Antipsychotics Disorders Medications Research Schizophrenia and Psychosis Side Effects

Less Weight Gain With ODT Olanzapine? Maybe.

July 28, 2026by Chris Aiken, MD0

The randomized trials were negative, but a meta-analysis finds a signal

STUDY: Bak M et al, Journal of Clinical Psychopharmacology 2026

STUDY TYPE: Systematic review and meta-analysis

FUNDING: Independent

Background

Olanzapine orally disintegrating tablet (ODT) is valued in emergency settings for its faster onset of action, peaking about an hour earlier than standard tablets (3.5 vs 4.4 hours).

When ODT was first released as Zyprexa Zydis, we saw reports of weight loss after switching to it, but the trials were not randomized. Later, four randomized trials found no difference, and the idea was put to rest.

Now, a meta-analysis detects a signal, so how do we make sense of these conflicting results?

The Study

Ten studies (five randomized trials, five cohort studies) comparing orally disintegrating olanzapine with standard tablets.
Follow-up ranged from 4 weeks to a year.

Results

ODT caused less weight gain in antipsychotic-naïve (a 2 lbs / 0.9 kg difference, p = 0.008), but not in patients already on antipsychotics (the had a 1.3 lb / 0.61 kg difference which was not statistically significant).

The results tell us about the difficulties of interpreting data. Here are two opposing ways to interpret them.

Argument for a Real Difference: Assay Sensitivity

The best way to show a difference is to test the treatment in patients who are likely to respond (assay sensitivity).

Antipsychotic-naive patients are very sensitive to weight gain, so it makes sense that trials focused on this population would detect a difference.

Also, if the difference was indeed small, it may not be detectable unless we pool together enough trials to d

Argument for No Difference: Publication Bias

We see this problem a lot in psychiatry. Early, non-randomized trials are positive, but followed by negative randomized trials.

Why? It’s easy to run non-randomized trials. Many clinicians test out ideas in practice, or scroll through EMRs looking for a signal, but only publish the positive results. For every positive trial, dozens of others that saw no difference may have kept quiet.

The same bias applies to secondary analyses of randomized trials, which are easy to run and unlikely to get published unless they turn up positive.

For olanzapine ODT, the only primary trials to show a difference were not randomized, and the only randomized trial to show a difference was a secondary analysis (and was only marginally positive, with 38 patients and a p value of 0.4). That suggests publication bias drove the signal.

A Biological Rationale?

When statistics are uncertain, a clear biological rationale may tip the balance. In statistics, this is the pretest probability: How likely was this idea to begin with?

The theory is that olanzapine ODT mostly skips first-pass metabolism in the liver, producing fewer metabolites. However, this doesn’t hold up, as there is no evidence that its metabolites cause weight gain. The most-studied metabolite, N-desmethyl-olanzapine, protects against weight gain and diabetes in rodents.