  20. 20.
    Hummer M, Kemmler G, Kurz M, et al. Weight gain induced by clozapine. Eur Neuropsychopharmacol 1995; 5: 437–40PubMedGoogle Scholar
  21. 21.
    Jalenques I, Coudert AJ. Clozapine et schizophrenies resistantes. Encephale 1994; 20(6): 767–75PubMedGoogle Scholar
  22. 22.
    Spivak B, Musin E, Mester R, et al. The effect of long-term antipsychotic treatment on the body weight of patients suffering from chronic schizophrenia: clozapine versus classical antipsychotic agents. Int Clin Psychopharmacol 1999; 14(4): 229–32PubMedCrossRefGoogle Scholar
  23. 23.
    Leppig M, Bosch B, Naber D, et al. Clozapine in the treatment of 121 out-patients. Psychopharmacology (Berl) 1989; 99Suppl.: S77–S79CrossRefGoogle Scholar
  24. 24.
    Povlsen UU, Noring U, Fog R, et al. Tolerability and therapeutic effect of clozapine. Acta Psychiatr Scand 1985; 71: 176–85CrossRefGoogle Scholar
  25. 25.
    Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 1999; 156(5): 702–9PubMedGoogle Scholar
  26. 26.
    Beasley CM, Sanger T, Satterlee W, et al. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology (Berl) 1996; 124: 159–67CrossRefGoogle Scholar
  27. 27.
    Tollefson GD, Beasley CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schzoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997; 154: 457–65PubMedGoogle Scholar
  28. 28.
    Tran PV, Tollefson GD, Sanger TM, et al. Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Br J Psychiatry 1999; 174: 15–22PubMedCrossRefGoogle Scholar
  29. 29.
    Conley RR, Mahmoud R, the Risperidone study group. Risperidone versus olanzapine in patients with schizophrenic and schizoaffective psychosis [oral presentation]. US Psychiatric and Mental Health Congress; 1999 Nov 11-14; AltantaGoogle Scholar
  30. 30.
    Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry 1999; 60(11): 767–70PubMedCrossRefGoogle Scholar
  31. 31.
    McElroy SL, Frye M, Denicoff K, et al. Olanzapine in treatment-resistant bipolar disorder. J Affect Disord 1998; 49(2): 119–22PubMedCrossRefGoogle Scholar
  32. 32.
    Gupta S, Droney T, Al-Samarrai S, et al. Olanzapine: weight gain and therapeutic efficacy. J Clin Psychopharmacol 1999; 19(3): 273–5PubMedCrossRefGoogle Scholar
  33. 33.
    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; 17: 407–18PubMedCrossRefGoogle Scholar
  34. 34.
    Beasley Jr CM, Tollefson GD, Tran PV. Safety of olanzapine. J Clin Psychiatry 1997; 58Suppl. 10: S13–S17Google Scholar
  35. 35.
    Borison R, Arvanitis LA, Miller BG, et al. USS 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
  36. 36.
    Copolov DL, Link CGG, Kowalcyk B. A comparison of quetiapine (ICI 204,636, ‘Seroquel’) and haloperidol in schizophrenia. Psychol Med 2000; 30: 95–105PubMedCrossRefGoogle Scholar
  37. 37.
    Peukens J, Link CGG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96: 265–73CrossRefGoogle Scholar
  38. 38.
    Arivanitis LA, Miller BG, and the Seroquel trial 13 study group. Multiple fixed doses of ‘Seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: Acomparison with haloperidol and placebo. Biol Psychiatry 1997; 42(4): 233–46CrossRefGoogle Scholar
  39. 39.
    Small JG, Hirsch SR, Arvantis LA, et al. Quetiapine in patients with schizophrenia. Arch Gen Psychiatry 1997; 54(6): 549–57PubMedCrossRefGoogle Scholar
  40. 40.
    King DJ, Link CGG, Kowalcyk B. A comparison of bd and tid dose regimens of quetiapine (Seroquel) in the treatment of schizophrenia. Psychopharmacology 1998; 137(2): 139–46PubMedCrossRefGoogle Scholar
  41. 41.
    Emsley RA, Ranwalla J, Bailey PJ, et al. A comparison of the effects of quetiapine (‘Seroquel’) and haloperidol in schizophrenic patients with a history of and a demostrated, partial response to conventional antipsychotic treatment. Int Clin Psychopharmacol 2000, 15: 121–31PubMedCrossRefGoogle Scholar
  42. 42.
    Peukens J, Risperidone Study Group. Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995; 166: 712–26CrossRefGoogle Scholar
  43. 43.
    Anderson C, Clark WR, True J, et al. Risperidone, a novel antipsychotic, and weight change [letter]. Pharmacotherapy 1993; 13: 292Google Scholar
  44. 44.
    Höyberg OJ, Fensbo C, Remvig J, et al. Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations. Acta Psychiatr Scand 1993; 88: 395–402PubMedCrossRefGoogle Scholar
  45. 45.
    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
  46. 46.
    Lott RS, Kerrick JM, Cohen SA. Clinical and economic aspects of risperidone treatment in adults with mental retardation and behavioral disturbance. Psychopharmacol Bull 1996; 32(4): 721–9PubMedGoogle Scholar
  47. 47.
    Csernansky J, Okamoto A, Brecher M. Risperidone vs. haloperidol as relapse prevention in schizophrenic and schizoaffective disorders [poster]. American Psychiatric Association Congress; 1999 May 15-20; Washington, DCGoogle Scholar
  48. 48.
    Daniel DG, Zimbroff DL, Potkin SG, et al. Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 1999; 20(5): 491–505PubMedCrossRefGoogle Scholar
  49. 49.
    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 (Berl) 1998; 140(2): 173–84CrossRefGoogle Scholar
  50. 50.
    Petit M, Raniwalla J, Tweed J, et al. Acomparison 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; 32; 81–7PubMedGoogle Scholar
  51. 51.
    Cohen S, Chiles J, MacNaughton A. Weight gain associated with clozapine. Am J Psychiatry 1990; 147(4): 503–4PubMedGoogle Scholar
  52. 52.
    Norris DL, Israelstam K. Clozapine (Leponex) overdosage [letter]. S Afr Med J 1975; 49: 385PubMedGoogle Scholar
  53. 53.
    Umbricht DS, Pollack S, Kane JM. Clozapine and weight gain. J Clin Psychiatry 1994; 55Suppl. B: S157–S60Google Scholar
  54. 54.
    Beasley CM, Tollefson G, Tran P, et al. Olanzapine versus placebo and haloperidol. Neuropsychopharmacology 1996; 14: 111–23PubMedCrossRefGoogle Scholar
  55. 55.
    Potenza MN, Holmes JP, Kanes SJ, et al. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol 1999; 19(1): 37–44PubMedCrossRefGoogle Scholar
  56. 56.
    Martin A, Koenig K, Scahill L, et al. Open-label quetiapine in the treatment of children and adolescents with autistic disorder. J Child Adolesc Psychopharmacol 1999; 9(2): 99–107PubMedCrossRefGoogle Scholar
  57. 57.
    Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord 1997; 27(3): 313–23PubMedCrossRefGoogle Scholar
  58. 58.
    Findling RL, Maxwell K, Wiznitzer M. An open clinical trial of risperidone monotherapy in young children with autistic disorder. Psychopharmacol Bull 1997, 33(1): 155–9PubMedGoogle Scholar
  59. 59.
    Lombroso PJ, Scahill L, King RA, et al. Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. J Am Acad Child Adolesc Psychiatry 1995; 34(9): 1147–52PubMedCrossRefGoogle Scholar
  60. 60.
    Kelly DL, Conley RR, Love RC, et al. Weight gain in adolescents treated with risperidone and conventional antipsychotics over six months. J Child Adolesc Psychopharmacol 1998; 8(3): 151–9PubMedCrossRefGoogle Scholar
  61. 61.
    McDougle CJ, Holmes JP, Bronson MR, et al. Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study. J Am Acad Child Adolesc Psychiatry 1997; 36(5): 685–93PubMedCrossRefGoogle Scholar
  62. 62.
    Szigethy E, Wiznitzer M, Branicky LA, et al. Risperidone-induced hepatotoxicity in children and adolescents? Achart review study. J Child Adolesc Psychopharmacol 1999; 9(2): 93–8PubMedCrossRefGoogle Scholar
  63. 63.
    Ceskova E, Svestka J. Double-blind comparison of risperidone and haloperidol in schizophrenic and schizoaffective psychoses. Pharmacopsychiatry 1993; 26: 121–4PubMedCrossRefGoogle Scholar
  64. 64.
    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
  65. 65.
    Klieser E, Lehmann E, Kinzler E, et al. Randomized, double-blind, controlled trial of risperidone versus clozapine in patients with chronic schizophrenia. J Clin Psychopharmacol 1995; 15Suppl. 1: S45–S51CrossRefGoogle Scholar
  66. 66.
    Song F. Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials. J Psychopharmacol 1997; 11(1): 65–71PubMedCrossRefGoogle Scholar
  67. 67.
    Wetterling T, Müssigbrodt H. Gewichtszunahme- eine Nebenwirkung von Nipolept (Zotepin)? Nervenarzt 1996; 67: 256–61PubMedGoogle Scholar
  68. 68.
    Gopalaswamy AK, Morgan R. Too many chronic mentally disabled patients are too fat. Acta Psychiatr Scand 258; 72: 254–8Google Scholar
  69. 69.
    Remington G, Kapur S. D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET. J Clin Psychiatry 1999; 60Suppl. 10: S15–S19Google Scholar
  70. 70.
    Blundell JE. Serotonin and appetite. Neuropharmacology 1984; 23: 1537–51PubMedCrossRefGoogle Scholar
  71. 71.
    Leibowitz SF. The role of serotonin in eating disorders. Drugs 1990; 39Suppl. 3: S33–S48CrossRefGoogle Scholar
  72. 72.
    Wurtman JJ, Wurtman RJ, Growdon JH, et al. Carbohydrate craving in obese people: suppression by treatments affecting serotoninergic transmission. Int J Eat Disord 1981; 1: 2–11CrossRefGoogle Scholar
  73. 73.
    Darga LL, Carroll-Michals L, Botsford SJ, et al. Fluoxetine’s effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54: 321–5PubMedGoogle Scholar
  74. 74.
    Garattini S, Caccia S, Mennini T, et al. Biochemical pharmacology of the anorectic drug fenfluramine: a review. Curr Med Res Opin 1987; 1: 15–27Google Scholar
  75. 75.
    Aulakh CS, Hill JL, Yoney HAT, et al. Evidence of involvement of 5-HT1c and 5-HT2 receptors in the food intake suppressant effects of 1-(2,5-dimethoxy-iodophenyl)-2-amidopropane (DOI). Psychopharmacology 1992; 109: 444–8PubMedCrossRefGoogle Scholar
  76. 76.
    Tecott LH, Sun M, Akana SF, et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 1995; 374: 542–6PubMedCrossRefGoogle Scholar
  77. 77.
    Popli AP, Konicki PE, Jurjus GJ, et al. Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997; 58(3): 108–11PubMedCrossRefGoogle Scholar
  78. 78.
    Wirshing DA, Spellberg BJ, Erhart SM, et al. Novel antipsychotics and new onset diabetes. Biol Psychiatry 1998; 44: 778–83PubMedCrossRefGoogle Scholar
  79. 79.
    Melkersson KI, Hulting AL, Brismar KE. Different influences of classical antipsychotics and clozapine on glucose-insulin homeostasis in patients with schizophrenia or related psychoses. J Clin Psychiatry 1999; 60(11): 783–91PubMedCrossRefGoogle Scholar
  80. 80.
    Hagg S, Joelson L, Mjorndal T, et al. Prevalence of diabetes and impaired glucose tolerance in patients treated with conventional depot neuroleptic medications. J Clin Psychiatry 1998; 59: 294–9PubMedCrossRefGoogle Scholar
  81. 81.
    Brömel T, Blum WF, Ziegler A, et al. Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry 1998; 3: 76–80PubMedCrossRefGoogle Scholar
  82. 82.
    Hughes JR, Hatsukami DK, Mitchell JE, et al. Prevalence of smoking among psychiatric outpatients. Am J Psychiatry 1986; 143: 993–7PubMedGoogle Scholar
  83. 83.
    George TP, Sernyak MJ, Ziedonis DM, et al. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry 1995; 56(8): 344–6PubMedGoogle Scholar
  84. 84.
    McEvoy J, Freudenreich O, McGee M, et al. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry 1995; 37(8): 550–2PubMedCrossRefGoogle Scholar
  85. 85.
    Jalenques I, Tauveron I, Albuisson E, et al. Weight gain as a predictor of long term clozapine efficiency. Clin Drug Invest 1996; 12: 16–25CrossRefGoogle Scholar
  86. 86.
    Howanitz E, Pardo M, Smelson DA, et al. The efficacy and safety of clozapine versus chlorpromazine in geriatric schizophrenia. J Clin Psychiatry 1999; 60(1): 41–4PubMedCrossRefGoogle Scholar
  87. 87.
    Bapista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand 1999; 100: 3–16CrossRefGoogle Scholar
  88. 88.
    Goodall E, Oxtoby C, Richards R, et al. Clinical trial of the efficacy and acceptability of D-fenfluramine in the treatment of neuroleptic-induced obesity. Br J Psychiatry 1988; 153: 208–13PubMedCrossRefGoogle Scholar
  89. 89.
    National Institute of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults — the evidence report. Obes Res 1998; 6 Suppl. 2: S51–S209Google Scholar
  90. 90.
    Willett WC, Manson JE, Stampler MJ, et al. Weight, weight change, and coronary heart disease in women: risk within the ‘normal’weight range. JAMA 1995; 273: 461–5PubMedCrossRefGoogle Scholar
  91. 91.
    Fenton WS, Blyler CF, Heinssen PK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997; 23: 637–51PubMedCrossRefGoogle Scholar
  92. 92.
    Vestergaard P, Amidsen A, Schou M. Clinically significant side-effects of lithium treatment. Asurvey of 237 patients in long-term treatment. Acta Psychiat Scand 1980; 62: 193–200PubMedCrossRefGoogle Scholar
  93. 93.
    Gaebel W. Towards the improvement of compliance: the significance of psycho-eduction and new antipsychotic drugs. Int Clin Psychopharmacol 1997; 12Suppl. 1: S537–S44Google Scholar

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© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Psychiatry and Psychotherapy IJohann Wolfgang Goethe UniversityFrankfurt/MainGermany

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