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In comes Ronald, a young man with obvious delusions but he’s keeping it together, just barely. Both you and he would like to avoid hospitalizing him for this, his first episode of psychosis. Good old olanzapine would be nice, fast, very likely to help including with his agitation as well as his thoughts. But what if it works, then what? Stay on it and gain weight? Maybe it would have been better to offer him something less likely to cause dramatic weight gain?
Hi! Jim Phelps here for the Psychopharmacology Institute. What if you could use olanzapine without causing weight gain? That would be appealing. Well, as you’ve likely heard, there’s a new version of olanzapine—combining it with samidorphan, an opiate antagonist with greater oral availability and stronger receptor affinity than naltrexone, added to the olanzapine for weight control. The simple question is: Does this new drug work? How much weight do people gain on it compared to olanzapine alone if they’ve never had an antipsychotic before? Well, now, we have a trial at least just that question. Oh, wait. First problem, 6 of the 9 authors work for the manufacturer, and the other 3 are consultants or speakers or received honoraria from the manufacturer. And the company paid the medical writers of the article. Okay, okay, these are extremely expensive studies to run and we should be glad that the company has done this and other trials, but you can be sure that everything was designed to obtain an outcome favoring their drug over placebo. So, I hope you’re already thinking, “Okay, no surprise, it was better than olanzapine alone.” But how much better? Do people taking olanzapine–samidorphan combination not gain weight at all we might hope? After all, this trial enrolled young first-episode patients. You’d hope for the best here.
Answer. Sorry. In a 12-week study, average weight gain on olanzapine alone was 4.7 kg. That’s 12 weeks. On olanzapine-samidorphan, 3.4 kg. There you have it. Over 3 months, patients on the combination gained 1.3 kg less, but they still gained a lot. In a longer trial, 24 weeks in people with a diagnosis of schizophrenia, the average weight gain on olanzapine was 5.1 kg vs 3.2 kg when combined with samidorphan. So, we’re looking at the wrong comparison, aren’t we? What you’d want to see is weight gain on olanzapine–samidorphan combination vs aripiprazole or risperidone. Does the combination bring weight gain with olanzapine down into the same range as other less problematic antipsychotics? But the drug company would be foolish to undertake that comparison, right? Why risk looking no better or worse than your competition? So, I’m about ready to just can this article and this drug, but let’s look at the discussion to see if there’s anything interesting or useful.
Oh, here’s one. Look at this. The adverse changes in lipids that you’d expect with olanzapine are also seen in patients who are taking the combination. In other words, although the combination attenuated weight gain somewhat, it did not prevent increases in triglycerides or total and LDL cholesterol or decreases in HDLs.
In summary, it does appear that olanzapine–samidorphan combination causes less weight gain than olanzapine by itself but not zero, indeed quite far from it. If it was the same price, then for patients who for one reason or another simply had to take on the metabolic risks of olanzapine, the combination would be better. So, what does it cost, say, for a month’s supply of 10 mg of olanzapine? With just a quick look at U.S. pharmacy prices, $1,500 for the combination vs $9 for generic olanzapine.
For more on this, look back at the longer 2020 trial, which was published in the American Journal of Psychiatry in the related references.
Abstract
Olanzapine/Samidorphan in Young Adults With Schizophrenia, Schizophreniform Disorder, or Bipolar I Disorder Who Are Early in Their Illness: Results of the Randomized, Controlled ENLIGHTEN-Early Study
René S Kahn, John M Kane, Christoph U Correll, Christina Arevalo, Adam Simmons, Christine Graham, Sergey Yagoda, Beibei Hu, David McDonnell
Objective: Patients with early-phase schizophrenia or bipolar I disorder (BD-I) are at greater risk for antipsychotic-associated weight gain. This 12-week, randomized, double-blind study conducted between June 2017 and December 2021 evaluated weight effects of combination olanzapine and samidorphan (OLZ/SAM) versus olanzapine in early-phase illness.
Methods: Young adults (16-39 years) with DSM-5 schizophrenia, schizophreniform disorder, or BD-I, < 4 years since symptom onset, body mass index < 30 kg/m2, and < 24 weeks' cumulative antipsychotic exposure were randomized to OLZ/SAM (5-20/10 mg/d) or olanzapine (5-20 mg/d). Primary endpoint was percent change from baseline body weight at week 12. Secondary endpoints, tested hierarchically, were proportions of patients with ≥ 10% or ≥ 7% weight gain, waist circumference change, and Clinical Global Impressions-Severity (CGI-S) change.
Results: Of 428 patients (OLZ/SAM, n = 213; olanzapine, n = 215), 408 had ≥ 1 postbaseline weight assessment and were analyzed. Percent weight change was significantly lower with OLZ/SAM versus olanzapine (4.91% vs 6.77%; least-squares mean [LSM] [SE] difference, -1.87% [0.75]; P = .012). Although fewer patients treated with OLZ/SAM had ≥ 10% weight gain, the difference was not statistically significant versus olanzapine (21.9% vs 30.4%, respectively; OR = 0.64; 95% CI = 0.39 to 1.05); hierarchical testing precluded further statistical evaluation of secondary endpoints. Proportions of patients with ≥ 7% weight gain (33.1% vs 44.8%; OR = 0.61, 95% CI = 0.39 to 0.94) and waist circumference change (2.99 vs 3.90 cm; LSM [SE] difference, -0.92 cm [0.58]; 95% CI = -2.06 to 0.22) favored OLZ/SAM. LSM (SE) CGI-S change with OLZ/SAM was -0.82 (0.06). OLZ/SAM and olanzapine had similar safety profiles, including small, similar metabolic parameter changes.
Conclusions: In patients with early-phase schizophrenia, schizophreniform disorder, or BD-I, OLZ/SAM treatment resulted in less weight gain versus olanzapine.
Trial Registration: ClinicalTrials.gov identifier: NCT03187769.
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Reference
Kahn, R. S., Kane, J. M., Correll, C. U., Arevalo, C., Simmons, A., Graham, C., Yagoda, S., Hu, B., & McDonnell, D. (2023). Olanzapine/Samidorphan in young adults with schizophrenia, schizophreniform disorder, or bipolar I disorder who are early in their illness. The Journal of Clinical Psychiatry, 84(3), 46259.
Related References
- Chaudhary, A. M. D., Khan, M. F., Dhillon, S. S., & Naveed, S. (2019). A review of samidorphan: a novel opioid antagonist. Cureus, 11(7).
- Correll, C. U., Newcomer, J. W., Silverman, B., DiPetrillo, L., Graham, C., Jiang, Y., … & Kahn, R. S. (2020). Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. American Journal of Psychiatry, 177 (12), 1168-1178.
