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Letter to the Editor   |    
Clozapine and Weight Gain
FRANK M. THEISEN, M.D.; SVEN CICHON, PH.D.; ANDRÉ LINDEN; MATTHIAS MARTIN, M.D.; HELMUT REMSCHMIDT, M.D., PH.D.; JOHANNES HEBEBRAND, M.D.
Am J Psychiatry 2001;158:816-816. doi:10.1176/appi.ajp.158.5.816

To the Editor: Weight gain is a common side effect of atypical antipsychotics. The mechanisms underlying weight gain are unknown; on the basis of the binding profile of clozapine (1) and other atypical antipsychotics, theories concerning the possible involvement of dopaminergic, serotonergic (5-HT), adrenergic, and/or histaminergic systems have been advanced. In molecular genetic studies, no association was found between specific alleles of dopamine D4(2) and 5-HT2C(3) receptor genes and clozapine-induced weight gain. To date, we know of no systematic formal genetic studies, such as twin studies concerning the influence of genetic factors. This is mainly due to the limited number of affected twin pairs with schizophrenia who have undergone the same antipsychotic treatment. Therefore, respective case reports can provide important insight into the influence of genetic factors on this side effect.

Mr. A and Mr. B were 19-year-old monozygotic (zygosity determined with microsatellite markers [4]) twins concordant for the paranoid type of schizophrenia (per DSM-IV). Before initiation of treatment with antipsychotics, both had a body mass index of 25.2 kg/m2 (Mr. A: 93 kg/192 cm; Mr. B: 92 kg/191 cm). Mr. A, whose antipsychotic treatment was initiated with risperidone (up to 5 mg/day) at age 17.4 years, gained 17 kg during an 11-month period. Mr. B was first treated at age 17.6 years with classic antipsychotics (haloperidol, chlorprothixene, and clopenthixol) for 2 months, during which time he gained 2 kg. Because of an insufficient clinical response, the twins were switched to clozapine (maximal daily doses: 500 mg and 450 mg, respectively), which they had been taking for the past 16 and 22 months, respectively.

With clozapine treatment, Mr. A, who was pretreated with risperidone, gained approximately 20 kg within 9 months. In contrast, Mr. B gained almost 40 kg within 14 months. Both twins maintained a steady body weight of about 132 kg for more than 6 months. Currently, the twins weigh 131 kg (body mass index of Mr. A: 35.5 kg/m2) and 132 kg (Mr. B: 36.2 kg/m2), respectively. Weight gain since the initiation of antipsychotic treatment has totaled 38 kg and 40 kg, respectively. After initiation of clozapine therapy, both twins developed binge eating episodes (two to three per week) that fulfilled the DSM-IV research criteria for binge eating disorder as evaluated by the Questionnaire on Eating and Weight Patterns (5). Both twins reported frequent hunger, consumption of large quantities of food, and lessened satiation.

To our knowledge, this is the first report illustrating that the body weights achieved and maintained with clozapine treatment are similar in a monozygotic twin pair. Despite the fact that the initial weight gain in Mr. A resulted from risperidone, each of the twins gained approximately 40 kg in total. Their similar current body mass indexes suggest that the weight plateau achieved with clozapine depends on the genotype. Our report also substantiates our previous finding that the eating behavior induced by clozapine treatment can fulfill the DSM-IV research criteria for binge eating disorder (6). Further formal genetic studies pertaining to the side effect of weight gain are warranted.

Brunello N, Masotto C, Steardo L, Markstein R, Racagni G: New insights into the biology of schizophrenia through the mechanism of action of clozapine. Neuropsychopharmacology  1995; 13:177–213
[PubMed]
[CrossRef]
 
Rietschel M, Naber D, Oberländer H, Holzbach R, Fimmers R, Eggermann K, Möller HJ, Propping P, Nöthen MM: Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology  1996; 15:491–496
[PubMed]
[CrossRef]
 
Rietschel M, Naber D, Fimmers R, Möller HJ, Propping P, Nöthen MM: Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 1997; 8:1999–  2003
 
Erdmann J, Nöthen MM, Stratmann M, Fimmers R, Franzek E, Propping P: The use of microsatellites in zygosity diagnosis of twins. Acta Genet Med Gemellol (Roma)  1993; 42:45–51
[PubMed]
 
Spitzer RL, Yanovski S, Wadden T, Wing R, Marcus MD, Stunkard A, Devlin M, Mitchell J, Hasin D, Horne RL: Binge eating disorder: its further validation in a multisite study. Int J Eat Disord  1993; 13:137–153
[PubMed]
 
Brömel T, Blum WF, Ziegler A, Schulz E, Bender M, Fleischhaker C, Remschmidt H, Krieg JC, Hebebrand J: Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry  1998; 3:76–80
[PubMed]
[CrossRef]
 
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References

Brunello N, Masotto C, Steardo L, Markstein R, Racagni G: New insights into the biology of schizophrenia through the mechanism of action of clozapine. Neuropsychopharmacology  1995; 13:177–213
[PubMed]
[CrossRef]
 
Rietschel M, Naber D, Oberländer H, Holzbach R, Fimmers R, Eggermann K, Möller HJ, Propping P, Nöthen MM: Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology  1996; 15:491–496
[PubMed]
[CrossRef]
 
Rietschel M, Naber D, Fimmers R, Möller HJ, Propping P, Nöthen MM: Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 1997; 8:1999–  2003
 
Erdmann J, Nöthen MM, Stratmann M, Fimmers R, Franzek E, Propping P: The use of microsatellites in zygosity diagnosis of twins. Acta Genet Med Gemellol (Roma)  1993; 42:45–51
[PubMed]
 
Spitzer RL, Yanovski S, Wadden T, Wing R, Marcus MD, Stunkard A, Devlin M, Mitchell J, Hasin D, Horne RL: Binge eating disorder: its further validation in a multisite study. Int J Eat Disord  1993; 13:137–153
[PubMed]
 
Brömel T, Blum WF, Ziegler A, Schulz E, Bender M, Fleischhaker C, Remschmidt H, Krieg JC, Hebebrand J: Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry  1998; 3:76–80
[PubMed]
[CrossRef]
 
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