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Year : 2009  |  Volume : 55  |  Issue : 4  |  Page : 317

Clozapine producing weight loss: A case series with possible clinical implications - A hypothesis

Department of Psychiatry, Christian Medical College, Vellore - 632 002, Tamil Nadu, India

Date of Web Publication14-Jan-2010

Correspondence Address:
N Thomas
Department of Psychiatry, Christian Medical College, Vellore - 632 002, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0022-3859.58947

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How to cite this article:
Thomas N, Ravan J R, Jebaraj P, Braganza D. Clozapine producing weight loss: A case series with possible clinical implications - A hypothesis. J Postgrad Med 2009;55:317

How to cite this URL:
Thomas N, Ravan J R, Jebaraj P, Braganza D. Clozapine producing weight loss: A case series with possible clinical implications - A hypothesis. J Postgrad Med [serial online] 2009 [cited 2023 Feb 7];55:317. Available from:


Most of the atypical antipsychotic medications are associated with variable weight gain [1] Five patients who were diagnosed to have schizophrenia on the basis of ICD-10 diagnostic criteria were determined to be treatment resistant, as per the guidelines given by Conley and Kelly for drug-refractory condition. [2] Therapy was then initiated with clozapine. However, they failed to respond to clozapine therapy and demonstrated varying weight loss [Table 1].

The atypical antipsychotic clozapine was reintroduced into the UK and USA in 1990, following the demonstration of its efficacy in patients with treatment-resistant schizophrenia. [3] Czobor and colleagues found that the therapeutic response to clozapine and olanzapine therapy correlated with weight gain. This was not the case with the therapeutic response to risperidone and haloperidol. [4] Clinical studies show that 5HT2C receptor gene promoter region polymorphism is associated with antipsychotic drug-induced weight gain and the clinical response to clozapine is partly decided by the polymorphism of 5HT2A and 2C receptor subtypes. [5],[6] In addition, basic science studies have shown that the 5HT2C receptor knocked out mice have hyperphagia and demonstrate significant weight gain. [7] In addition to this, the drug fenfluramine, a 5HT2A/2C receptor partial agonist, is associated with hypophagia and weight loss and gives further evidence that serotonin receptor polymorphism in its gene or in its promoter region are responsible for both decreased clinical efficacy and weight loss. [8] Histamine (H1) receptor antagonism of antipsychotic drugs may also play a role in increased appetite and it depends on the receptor affinity of the antipsychotic drugs. Investigation of 568 variants of promoter gene for histamine 1 and 2 receptor in people with schizophrenia favored the differential effect of different histamine receptor subtypes in clinical response and weight change. [9] Thus, early weight loss with clozapine therapy in patients with treatment-resistant schizophrenia may be a clinical indicator of eventual poor response to clozapine. Well-conducted case control and cohort studies are required to evaluate these hypotheses.

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1.Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999;156:1686-96.   Back to cited text no. 1      
2.Conley RR, Kelly DL. Management of treatment resistance in schizophrenia. Biol Psychiatry 2001;50:898-911.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Kane JM. Clinical efficacy of clozapine in treatment-refractory schizophrenia: An overview. Br J Psychiatry Suppl 1992;17:41-5.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Czobor P, Volavka J, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, et al. Antipsychotic-induced weight gain and therapeutic response: A differential association. J Clin Psychopharmacol 2002;22:244-51.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002;359:2086-7.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Masellis M, Basile V, Meltzer HY, Lieberman JA, Sevy S, Macciardi FM, et al. Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology 1998;19:123-32.  Back to cited text no. 6  [PUBMED]  [FULLTEXT]  
7.Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, Dallman MF, et al. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 1995;374:542-6.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Atchley DP, Eckel LA. Fenfluramine treatment in female rats accelerates the weight loss associated with activity-based anorexia. Pharmacol Biochem Behav 2005;80:273-9.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Mancama D, Arranz MJ, Munro J, Osborne S, Makoff A, Collier D, et al. Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response. Neurosci Lett 2002;33:207-11.  Back to cited text no. 9      


  [Table 1]

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1 Dramatic weight loss associated with commencing clozapine
Lally, J. and McDonald, C.
BMJ Case Reports. 2011;


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