New Antipsychotic Combo for Bipolar Disorder Approved by FDA

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When I had a severe manic episode a couple years ago, I was prescribed olanzapine (Zyprexa). I responded to it quickly. It helped me to sleep when I had only been able to doze off for a few minutes a night. My grandiose plans and flights of fancy were tamped down, and my "super-senses" and hyper-religiosity subsided.

I also gained 20 pounds in a month. I had gone from burning calories faster than I could take them in to feeling like Lucy and Ethel in the chocolate factory—the calories just kept coming faster and faster and my body couldn't do anything but stuff them wherever it could. That and severe muscle soreness led to trying other medications, and my story isn't unique. Weight gain from antipsychotics is a major contributor to patient noncompliance, and olanzapine causes significantly more weight gain than most other antipsychotics. Patients on olanzapine gain an average of 9 to 17 pounds in the first eight to 10 weeks of treatment.

The high risk for weight gain with olanzapine has been linked to its actions at serotonin 5-HT2A and 5-HT2C receptors, dopamine D2 and D3 receptors, histamine H1 receptors, and muscarinic M3 receptors. Olanzapine affects neuropeptides associated with appetite control and energy metabolism such as leptin, adiponectin, and ghrelin, and has been shown to induce food craving and binge eating.

Which is why the June 1 press release from biopharmaceutical company Alkermes is potentially so significant. The Dublin-based drugmaker announced that the U.S. Food and Drug Administration (FDA) has approved its new treatment for adults with bipolar I disorder or schizophrenia: a monotherapy that provides the same efficacy as olanzapine but with less weight gain. The monotherapy is named LYBALVI™ and comprises olanzapine combined with the new chemical entity, samidorphan.

Samidorphan is a novel antagonist of µ-opioid receptors, one of the three types of opioid receptors to which endogenous opioid peptides bind. The effect of the opioid system on homeostatic and hedonistic control of food consumption has been well established, although the precise mechanism by which opioids impact food intake is not clearly understood.

Source: Photo by Anna Shvets from Pexels.

"Samidorphan is believed to limit the pleasure of food intake that has been enhanced by olanzapine," explained Joseph McEvoy, the leader of phase III clinical trials on the olanzapine-samidorphan combination and a professor of psychiatry at Augusta University and Duke University Medical Center. Patients in the study had a 50% reduced chance of gaining a clinically significant amount of weight compared to olanzapine alone while still showing significant improvement and maintenance in clinical measures of efficacy.

Due to cerebrovascular adverse reactions in certain elderly patients, LYBALVI™ is not approved for patients with dementia-related psychosis. The olanzapine-samidorphan combination is also contraindicated for patients using opioids or currently undergoing opioid withdrawal, due to the tendency for samidorphan to precipitate withdrawal in patients who are dependent on opioids.

For schizophrenia, the combination of olanzapine and samidorphan is indicated as a once-daily, oral maintenance monotherapy, while for bipolar I disorder the drug is approved as either a maintenance monotherapy or for the acute treatment of manic or mixed episodes as an adjunct to lithium or valproate. The new atypical antipsychotic will be formulated in fixed-dosage strengths containing 10 mg of samidorphan and either 5 mg, 10 mg, 15 mg, or 20 mg of olanzapine.

LYBALVI™ is expected to be available in the U.S. in the fourth quarter of 2021.