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Randomized Controlled Trial
. 2024 Sep;38(9):818-826.
doi: 10.1177/02698811241267836. Epub 2024 Sep 5.

Beneficial adjunctive effects of the 5HT3 receptor antagonist ondansetron on symptoms, function and cognition in early phase schizophrenia in a double-blind, 2 × 2 factorial design, randomised controlled comparison with simvastatin

Imran B Chaudhry  1   2   3   4 , Muhammad Omair Husain  5   6 , Ameer B Khoso  3 , Tayyeba Kiran  3 , Muhammad Ishrat Husain  5   6 , Inti Qurashi  7 , Raza Ur Rahman  2 , Nasir Mehmood  3 , Richard Drake  4   8 , Nusrat Husain  4   8   9 , Bill Deakin  4   8
Affiliations
Randomized Controlled Trial

Beneficial adjunctive effects of the 5HT3 receptor antagonist ondansetron on symptoms, function and cognition in early phase schizophrenia in a double-blind, 2 × 2 factorial design, randomised controlled comparison with simvastatin

Imran B Chaudhry et al. J Psychopharmacol. 2024 Sep.

Abstract

Background: Variable benefits have been reported from the adjunctive use of simvastatin and the 5HT3 receptor antagonist, ondansetron, in patients with schizophrenia. We investigated their independent efficacy and possible synergy to improve negative symptoms of schizophrenia within a single trial.

Methods: A 6-month, randomised, double-blind, placebo-controlled trial with a 4-arm, 2 × 2 factorial design, in three centres in Pakistan. In total, 303 people with stable treated schizophrenia aged 18-65 were randomly allocated to add-on ondansetron, simvastatin, both or neither. The primary outcome was a Positive and Negative Syndrome Scale (PANSS) negative score at 3 and 6 months.

Results: Mixed model analysis and analysis of covariance revealed no main effects of simvastatin or ondansetron but a significant negative interaction between them (p = 0.03); when given alone, both drugs significantly reduced negative symptoms compared to placebo but they were ineffective in combination. Individual treatment effects versus placebo were -1.9 points (95%CIs -3.23, -0.49; p = 0.01) for simvastatin and -1.6 points for ondansetron (95%CIs -3.00, -0.14; p = 0.03). Combined treatment significantly increased depression and side effects. In those with less than the median 5 years of treatment, ondansetron improved all PANSS subscales, global functioning measures and verbal learning and fluency, whereas simvastatin did not.

Conclusion: Small improvement in negative symptoms on simvastatin and ondansetron individually are not synergistic in combination in treating negative symptoms of schizophrenia. Ondansetron showed broad efficacy in patients on stable antipsychotic treatment within 5 years of illness. The findings suggest that ondansetron should be evaluated in patients at risk of psychosis or early in treatment.

Keywords: Ondansetron; clinical trial; negative symptoms; schizophrenia; simvastatin.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: I.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. M.I.H. has served as an advisor to MindSet Pharma, Psyched Therapeutics and Wake Network and reports grants from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research, CAMH Foundation, Physician’s Services Incorporated Foundation and University of Toronto. M.I.H., I.B.C. and N.H. were previously trustees of the Pakistan Institute of Learning and Living. B.D. has share options in P1vital.com and is a PI on MRC grant MRC grant MR/S037675/1.

Figures

Figure 1.
Figure 1.
Patient flow through the study.
Figure 2.
Figure 2.
Ondansetron has a greater therapeutic effect in those with less than 5 years of illness. Grey histograms: Mean + SEM baseline scores PANSS total and Social Functioning Scores; blue and pink histograms are overall endpoint scores, respectively, of those with above and below median durations of illness. The ondansetron group improved significantly more than the Pbo-Pbo group in those with shorter durations of illness. No effect of treatment group in those with longer illnesses. The minimum score on PANSS total is 30. PANSS: Positive and Negative Syndrome Scale; Pbo: Placebo; Ondansetron: ondansetron + placebo simvastatin; Simvastatin: simvastatin + placebo ondansetron; Ond + Sim: ondansetron + simvastatin combination.
See this image and copyright information in PMC

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