Since their introduction in 1990, atypical antipsychotics (AAPs) have become the most common treatment for patients with a variety of psychotic disorders.¹ However, compelling evidence indicates that the use of AAPs is related to potentially serious adverse metabolic effects, including obesity, dyslipidemia, hyperglycemia, and type 2 diabetes mellitus.^2,3 These metabolic disturbances may lead to an increase in the risk of cardiovascular diseases and premature mortality.⁴

A growing body of research has compared the metabolic side effects of different AAPs, and the findings indicate that different AAPs are associated with different levels of risk for metabolic disturbances.^5,6,7 However, the pathophysiological mechanisms underlying metabolic side effects are not fully understood. AAP-induced weight gain has been the primary focus of attention because obesity is an easily detectable side effect, and researchers have assumed that the initiating pathophysiology is weight gain. Obesity is known to predispose individuals to develop dyslipidemia and glucose intolerance Thus, it is conceivable that AAP-associated metabolic disturbances are associated with weight gain, and this has been supported by several reports.¹ Nevertheless, considerable evidence suggests that AAPs can cause metabolic disturbances in a manner that cannot be explained by weight gain alone. A cross-sectional naturalistic study of 242 individuals with severe mental disorders revealed that, despite similar body mass indices (BMIs), hypertriglyceridemia was significantly more prevalent in clozapine- or olanzapine treated than in unmedicated subjects.² Moreover, several studies of AAPs have found no strong association between the severity of the observed hypertriglyceridemia and weight gain.^3,4,6 Henderson et al.⁸ reported that clozapine- and olanzapine treated subjects displayed significant insulin resistance and impaired glucose effectiveness compared with BMI-matched risperidone-treated subjects. These findings may suggest that AAPs directly affect metabolic disturbances, rather than simply increase the effects of known risk factors such as obesity. Therefore, the association between AAP-induced metabolic disturbances and obesity needs to be further investigated. A precise understanding of the mechanism underlying this association should enable the development of effective measures to reduce the metabolic risk for patients taking AAPs.

In the present study, we compared the metabolic disturbances of three groups treated with different AAPs, which are known to differ in terms of the risk of weight gain, after adjusting for BMI. The primary objective of this study is to investigate whether any metabolic disturbances differ independently from body mass in patients with schizophrenia taking three AAP group with different risk of metabolic side effect.

This naturalistic study revealed that patients with schizophrenia who received different AAPs for 1 year differed significantly in terms of metabolic disturbances involving lipid and glucose levels even after adjusting for BMI.

The risk of antipsychotic-induced weight gain differs among antipsychotic drugs.³ However, we found no significant intergroup differences in the prevalence of obesity or BMI before or after adjusting for clinical variables. We do not consider this finding to contradict the results of previous studies; our results may be attributable to the characteristics of our sample. All subjects had been continuously receiving the same AAP in a naturalistic clinical setting for more than one year. Therefore, those who gained excessive weight may have had their antipsychotics switched to a less metabolically active medication before entering the study. We found that the majority of subjects of three AAP group had been treated with another various antipsychotics before entering this study.

Unlike the prevalence of obesity, the prevalence of MetS differed significantly among the three antipsychotic groups. This finding suggests that obesity is not completely correlated with dysglycemia or dyslipidemia in patients receiving an AAP, which is consistent with the findings reported by Meyer et al.¹⁴ The high rate of MetS in patients treated with AAPs develop through several mechanisms such as increased appetite, decreased physical activity, weight gain, insulin resistance and direct modification of metabolic parameters. It is important to investigate these potential mechanisms separately. Each potential factors need to be investigated separately to resolve the fundamental mechanism.

Our finding that those in group CL/OL/QT exhibited both more hypertriglyceridemia and higher triglyceride level than those in group RSP is consistent with a previous report that suggested that dibenzodizepine-derived compounds are associated with dyslipidemia.⁷ Individual antipsychotics differ in their tendency to induce hypertriglyceridemia.^14,15,16 Several studies have reported positive correlations between changes in triglyceride levels and BMI in dibenzodiazepine-derived compounds.^15,17 Obesity has been repeatedly associated with insulin resistance, which is believed to be a primary underlying metabolic defect in the development of the characteristic dyslipide-mia observed in obesity.¹⁸ However, our finding of intergroup differences in hypertriglyceridemia after adjusting for BMI is consistent with the findings of several studies of AAPs that found no strong association between the severity of the observed triglyceridemia and weight gain.^19,20,21,22 Therefore, some AAPs may have a direct effect on triglyceride metabolism. Yan et al.²³ recently reviewed the potential mechanisms by which AAPs may contribute to hypertriglyceridemia and suggested that several lines of evidence indicate that AAPs may have a direct effect on triglyceride metabolism either by stimulating hepatic triglyceride production and secretion or by inhibiting lipoprotein lipase-mediated triglyceride hydrolysis.

A recent study reported the effects of several AAPs (clozapine, risperidone, zipasidone) on lipid metabolism, intracellular cholesterol traffic, and lipid secretion in vitro.²⁴ They found that AAPs showed inhibit cholesterol biosynthesis and produce changed in the sterol composition of cells. Assuming that feedback mechanisms are triggered by the decrease in intracellular cholesterol levels and these results are in line with increased expression of gene involved in cholesterol biosynthesis induced by AAPs. They also found significant differences among AAPs in terms with the affected enzymes and the extent of activation of enzymes. They suggested that there effects may be relevant in the metabolic side effects of antipsychotics.

Our finding of more prevalent hyperglycemia and higher plasma glucose levels in patients taking CL/OL/QT compared with risperidone after adjusting for BMI is also consistent with the findings of previous reports: patients taking clozapine and olanzapine reportedly exhibit abnormal glucose metabolism, including elevated fasting insulin levels.^25,26 Additionally, patients receiving risperidone exhibited less severe abnormalities in glucose regulation than did those receiving clozapine or olanzapine.^8,25 These results support previous findings that clinically significant hyperglycemia can occur during some antipsychotic treatment with or without changes in weight.²⁵ Recently, Teff et al.²⁷ reported that healthy subjects developed insulin resistance after administration of olanzapine and aripiprazole, along with an absence of weight gain, increase in food intake and hunger, or psychiatric illness, supporting the hypothesis that AAPs exert direct effects on tissue, independent of the me-chanisms regulating eating behavior.

Obesity and subjective distress related to weight gain are reportedly predictors of antipsychotic noncompliance.²⁸ Because weight gain is easily recognized by patients and clinicians, it is possible to take action to combat obesity. In contrast, it is impossible to detect abnormalities in plasma glucose and lipid levels without laboratory tests. Although many clinical guidelines recommend routine laboratory screening,^29,30 the rate of metabolic monitoring is concerningly low in people prescribed antipsychotic medication in routine clinical practice.^31,32

Patients treated with AAPs encounter increased risk of comorbidities. It is well known that the number and the seriousness of comorbid disease which is assessed with comorbidity scoring system such as the Charlson Index³³ are significantly associated with the mortality rate in longitudinal studies. This fact can be applicable to psychiatric patients with metabolic disturbances. That is, it may be possible that the number and the severity of comorbid metabolic disturbances are likely to have important deleterious effects on mortality rates. Clinicians should make an effort to manage the metabolic side effects.

The strength of the present study is that we controlled for major clinical variables that have significant effects on metabolic status, such as smoking, use of mood stabilizers, and treatment with antidepressants associated with weight gain, by excluding patients who were current smokers and those receiving the aforementioned medications. Smoking is known to be associated with an increased prevalence of MetS independent of BMI class, and this increased risk is related primarily to lower HDL-cholesterol and higher triglyceride levels.³⁴ Several mood stabilizers have been associated with weight gain,³⁵ and the combination of antipsychotics and mood stabilizers seems to lead to greater weight gain compared with treatment involving one or two mood stabilizers.³⁶ Another important strength of this study is that all subjects had been continuously receiving the same antipsychotic medication for more than one year and were treated in a naturalistic clinical setting.

This study has several limitations. First, its cross-sectional design precludes inferences about causal relationships between drug exposure and outcome. Second, the small sample may not be representative of all patients treated with AAPs and is the pivotal drawback to generalize the study finding. Third, even though we controlled for confounding factors which can affect the metabolic states such as smoking and concomitant psychiatric medications, we did not assess other factors that may be related to metabolic disturbances, such as diet and exercise. Subjects were recruited from both inpatient and outpatient settings, which can also affect the metabolic states and activity levels of such patients. Fourth, subjective report on comorbidity is usually known not to be accurate in regarding to MetS related study.

In conclusion, metabolic disturbances are significantly different in AAP groups even after adjusting BMI. AAPs may have direct effect on metabolic parameters. Blood lipid and glucose levels should be monitored regularly regardless of whether patients tend to gain weight.