Prophylactic Efficacy of Riluzole against Anxiety- and Depressive-Like Behaviors in Two Rodent Stress Models

Yashika Bansal; Corey Fee; Keith A Misquitta; Sierra A Codeluppi; Etienne Sibille; Robert M Berman; Vladimir Coric; Gerard Sanacora; Mounira Banasr

doi:10.1159/000529534

Prophylactic Efficacy of Riluzole against Anxiety- and Depressive-Like Behaviors in Two Rodent Stress Models

Complex Psychiatry. 2023 Feb 3;9(1-4):57-69. doi: 10.1159/000529534. eCollection 2023 Jan-Dec.

Authors

Yashika Bansal¹, Corey Fee^{1

2}, Keith A Misquitta^{1

2}, Sierra A Codeluppi^{1

2}, Etienne Sibille^{1

2

3}, Robert M Berman⁴, Vladimir Coric⁴, Gerard Sanacora⁵, Mounira Banasr^{1

2

3

5}

Affiliations

¹ Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
² Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
³ Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
⁴ Biohaven Pharmaceuticals, New Haven, CT, USA.
⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.

Abstract

Introduction: Chronic stress-related illnesses such as major depressive disorder and post-traumatic stress disorder share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs, which do not directly target Glu signaling, fail to provide adequate benefit for many patients and are associated with high relapse rates. Riluzole modulates glutamatergic neurotransmission by increasing metabolic cycling and modulating signal transduction. Clinical studies exploring riluzole's efficacy in stress-related disorders have provided varied results. However, the utility of riluzole for treating specific symptom dimensions or as a prophylactic treatment has not been comprehensively assessed.

Methods: We investigated whether chronic prophylactic riluzole (∼12-15 mg/kg/day p.o.) could prevent the emergence of behavioral deficits induced by unpredictable chronic mild stress (UCMS) in mice. We assessed (i) anxiety-like behavior using the elevated-plus maze, open-field test, and novelty-suppressed feeding, (ii) mixed anxiety/anhedonia-like behavior in the novelty-induced hypophagia test, and (iii) anhedonia-like behavior using the sucrose consumption test. Z-scoring summarized changes across tests measuring similar dimensions. In a separate learned helplessness (LH) cohort, we investigated whether chronic prophylactic riluzole treatment could block the development of helplessness-like behavior.

Results: UCMS induced an elevation in anhedonia-like behavior and overall behavioral emotionality that was blocked by prophylactic riluzole. In the LH cohort, prophylactic riluzole blocked the development of helplessness-like behavior.

Discussion/conclusion: This study supports the utility of riluzole as a prophylactic medication for preventing anhedonia and helplessness symptoms associated with stress-related disorders.

Keywords: Antidepressants; Chronic stress; Depression; Prophylactic riluzole; Riluzole.

Grants and funding

Biohaven Pharmaceuticals provided funding for this study.