Efficacy and safety of riluzole for depressive disorder: A systematic review and meta-analysis of randomized placebo-controlled trials

Yao, Ru-Zhan; Wang, Haiquan; Yuan, Mingqi; Wang, Guanglin; Wu, Changjing

doi:10.1016/j.psychres.2020.112750

Cited by 11 publications

(11 citation statements)

References 25 publications

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“…Collectively, animal studies using classical chronic AD dosing regimens indicated antidepressant-like efficacy of riluzole, paralleling the early success observed in open label clinical studies (Zarate et al, 2004(Zarate et al, , 2005Sanacora et al, 2007;Brennan et al, 2010). However, later (and larger) clinical RDBPCs found limited efficacy of riluzole monotherapy or adjunctive therapy to monoaminergic ADs or ketamine (Pittenger et al, 2008b;Mathew et al, 2010Mathew et al, , 2017Ibrahim et al, 2012;Yao et al, 2020). Our findings of enhanced stress resilience from prophylactic treatment may instead suggest that riluzole's Glu-modulating mechanisms are well-suited for currently remitted MDD or BPD patients who are at high risk for relapse.…”

Section: Discussionmentioning

confidence: 79%

“…In patients with schizophrenia, riluzole used adjunctively to risperidone improved intractable negative symptoms (Farokhnia et al, 2014). Although positive effects and strong tolerability were found, the therapeutic efficacy of riluzole in psychiatric disease generally (de Boer et al, 2019) or depressive disorders specifically (Yao et al, 2020) was not confirmed by recent meta-analyses of RDBPCs. The variability in these outcomes ultimately raises questions about whether riluzole has value for targeting specific symptom dimensions of chronic stress-related illnesses, or whether riluzole therapy could be improved with alternative treatment strategies.…”

Section: Introductionmentioning

confidence: 94%

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Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

Fee

Misquitta

Sibille

et al. 2020

Preprint

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BackgroundChronic stress-related illnesses, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD), share symptomatology, including anxiety, anhedonia, and helplessness. Across disorders, neurotoxic dysregulated glutamate (Glu) signaling may underlie symptom emergence. Current first-line antidepressant drugs (ADs), 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.MethodsWe investigated whether chronic prophylactic riluzole (∼12-15/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 outcomes. In a separate learned helplessness (LH) cohort, we investigated whether chronic preventative riluzole treatment could block the development of helplessness-like behavior.ResultsUCMS induced an elevation in anxiety-, anhedonia-like behavior, and overall behavioral emotionality that was blocked by prophylactic riluzole. In the LH cohort, preventative riluzole blocked the development of helplessness-like behavior.ConclusionThis study supports the utility of riluzole as a prophylactic medication, and potential relapse-preventing treatment targeting anhedonia, anxiety, and helplessness symptoms associated with stress-related disorders.Significance StatementRiluzole is a glutamate-modulating drug with mixed evidence of efficacy in clinical studies of patients with stress-related disorders. Based on evidence suggesting that glutamatergic dysfunction contributes to the pathogenesis of stress-related disorders, we investigated whether prophylactic treatment with riluzole could prevent the onset of behavioral deficits induced by unpredictable chronic mild stress or learned helplessness in mice. Riluzole effectively prevented the emergence of anxiety-, anhedonia-like behavior, and overall behavioral emotionality in mice exposed to unpredictable chronic mild stress. In a separate cohort, riluzole blocked the emergence of helplessness-like behavior as measured in an active avoidance paradigm. These results support testing riluzole as a prophylactic treatment strategy in stress-related illnesses such as major depressive disorder or post-traumatic stress disorder.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 94%

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

Fee

Misquitta

Sibille

et al. 2020

Preprint

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“…Two agents modulating AMPAR, riluzole and Org 26576, have been studied in patients with MDD. 52 , 53 Org 26576 is an AMPAR positive allosteric modulator which demonstrated tolerability and promising antidepressant efficacy in phase I trials. 52 It failed to meet statistical significance in a phase II trial and has not been studied in MDD further.…”

Section: Resultsmentioning

confidence: 99%

“…In 2018, a clinical trial 58 demonstrated an association between lower serum brain derived neurotrophic factor (BDNF) levels at baseline in depressed patients and response to riluzole. A more recent meta-analysis 53 concluded that overall, riluzole did not demonstrate antidepressant efficacy. Alternatively, perampanel, an AED that antagonizes AMPAR, is associated with increased risk of depression in patients with and without epilepsy.…”

Section: Resultsmentioning

confidence: 99%

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Irwin

VandenBerg

2021

Mental Health Clinician

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Introduction MDD represents a significant burden worldwide, and while a number of approved treatments exist, there are high rates of treatment resistance and refractoriness. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, is a novel, rapid-acting antidepressant, however the mechanisms underlying the efficacy of ketamine are not well understood and many other mechanisms outside of NMDAR antagonism have been postulated based on preclinical data. This focused review aims to present a summary of the proposed mechanisms of action by which ketamine functions in depressive disorders supported by preclinical data and clinical studies in humans. Methods A literature search was completed using the PubMed and Google Scholar databases. Results were limited to clinical trials and case studies in humans that were published in English. The findings were used to compile this article. Results The antidepressant effects associated with ketamine are mediated via a complex interplay of mechanisms; key steps include NMDAR blockade on γ-aminobutyric acid interneurons, glutamate surge, and subsequent activation and upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Discussion Coadministration of ketamine for MDD with other psychotropic agents, for example benzodiazepines, may attenuate antidepressant effects. Limited evidence exists for these effects and should be evaluated on a case-by-case basis.

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“…Sin embargo, riluzol potenció el efecto antidepresivo cuando se asoció al citalopram [123]. En general, el riluzol fue bien tolerado en estos estudios y no se observaron efectos psicotomiméticos [124]. Su empleo antidepresivo es compasivo y parece que su eficacia se manifiesta en asociación con otros antidepresivos.…”

Section: Potenciador De La Recaptación De Glu E Inhibidor De La Liberunclassified

Algo más que monoaminas en el tratamiento de la depresión: Mecanismos neurobiológicos emergentes de los antidepresivos del siglo XXI

González¹,

Zaragozá

López‐Muñoz

2020

RIECS

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Clásicamente, el tratamiento farmacológico de la depresión se ha realizado con antidepresivos monoaminérgicos, que presentan una serie de limitaciones, como un lento inicio de acción, una inadecuada respuesta antidepresiva, disfunción sexual o tolerabilidad mejorable. En esta revisión analizaremos nuevos mecanismos fisiopatológicos implicados en la depresión como dianas para la búsqueda de antidepresivos diferentes. En el ámbito de la endocrinología los resultados son desalentadores, efímeros (TRH), limitados (hormonas tiroideas), dudosos (antagonistas CRH1), controvertidos (estrógenos) o poco eficaces (andrógenos). Varios neuropéptidos están implicados en la patogenia de la depresión, como la hormona antidiurética, la oxitocina, la sustancia P, el neuropéptido Y o la galanina, pero su abordaje desde el punto de vista terapéutico no ha dado resultados terapéuticos. La relación entre depresión y procesos inflamatorios es patente, pero los datos de eficacia, muchas veces anecdóticos, de algunos antiinflamatorios, antagonistas de TNF o anticuerpos monoclonales no pueden generalizarse. La participación del sistema opioide endógeno también se ha explorado, pero su potencial adictivo hace que no dispongamos en estos momentos “opioides antidepresivos”. La hipótesis glutamatérgica de la depresión ha sido trabajada durante más de 3 décadas y por fin parece que ha dado resultados: la esketamina, un isómero de la ketamina, ha demostrado, gracias a un programa de desarrollo clínico robusto, que es un antidepresivo de acción rápida, eficaz en depresión resistente, con una tolerabilidad aceptable, lo que ha motivado su autorización en depresión resistente en asociación con antidepresivos convencionales. La esketamina es la respuesta terapéutica a la “hipótesis glutamatérgica de la depresión”.

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Efficacy and safety of riluzole for depressive disorder: A systematic review and meta-analysis of randomized placebo-controlled trials

Cited by 11 publications

References 25 publications

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

Prophylactic efficacy of riluzole against anxiety- and depressive-like behaviors in two rodent stress models

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

Algo más que monoaminas en el tratamiento de la depresión: Mecanismos neurobiológicos emergentes de los antidepresivos del siglo XXI

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