Second-Generation Antipsychotics Cause a Rapid Switch to Fat Oxidation That Is Required for Survival in C57BL/6J Mice

Abstract

Some second-generation antipsychotics (SGAs) increase insulin resistance and fat oxidation, but counter intuitively they do not activate lipolysis. This seems unsustainable for meeting energy demands. Here, we measured dose-dependent effects of SGAs on rates of oxygen consumption (VO 2 ), respiratory exchange ratio (RER), and physical activity in C57BL/6J mice. The role of H1-histamine receptors and consequences of blocking fat oxidation were also examined. Olanzapine, risperidone, and clozapine (2.5-10 mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO 2 , and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO 2 , in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO 2 , or physical activity. The VO 2 and RER effects appear independent of sedation/ physical activity or H1-receptors. CPT-1 inhibitors can enhance muscle glucose utilization and prevent fat oxidation. However, after etomoxir (2 × 30 mg/kg), a low dose of olanzapine that did not significantly affect VO 2 by itself caused precipitous drops in VO 2 and body temperature, leading to death within hours or a moribund state requiring euthanasia. One 30 mg/kg dose of either etomoxir or 2-tetradecylglycidate followed by olanzapine, risperidone, or clozapine, but not aripiprazole, dramatically lowered VO 2 and body temperature. Thus, mice treated with some SGAs shift their fuel utilization to mostly fat but are unable to either switch back to glucose or meet their energy demands when either higher doses are used or when fat oxidation is blocked.

AICAR Prevents Acute Olanzapine-Induced Disturbances in Glucose Homeostasis

“…OLZ is reported to increase reliance on fat oxidation (reduces RER), which can lead to plasma glucose accumulation (Klingerman et al, 2014;Klingerman et al, 2015). This has been thought to be due to central effects of OLZ (Klingerman et al, 2015).…”

“…The final version may differ from this version. One of the side effects of OLZ that is thought to perhaps contribute to increased blood glucose is up-regulated fat oxidation (Klingerman et al, 2014). To assess this and to determine whether AICAR can alter or improve these and other metabolic parameters such as activity and heat production, mice were housed in CLAMS metabolic cages and were given one of the four drug treatments.…”

“…Although the mechanisms are still under investigation, OLZ-induced hyperglycaemia is thought to involve increases in hepatic glucose production (Chintoh et al, 2009;Ikegami et al, 2013), impaired insulin release (Boyda et al, 2010), systemic insulin resistance (Chintoh et al, 2008;Boyda et al, 2010) and an increased reliance on fat oxidation (Klingerman et al, 2014). In This article has not been copyedited and formatted.…”

Some side effects and effcts on physical activity of second-generation antipsychotics: A study in children and adolescents

“…Presumably, decreased level of physical activity could be partially due to the sedative effects of the drugs. [ 44 ] A prolonged decrease in physical activity without reduction of food intake causes the accumulation of adipose tissue,[ 45 ] which was mentioned above as a potential cause of insulin resistance. Hence, the combination of metabolic adverse effects and inactivity can lead to obesity, while obesity and inactivity can adversely affect the metabolic parameters as well.…”

Olanzapine-mediated cardiotoxicity is associated with altered energy metabolism in isolated rat hearts

“…It is well known that schizophrenic patients suffer from cardiometabolic disorders (Jones et al, 2013;Pasternak et al, 2014;Wang et al, 2014), and administration of antipsychotic drugs is followed by higher morbidity and mortality (Jones et al, 2013). Several adverse effects, particularly prolonged QT intervals, higher rates of arrhythmias (Dineen et al, 2003;Drici et al, 1998;Gurovich et al, 2003), elevated risk of hyperlipidemia (Dudek et al, 2016;Horska et al, 2016;Takeuchi et al, 2015), increased blood glucose and lower circulating levels of free fatty acids (Albaugh et al, 2012;Klingerman et al, 2014) have been reported after olanzapine administration. Despite the fact that the incidence of sudden cardiac or sudden unexpected death in olanzapine-treated patients is twice as high as in nonusers (Salvo et al, 2016), the mechanism underlying the severe, adverse cardiac effects remains poorly understood.…”