Long-term side effects of antipsychotics

• Main Authors: Ya Mei Bai, 白雅美
• Other Authors: Pesus Chou
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/73830123008285464888

博士 === 國立陽明大學 === 公共衛生研究所 === 94 === Adverse metabolic effects have emerged as the most serious medical consequences of pharmacotherapy with some atypical antipsychotics. With the widespread use of atypical antipsychotics over the past several years, the associated side effect as weight gain, diabetes mellitus and dyslipidemia became apparent. The metabolic side effects were associated with increased relapse rate due to poor drug compliance, higher rates of morbidity and mortality due to an increased risk for cardiovascular and malignant disorders. Although numerous reports focused on the metabolic side effect with atypical antipsychotics, selection bias was associated with reports from side effect surveillance or claim data. Large- scaled longitudinal cohort study and reports about the prevalence of metabolic syndrome (MS) were sparse. Furthermore, although the non-Caucasians had been identified as the risk factor for developing DM, few reports of Chinese patients were published. The study was performed among the hospitalized patients in the Yu-Li Veterans Hospital, with the advantage of optimally control for possible confounding factors of diet, activity level and drug compliance. First part of the study is the long-term cohort study for weight change up to ten years among 876 patients on clozapine (n=349), olanzapine (n=188), and first generation antipsychotic (FGA,n=342). The second part is a survey of metabolic syndrome among 510 patients on clozapine (n=188), olanzpine (n=94), and risperidone (n=228). The related genetic polymorphism, adiponectin level, prolactin level and pharmacokinetic metabolites concentration were also evaluated to have an integrated analysis from long-term clinical data and related biomarkers. Cohort study for weight change (1) The first study sample was 96 patients on clozapine without exposure of other atypical antipsychotics. The multiple linear regression model showed two factors, significant initial clinical response and lower BBMI, were associated with more weight gain. The patients with significant initial clinical response had more 8-year weight gain than those without good initial clinical response (13.8±8.4 vs 4.5±12.0kg, respectively, p=0.03), and the significance showed since the third month. The genetic polymorphism data was further integrated into the GEE model for 8-year weight change showed alpha 2a-1291C>G and C825T polymorphism in the human G protein beta3 could predict 14-monthweight change, and TNF-α polymorphism could predict weight change up to 8 years. (2) Among 349 patients on clozapine (mixed subjects with and without exposure of other atypical antipsychotics), duration of clozapine treatment and baseline BMI were significant predictors for 8-year weight change. And the linear mixed model showed the weight gain reached a plateau until the 42th month, a consistent result with previous report. The clozapine metabolites concentration and CYP 1A2-t155g genetic polymorphism were not significant predictors for weight change. (3) Among total 876 cases, the GEE model showed four significant factors: antipsychotic classes, baseline BMI, treatment duration and age on initiation of atnispychtics, were to 12-month weight change. Olanzapine (p<0.0001) and clozapine (p<0.0007) had significantly more weight gain than FGA. The patients with baseline BMI less than 25 had more weight gain of 2.8 kg (p<0.0001). The younger to begin antipsychotic treatment, the more weight gain will be noted (p=0.0023) Prevalence of metabolic syndrome and predictive factors. According to the 2005 IDF criteria, the prevalence of central obesity, hypertriglycemia, low-HDL, hypertension, hyperglycemia and MS was 38.2%, 20.5%, 69.2%, 30.4%, 20.4%, and 23.5%, respectively; or 23.1% by NECP ATP III criteria, twice higher than that of Taiwan general population (12.9%). Compared to olanzapine and risperidone, the patients on clozapine had higher prevalence of central obesity, hypertryglycemia and metabolic syndrome. Weight gain is the significant predictors for metabolic syndrome and all metabolic components among patients on clozapine.The prevalence of diabetes mellitus was 14.5%, although no difference of prevalence was noted between different antipsychotics, the patients with DM in the clozapine group were significantly younger than that of patients on olanzapine and risperidone (p=0.001), and the GEE model showed treatment duration of clozapine and TNF-α were predictors for DM. Conclusion: The study was the largest Chinese cohort for weight gain and metabolic syndrome mong patients with mental disorders. The result showed atypical antipsychotics, clozapien and olanzapine, had significant higher risk of weight gain than FGA; and the earlier age at initiation of antipschotics, treatment duration, normal baseline BMI were risk factors for subsequent weight gain. The initial clinical response and TNF-α polymorphism can predict the weight gain associated with clozapie up to 8 years. The prevalence of MS among patients on atypical antipsychotics is 23.5%, which is higher than that of general population. The patients treated with clozapine had significantly higher prevalence of metabolic syndrome and hypertriglycemia than patients treated with olanzapine and risperidone. The patients with DM in the clozapine group were significantly younger than that of patients on olanzapine and risperidone; treatment duration and TNF-α were predictors for patients on clozapine developed DM. Limitation of the study was the nature of observation study, that the risk metabolic syndrome with olanzapine may have been underestimated due to high rate of disconinuation. In conclusion, the result showed metabolic syndrome was important issue for long-term care of patients with mental disorder, close monitoring and early intervention may be required for patients with risk factors.