Genetic Predictors And Preventing Methods In Antipsychotic Induced Weight Gain

Objective:To test the Genetic predictors and preventing methods in antipsychotic induced weight gain.(1) To determine associations between weight gain induced by antipsychotic and the polymorphisms of HTR2C gene -759C/T and -697G/C, histamine-1 receptor gene, leptine gene -2548G/A, and adiponectin gene +276G/T and +45T/G.(2) To test the efficacy of lifestyle intervention and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity.(3) To assess the efficacy of metformin in preventing olanzapine-induced weight gain and glucose metabolic dysfunction.Method:(1) It is a case-matched controlled study. 85 patients who had weight gain more than 7% of their pre-drug body weight were divided as study group and 85 patients who had weight gain less than 7% of their pre-drug body weight were divided as control group. The patients of control group were matched with that of study group in the kinds of antipsychotic and duration of antipsychotic treatment. The ligation detection reaction technique was used to analysis the frequencies of all gene polymorphisms.(2) One hundred and twenty eight schizophrenic patients who have weight gain more than 10% of their pre-drug body weight were divided into one of four 12-week individual treatments: lifestyle intervention plus metformin (750mg/d), metformin (750mg/d), lifestyle intervention plus placebo or placebo. Before and after four-week, eight-week and twelve-week treatment, the height, body weight, waist circumference, and the fasting blood glucose and insulin were measured. In addition, the body mass index (BMI) and insulin resistance index (IRI) were calculated.(3) 37 drug-naive schizophrenic patients were randomly divided to the treatment for 12-week either with olanzapine (15 mg/d) plus metformin (750 mg/d) (n=18) or olanapine (15 mg/d) plus placebo (n=19). Planned assessments included body weight, body mass index (BMI), the proportion of patients gained more than 7% at the end of the 12-week treatment, waist circumference, hip circumference, waist-hip-ratio (WHR), fasting glucose and insulin, insulin resistance index (IRI), the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS). Results:(1) The patients in study group were more likely to be homozygous for the -759C hemizygote (for male) and -759CC genotype. The presence of the -759C was significantly higher in subjects of study group compared to those in control group. The patients with -759C were higher risk to gain weight than those with -759T after antipsychotic treatment.(2) The patients in study group were more likely to be homozygous for the -697G hemizygote (for male) and -697CG/GG genotype. The presence of the -697G was significantly higher in subjects of study group compared to those in control group. The patients with -697G were higher risk to gain weight than those with -697G after antipsychotic treatment.(3) The 170 patients were homozygous for glu349asp TT genotype in histamine-1 receptor gene.(4) The patients in study group were more likely to be homozygous for AA genotype of leptin gene. The presence of the A variant allele of leptin gene was significantly higher in subjects of study group compared to those in control group. The patients with AA of leptin gene were higher risk to gain weight than those with AG and GG of leptin gene after antipsychotic treatment.(5) The patients in study group were more likely to be homozygous for +276GG genotype. The presence of the +276G was significantly higher in subjects of study group compared to those in control group. The patients with +276GG and +276GT were higher risk to gain weight than those with +276TT after antipsychotic treatment.(6) there were no significant difference between the study group and control group in the frequent of +45T allele and +45TT genotype.(7) After treatment, the weight, BMI, waist circumference, insulin, fasting glucose and IRI levels decreased significantly in the lifestyle intervention plus metformin, metformin and lifestyle intervention plus placebo groups and increased in the placebo group. At week 4, the decreases in weight and BMI values were not significantly different between lifestyle intervention plus metformin and metformin groups but were significantly lesser in the lifestyle intervention plus placebo group. At week 8 and 12, the decreases of weight and BMI levels from high to low were as follows: lifestyle intervention plus metformin, meformin and lifestyle intervention plus placebo. At week 4, 8 and 12, the decreases of insulin and IRI levels were not significantly different between lifestyle intervention plus metformin and metformin groups but were significantly lesser in the lifestyle intervention plus placebo group.(8) There was a significant increase in body weight and BMI within each group from baseline to week 12 [olanzapine plus metformin(1.90±2.72) kg and (0.54±0.92) kg/m~2; olanzapine plus placebo(6.87±4.23) kg and (2.26±1.12) kg/m~2] (P<0.05) . The increase inweight, BMI, WHR, insulin and IRI values of olanzapine plus placebo group was more than that of olanzapine plus metformin group (P<0.05). Significantly fewer metformin patients [3 (17%)] than placebo patients [12 (65%)] increased their baseline weight by more than 7% (P<0.05) , the cutoff for clinically meaningful weight gain.Conclusions:(1) The -759C/T and -697G/C polymorphisms of the promoter region of 5HT2C receptor gene, -2548A/G polymorphisms of leptin gene and +276G/T polymorphisms of adiponectin gene may be associated with antipsychotic induced weight gain. The glu349asp polymorphisms of histamine-1 receptor gene was not associated with antipsychotic induced weight gain.(2) Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic induced weight gain, and lifestyle intervention plus metformin showed the best effect on weight loss. lifestyle intervention plus metformin and metformin similarly improved the insulin sensitivity. Lifestyle intervention plus metformin and metformin similarly improved the insulin sensitivity.(3) Metformin addition was effective and safe in attenuating olanzapine-induced weight gain and insulin resistance in drug-naive schizophrenia patients...