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Clinical Trial
. 2025 Apr 10;31(4):1010-1017.
doi: 10.1093/ibd/izae136.

Concomitant Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis or Relapsing Multiple Sclerosis

Miguel Regueiro  1 , Britta Siegmund  2 , Sara Horst  3 , Ryan Moslin  4 , Lorna Charles  4 , AnnKatrin Petersen  4 , Daniel Tatosian  4 , Hsiuanlin Wu  4 , Garrett Lawlor  4 , Monika Fischer  5 , Geert D'Haens  6 , Jean-Frederic Colombel  7
Affiliations
Clinical Trial

Concomitant Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis or Relapsing Multiple Sclerosis

Miguel Regueiro et al. Inflamm Bowel Dis. .

Abstract

Background: Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK.

Methods: Data for ozanimod 0.92 mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search ("serotonin syndrome," "neuroleptic malignant syndrome," and "malignant hyperthermia") and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred.

Results: No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies.

Conclusions: No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs.

Clinical trial registration: NCT01647516, NCT02531126, NCT02435992, NCT02576717.

Keywords: ozanimod; safety; serotonergic antidepressants; serotonin accumulation; ulcerative colitis.

Plain language summary

No evidence of increased treatment-emergent adverse effects potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and serotonergic antidepressants. Our findings support the absence of clinically meaningful ozanimod monoamine oxidase B inhibition in vivo.

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Conflict of interest statement

M.R. has served on advisory boards or as a consultant for AbbVie, Alfasigma, Allergan, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Miraca Life Sciences, Pfizer, Prometheus, Salix, Seres, Takeda, Target RWE, and UCB. B.S. has served as a consultant for AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Endpoint Health, Falk Pharma, Galapagos, Janssen, Landos, Pfizer, Prometheus, and Takeda; and has received speaker fees from AbbVie, CED Service GmbH, Eli Lilly, Falk Pharma, Ferring, Galapagos, Janssen, Novartis, Pfizer, and Takeda. S.H. has received consulting fees from AbbVie, Gilead, Janssen, and Takeda. R.M., L.C., A.P., D.T., H.W., and G.L. are employees and/or shareholders of Bristol Myers Squibb. M.F. has received consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Ferring, Pfizer, Scioto, and Seres; has received fees for lectures from Bristol Myers Squibb, Eli Lilly, and Janssen; has served on the data safety monitoring board for Rebiotix; and holds stock options with Jona Pharma. G.D. has served as a consultant for AbbVie, American Regent, Celgene, Cellceutix, Eli Lilly, Endo, Ferring Pharmaceuticals, Gilead, Janssen Ortho Biotech, Merck, Morphic, Pfizer, Prometheus Laboratories, Romark, Salix Pharmaceuticals/Valeant, Shire Pharmaceuticals, Takeda, and UCB; conducted research for Janssen Ortho Biotech and UCB; served as editor (honorarium) for Gastroenterology and Hepatology (Gastro-Hep Communications) and Springer Science and Business Media; and received book royalties from Professional Communications, Inc., and SLACK, Inc. J.-F.C. has received research grants from AbbVie, Janssen, and Takeda; has received payment for lectures from AbbVie, Amgen, Allergan, Bristol Myers Squibb, Ferring, Shire, and Takeda; has received consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Enterome, Ferring, Genentech, Gilead, Iterative Scopes, Ipsen, Immunic, Imtbio, Inotrem, Janssen, Landos, LimmaTech Biologics AG, MedImmune, Merck, Novartis, OMass, Otsuka, Pfizer, Shire, Takeda, TiGenix, and Viela Bio; and holds stock options in Intestinal Biotech Development.

Figures

Graphical Abstract
Graphical Abstract
Figure 1.
Figure 1.
Study design of the (A) pooled ulcerative colitis (UC) studies and (B) relapsing multiple sclerosis (RMS) DAYBREAK study.,aPatients randomized to ozanimod received ozanimod 0.23 mg (equivalent to ozanimod hydrochloride 0.25 mg) on days 1 to 4, ozanimod 0.46 mg (equivalent to ozanimod hydrochloride 0.5 mg) on days 5 to 7, and their assigned dose of ozanimod 0.46 or ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) starting on day 8. bPatients stratified by prior tumor necrosis factor (TNF) inhibitor exposure (yes/no). cReduction in 4-component Mayo score of ≥3 points and ≥30%, and reduction in rectal bleeding subscore (RBS) of ≥1 point or absolute RBS of ≤1 point. dDisease relapse was defined as partial Mayo score increase ≥2 points vs the partial Mayo score at maintenance period (MP) entry and absolute partial Mayo score ≥4 points, endoscopic subscore of ≥2 points, and exclusion of other causes of an increase in disease activity unrelated to underlying UC. eIn 2019, the sponsor ended the open-label extension (OLE) and rolled over all active patients who consented to a phase 3 program (all had completed at least OLE week 200). fPatients stratified by prior TNF inhibitor exposure (yes/no) and corticosteroid use (yes/no) at screening. gReduction in 3-component Mayo score of ≥2 points and ≥35%, or reduction in 4-component Mayo score of ≥3 points and ≥30%, and reduction in RBS of ≥1 point or absolute RBS of ≤1 point. hResponders assigned to ozanimod (cohorts 1 and 2) in the induction period (IP) were rerandomized 1:1 to ozanimod or placebo in a double-blind manner when entering the MP; adult patients in clinical response at week 10 of the IP who were randomized to placebo (cohort 1) continued to receive placebo in the MP in a double-blind manner. iPatients who entered from a blinded parent study or treatment period (True North cohort 1) underwent the 1-week dose escalation for ozanimod. IFN, interferon; IM, intramuscular.
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