Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice

Schizophr Bull. 2014 Mar;40(2):327-40. doi: 10.1093/schbul/sbs196. Epub 2013 Jan 17.


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 (VO2), 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 (2.5-10mg/kg) elicited rapid drops in dark-cycle RER (~0.7) within minutes, whereas aripiprazole exerted only modest changes. Higher doses of olanzapine decreased VO2, and this was associated with accumulation of glucose in plasma. Clozapine and risperidone also lowered VO2, in contrast to aripiprazole, whereas all decreased physical activity. Astemizole and terfenadine had no significant effects on RER, VO2, or physical activity. The VO2 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 VO2 by itself caused precipitous drops in VO2 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 VO2 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.

Keywords: body temperature; clozapine; fat oxidation; glucose; histamine; olanzapine; oxygen consumption; respiratory exchange ration; risperidone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / pharmacology*
  • Aripiprazole
  • Astemizole / administration & dosage
  • Astemizole / pharmacology
  • Behavior, Animal / drug effects
  • Benzodiazepines / administration & dosage
  • Benzodiazepines / pharmacology
  • Clozapine / administration & dosage
  • Clozapine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Energy Metabolism / drug effects*
  • Epoxy Compounds / administration & dosage
  • Epoxy Compounds / pharmacology
  • Fatty Acids / metabolism*
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL / metabolism*
  • Motor Activity / drug effects
  • Olanzapine
  • Oxygen Consumption / drug effects
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Quinolones / administration & dosage
  • Quinolones / pharmacology
  • Receptors, Histamine H1 / metabolism
  • Respiration / drug effects
  • Risperidone / administration & dosage
  • Risperidone / pharmacology
  • Terfenadine / administration & dosage
  • Terfenadine / pharmacology
  • Time Factors


  • Antipsychotic Agents
  • Epoxy Compounds
  • Fatty Acids
  • Hypoglycemic Agents
  • Piperazines
  • Quinolones
  • Receptors, Histamine H1
  • Benzodiazepines
  • Terfenadine
  • Astemizole
  • Aripiprazole
  • Clozapine
  • Risperidone
  • etomoxir
  • Olanzapine
  • 2-tetradecylglycidic acid