Efficacy and Safety of Roluperidone for the Treatment of Negative Symptoms of Schizophrenia

Overview

Journal Schizophr Bull

Publisher Oxford University Press

Specialty Psychiatry

Date 2022 Feb 25

PMID 35211743

Authors

Michael Davidson

Jay Saoud

Corinne Staner

Nadine Noel

Sandra Werner

Elisabeth Luthringer

David Walling

Mark Weiser

Philip D Harvey

Gregory P Strauss

Remy Luthringer

Affiliations

Soon will be listed here.

Abstract

Background: This is a placebo-controlled multi-national trial of roluperidone, a compound with antagonist properties for 5-HT2A, sigma2, and α1A-adrenergic receptors, targeting negative symptoms in patients with schizophrenia. This trial follows a previous trial that demonstrated roluperidone superiority over placebo in a similar patient population.

Methods: Roluperidone 32 mg/day, roluperidone 64 mg/day, or placebo was administered for 12 weeks to 513 patients with schizophrenia with moderate to severe negative symptoms. The primary endpoint was the PANSS-derived Negative Symptom Factor Score (NSFS) and the key secondary endpoint was Personal and Social Performance scale (PSP) total score.

Results: NSFS scores were lower (improved) for roluperidone 64 mg compared to placebo and marginally missing statistical significance for the intent-to-treat (ITT) analysis data set (P ≤ .064), but reached nominal significance (P ≤ .044) for the modified-ITT (m-ITT) data set. Changes in PSP total score were statistically significantly better on roluperidone 64 mg compared to placebo for both ITT and m-ITT (P ≤ .021 and P ≤ .017, respectively).

Conclusions: Results of this trial confirm the potential of roluperidone as a treatment of negative symptoms and improving everyday functioning in patients with schizophrenia. Study registration: Eudra-CT: 2017-003333-29; NCT03397134.

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References

Kirkpatrick B, Saoud J, Strauss G, Ahmed A, Tatsumi K, Opler M . The brief negative symptom scale (BNSS): Sensitivity to treatment effects. Schizophr Res. 2017; 197:269-273. DOI: 10.1016/j.schres.2017.11.031. View

Bogers J, Hambarian G, Walburgh Schmidt N, Vermeulen J, de Haan L . Risk Factors for Psychotic Relapse After Dose Reduction or Discontinuation of Antipsychotics in Patients With Chronic Schizophrenia. A Meta-Analysis of Randomized Controlled Trials. Schizophr Bull. 2022; 49(1):11-23. PMC: 9810020. DOI: 10.1093/schbul/sbac138. View

Bugarski-Kirola D, Blaettler T, Arango C, Fleischhacker W, Garibaldi G, Wang A . Bitopertin in Negative Symptoms of Schizophrenia-Results From the Phase III FlashLyte and DayLyte Studies. Biol Psychiatry. 2017; 82(1):8-16. DOI: 10.1016/j.biopsych.2016.11.014. View

Millan M, Fone K, Steckler T, Horan W . Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol. 2014; 24(5):645-92. DOI: 10.1016/j.euroneuro.2014.03.008. View

Davidson M . The debate regarding maintenance treatment with antipsychotic drugs in schizophrenia. Dialogues Clin Neurosci. 2018; 20(3):215-221. PMC: 6296388. View

Carriere P, Bonhomme D, Lemperiere T . Amisulpride has a superior benefit/risk profile to haloperidol in schizophrenia: results of a multicentre, double-blind study (the Amisulpride Study Group). Eur Psychiatry. 2000; 15(5):321-9. DOI: 10.1016/s0924-9338(00)00401-6. View

Katz J, Su T, Hiranita T, Hayashi T, Tanda G, Kopajtic T . A Role for Sigma Receptors in Stimulant Self Administration and Addiction. Pharmaceuticals (Basel). 2011; 4(6):880-914. PMC: 3167211. DOI: 10.3390/ph4060880. View

Harrow M, Jobe T, Faull R . Does treatment of schizophrenia with antipsychotic medications eliminate or reduce psychosis? A 20-year multi-follow-up study. Psychol Med. 2014; 44(14):3007-16. DOI: 10.1017/S0033291714000610. View

Bobes J, Arango C, Garcia-Garcia M, Rejas J . Prevalence of negative symptoms in outpatients with schizophrenia spectrum disorders treated with antipsychotics in routine clinical practice: findings from the CLAMORS study. J Clin Psychiatry. 2009; 71(3):280-6. DOI: 10.4088/JCP.08m04250yel. View

10.

Szczypinski J, Gola M . Dopamine dysregulation hypothesis: the common basis for motivational anhedonia in major depressive disorder and schizophrenia?. Rev Neurosci. 2018; 29(7):727-744. DOI: 10.1515/revneuro-2017-0091. View

11.

Murray R, Quattrone D, Natesan S, van Os J, Nordentoft M, Howes O . Should psychiatrists be more cautious about the long-term prophylactic use of antipsychotics?. Br J Psychiatry. 2016; 209(5):361-365. DOI: 10.1192/bjp.bp.116.182683. View

12.

Rabinowitz J, Badescu S, Palamarchuk P, Filyk V, Voloshchuk A, Rud V . Personal and social adjustment effects of roluperidone in patients with schizophrenia and negative symptoms: Results from an exploratory outcome of a randomized placebo-controlled trial. Schizophr Res. 2019; 211:103-104. DOI: 10.1016/j.schres.2019.07.029. View

13.

Skuza G . Pharmacology of sigma (σ) receptor ligands from a behavioral perspective. Curr Pharm Des. 2012; 18(7):863-74. DOI: 10.2174/138161212799436458. View

14.

Culbreth A, Moran E, Kandala S, Westbrook A, Barch D . Effort, avolition and motivational experience in schizophrenia: Analysis of behavioral and neuroimaging data with relationships to daily motivational experience. Clin Psychol Sci. 2021; 8(3):555-568. PMC: 7983405. DOI: 10.1177/2167702620901558. View

15.

Leucht S, Chaimani A, Mavridis D, Leucht C, Huhn M, Helfer B . Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis. Neuropsychopharmacology. 2019; 44(11):1955-1966. PMC: 6785090. DOI: 10.1038/s41386-019-0440-6. View

16.

Perez D . α-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition. Front Pharmacol. 2020; 11:581098. PMC: 7553051. DOI: 10.3389/fphar.2020.581098. View

17.

Cohen A, Schwartz E, Le T, Cowan T, Kirkpatrick B, Raugh I . Digital phenotyping of negative symptoms: the relationship to clinician ratings. Schizophr Bull. 2020; 47(1):44-53. PMC: 7825094. DOI: 10.1093/schbul/sbaa065. View

18.

Dunayevich E, Chen C, Marder S, Rabinowitz J . Restrictive symptomatic inclusion criteria create barriers to clinical research in schizophrenia negative symptoms: an analysis of the CATIE dataset. Eur Neuropsychopharmacol. 2014; 24(10):1615-21. DOI: 10.1016/j.euroneuro.2014.08.004. View

19.

McGorry P, Alvarez-Jimenez M, Killackey E . Antipsychotic medication during the critical period following remission from first-episode psychosis: less is more. JAMA Psychiatry. 2013; 70(9):898-900. DOI: 10.1001/jamapsychiatry.2013.264. View

20.

Strauss G, Bartolomeo L, Harvey P . Avolition as the core negative symptom in schizophrenia: relevance to pharmacological treatment development. NPJ Schizophr. 2021; 7(1):16. PMC: 7910596. DOI: 10.1038/s41537-021-00145-4. View