CHICAGO — Atypical antipsychotics impact metabolic risk independent of weight gain, according to a carefully-controlled laboratory monitoring study.

Olanzapine (Zyprexa) induced insulin resistance and postprandial dysregulation over less than 2 weeks in healthy volunteers before any weight gain occurred, Karen Teff, PhD, then of the University of Pennsylvania in Philadelphia, and colleagues found.

Aripiprazole (Abilify) also induced insulin resistance that didn’t parallel the normal mechanisms in diabetes, without any free fatty acid or weight increase, the group reported here at the American Diabetes Association meeting.

”The metabolic abnormalities seen with the administration of atypical antipsychotics are generally assumed a consequence of increased body adiposity secondary to CNS-mediated changes in appetite,” Teff explained at the session.

But these findings suggest a possible class effect of the second-generation antipsychotics that can’t be entirely blamed on the weight gain they cause or the psychiatric disease they are prescribed to treat, noted Teff, who now works for the National Institute of Diabetes and Digestive and Kidney Diseases.

”From a clinical point of view, if you have someone who is actively psychotic, you need to treat them and you’re not worrying about 20 years down the road,” she told MedPage Today. ”A lot of psychiatrists are moving away from like olanzapine as a first treatment for people and they try something else, and see if something else will work first.”

While aripiprazole is considered among the least metabolically risky in the class, it wasn’t benign either.

”I actually think the aripiprazole data is even more important since that drug in particular is being touted as metabolically neutral, because it is relatively neutral with respect to weight gain,” Marilyn Ader, PhD, of Cedars-Sinai Medical Center in Los Angeles, commented from the audience.

Teff’s group kept 30 healthy men and women of normal weight and no psychiatric disease in the lab for 12 days while randomized to take olanzapine, aripiprazole, or placebo.

Their exercise was held constant to what they averaged during a week of pre-study monitoring at home.

They were allowed to eat what they wanted — surreptitiously monitored for quantity — after having completed a hunger questionnaire for every meal and snack.

Those assessment and repeats after eating showed no effect of either drug on hunger or fullness compared with placebo.

Weight, food intake, and activity levels didn’t differ at the end of the study compared with baseline.

Fasting or postprandial glucose levels and rate of glucose absorption didn’t change either.

But insulin did increase over baseline with olanzapine (change +1.2 versus -1.1 uU/mL on placebo, P=0.05), as did postprandial insulin concentrations, postprandial GLP-1, and glucagon.

C-peptide as a measure of beta-cell activity were modestly, but not statistically significantly, elevated with olanzapine.

Euglycemic, hyperinsulinemic clamping showed no pre- versus post-antipsychotic treatment impacts for endogenous glucose production, ”meaning insulin was suppressed appropriately so there was no effect on hepatic insulin sensitivity.”

But in contrast, glucose disposal and glucose infusion rate were significantly decreased with both drugs.

A mixed nutrient meal challenge showed significantly elevated insulin release after the meal among those on olanzapine, ”which may be an initiating factor in the etiology of the metabolic impairments,” Teff told attendees.

Both groups on the antipsychotic drugs showed significantly decreased insulin sensitivity, adjusted for difference in basal insulin and glucose, with no change in the disposal index.

Overall, the picture was of direct effects on tissue function independent of weight gain in this short period of dosing, although the weight gain that does occur will exacerbate the metabolic effects, Teff pointed out.

”I am sure if they are maintained on these drugs we are going to see an increase,” she said.

Study limitations included the short duration, lack of data on body composition, and less than optimal methods to measure hepatic insulin clearance.

”It’s short-term and the half-life is 54 days. Five half-lives is where you get the appropriate drug level,” commented David Klein, MD, PhD, who works in the residential psychiatric facility of Cincinnati Children’s Hospital. ”There would have been a lot greater effect if they had waited until the drug achieved its steady state and these are not psychiatric patients.”

Also, the study may have been underpowered to detect small differences with aripiprazole, Teff noted. Aripiprazole was ”clearly not metabolically neutral” and increased body adiposity in a prior animal study done by Ader’s group.