CORRESPONDENCE
visits by UK lecturers to teach on the course. Another masters degree in community medicine is supported by a German non-governmental organisation and aims to train doctors for district hospitals. Students spend 3 years working in hospital departments and district hospitals, and at the end of the course they are able to provide a broad range of services in isolated hospitals where they will often be the only doctor on call. Kavalier rightly praised the positive attitude of the students; this enthusiasm still characterises our students who undertake much of the ward work, including lumbar punctures, suturing, and dressings. They are conscientious and enthusiastic in the face of daily obstacles to their learning, and possess clinical knowledge comparable to students in the UK. A lot has changed in the past 4 years, and there is still much to do. An infectious enthusiasm exists among the doctors and medical students and, given appropriate support, we believe that Mbarara University Teaching Hospital is sure to succeed in the future. Tristan Lench, *Yasmin Ismail Departments of Surgery and *Internal Medicine, Mbarara University Teaching Hospital, Uganda (e-mail:
[email protected]) 1
Kavalier F. Uganda: death is always just around the corner. Lancet 1998; 352: 141–42.
–759C/T genetic variation of 5HT2C receptor and clozapine-induced weight gain Sir—G P Reynolds and colleagues (June 15, p 2086)1 report an association between antipsychoticdrug-induced weight gain and carriage of the 5-hydroxytryptamine type 2C (5HT2C) receptor gene polymorphism (–759C/T) for Han Chinese patients. They show significantly less weight gain for patients with the –759C/T allele than for those without. This finding is in line with animal studies, in which the 5HT2C receptor plays a major role in feeding control and satiety.2 We have investigated several polymorphisms of genes related to 5HT neurotransmission, including the 5HT2C 68G/C polymorphism in Chinese patients, but noted no association between these genetic variants and clozapine-induced
1790
BMI Initial (kg/m2)
Change (kg/m2)
Percentage change (%)
All patients Wild type 22·3 (3·6) 0·82 (1·53) 4·0 (7·1) (n=67) Variants 22·5 (4·9) 0·59 (2·60) 4·1 (11·1) (n=13) p 0·82 0·67 0·97 Men Wild type (n=47) Variants (n=5) p Women Wild type (n=20) Variants (n=8) p
22·3 (3·6) 0·70 (1·53) 3·5 (7·6) 22·0 (5·6) –0·16 (3·47) 1·8 (12·5) 0·88
0·62
0·66
22·2 (3·9) 1·10 (1·28) 5·2 (5·7) 22·8 (4·8) 1·06 (2·01) 5·6 (10·7) 0·70
0·94
0·90
Variant (759T) is hemizygote in men, heterozygote in women.
Mean (SD) change in BMI after 4 months of clozapine treatment
weight gain.3 We did not test for an association with the 5HT2C 68G/C polymorphism since only one patient had the 5-HT2C 68C allele. However, in a white population, Rietschel and colleagues4 reported no association between that polymorphism and clozapine-induced weight gain. Reynolds and colleagues investigate mostly chlorpromazine and risperidone. Clozapine is the most effective antipsychotic, but it has the largest associated weight gain. Therefore, we investigated the relation between the 5HT2C –759C/T polymorphism and clozapine-induced weight gain in a Chinese population of 80 ethnic Han Chinese schizophrenic or schizoaffective patients (52 men, 28 women; mean age 36·7 years [SD 8·4]) treated with clozapine. We measured bodyweight before and after 4 months of clozapine treatment. Genotyping of the 5HT2C –759C/T polymorphism was done according to a previously described method.5 Patients gained a mean of 2·1 kg (SD 4·7), or 4%, of their baseline bodyweight, after 4 months. We saw no association between change in body-mass index (BMI) and carriage of the 5HT2C –759C/T genotype (table). In analysis of BMI change as the dependent variable, and age, sex, duration of antipsychotic treatment, baseline BMI, drug dose, and 5HT2C genotype as predictor variables, only initial BMI had a significant effect on BMI change (p=0·001). Although a higher proportion of patients with the variant genotype exceeded the weight-gain
cut-off criterion of 7% or more than those with the wild-type genotype (39 vs 30%), this result was not significant. Bodyweight change after antipsychotic treatment is related to initial BMI but not carriage of the –759C/T polymorphism. 5HT2C There are several possible explanations for the discrepancy between our findings and those of Reynolds and colleagues, the most plausible of which include the possibility of false-positive or falsenegative findings, and differences in the type of antipsychotic medication used. In addition, Reynolds and colleagues’ sample consisted entirely of first-episode schizophrenic patients, whereas our patients were treatment-resistant individuals who had already received high doses of traditional antipsychotics. A tendency to bodyweight change may, therefore, have already been triggered. The predictive validity for the 5HT2C –759C/T polymorphism for antipsychotic-induced weight gain needs to be assessed further. *Shih-Jen Tsai, Chen-Jee Hong, Younger W-Y Yu, Ching-Hua Lin *Department of Psychiatry, Veterans General Hospital, 11217 Taipei, Taiwan; Division of Psychiatry, School of Medicine, National YangMing University, Taipei; Yu’s Psychiatric Clinic, Kaohsiung; Kai-Suan Psychiatric Hospital, Kaohsiung, Taiwan (e-mail:
[email protected]) 1
2
3
4
5
Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359: 2086–87. Halford JC, Lawton CL, Blundell JE. The 5-HT2 receptor agonist MK-212 reduces food intake and increases resting but prevents the behavioural satiety sequence. Pharmacol Biochem Behav 1997; 56: 41–46. Hong CJ, Lin CH, Yu YW, Yang KH, Tsai SJ. Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics 2001; 11: 265–68. Rietschel M, Naber D, Fimmers R, Moller HJ, Propping P, Nothen MM. Efficacy and side-effects of clozapine not associated with variation in the 5-HT2C receptor. Neuroreport 1997; 8: 1999–2003. Yuan X, Yamada K, IshiyamaShigemoto S, Koyama W, Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia 2000; 43: 373–76.
Sir—We attempted to replicate in clozapine-treated patients the finding of an association between the 5HT2C –759C/T promoter polymorphism and antipsychotic-induced weight
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