Liraglutide prevents metabolic side-effects and improves recognition and working memory during antipsychotic treatment in rats

J Psychopharmacol. 2018 May;32(5):578-590. doi: 10.1177/0269881118756061. Epub 2018 Mar 1.


Background: Antipsychotic drugs (APDs), olanzapine and clozapine, do not effectively address the cognitive symptoms of schizophrenia and can cause serious metabolic side-effects. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties. The aim of this study was to examine whether liraglutide prevents weight gain/hyperglycaemia side-effects and cognitive deficits when co-administered from the commencement of olanzapine and clozapine treatment.

Methods: Rats were administered olanzapine (2 mg/kg, three times daily (t.i.d.)), clozapine (12 mg/kg, t.i.d.), liraglutide (0.2 mg/kg, twice daily (b.i.d.)), olanzapine + liraglutide co-treatment, clozapine + liraglutide co-treatment or vehicle (Control) ( n = 12/group, 6 weeks). Recognition and working memory were examined using Novel Object Recognition (NOR) and T-Maze tests. Body weight, food intake, adiposity, locomotor activity and glucose tolerance were examined.

Results: Liraglutide co-treatment prevented olanzapine- and clozapine-induced reductions in the NOR test discrimination ratio ( p < 0.001). Olanzapine, but not clozapine, reduced correct entries in the T-Maze test ( p < 0.05 versus Control) while liraglutide prevented this deficit. Liraglutide reduced olanzapine-induced weight gain and adiposity. Olanzapine significantly decreased voluntary locomotor activity and liraglutide co-treatment partially reversed this effect. Liraglutide improved clozapine-induced glucose intolerance.

Conclusion: Liraglutide co-treatment improved aspects of cognition, prevented obesity side-effects of olanzapine, and the hyperglycaemia caused by clozapine, when administered from the start of APD treatment. The results demonstrate a potential treatment for individuals at a high risk of experiencing adverse effects of APDs.

Keywords: Cognition; antipsychotic; glucagon-like peptide-1; liraglutide; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / drug effects*
  • Animals
  • Body Weight / drug effects*
  • Clozapine / adverse effects
  • Clozapine / antagonists & inhibitors
  • Eating / drug effects
  • Glucose Tolerance Test
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology
  • Liraglutide / pharmacology*
  • Locomotion / drug effects
  • Male
  • Maze Learning / drug effects
  • Memory, Short-Term / drug effects*
  • Olanzapine / adverse effects
  • Olanzapine / antagonists & inhibitors
  • Rats
  • Recognition, Psychology / drug effects*
  • Weight Gain / drug effects*


  • Hypoglycemic Agents
  • Liraglutide
  • Clozapine
  • Olanzapine