| Background and Objective:With the dramatic improvement achieved in clinical psychiatry by the use of second generation antipsychotics, the risk of metabolic syndrome(MS) induced by the antipsychotic drugs has gradually been a main concern in current clinical practice. MS can cause serious disease such as type 2 diabetes, cardiovascular disease, etc. The effective intervention has important clinical significance.Clinical practice found that metformin, as a hepatic insulin sensitizing agents, can prevent or manage multiple metabolic derangements. In general population patients, metformin has widely been used to regulate blood glucose levels, weight gain, dyslipidemia and other metabolic dysregulation. Accumulating evidences in the schizophrenic population have demonstrated that metformin is effective and safe in improving weight gain and insulin resistance induced by olanzapine. However, the previous evaluation of metformin, especially its intervention effects on MS in schizophrenia patients with olanzapine-induced weight gain, focused on the decline of index of body fat and improvement of glucose and lipid metabolism. Or we understand metformin interventional mechanism from its effect on insulin resistance. Indicators in previous studies have the lack of ability to predict MS and fail to cover the metformin intervention mechanism comprehensively.Ectopic fat storage, the storage of triglyceride(TG) droplets in nonadipose tissues(such as liver or skeletal muscle), is one of the important pathophysiological basis of insulin resistance. The liver,as the core organ of glucolipid metabolism, is vulnerable to ectopic fat deposition. Studies have shown that liver fat content(LFC) is one of the strongest predictive indicators of MS. Liver fat accumulation is also the most important pathogenesis explaining MS formation and may be the origin and initial factor of insulin resistance. Therefore, LFC should be an optimization evaluation for metformin intervening in olanzapine-induced weight gain in schizophrenia. At the same time, it is also an important way to understand its intervention effects.This study attempts to analysize the dynamic change trend of LFC(LFC as the main index)before and after metformin addition, and from the perspective of fatty liver, explore and evaluate the role of metformin in reducing the risk of MS. The parallel analysis of the trends on LFC and body fat index, indicators of glucose and lipid metabolism observed in previous studies, further validate the clinical significance and importance about the impact of metformin on LFC. From the correlation analysis of the changing trends on the LFC, insulin resistance and adipokines before and after intervention, the understanding on the mechanism of metformin intervention may be broadened.Methods:The present study is divided into the following two parts.Part 1:In a double-blind study, thirty-one clinically stable inpatiens with first-episode schizophrenia who gain more than 7% of their predrug weight were randomly assigned to two groups, one with olanzapine plus metformin(1000mg/d), the other with olanzapine plus placebo for 16 weeks. All patients continued to maintain the original olanzapine dosage. Liver fat content was measured by MRI in the baseline and at the end of 4, 8, 12,16 weeks.Part 2:In the patients receiving metformin treatment, at baseline and at the end of 16 week, LFC, anthropometric measurements(including weight, body mass index, waist circumference, waist/height ratio), glucose and lipid metabolism(including fasting blood glucose, glycosylated hemoglobin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), homeostasis model assessment of insulin resistance index, adipokines(including leptin, adiponectin, retinol binding protein 4) were measured, analysing the correlation between the change value of LFC and other indicators.Results:1. Over the 16-week study period, LFC value in metformin group decreased compared with baseline [(16.55 ± 7.51)% vs(19.47 ± 8.99)%, P = 0.011]. There was no significant change at each follow-up visit in the placebo group.2. A two-way repeated ANOVA(Drug × Time) of liver fat content showed a significant interaction between the two factors(F=8.437, P=0.007). LFC change across the 16-week treatment period was-2.91% for the metformin group and 0.59% for the placebo group, with a between-group difference of-3.5%(95%CI=-6.08 to-0.93, P=0.009). The between-group difference demonstrated a significant time-by-treatment interaction.3. Compared to baseline, the mean weight, body mass index, waist circumference and waist-hight ratio decreased significantly in the metformin group at 16 weeks(P<0.05). The change of LFC was positively correlated with the changes of waist circumference, waist-height ratio(r= 0.495~0.523, P <0.05), but was not related with weight, body mass index(P>0.05).4. At weeks 16, in the metformin group, triglyceride reduced significantly, and high density lipoprotein cholesterol increased significantly(all P<0.05). There was no significant changes in fasting blood glucose, glycosylated hemoglobin, total cholesterol and low-density lipoprotein cholesterol from baseline(all P> 0.05). There was positive correlation between LFC changes and triglycerides changes at weeks 16, compared to baseline(r=0.505, P<0.05), while there were no significant correlations between changes in LFC and changes in fasting blood glucose, glycosylated hemoglobin, total cholesterol, high-density lipoprotein cholesterol, or low density lipoprotein cholesterol.5. In the metformin group, the steady-state model assessment of insulin resistance index(HOMA-IR) reduced significantly at weeks 16, comared to baseline(P <0.05). There was positive correlation between LFC changes and HOMA-IR changes significantly(r=0.578,P<0.05).6. In the metformin group, leptin, retinol binding protein 4 decreased significantly, while adiponectin levels increased significantly at weeks 16, comared to baseline(P <0.05). There was positive correlation between changes in LFC and leptin at week 16(r=0.497,P<0.05). There was negative correlation between LFC changes and adiponectin changes(r=-0.553,P<0.05). No significant changes in LFC and retinol binding protein 4 were detected(P>0.05).Conclusions:Metformin can significantly attenuate liver fat content with olanzapine-induced weight gain in first episode schizophrenia patients.In the process of metformin intervening in olanzapine-induced weight gain in schizophrenia, LFC reduces, accompanied by significant changes in some anthropometric measurements, metbabolic parameters(including glucose and lipid metabolism, insulin resistance levels and adipokines). There are different degrees of magnitude correlations between LFC changes and these parameters changes above. |
