A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers

Abstract

Background and RationaleAtypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans.Methodology/Principal FindingsA double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged.Conclusions/SignificanceOlanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.Trial RegistrationClinicalTrials.gov NCT00741026

Second-Generation Antipsychotics Cause a Rapid Switch to Fat Oxidation That Is Required for Survival in C57BL/6J Mice

“…We observed this previously with olanzapine in rodents, 11,13 and in humans FFA lowering is also observed. 10,12,17 SGAs have a very short half-life in rodents, so it is tempting to speculate that with longer exposures facilitated by higher doses, plasma concentrations of FFA may reach a critical concentration that is insufficient to maintain energy requirements leading to the observed drops in the VO 2 at higher SGA doses. It does not seem likely that the VO 2 lowering is secondary to sedation because decreased physical activity was also observed in animals treated with aripiprazole, which did not affect VO 2 , and ANCOVA testing failed to reveal an interaction between these variables after any treatment.…”

“…In contrast, olanzapine does not increase glycerol rates of appearance in humans 17 despite causing glucose intolerance within days. 12 Furthermore, in both acute and chronic preclinical studies, basal and isoproterenolstimulated lipolyses were actually impaired in vivo by olanzapine. 13 From an energy-balance standpoint, increasing reliance on fat as a fuel while not increasing lipolysis would seem to be a potentially unsustainable situation.…”

“…For example, elevated plasma glucose, glucose intolerance, or lower glucose infusion rates during a euglycemic clamp have been observed acutely in preclinical and clinical studies within minutes or days. [11][12][13][14][15][16] Another metabolic disturbance, decreased circulating free fatty acids (FFA), has also been described after both acute (1 h to 3 days) and chronic (2-3 weeks) treatment. [11][12][13]17,18 The converse effects of SGAs on glycemia and FFA are of interest for several reasons.…”

“…For example, FFA lowering was found after risperidone and olanzapine treatment but not after aripiprazole or haloperidol treatment in humans. 10,12,17 In diabetes and other insulin-resistant states, peripheral tissues increasingly utilize fat rather than glucose as a fuel, leading to the accumulation of glucose in plasma. Similarly, in olanzapine-treated, ad libitum-fed rodents, a dramatic increase in FFA metabolic rate is observed (~2-fold), coinciding with a rapid fall in the dark-cycle respiratory exchange ratio (RER) to ~0.7, as well as glucose accumulation in plasma.…”

Atypical antipsychotics alter cholesterol and fatty acid metabolism in vitro

“…chotics has not been studied thus far. Several studies have shown decreased plasma concentration of HDL-cholesterol in subjects treated with SGAs for a long term ( 10,46,47 ). Whether the change in ABCA1 gene expression induced by antipsychotics contributes to the reduction of HDL-cholesterol levels is not known; more detailed studies are required to elucidate this important issue.…”