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

Overview

Journal J Psychopharmacol

Publisher Sage Publications

Specialty Pharmacology

Date 2024 Sep 5

PMID 39233601

Authors

Imran B Chaudhry

Muhammad Omair Husain

Ameer B Khoso

Tayyeba Kiran

Muhammad Ishrat Husain

Inti Qurashi

Raza Ur Rahman

Nasir Mehmood

Richard Drake

Nusrat Husain

Bill Deakin

Affiliations

Soon will be listed here.

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 ( = 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; = 0.01) for simvastatin and -1.6 points for ondansetron (95%CIs -3.00, -0.14; = 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.

References

Fiebich B, Akundi R, Lieb K, Candelario-Jalil E, Gmeiner D, Haus U . Antiinflammatory effects of 5-HT3 receptor antagonists in lipopolysaccharide-stimulated primary human monocytes. Scand J Rheumatol Suppl. 2004; 119:28-32. View

Ghanizadeh A, Rezaee Z, Dehbozorgi S, Berk M, Akhondzadeh S . Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial. Psychiatry Res. 2014; 219(3):431-5. DOI: 10.1016/j.psychres.2014.06.039. View

Sommer I, de Witte L, Begemann M, Kahn R . Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012; 73(4):414-9. DOI: 10.4088/JCP.10r06823. View

Noroozian M, Ghasemi S, Hosseini S, Modabbernia A, Khodaie-Ardakani M, Mirshafiee O . A placebo-controlled study of tropisetron added to risperidone for the treatment of negative symptoms in chronic and stable schizophrenia. Psychopharmacology (Berl). 2013; 228(4):595-602. DOI: 10.1007/s00213-013-3064-2. View

Costall B, Naylor R . Astra Award Lecture. The psychopharmacology of 5-HT3 receptors. Pharmacol Toxicol. 1992; 71(6):401-15. DOI: 10.1111/j.1600-0773.1992.tb00570.x. View

Ohlsen R, Williamson R, Yusufi B, Mullan J, Irving D, Mukherjee S . Interrater reliability of the Antipsychotic Non-Neurological Side-Effects Rating Scale measured in patients treated with clozapine. J Psychopharmacol. 2008; 22(3):323-9. DOI: 10.1177/0269881108091069. View

Khodaie-Ardakani M, Seddighi S, Modabbernia A, Rezaei F, Salehi B, Ashrafi M . Granisetron as an add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. J Psychiatr Res. 2013; 47(4):472-8. DOI: 10.1016/j.jpsychires.2013.01.011. View

Sakata K, Gamou T, Tada H, Hayashi K, Ino H, Yamagishi M . Low Baseline High-Sensitive C-Reactive Protein is Associated with Coronary Atherosclerosis Regression: Insights from the MILLION Study. J Atheroscler Thromb. 2018; 26(5):442-451. PMC: 6514178. DOI: 10.5551/jat.44255. View

. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990; 16(3):199-208. DOI: 10.1016/0168-8510(90)90421-9. View

10.

Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, Shariat S, Rezaei F, Salehi B . Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. Int Clin Psychopharmacol. 2016; 32(2):87-94. DOI: 10.1097/YIC.0000000000000159. View

11.

Hall R . Global assessment of functioning. A modified scale. Psychosomatics. 1995; 36(3):267-75. DOI: 10.1016/S0033-3182(95)71666-8. View

12.

Addington J, Shah H, Liu L, Addington D . Reliability and validity of the Calgary Depression Scale for Schizophrenia (CDSS) in youth at clinical high risk for psychosis. Schizophr Res. 2014; 153(1-3):64-7. PMC: 3982913. DOI: 10.1016/j.schres.2013.12.014. View

13.

Vincenzi B, Stock S, Borba C, Cleary S, Oppenheim C, Petruzzi L . A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism. Schizophr Res. 2014; 159(2-3):395-403. PMC: 4311769. DOI: 10.1016/j.schres.2014.08.021. View

14.

Weiser M, Levi L, Park J, Nastas I, Matei V, Davidson M . A randomized controlled trial of add-on naproxen, simvastatin and their combination for the treatment of schizophrenia or schizoaffective disorder. Eur Neuropsychopharmacol. 2023; 73:65-74. DOI: 10.1016/j.euroneuro.2023.04.007. View

15.

Kulkarni J, Thomas N, Hudaib A, Gavrilidis E, Gurvich C . Ondansetron - a promising adjunctive treatment for persistent schizophrenia. J Psychopharmacol. 2018; 32(11):1204-1211. DOI: 10.1177/0269881118798608. View

16.

Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K . Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet. 2014; 383(9936):2213-21. DOI: 10.1016/S0140-6736(13)62242-4. View

17.

Tang T, Song Y, Ding Y, Liao Y, Yu X, Du R . Atorvastatin upregulates regulatory T cells and reduces clinical disease activity in patients with rheumatoid arthritis. J Lipid Res. 2011; 52(5):1023-32. PMC: 3073458. DOI: 10.1194/jlr.M010876. View

18.

Levkovitz Y, Arnest G, Mendlovic S, Treves I, Fennig S . The effect of Ondansetron on memory in schizophrenic patients. Brain Res Bull. 2005; 65(4):291-5. DOI: 10.1016/j.brainresbull.2003.09.022. View

19.

Akhondzadeh S, Mohammadi N, Noroozian M, Karamghadiri N, Ghoreishi A, Jamshidi A . Added ondansetron for stable schizophrenia: a double blind, placebo controlled trial. Schizophr Res. 2008; 107(2-3):206-12. DOI: 10.1016/j.schres.2008.08.004. View

20.

Birchwood M, Smith J, Cochrane R, Wetton S, Copestake S . The Social Functioning Scale. The development and validation of a new scale of social adjustment for use in family intervention programmes with schizophrenic patients. Br J Psychiatry. 1990; 157:853-9. DOI: 10.1192/bjp.157.6.853. View