二甲双胍对奥氮平所致精神分裂症患者体质量增加的影响

目的 验证二甲双胍预防奥氮平引起精神分裂症患者的体质量增加和糖代谢紊乱的效果.方法 将37例未服过抗精神病药的精神分裂症患者,随机分为奥氮平(15 mg/d)联合二甲双胍组(750 ms/d;A组,18例)和奥氮平(15 mg/d)联合安慰剂组(B组,19例),治疗12周.于治疗前和治疗第4周末、8周末及12周末测定空腹血糖、胰岛素(INS)、身高、体质量、腰围、臀围,计算体质量指数(BMI)、腰臀比(WHR)、胰岛素抵抗指数(IRI)及治疗12周末体质量增加大于7%的比率.用阳性症状量表(SAPS)、阴性症状量表(SANS)于治疗前和治疗12周末评定疗效.结果 治疗12周末,A、B两组的体质量、BMI、WHR及B组患者的空腹INS和IRI较治疗前均升高(P＜0.05).治疗第8,12周末,B组的体质量、BMI、空腹INS和IRI的变化值高于A组(P＜0.05).B组体质量增加大于7%的比率(63%,12例)高于A组(17%,3例;P＜0.01).A、B两组的SAPS及SANS评分均显著低于治疗前(均P＜0.05),但组间差异均无统计学意义(P＞0.05).结论 二甲双胍能有效减轻奥氮平引起的体质量增加和糖代谢紊乱.     

Plasma nitric oxide and leptin values in patients with olanzapine-induced weight gain

We previously investigated leptin levels in antipsychotic-induced weight gain and found that atypical antipsychotic, especially clozapine and olanzapine-induced weight gain is related to increased levels of leptin. It has been suggested that nitric oxide (NO) is a potential regulator of leptin-induced lipolysis. To explore the pathophysiology of weight gain during atypical antipsychotic treatment, we planned to investigate olanzapine's influence on leptin and NO levels and weight gain. The study comprised 21 patients with schizophrenia who were enrolled in olanzapine monotherapy, and 21 healthy controls. The fasting plasma NO and leptin levels were measured in both patients and controls at baseline. The patients were also evaluated at sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, serum leptin and NO levels. At baseline, the mean leptin level in the olanzapine group was not different compared to that in controls after BMI or age adjustment. A significant increase in leptin levels by means of olanzapine use was seen (P<0.01). Higher plasma NO levels were observed in patients with schizophrenia compared with the control group at baseline (P<0.01). At the evaluation of week 6, a significant decrease in the mean plasma NO level was found in the olanzapine group (P<0.05). The changes in total PANSS scores were correlated with change in leptin levels (r=0.58, P<0.05), and with the change in weight (r=0.54, P<0.05). In addition, there was a severe significant negative correlation between the changes in leptin levels and NO levels (r=0.73, P<0.01). The results confirmed that leptin and NO might be associated with olanzapine-induced weight gain.     

Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain

Background

Antipsychotic-induced weight gain (AIWG) is a serious side-effect of antipsychotic medication leading to metabolic syndrome and increased cardiovascular morbidity. Unfortunately, there are still no valid predictors to assess an individual's risk to gain weight. Previous studies have indicated an impact of genetic variation in the genes encoding leptin, LEP, and leptin receptor, LEPR, on AIWG, but results have not been conclusive. Thus, we investigated polymorphisms in both genes for an association with AIWG.

Methods

A total of 181 schizophrenic and schizoaffective patients treated with various antipsychotics were included. In a small subset of patients, leptin plasma levels were additionally obtained. Five polymorphisms in LEP and LEPR (LEP: rs7799039 (-2548G/A polymorphism), rs10954173, rs3828942; LEPR: rs1327120, rs1137101 (Q223R polymorphism) were genotyped using TaqMan assays. Statistical association with % weight change from baseline weight was performed using ANCOVA with baseline weight as covariate.

Results

ANCOVA showed a non-significant trend for genotype association of the rs7799039 marker (p = .068). No significant association of the other LEP and LEPR SNPs with AIWG was detected. However, we found a significant association between a haplotype of LEP rs7799039G–rs10954173G–rs3828942G (p = .035) and AIWG. The rs7799039 G-allele (p = .042) and G-allele of rs3828942 (p = .032) were associated with higher weight gain.

Conclusion

Our study supports the hypothesis of an impact of LEP gene variation on AIWG. Limitations of our study include heterogeneous samples, short treatment duration and multiple comparisons. Our findings were compared to previous studies in detail in order to provide the readers with a more conclusive picture. However, further studies are warranted including more gene variants and interaction analyses with other genes of the leptin–melanocortin pathway.     

Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: a double-blind,placebo-controlled study

OBJECTIVE: Since increased norepinephrine availability may account for the weight-reducing effect of appetite suppressants, the authors hypothesized that the addition of the selective norepinephrine reuptake inhibitor reboxetine may prevent or attenuate olanzapine-induced weight gain. METHOD: Twenty-six patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in the study. In addition to 6 weeks of treatment with olanzapine, 10 mg/day, patients were randomly allocated in a double-blind design to receive either reboxetine, 4 mg/day, (N=13) or placebo (N=13). RESULTS: Ten patients in each group completed the 6-week trial. Patients given olanzapine and reboxetine demonstrated a significantly lower increase in body weight (mean=2.5 kg, SD=2.7) than those given olanzapine and placebo (mean=5.5 kg, SD=3.1). Significantly fewer patients in the olanzapine/reboxetine group (N=2 of 10) than in the olanzapine/placebo group (N=7 of 10) gained at least 7% of their initial weight, the cutoff for clinically significant weight gain. The addition of reboxetine to olanzapine treatment was safe and well tolerated by the patients. A between-group difference in the reduction of Hamilton depression scale scores was seen that favored the olanzapine/reboxetine group (mean difference=-3.1, SD=1.25). CONCLUSIONS: The selective norepinephrine reuptake inhibitor reboxetine may reduce olanzapine-induced weight gain in schizophrenia patients, and activation of the adrenergic system may attenuate weight gain induced by atypical antipsychotic agents.     

Smokers and nonsmokers equally affected by olanzapine-induced weight gain: metabolic implications

OBJECTIVE: To examine the impact of smoking status on antipsychotic-associated weight gain. METHOD: In two double-blind studies, 552 adult and elderly patients with schizophrenia or schizoaffective disorder were randomly assigned to risperidone or olanzapine treatment for 8 weeks. Smoking status at baseline was recorded together with other background characteristics. RESULTS: In both adult and elderly patients, olanzapine-treated smokers and nonsmokers gained weight at a similar rate, whereas risperidone-treated smokers gained less weight than did nonsmokers. Olanzapine was associated with significantly greater weight gain than was risperidone across all measures in both adult and elderly patients. CONCLUSION: These findings support a quantitatively or qualitatively different effect of risperidone and olanzapine on the metabolic changes underlying antipsychotic-associated weight gain. Mechanisms responsible for olanzapine's effect on weight appear to counteract smokers' physiologic bias toward weight loss, an effect not seen among risperidone-treated patients.     

The efficacy of mifepristone in the reduction and prevention of olanzapine-induced weight gain in rats

Atypical antipsychotics, such as olanzapine, have been associated with clinically significant weight gain. Changes to the hypothalamic pituitary adrenal axis may partially mediate this weight increase. Two experiments were conducted to test the effects of mifepristone on both mitigating and preventing olanzapine-induced weight gain. In the first experiment, adult female Sprague-Dawley rats gained significantly more weight on average when administered olanzapine for 35 days compared to vehicle controls. Subsequently, the olanzapine-treated rats were randomized to three dose levels of mifepristone (20, 60, and 200 mg/kg) in conjunction with olanzapine. Weight measurements were taken for 21 additional days. Rats receiving olanzapine plus mifepristone rapidly lost a significant portion of the weight gained during the olanzapine only phase (p = 0.0001). Rats in the 200 mg/kg dose group had significantly less abdominal fat compared to controls (p < 0.001) at study end. In the second experiment, daily mifepristone (20, 60, 200 mg/kg) initiated concomitantly with olanzapine was compared with olanzapine alone to determine if mifepristone prevented olanzapine-induced weight gain. After 21 days of treatment, mifepristone treated rats gained significantly less weight and had significantly less abdominal fat than rats administered olanzapine alone (p = 0.0002). Results suggest that mifepristone, a potent glucocorticoid antagonist, may both reduce and prevent olanzapine-induced weight gain in rats.     

Association of orexin receptor polymorphisms with antipsychotic-induced weight gain

Objectives: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. Methods: Schizophrenia or schizoaffective disorder subjects (n?=?218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (n?=?122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. Results: Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (P<0.05). In the replication analysis two SNPs rs3134701 (P?=?0.043) and rs12662510 (P?=?0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. Conclusion: This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.     

Association of antipsychotic induced weight gain and body mass index with GNB3 gene: a meta-analysis

It has been reported that C825T variant in the gene encoding the G-protein subunit β3 (GNB3) is associated with antipsychotic-induced weight gain and obesity. We investigated the association of the GNB3 and antipsychotic-induced weight gain as well as body mass index (BMI) using meta-analytical techniques. Our analysis of 402 schizophrenia subjects showed a trend (p = 0.072) only under a fixed-model. As it was observed heterogeneity among the studies (p = 0.007), we re-analyzed using a random-effects framework and no significance was found (p = 0.339). No evidence for bias publication was reported (p = 0.868). Our analysis of 18,903 subjects showed a trend (p = 0.053) associating CC and lower BMI under a fixed model. Although no significant association was found, the same pattern (CC and lower antipsychotic-induced weight gain) was observed. Our meta-analysis indicates that firmly establishing the role of pharmacogenetics in clinical psychiatry requires much larger sample sizes that have been reported.     

Role of dietary fat in calorie intake and weight gain

This paper reviews the literature on the role of dietary fat in calorie intake and body weight gain in humans and laboratory animals. An overview of 40 animal studies which compared growth on high-fat (HF) and high-carbohydrate (HC) solid/powdered diets indicated that the HF diet elicited greater weight gain in 33 out of 40 studies. Enhanced growth on the HF diet was often, but not exclusively, attributable to greater caloric intake. Additional evidence for the growth-enhancing effect of HF diets emerges from "diet option" and "supermarket" feeding studies in rats, and experimental and epidemiological studies in humans. Three principal factors that contribute to the different responses to HF and HC diets are (a) caloric density, (b) sensory properties and palatability, and (c) postabsorptive processing. It is concluded that both calorie intake and metabolic energy expenditure are biased towards weight gain when a HF diet is consumed, and that the high caloric density of high-fat diets plays a primary role in weight gain. Humans may be biologically predisposed to gain weight when a HF diet is consumed.     

Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study

OBJECTIVE: The purpose of this study was to assess the efficacy of metformin in preventing olanzapine-induced weight gain. METHOD: Forty patients with schizophrenia were randomly assigned to treatment for 12 weeks with olanzapine, 15 mg/day, plus metformin, 750 mg/day (N=20), or olanzapine, 15 mg/day, plus placebo (N=20). This investigation was conducted in a double-blind fashion. Planned assessments included body weight, body mass index, proportion of patients who gained more than 7% of their baseline weight at the end of the 12-week treatment, waist circumference, waist-to-hip ratio, fasting glucose and insulin, insulin resistance index, and scores on the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). RESULTS: Of the 40 patients who were randomly assigned, 37 (92.5%) completed treatments. The weight, body mass index, waist circumference, and waist-to-hip ratio levels increased less in the olanzapine plus metformin group relative to the olanzapine plus placebo group during the 12-week follow-up period. The insulin and insulin resistance index values of the olanzapine plus placebo group increased significantly at weeks 8 and 12. In contrast, the insulin and insulin resistance index levels of the olanzapine plus metformin group remained unchanged. Significantly fewer patients in the olanzapine plus metformin group relative to patients in the olanzapine plus placebo group increased their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight gain. There was a significant decrease in SAPS and SANS scores within each group from baseline to week 12, with no between-group differences. Metformin was tolerated well by all patients. CONCLUSIONS: Metformin was effective and safe in attenuating olanzapine-induced weight gain and insulin resistance in drug-naive first-episode schizophrenia patients. Patients displayed good adherence to this type of preventive intervention.     

The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.     

Diet-induced weight gain produces a graded increase in behavioral responses to an acute immune challenge

Sickness behaviors and fever during infection constitute an adaptive and tightly regulated mechanism designed to efficiently clear the invading pathogen from the body. Recent literature has demonstrated that changes in energy status can profoundly affect the fever response to an acute immune challenge. The purpose of the present study was to investigate whether the exacerbating effect of diet induced obesity (DIO) on the LPS-induced fever response demonstrated previously would generalize to other sickness behaviors and, further, whether incremental changes in body weight would influence these responses. Results showed that DIO male Wistar rats exhibited a higher number of sickness symptoms for a longer period after lipopolysaccharide (LPS) injection (100 μg/kg) than lean rats. Similarly, they showed a more prolonged fever and a delayed recovery from LPS-induced suppression of social interaction. No difference in locomotor activity was observed between obese and lean groups. Comparisons among groups that varied in body weight showed that an 11% increase in body weight was sufficient to increase the number and duration of sickness symptoms displayed after an LPS-injection and that the severity of sickness symptoms increased with increasing body weight. Together these data suggest that DIO can have profound effects on multiple behavioral responses to an acute immune challenge placing obese organisms at higher risk of the consequences of prolonged inflammation.     

HTR2C polymorphisms,olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: A meta-analysis

Objective. To conduct meta-analyses of all published association studies on the HTR2C -759C/T (rs3813829) polymorphism and olanzapine-induced weight gain in schizophrenia patients and on the HTR2C -759C/T, -697G/C (rs518147) and rs1414334:C> G polymorphisms and olanzapine/clozapine/risperidone-induced metabolic syndrome in schizophrenia patients. Methods. Eligible studies were identified by searching PubMed and Web of Science databases. Meta-analyses were performed using Cochrane Review Manager (RevMan, version 5.2) to calculate the pooled odds ratio (OR) and its corresponding 95% confidence interval (CI). Results. Our meta-analyses revealed both a significant positive association between the rs1414334 C allele and olanzapine/clozapine/risperidone-induced metabolic syndrome and a marginally significant positive association between the -697C allele and the induced metabolic syndrome in schizophrenia patients, but no significant association between the -759C/T polymorphism and the induced metabolic syndrome in schizophrenia patients. Our analysis further revealed a pronounced trend toward a significant negative association between the -759T allele and high olanzapine-induced weight gain and a trend toward a significant positive association between the -759C allele and high olanzapine-induced weight gain in Caucasian schizophrenia patients. Conclusions. Our results support that HTR2C polymorphisms play a role in antipsychotic-induced metabolic disturbance. More association studies are needed to further elucidate association of different HTR2C polymorphisms and antipsychotic-induced metabolic disturbance.     

Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain

Antipsychotic-induced weight gain has important effects on treatment compliance and long-term health. Several reports have indicated that a -2548A/G single-nucleotide polymorphism (SNP) of the leptin gene is associated with antipsychotic-induced weight gain. We hypothesized that there is a similar relationship between the -2548A/G SNP and olanzapine-induced weight gain. A total of 74 Korean schizophrenic patients were examined. Their weight was measured before starting olanzapine and after long-term treatment lasting for at least 3 months. The weight gain was significantly higher for patients with the AG genotype than for those with the AA genotype (p=0.029). Analysis of covariance also showed the difference of weight gain was still significant when adjusted for sex and treatment duration (p=0.046). This finding supports the presence of a relationship between the -2548A/G SNP of the leptin gene and weight gain in Korean schizophrenic patients receiving olanzapine treatment.     

氯氮平所致体质量增加与生长激素释放肽、瘦素的相关性研究

目的探讨氯氮平所致体质量增加与生长激素释放肽、瘦素的关系。方法 30例接受氯氮平[250～400(323±53)mg/d]、30例接受氟哌啶醇[10～20(14±3)mg/d]治疗的精神分裂症患者,分别于基线、治疗第3周、6周测定体质量(BM)和生长激素释放肽(ghrelin)、瘦素(leptin)水平。结果 (1)氯氮平组体质量、ghrelin,按基线、3周、6周的顺序依次升高(F=4.405～41.505,P=0.048～0.000),leptin则于6周时开始升高(F=6.376,P=0.027);氟哌啶醇组体质量、ghrelin、leptin,在各时点无显著差异(F=0.089-0.370,P=0.915-0.695)。(2)体质量、ghrelin、leptin各时点的变化趋势,在氯氮平组、氟哌啶醇组之间有显著差异,存在组别×时间的交互作用(F=6.088～6.997,P=0.005～0.002)。(3)6周时,氯氮平组体质量变化率与ghrelin变化率正性相关(rs=0.567,P=0.043)。结论 ghrelin、leptin与氯氮平所致体质量增加相关,ghrelin的改变可能是体质量增加的始动因素,而leptin的改变可能是机体对体质量增加适应性调节的结果。