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Antipsychotic (AP) medications are associated with an increased risk for developing metabolic side effects including weight gain, dyslipidemia, hypertension, type 2 diabetes (T2D), and cardiovascular disease. Previous reviews have focused on the chronic metabolic side effects associated with AP use. However, an underappreciated aspect of APs are the rapid perturbations in glucose and lipid metabolism that occur with each dose of drug. The purpose of this narrative review is to summarize work examining the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances. We also discuss recent studies that have attempted to elucidate treatment approaches to mitigate AP-induced impairments in fuel metabolism., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach. NEW & NOTEWORTHY Antipsychotic drugs cause rapid perturbations in glucose and lipid metabolism. In the present study we have demonstrated that cotreatment with glucagon-like peptide 1 (GLP1) receptor agonists, such as liraglutide, protects against metabolic dysregulation caused by the antipsychotic drug olanzapine. These findings suggest that pharmacological targeting of the GLP1 receptor could be an effective adjunct approach to mitigate the harmful acute metabolic side effects of antipsychotic drugs.

Olanzapine is a second-generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off-label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are believed to be mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. Further, the acute lipidemic response to olanzapine has been largely unexplored. While females have been reported to be more susceptible to olanzapine-induced weight gain, there is little known about the impact of sex on the acute response to SGAs. The purpose of this study was to determine if the acute effects of SGAs on glucose and lipid metabolism display a sexually dimorphic response in C57BL/6 J mice and examine potential mechanisms mediating this effect. Age matched male and female C57BL/6 J mice were treated with olanzapine (5 mg/ kg, IP) or vehicle control and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 min post-treatment and tissues and serum harvested. These experiments were repeated, and mice underwent an insulin (0.5 IU/kg) or pyruvate tolerance test (2 g/kg) following 60 min of olanzapine treatment. Females were protected against olanzapine-induced increases in blood glucose and pyruvate intolerance compared to male mice, and this occurred despite the development of severe insulin resistance. In male mice olanzapine increased the glucagon:insulin ratio whereas in females this ratio was reduced. When challenged with exogenous glucagon (1 mg/kg IP), females were less responsive than males. Male and female mice displayed similar increases in whole body fatty acid oxidation, serum fatty acids and liver triglyceride accumulation. Our findings provide evidence that while there are no apparent sex differences in the lipid metabolism response to olanzapine, that females are protected from acute olanzapine-induced excursions in blood glucose. This is likely due in part to reductions in the glucagon:insulin ratio and glucagon responsiveness which could impact olanzapine induced increases in liver glucose production., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK β1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK β1 suppresses these effects. Female AMPK β1 -/- or wild-type (WT) control mice were treated with OLZ, and changes in blood glucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK β1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK β1 -/- mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK β1 -/- mice, consistent with A769662's specificity for the AMPK β1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK β1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.-Shamshoum, H., Medak, K. D., Townsend, L. K., Ashworth, K. E., Bush, N. D., Hahn, M. K., Kemp, B. E., Wright, D. C. AMPK β1 activation suppresses antipsychotic-induced hyperglycemia in mice.

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and several on- and off-label conditions. While effective in reducing psychoses, acute olanzapine treatment causes rapid hyperglycemia, insulin resistance, and dyslipidemia and these perturbations are linked to an increased risk of developing cardiometabolic disease. Pharmacological agonists of the glucagon-like peptide-1 (GLP1) receptor have been shown to offset weight-gain associated with chronic SGA administration and mitigate the acute metabolic side effects of SGAs. The purpose of this study was to determine if increasing endogenous GLP1 is sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine, in the absence or presence of an oral glucose tolerance test (OGTT), and a combination of compounds to increase endogenous GLP1. These include the non-nutritive sweetener allulose which acts to induce GLP1 secretion but not other incretins, the DPPiv inhibitor sitagliptin which prevents degradation of active GLP1, and an SSTR5 antagonist which relieves inhibition on GLP1 secretion. We hypothesized that this cocktail of agents would increase circulating GLP1 to supraphysiological concentrations and would protect against olanzapine-induced perturbations in glucose and lipid homeostasis. We found that 'triple treatment' increased both active and total GLP1 and protected against olanzapine-induced perturbations in lipid and glucose metabolism under glucose stimulated conditions and this was paralleled by an attenuation in the olanzapine induced increase in the glucagon:insulin ratio. Our findings provide evidence that pharmacological approaches to increase endogenous GLP1 could be a useful adjunct approach to reduce acute olanzapine-induced perturbations in lipid and glucose metabolism. [ABSTRACT FROM AUTHOR]

Objective: In contrast to what is seen clinically, male mice are resistant to antipsychotic‐induced obesity. This is problematic as preclinical studies examining mechanisms of antipsychotic‐induced metabolic dysfunction might be relevant to only half the population. This study sought to determine whether housing mice at thermoneutrality and under conditions of preexisting obesity, steps that have not been previously considered, would uncover a greater obesogenic effect of the antipsychotic olanzapine (OLZ). Methods: C57BL6/J mice were fed a low‐ or high‐fat diet (HFD) for 4 weeks and then switched to a control HFD or an HFD supplemented with OLZ for 6 weeks. Results: Irrespective of obesity, OLZ treatment attenuated weight gain and increased energy expenditure in male mice. In females, OLZ increased food intake and potentiated weight gain in mice with preexisting obesity. Conclusions: Despite taking steps to increase clinical translatability, this study did not unmask an obesogenic effect of OLZ in male mice. Interestingly, prior studies in female mice could have been underestimating the metabolic consequences of OLZ by not considering the importance of preexisting obesity. Uncovering the mechanisms conferring resistance to weight gain in males may provide clues for approaches to counter the metabolic side effects of antipsychotics clinically. [ABSTRACT FROM AUTHOR]

Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications. • Antipsychotic drugs have harmful metabolic side effects including weight gain. • Metformin is used to counter metabolic side effects but is not effective in all patients. • Salsalate prevented antipsychotic weight gain and liver fat accumulation. • Salsalate and metformin increased energy expenditure and glucose tolerance. [ABSTRACT FROM AUTHOR]