title: Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity.
abstract: Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, and 6mg/kg/d), paliperidone (1.5, 3, and 6mg/kg/d), olanzapine (2.5, 5, and 10mg/kg/d), quetiapine (5, 10, and 20mg/kg/d), haloperidol (1, and 3mg/kg/d) or vehicle through their drinking water for 40days. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, 'desaturation index') were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG and glucose levels, and that concomitant elevations in PUFA biosynthesis oppose these effects.
authors.affiliation: Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45219, United States. robert.mcnamara@uc.edu
authors.forename: Robert K
authors.initials: RK
authors.lastname: McNamara
authors.forename: Ronald
authors.initials: R
authors.lastname: Jandacek
authors.forename: Therese
authors.initials: T
authors.lastname: Rider
authors.forename: Patrick
authors.initials: P
authors.lastname: Tso
authors.forename: Allyson
authors.initials: A
authors.lastname: Cole-Strauss
authors.forename: Jack W
authors.initials: JW
authors.lastname: Lipton
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D060766:Drinking Water / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019518:Postprandial Period / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood*
chemical_list: D014150:Antipsychotic Agents; D060766:Drinking Water; D012333:RNA, Messenger; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase; D005947:Glucose