PM426. Effect of a glucagon-like peptide 1 (GLP-1) receptor agonist, liraglutide, on cognition and body weight during antipsychotic treatment

Abstract Background: Second-generation antipsychotics (SGAs), such as olanzapine, are used to treat schizophrenia; however, they have minimal benefits for cognitive deficits and cause metabolic side-effects such as obesity [1, 2]. Obesity has been linked to increased cognitive impairment [3], complicating the health issues of people with schizophrenia. Liraglutide is a synthetic glucagon-like peptide-1 (GLP-1) receptor agonist with anti-obesity and neuroprotective properties [4, 5]; however, whether liraglutide can improve cognition during olanzapine treatment is unclear. The aim of this study was to examine the effects of liraglutide co-treatment on cognition and metabolic parameters during olanzapine treatment. Methods: Sprague-Dawley rats were administered olanzapine (2mg/kg), liraglutide (0.4mg/kg), olanzapine+liraglutide co-treatment or vehicle (control) (n=12/group) for six weeks. Body weight, food intake and locomotor activity were recorded. Novel object recognition (NOR) and T-maze tests were conducted to examine recognition and working memory. Post-mortem white adipose tissue weight was recorded. Results: Olanzapine caused significant body weight gain and increased white adipose tissue mass (p<0.05 vs control), whereas liraglutide co-treatment significantly reduced body weight and adiposity (p<0.001 vs olanzapine). Olanzapine induced hypolocomotion (p<0.001 vs control), whereas liraglutide co-treatment significantly increased locomotor activity (p<0.05 vs olanzapine). In the NOR test, olanzapine-treated rats spent significantly less time exploring the novel object, and this was significantly improved in the liraglutide co-treatment group (p<0.01 vs olanzapine). There was no effect of treatment on correct entries in the T-maze test (p>0.05 vs control). Conclusion: This study demonstrates that liraglutide co-treatment can improve locomotor activity, decrease adiposity and prevent weight gain side-effects associated with olanzapine administration. Liraglutide co-treatment was able to improve recognition memory impairment caused by olanzapine treatment; however, it had no effect on working memory. Further studies are required to understand the mechanisms underlying these changes, and to elucidate whether a link exists between olanzapine-induced obesity and liraglutide’s effect on cognition. Reference 1. Keefe, R.E., et al., Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the catie trial. Archives of General Psychiatry, 2007. 64(6): p. 633–647. 2. Weston-Green, K., X.-F. Huang, and C. Deng, Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor. CNS Drugs, 2013. 27(12): p. 1069–80. 3. Prickett, C., L. Brennan, and R. Stolwyk, Examining the relationship between obesity and cognitive function: a systematic literature review. Obes Res Clin Pract, 2015. 9(2): p. 93–113. 4. McClean, P.L., et al., The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci, 2011. 31(17): p. 6587–94. 5. Porter, W.D., et al., Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice. International Journal of Obesity, 2013. 37(5): p. 678–84.