Letter to the Editor

Alpha Psychiatry 2022;23(4):210-211

DOI: 10.5152/alphapsychiatry.2022.22881

The Facts and Fiction of Olanzapine-Samidorphan Fixed Dose Combination

Nileswar Das¹

Abdul Faheem²

Sheikh Shoib³

¹ All India Institute of Medical Sciences, New Delhi, India

² Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry, India

³ Jawaharlal Nehru Memorial Hospital, Srinagar, Kashmir, India

Corresponding author: Nileswar Das ✉ dr.nileswar@aiims.edu

Cite this article as: Das N, Faheem A, Shoib S. The facts and fiction of olanzapinesamidorphan fixed dose combination. Alpha Psychiatry. 2022;23(4):210-211.

Dear Editor,

Olanzapine is one of the oldest (patented in 1971) second-generation antipsychotic (SGA) but remained a first-line treatment option for both schizophrenia and bipolar affective disorder (BPAD) in most treatment guidelines to date. A significant side effect of olanzapine is higher rates of weight gain and metabolic derangements. Several strategies have been adopted to mitigate the side effect of weight gain, including behavioral modifications, dose optimization, and the addition of other agents like metformin, topiramate, or, lately, samidorphan.

Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a μ-opioid receptor antagonist and a partial agonist at the κ- and δ-opioid receptors. It has been tested as a sole agent or in various combinations to treat different psychiatric illnesses. One such combination is ALKS-3831, a fixed-dose combination of olanzapine and samidorphan, recently approved by USFDA for schizophrenia and BPAD-I. Multiple studies have been conducted to assess the effectiveness of olanzapine and samidorphan combination (OSC) to alleviate the issue of weight gain.¹,² For example, Correll et al³ did a 24-week double-blind, randomized clinical trial demonstrating significantly lesser weight gain with OSC than olanzapine. Similar results were produced by Silverman⁴ on healthy adults and Martin⁵ on individuals with schizophrenia.

Despite the renewed interest, a few key questions regarding OSC remain unanswered. Firstly, the response of lesser weight gain was not translated into the changes in the biochemical parameters (e.g., insulin insensitivity, blood glucose, serum lipid), unlike the findings from animal studies.² Therefore, it is unknown if the benefit of lesser (unknown if lower or slower) weight gain extends beyond the cosmetic effects! Considering newer SGAs with minimum metabolic side effects (e.g., aripiprazole, lurasidone), future trials are needed to compare each against OSC. Secondly, available studies have demonstrated the effectiveness of OSC in comparison to olanzapine plus placebo. Although in a real-world scenario, a more precise way of testing this hypothesis may be achieved by comparing OSC with olanzapine plus metformin or topiramate.⁶ Not only because metformin and topiramate are already existing cheaper therapeutic options but also because they are known to improve metabolic dysfunctions. Thirdly, the long-term effectiveness and adherence to treatment of samidorphan, especially in individuals with pre-existing mood disorders, is yet to be explored. Theoretically, opioid receptor modulation can alter mood symptoms. Understandably, the long-term safety of samidorphan in BPAD and schizoaffective disorder needs to be evaluated with more precise research hypotheses. Fourthly, OSC is likely to provide a better treatment adherence due to reduced pill burden but limits the flexibility of samidorphan dose titration in the post-marketing trials. It is important from an ethnopharmacological perspective because of known genetic variation in drug metabolism. Finally, in the absence of an established mechanism, guarded metabolic improvement, and the added cost of treatment, the long-term “overall benefit” of OSC remained untested, especially for illnesses like schizophrenia or BPAD, where long-term medication treatment is a norm.

To sum up, the addition of samidorphan to olanzapine has shown to mitigate the side effect of weight gain. Some puzzles in the bigger landscape comparing OSC with available pharmacotherapy remained unsolved. The impact of cost-of-care analyses can be guideline-changing.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - N.D.; Design - N.D., A.F.; Supervision - S.S.; Resource - N.D., A.F.; Materials - N.D., A.F.; Data Collection and/or Processing - N.D., A.F.; Analysis and/or Interpretation - N.D., A.F., S.S.; Literature Search - N.D.; Writing - N.D.; Critical Reviews - A.F., S.S.

Declaration of Interests: The authors have no conflicts of interest to declare.

Funding: The authors declared that this study has received no financial support.

References

  1. Kahn, RS, Silverman, BL, & DiPetrillo, L. (2021). A phase 3, multicenter study to assess the 1-year safety and tolerability of a combination of olanzapine and samidorphan in patients with schizophrenia: results from the ENLIGHTEN-2 long-term extension. Schizophr Res, 232, 45-53, (https://doi.org/10.1016/j.schres.2021.04.009).

  2. Srisurapanont, M, Suttajit, S, & Likhitsathian, S. (2021). A meta-analysis comparing short-term weight and cardiometabolic changes between olanzapine/samidorphan and olanzapine. Sci Rep, 11, 7583.

  3. Correll, CU, Newcomer, JW, & Silverman, B. (2020). Effects of olanzapine combined with Samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry, 177(12), 1168-1178, (https://doi.org/10.1176/appi.ajp.2020.19121279).

  4. Silverman, BL, Martin, W, Memisoglu, A, DiPetrillo, L, Correll, CU, & Kane, JM. (2018). A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. Schizophr Res, 195, 245-251, (https://doi.org/10.1016/j.schres.2017.10.014).

  5. Martin, WF, Correll, CU, & Weiden, PJ. (2019). Mitigation of olanzapine-induced weight gain with Samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. Am J Psychiatry, 176(6), 457-467, (https://doi.org/10.1176/appi.ajp.2018.18030280).

  6. Buchanan, RW. (2020). How much of an advance is the addition of Samidorphan to olanzapine? Am J Psychiatry, 177(12), 1113-1114, (https://doi.org/10.1176/appi.ajp.2020.20091425).

Received: February 14, 2022
Accepted:9 April 2022

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