Review of: Attia E et al, Am J Psychiatry 2019;176(6):449–456 

Type of study: Randomized, double-blind, placebo-controlled trial

Antipsychotics have been tried in anorexia since 1960, but their success has been mixed and often outweighed by their risks. Seven controlled trials have tested atypical antipsychotics in anorexia, and although most were positive, their pooled benefits were too small to be detected in a ­meta-analysis (Dodd M et al, Psychother Psychosom 2015,84(2):110–116). That leaves us with an uncertainty that is best answered by a larger controlled trial, which is where this new research comes in.

In this randomized placebo-controlled trial, researchers studied the effects of olanzapine on change in body weight and obsessionality in adult outpatients (n = 152) with anorexia nervosa for 16 weeks. Nearly all patients were female (96%) and most were taking psychotropics (41%, mainly antidepressants). Average BMI was 17 and Yale-Brown Obsessive Compulsive Scale (YBOCS) was 16.5 (moderate severity). Olanzapine was started at 2.5 mg/day x 2 weeks, titrated to 5 mg/day x 2 weeks, and then increased to 10 mg/day as tolerated (average final dose 7.8 mg/day). Primary outcome measures were (1) rate of change in body weight and (2) rate of change in obsessionality measured by the YBOCS.

Relative to placebo, the olanzapine group experienced a significant increase of 0.165 BMI points, which is approximately 1 pound per month over the 16 weeks. Relative to placebo, the olanzapine group did not see a benefit in obsessionality or cognitive symptoms of anorexia, and had significantly more concerns about body weight. Lab abnormalities and hospitalization rates did not differ between the groups.

This study’s strengths include the large sample size and enrollment of diverse patients with various comorbidities that are more reflective of outpatient practice. The sample size is almost as large as all the past atypical antipsychotic studies of anorexia combined. The study’s main weaknesses include the large dropout rate (45%) and a duration that was probably not long enough to detect lab abnormality differences. On the other hand, the dropout rate was similar for olanzapine and placebo, and the data was analyzed on an intent-to-treat basis.

TCPR’s Take
Despite a positive result, these modest gains in weight do not inspire a ringing endorsement of olanzapine for anorexia. The study can’t tell us whether that weight gain was due to a therapeutic effect on anorexia or to olanzapine’s known metabolic effects, but the lack of improvement in other anorexia symptoms gives us pause. Reserve olanzapine for severe, treatment-resistant patients where weight restoration is essential, or for patients with anorexia who have comorbidities—like mood disorders—where olanzapine is indicated.