Pathophysiology of drug induced weight and metabolic effects: findings from an RCT in healthy volunteers treated with olanzapine, iloperidone, or placebo

Abstract

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Trial registration: ClinicalTrials.gov NCT01920802.

Keywords: Antipsychotic drugs; glucose homeostasis; obesity; randomized clinical trial; weight gain.

Conflict of interest statement

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JSB has received research funding from Novartis, Alkermes, and Otsuka. JSB serves on an advisory board for Alkermes, and is a subject matter expert for Pear Therapeutics. JAL serves on the advisory boards of Clintara, Intra-Cellular Therapies and Pierre Fabre. JAL receives grant support from Alkermes and Novartis/Novation and holds a patent from Repligen. UBP, ZF, RF, LSM, GJH, JS, SMB, IC, MR, and RLL report no competing interests.

Figures

Figure 1.

Olanzapine induces significant weight gain in healthy volunteers. (a) Subjects randomized to the olanzapine group exhibited significant weight gain (p = 0.018); placebo-treated (p = 0.43) and iloperidone-treated (p = 0.32) participants did not show any change from baseline measurement. (b) Clinically significant weight gain, defined as having gained ≥5% of initial body weight during the 28-day medication exposure, was observed in 5/7 (71%) of subjects randomized to olanzapine versus 2/7 (29%) and 0/10 in iloperidone and placebo-treated subjects, respectively.

Figure 2.

Olanzapine-induced weight gain is associated with increased caloric intake, and a tendency towards increased fat mass. (a) After 28 days of treatment, olanzapine-treated subjects showed increased caloric intake in a standardized, laboratory lunch meal (+267 kcal), whereas placeboand iloperidone-treated participants showed no change from baseline measurements. (b) Total fat mass, as assessed by DXA, was unchanged by placebo treatment, but subjects randomized to olanzapine and iloperidone groups tended towards increased truncal fat mass, as well as total adiposity from baseline measurements.