Assessment of lipid response to acute olanzapine administration in healthy adults

Abstract Background Atypical antipsychotics (AAP) can induce hypertriglyceridaemia and type 2 diabetes. Weight gain contributes to these effects, but there is evidence that AAP can have acute metabolic effects on glycaemia independent of weight change. Aims We undertook a single‐blind crossover study in eight healthy volunteers to assess whether the AAP olanzapine acutely increases triglyceride and free fatty acid in response to a high‐fat oral load (50 g fat with no carbohydrate) and whether these effects are attenuated by the dopamine D2 receptor agonist bromocriptine. Methods Participants underwent three treatments in random order: Olanzapine 10 mg plus placebo (OL + PL), Olanzapine 10 mg plus bromocriptine 5 mg (OL + BR) and placebo plus placebo (PL + PL). Results Olanzapine increased plasma prolactin, an effect that was reversed by co‐administration of the D2 receptor agonist bromocriptine (P = .0002). There were no significant differences in postprandial triglyceride (P = .8), free fatty acid (P = .4) or glucose (P = .8). Conclusion These results suggest that AAPs likely do not directly increase postprandial lipids but may do so indirectly via changes in body weight and/or glycaemia.


| INTRODUC TI ON
Insulin resistance and type 2 diabetes are associated with increased triglyceride (TG)-rich lipoproteins in the fasted and fed state. There is considerable evidence that postprandial hypertriglyceridaemia is a major cardiovascular risk factor.( 1,2 ) Atypical antipsychotics (AAPs) such as olanzapine are effective therapies for schizophrenia and psychosis but increase the risk for insulin resistance, type 2 diabetes and hypertriglyceridaemia.( 3 ) Weight gain, a recognized adverse effect of AAPs, is likely a major contributor to these adverse metabolic effects.
However, there is evidence that AAPs can have acute metabolic effects independent of weight gain. A single dose of olanzapine prior to a frequently sampled intravenous glucose tolerance test in healthy volunteers decreased glucose effectiveness, raised fasting glucose and decreased fasting free fatty acids.( 4 ) The mechanisms underlying these effects are not fully elucidated but D2 receptor antagonism may contribute. Notably, bromocriptine, a D2 receptor agonist, is an approved treatment for type 2 diabetes and reduces plasma TG. ( 5,6 ) The acute effects of AAPs, independent of weight gain, on postprandial lipids have not been established. Further, whether these effects are dependent on acute changes in glycaemia and insulin sensitivity has not been determined. In addition, the role of D2 receptor antagonism in these potential metabolic effects is unknown. In this study, we assessed the acute effects of olanzapine on postprandial TG and free fatty acid in healthy, lean volunteers.
As carbohydrate ingestion and changes in postprandial insulin can affect circulating lipids,( 7-9 ) we assessed the acute effect of a 50-g fat load with negligible carbohydrate and protein. This study design enabled us to evaluate the acute effect of olanzapine independent of weight change and acute changes in glycaemia. We also investigated whether co-administration of bromocriptine, a dopamine (D2) receptor agonist, attenuated/reversed any acute effects of olanzapine.

| S TUDY DE S I G N AND ME THODS
The study was approved by the Institutional Review Board of University Health Network in accordance with the Declaration of Helsinki. All participants gave written, informed consent.
Healthy adults with no co-morbidities or prescription medications were recruited (Table 1) in this single-blind crossover study with 3 visits in random order separated by 2-4 weeks: Olanzapine 10 mg plus placebo (OLA + PL), Olanzapine 10 mg plus bromocriptine 5 mg (OLA + BR) and placebo plus placebo (PL + PL). Following an overnight fast, subjects ingested a high-fat drink providing 50 g of fat with no carbohydrate and protein (Calogen, Nutricia). Concomitantly, subjects were given oral olanzapine/bromocriptine/placebo treatments.
Following treatment administration, hourly BP and pulse rate measurements were taken. Blood samples were collected at regular intervals for 8 hours after treatment. Samples were centrifuged and plasma extracted and stored at −20°C until further analysis. Plasma was analysed for glucose, TGs and free fatty acids by enzymatic assay. Plasma insulin and serum prolactin were analysed by radioimmunoassay and a chemiluminescent detection (Abbott Architect), respectively.
We recruited thirteen participants, of whom eight subjects completed all visits with generation of data. Of the remaining five participants, 1 did not fit study inclusion criteria and was withdrawn, 1 withdrew consent and 2 were lost to follow-up after their screening visit. A 5th participant completed 1 study visit only with administration of placebo/placebo. Here, we have presented data on the eight participants who completed all three study visits.
Incremental area under the curve was calculated by the trapezoid method for data normalized to baseline and analysed by PROC GLM with Tukey's adjustment (SAS version 9.4, SAS Institute Inc).
Time courses were analysed by PROC MIXED of SAS with time as a repeated measure, where time, treatment and treatment × time interaction were considered fixed effects and participants were considered random effects. First-order autoregressive covariance structure was assumed. All data are expressed as mean ± SEM.  This study was designed to assess the acute effect of olanzapine independent of changes in glycaemia, and therefore, we used a high-fat liquid with negligible carbohydrate and protein. As expected, no changes were seen in plasma glucose across treatments.

| D ISCUSS I ON
Further studies are needed to assess the acute response to a mixed macro-nutrient meal following administration of olanzapine.
The inherent limitations of small number of subjects and a single dose design preclude definitive conclusions; however, our study did not show a direct effect of olanzapine on lipid metabolism, and thus favours prolonged weight gain and/or dysglycaemia as a major mechanism for dyslipidaemia observed in patients receiving atypical antipsychotic drugs.

ACK N OWLED G EM ENTS
The authors wish to acknowledge Suzana Tavares, Brenda Hughes and Carla Lorenco for nursing assistance and Linda Szeto for

CO N FLI C T O F I NTE R E S T
SD has received consulting fees and speaker fees from Eli Lilly and Novo Nordisk.

AUTH O R CO NTR I B UTI O N S
SD designed the experiments. P.S and AN performed data analyses and prepared the manuscript. SD edited the manuscript.

E TH I C S S TATEM ENT
This study was approved by the Research Ethics Board, University Health Network and Health Canada.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no additional data were created or analysed in this study.