Review of: Kahn RS et al, J Clin Psychiatry 2023;84(3):22m14674

STUDY Type: Randomized controlled trial

Olanzapine is approved for use in teens 13–17 years for schizophrenia and acute mania and for ages 10 and up for bipolar depression (in combination with fluoxetine). Despite its efficacy, olanzapine is associated with profound weight gain and metabolic side effects, limiting its use in children and teens. In our treatment algorithms for managing weight gain with D2 agonists (aka antipsychotics), we often use off-label approaches including medications that are FDA approved for adults. OLZ/SAM, a combination of olanzapine with samidorphan, was approved in 2021 for adults with schizophrenia, acute mania, and mixed episodes of bipolar I disorder. Samidorphan is an opioid antagonist meant to reduce weight gain. Could OLZ/SAM become an effective off-label approach in children and teens?

In this industry-funded randomized controlled trial, researchers looked at 428 young adults between ages 16 and 39. All study participants presented within four years of symptom onset of schizophrenia, schizophreniform disorder, or bipolar I disorder. The study assessed the comparative weight-sparing effect of OLZ/SAM versus olanzapine alone. None of the patients were obese at the outset of the study. At the end of 12 weeks, patients taking OLZ/SAM were less likely to have gained weight than those on olanzapine alone (4.9% compared to 6.8%). Those on OLZ/SAM who did gain weight gained an average of 3.4 kg, while those on olanzapine gained an average of 4.7 kg. The difference in weight gain was apparent at six weeks and continued until the end of the study.

Equal numbers of patients in these groups experienced mild to moderate side effects, which included sleepiness, dry mouth, and constipation. Both groups had similarly modest changes in metabolic laboratory parameters, including lipids and glucose. More study participants experienced severe adverse effects on olanzapine alone (5.1% compared to 0.9%). One participant had a seizure from OLZ/SAM.

Carlat Take

Longer studies free from industry influence are needed since these conditions require long-term medication treatment and industry influences tend to be associated with optimistic results. Studies in children would also be useful. For now, we should stick with our current toolkit of agents used to treat or prevent antipsychotic-induced weight gain, such as metformin and topiramate, and we should favor antipsychotics with less metabolic impact when possible, such as ziprasidone and lurasidone.