Received for publication January 29, 2008.
Revised June 19, 2008.
Accepted for publication June 19, 2008.

Olanzapine but not the novel atypical antipsychotic ST2472 chronic administration induces weight gain, hyperphagia and metabolic dysregulation in mice

Abstract

A mouse model of atypical antipsychotic (AAP)-associated adverse effects was used to compare the liability to induce weight gain, food intake and metabolic alterations following chronic olanzapine (OL) and ST2472 (ST) administration. By adding two equipotent doses (3 and 6 mg/kg) of either OL or ST to a high-sweet high-fat (HS-HF) diet, mice were allowed to self-administer drugs up to fifty days. Body weight and food intake were evaluated daily. Locomotor activity was recorded over 48 hours at two different time points. Dyslipidemia was measured by central visceral obesity. Blood serum levels of insulin (IN), glucose (Glu), triglycerides (TR), non-esterified fatty acids (NEFA), cholesterol (Ch) and ketone bodies (Ke) were quantified. OL treatment at 3 mg/kg enhanced body weight whereas, at the highest dose, the increase became evident only during the last ten days of treatment. OL (3 mg/kg) increased HS-HF intake over time, while the highest dose reduced intake during the second ten and final ten days of administration. Both compounds induced nocturnal hypomotility at the highest dose. In contrast to ST, 3 mg/kg OL elevated serum levels of IN, Glu, TR, NEFA, Ch and Ke while 6 mg/kg those of Glu, TR and Ch. By contrast, ST did not affect weight gain, food intake and metabolic markers. Given the similarities between OL-induced obesogenic effects and medical reports, this study further supports the view that ST may represent a new class of agents characterized by a low propensity to induce side-effects with promising clinical safety.

Key words: ST2472, adverse effects, atypical antipsychotics, metabolic dysregulation, obesity, olanzapine