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

Candice M Klingerman1, Michelle E Stipanovic, Mohammad Bader

  • 1*To whom correspondence should be addressed; Department of Cellular & Molecular Physiology, Penn State College of Medicine, 500 University Drive, MC-H166, Hershey, PA 17033, US; tel: 717-531-5170, fax: 717-531-7667,

Schizophrenia Bulletin
|January 19, 2013
PubMed

Insights

Second-generation antipsychotics (SGAs) disrupt energy metabolism in mice, impairing fat oxidation and leading to potentially fatal metabolic collapse when combined with fat oxidation blockers. This highlights critical risks associated with these drugs.

Area of Science:

  • Pharmacology
  • Metabolic Science
  • Neuroscience

Background:

  • Second-generation antipsychotics (SGAs) are known to increase insulin resistance and fat oxidation, yet paradoxically do not activate lipolysis.
  • This metabolic profile raises questions about the sustainability of energy demands and the underlying mechanisms.

Purpose of the Study:

  • To investigate the dose-dependent effects of SGAs on metabolic parameters including oxygen consumption (VO2), respiratory exchange ratio (RER), and physical activity in mice.
  • To explore the involvement of H1-histamine receptors and the consequences of blocking fat oxidation in SGA-induced metabolic changes.

Main Methods:

  • Dose-dependent administration of olanzapine, risperidone, clozapine, and aripiprazole to C57BL/6J mice.
  • Measurement of VO2, RER, and physical activity.
  • Assessment of effects using H1-receptor antagonists (astemizole, terfenadine) and carnitine palmitoyltransferase 1 (CPT-1) inhibitors (etomoxir, 2-tetradecylglycidate).

Main Results:

  • Olanzapine, risperidone, and clozapine rapidly decreased RER, indicating a shift towards glucose utilization, while aripiprazole had minimal effect.
  • Higher doses of olanzapine, clozapine, and risperidone reduced VO2 and physical activity, with olanzapine associated with hyperglycemia.
  • Blocking fat oxidation with etomoxir followed by certain SGAs (olanzapine, risperidone, clozapine) led to severe drops in VO2 and body temperature, often resulting in mortality.

Conclusions:

  • Some SGAs induce a metabolic state reliant on fat oxidation, but impair the ability to switch back to glucose or meet energy demands, especially at higher doses or when fat oxidation is inhibited.
  • The observed metabolic effects appear independent of H1-receptor antagonism or sedation.
  • Combined treatment with specific SGAs and fat oxidation inhibitors poses a significant risk of metabolic collapse in mice.
Keywords:
body temperatureclozapinefat oxidationglucosehistamineolanzapineoxygen consumptionrespiratory exchange rationrisperidone

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