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. Author manuscript; available in PMC: 2020 Nov 1.
Published in final edited form as: J Affect Disord. 2019 Jul 2;258:102–108. doi: 10.1016/j.jad.2019.06.065

Longer-term Open-label Study of Adjunctive Riluzole in Treatment-resistant Depression

Hitoshi Sakurai a,b, Christina Dording a, Albert Yeung a, Simmie Foster a, Felipe Jain a, Trina Chang a, Nhi-Ha Trinh a, Richard Bernard a, Sean Boyden a, Syed Z Iqbal c,d, Samuel T Wilkinson e, Sanjay J Mathew c,d, David Mischoulon a, Maurizio Fava a, Cristina Cusin a
PMCID: PMC6710149  NIHMSID: NIHMS1536883  PMID: 31400624

Abstract

Background:

While riluzole has been investigated for the treatment of depression, little is known about its longer-term efficacy and optimal treatment duration in treatment-resistant depression (TRD). The objective of this study is to characterize the longer-term outcome of adjunctive riluzole therapy for TRD in an open-label extension of an 8-week acute treatment trial.

Methods:

The data from 66 patients with TRD who received adjunctive riluzole in a 12-week open-label extension phase were analyzed. Response rates (≥50% reduction in the Mongomery-Asberg Depression Rating Scale [MADRS] score), relapse rates (a MADRS score of ≥22 in patients who had previously achieved response), and adverse events were examined in patients who had achieved response at the end of the acute phase and those who had not.

Results:

Among acute phase responders, the maintained response rate was 66.7% (8/12) and the relapse rate was 8.3% (1/12). In acute phase non-responders, the response rate was 24.1% (13/54). The most commonly reported adverse event was fatigue (9.1%). Three cases were considered serious adverse events; vomiting (n=1), shortness of breath (n=1), and aborted suicide attempt (n=1).

Limitations:

This longer-term study was open-label and uncontrolled. The sample size was relatively small.

Conclusions:

Longer-term adjunctive riluzole appears relatively well tolerated and beneficial for maintaining previous response. Additionally, approximately one fourth of patients who did not respond to 8-week antidepressant treatment might respond if treated with riluzole for 12 weeks. Those findings warrant further investigation because adjunctive riluzole could represent an option for treatment of depression when standard antidepressants have failed.

Keywords: longer-term, relapse, response, riluzole, treatment-resistant depression, tolerability

Introduction

Given the extraordinary morbidity of major depressive disorder (Baldessarini et al., 2017), the limited efficacy of current drug treatments for depression represents an extraordinary need for discovering and applying novel antidepressant mechanisms beyond the monoamines (Papakostas and Ionescu, 2015; Newport et al., 2015; Chang and Fava, 2010). In recent reports, brain network dysfunction associated with the glutamatergic system has been identified in both animal and human studies of depression (Lener et al., 2017). Furthermore, the glutamatergic system has been reported to play important roles in regulation of synaptic plasticity and to have a significant effect on mood, cognition, and reward circuitry (Abdallah et al., 2014; Duman et al., 2016). For these reasons, drugs that have an impact on the glutamatergic system have been investigated as potential new antidepressants (Wilkinson and Sanacora, 2018).

Riluzole is an oral medication approved by the US Food and Drug Administration in 1994 for the treatment of amyotrophic lateral sclerosis (ALS). Its mechanism of action is thought to be inhibition of presynaptic release of glutamate via inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals (Pittenger et al., 2008; Doble, 1996). Riluzole also inhibits voltage-gated calcium channels, leading to reduction of calcium influx and glutamate release (Wang et al., 2004). Moreover, riluzole can act directly on the N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, and kainate receptor (Debono et al., 1993; Zona et al., 2002; Albo et al., 2004). Additionally, riluzole has been shown to increase excitatory amino acid transporter 2 (EAAT2) expression and function in preclinical rodent studies, which may prevent excitotoxic effects of extracellular glutamate and protect neurons from stress- or injury-related insults (Banasr et al., 2010; Gourley et al., 2012).

Although riluzole has shown promise as monotherapy or augmentation therapy in treatment-resistant mood disorders in open-label human studies (Zarate et al., 2004; Zarate et al., 2005; Sanacora et al., 2007; Brennan et al., 2010), it was not more effective than placebo for the treatment of bipolar depression in the two published double-blind studies (Park et al., 2017; ClinicalTrial.gov identifier: ). With regard to double-blind studies of riluzole in major depressive disorder, the two published reports have produced inconsistent findings. In the most recent placebo-controlled trial of riluzole in 104 patients with treatment-resistant depression (TRD), conducted in our three sites, riluzole did not show superior efficacy as an adjunctive treatment to ongoing antidepressant medications compared to adjunctive placebo (Mathew et al., 2017). In contrast, a placebo-controlled trial in 60 inpatients with major depressive disorder (MDD) found augmentation of citalopram with riluzole was superior to the combination of citalopram and placebo (Salardini et al., 2016). Possible explanations for discrepancy in these results are the differences in patients’ characteristics and study design; for example, in the former study, patients with TRD continued treatment with various ongoing antidepressant medications; in the latter study, inpatients with MDD received citalopram as the base antidepressant. As the data from both of those studies are limited acute outcomes (4–8 weeks), the efficacy of longer-term adjunctive riluzole remains unknown. While rapid-acting ketamine targets postsynaptic NMDA receptors of glutamatergic neurons and may have indirect effects on AMPA receptors, riluzole reduces excitation of extrasynaptic glutamate receptors through indirect regulation, suggesting that ketamine and riluzole might show different trajectories of improvement over time (Machado-Vieira et al., 2009). Moreover, riluzole has the longer-term potential to provide neuroprotection and neuroplasticity, especially due to the increased activity of glutamate transporters (Banasr et al., 2010) and expression and release of brain-derived neurotrophic factor (BDNF) (Machado-Vieira et al., 2009; Zarate and Manji, 2008; Katoh-Semba et al., 1997; Manji et al., 2003). We therefore examined the longer-term efficacy of adjunctive riluzole in an open-label extension phase of the multicenter acute-phase double-blind trial that had shown no effects of riluzole in the randomized 8-week sequential parallel comparison design (SPCD) phase (Mathew et al., 2017).

Methods

Study Design

The parent study enrolled patients at three academic medical centers between June 2011 and February 2015 and results were published in 2017 (Mathew et al., 2017). The Institutional Review Boards at each of the participating sites approved the study. After complete description of the study, written informed consent was obtained from all participating subjects. In the acute phase, 64 patients with TRD were randomized using the SPCD (Fava et al., 2003). Per this design, subjects were assigned at random to one of three arms: 1) adjunctive riluzole (50 mg twice per day (b.i.d.)) for 8 weeks (n=25); 2) placebo for 8 weeks (n=39); or 3) placebo for 4 weeks followed by riluzole (50 mg b.i.d.) for 4 weeks (n=40). Analysis of results from the acute phase, including rationale for the SPCD design and findings for each arm, are detailed in the parent study (Mathew et al., 2017). Overall design and subject flow are illustrated in Figure 1.

Figure 1.

Figure 1.

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Patient Flow

At the end of the acute double-blind treatment phase, 85 completers, regardless of original treatment assignment, were offered the opportunity to enter an open-label extension phase, the data of which are presented here. In the extension phase, all patients were prescribed 50 mg twice per day of riluzole up to 12 weeks. Dose reduction could be applied at the discretion of the treating physicians in cases of intolerable side effects.

Study Population

Inclusion and exclusion criteria of the parent study were reported elsewhere (Mathew et al., 2017). Briefly, patients (1) were between 18 and 65 years of age, (2) had a primary diagnosis of MDD, assessed by the Structured Clinical Interview for DSM-IV-TR—Axis I disorders (First et al., 2007), (3) had an inadequate response to at least one but no greater than four adequate trials of an antidepressant, and (4) had at least moderate depressive symptom severity, with a Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) score ≥18 and an Inventory of Depressive Symptomatology-Self Rated (IDS-SR) (Rush et al., 1996) score ≥20. Patients were excluded if they (1) were deemed to have a serious suicide risk, (2) had substance use disorders within the last 6 months, (3) had lifetime histories of bipolar disorder or psychotic disorders, or (4) had severe and unstable medical illness. Patients who completed the acute double-blind phase, entered the open-label extension phase, and completed at least one follow-up visit of the extension phase were included in the present analysis.

Assessment Measures

MADRS was performed at baseline of extension phase and weeks 2, 4, 8, and 12. Additional assessments were performed at baseline and weeks 1, 2, 3, 4, 8, and 12: Clinical Global Impressions-Severity/Improvement (CGI-S/I), Inventory of Depressive Symptomatology-Self Rated (IDS-SR), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) (Fava et al., 2009), Sheehan Disability Scale (SDS) (Leon et al., 1992), and Systematic Assessment for Treatment Emergent Events (SAFTEE) (Levine and Schooler, 1986).

To examine the outcomes, patients were divided into four groups based on whether they had received riluzole or placebo during the acute phase and achieved response (i.e. a ≥50% reduction in the MADRS total score) or not at the end of the acute phase (RIL-R group: patients who had received riluzole and achieved response, PBO-R group: patients who had received placebo and achieved response, RIL-NR group: patients who had received riluzole and not achieved response, and PBO-NR group: patients who had received placebo and not achieved response). The outcomes of principal interest in the RIL-R group and PBO-R group were the rates of maintained response (i.e. rate of patients who maintained a ≥50% reduction in the MADRS total score during the extension phase) and relapse (i.e. rate of patients who showed a MADRS score of ≥22 (Montgomery and Rasmussen, 1992)) by week 12. The outcome of principal interest in the RIL-NR group and PBO-NR group was the response rate at week 12 (i.e. rate of patients who showed a ≥50% reduction in the MADRS total score compared to entry in the extension phase). The outcomes of secondary interest included the total MADRS score change, the CGI-I scale scores, proportion of subjects scoring ≤2 on the CGI-I, the total IDS-SR score change, the total CPFQ score change, and the total SDS score change, all at week 12.

Statistical Analysis

The maintained response rates, relapse rates, and rates of subjects scoring ≤2 on the CGI-I were compared between the RIL-R and PBO-R groups by Pearson’s chi-squared test or Fisher’s exact test using last observation carried forward (LOCF). Other treatment outcomes were similarly compared by the Student’s t test or the Mann-Whitney U test, where appropriate. Kaplan-Meier survival curve estimated the cumulative proportion of non-response status in the RIL-R and PBO-R groups. Log-rank test was used to test for the difference in the proportion between the groups. Those analyses were also conducted between the RIL-NR and PBO-NR groups. Additionally, in the RIL-R group and RIL-NR group, treatment outcomes were compared between the patients who received 4 weeks of riluzole in the acute phase and those who received 8 weeks. A two-tailed P value of <0.05 was considered statistically significant for all tests. All statistical analyses were conducted using the Statistical Package for Social Science (SPSS) version 24.0 for Windows (IBM Corporation, Armonk, NY).

Results

Subject Characteristics

Of the 85 acute phase completers, 66 agreed to participate in the extension phase and received at least one visit beyond the baseline visit of the extension phase. Of these participants, 12 had achieved response at the entry of the extension phase and 54 had not (Figure 1). Table 1 summarizes sociodemographic and clinical characteristics of the study sample. Among 19 patients who did not participate in the extension phase, 3 had achieved response at the end of the acute phase and 16 had not.

Table 1.

Baseline Demographic and Clinical Characteristics

Characteristics RIL-R (n=7) PBO-R (n=5) RIL-NR (n=30) PBO-NR (n=24)
Age, years, mean (SD) 45.8 (12.9) 49.9 (9.3) 46.3 (12.1) 47.1 (14.0)
Female, n (%) 4 (57.1%) 4 (80.0%) 13 (43.3%) 10 (41.7%)
Race/Ethnicity, n (%)
 Caucasian 6 (85.7%) 3 (60.0%) 27 (90.0%) 20 (83.3%)
 African American 1 (14.3%) 1 (20.0%) 0 1 (4.2%)
 Hispanic 1 (14.3%) 0 0 3 (12.5%)
 Other 0 1 (20.0%) 3 (10.0%) 0
Education completed, n (%)
 Grade 6–12 or graduated high school 0 0 5 (17.2%) 2 (8.7%)
 Some college 2 (28.6%) 1 (20.0%) 8 (27.6%) 10 (43.5%)
 Graduated 4-year college 3 (42.9%) 3 (60.0%) 9 (31.0%) 6 (26.1%)
 Graduate/professional degree 2 (28.6%) 1 (20.0%) 7 (24.1%) 5 (21.7%)
Current marital status, n (%)
 Single, never married 3 (42.9%) 2 (40.0%) 11 (40.7%) 12 (60.0%)
 Married, civil union, cohabitating 3 (42.9%) 2 (40.0%) 11 (40.7%) 4 (20.0%)
 Separated, divorced, widowed 1 (14.3%) 1 (20.0%) 5 (18.5%) 4 (20.0%)
Current employment status, n (%)
 Full-time 3 (42.9%) 1 (20.0%) 8 (27.6%) 6 (26.1%)
 Part-time 1 (14.3%) 1 (20.0%) 3 (10.3%) 8 (34.8%)
 Not employed 3 (42.9%) 3 (60.0%) 18 (62.1%) 9 (39.1%)
History of suicidal behavior, n (%) 2 (28.6%) 1 (20.0%) 7 (24.1%) 2 (8.3%)
Comorbid anxiety disorder, n (%) 0 2 (40.0%) 5 (16.7%) 8 (33.3%)
MADRS at acute phase entry, mean (SD) 28.1 (5.6) 29.2 (2.6) 29.9 (5.7) 29.7 (7.1)
MADRS at extension entry, mean (SD) 6.7 (5.7) 12.8 (2.5) 26.2 (7.6) 25.9 (8.8)
CGI-S at extension entry, mean (SD) 1.6 (0.5) 2.4 (0.5) 4.1 (0.9) 3.9 (0.9)
IDS-SR at extension entry, mean (SD) 12.7 (9.9) 23.3 (4.6) 39.6 (12.3) 37.6 (13.0)
CPFQ at extension entry, mean (SD) 18.0 (3.3) 19.8 (3.4) 28.5 (6.2) 24.6 (6.7)
SDS total score at extension entry, mean (SD) 6.0 (5.4) 8.4 (4.3) 18.2 (7.2) 17.3 (7.3)
SDS work score at extension entry, mean (SD) 2.8 (3.2) 3.6 (3.4) 5.5 (3.2) 5.7 (2.5)
SDS social life score at extension entry, mean (SD) 1.4 (1.4) 3.0 (1.1) 6.2 (2.4) 6.0 (2.4)
SDS family life score at extension entry, mean (SD) 1.7 (1.5) 1.8 (1.0) 6.0 (2.5) 5.6 (2.5)
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CGI-S, Clinical Global Impressions-Severity of Illness; CPFQ, Cognitive and Physical Functioning Questionnaire; IDS-SR, Inventory of Depressive Symptomatology Self Report; MADRS, Montgomery-Asberg Depression Rating Scale; PBO-NR, Placebo non-responder; PBO-R, Placebo responder; RIL-NR, Riluzole non-responder; RIL-R, Riluzole responder; SD, Standard deviation; SDS, Sheehan Disability Scale

Outcome Measures

Among all acute phase responders (i.e. RIL-R and PBO-R patients who maintained a ≥50% reduction in the MADRS total score during the 12-week extension phase) the maintained response rate was 66.7% (8/12). Only 1 out of 12 combined patients (8.3%) who had achieved response at the end of the acute phase relapsed in this extension phase (i.e. a MADRS score of ≥22). Among acute phase non-responders (i.e. RIL-NR and PBO-NR patients who showed a ≥50% reduction in the MADRS total score at 12 weeks compared to baseline visit of the extension phase) the rate of response was 24.1% (13/54). Out of 54 combined non-responders, 8 patients (14.8%) showed a 25–50% reduction in the MADRS total score in the extension phase while 3 patients (5.6%) showed a worsening of 25% or more in MADRS score.

Out of 7 patients in the RIL-R group, 5 patients maintained response during the extension phase, 1 patient relapsed, and 1 patient was lost to follow-up. Out of 5 patients in the PBO-R group, 2 patients were responders at 12 weeks of the extension phase, 1 patient maintained response but dropped out due to the adverse event, 1 patient became a non-responder, and 1 patient was lost to follow-up. The maintained response rates did not differ significantly between the RIL-R group and PBO-R group (71.4% vs. 60.0%, p=0.52) (Table 2 and Figure 2). Relapse rates did not differ significantly between the RIL-R group and PBO-R group (14.3% vs. 0.0%, p=1.00). No statistically significant differences were found in any of the secondary outcome measures (MADRS, CGI-I, IDS-SR, CPFQ, and SDS) between the RILR and PBO-R groups.

Table 2.

Outcome Measures in Acute Phase Responders (LOCF)

Characteristics RIL-R PBO-R Statistics P-value
Maintained response rate, % 71.4% (5/7) 60.0% (3/5) n.a. 0.52a
Relapse rate, % 14.3% (1/7) 0.0% (0/5) n.a. 1.00a
MADRS score change, mean (SD) 2.7 (11.9) −0.4 (4.6) z=−0.41 0.68
CGI-I, mean (SD) 2.0 (1.3) 2.6 (1.6) z=−0.70 0.48
Rate of those who score ≤2 on the CGI-I, % 71.4% (5/7) 60.0% (3/5) n.a. 1.00a
IDS-SR score change, mean (SD) 4.7 (19.2) −4.5 (3.5) z=−0.96 0.34
CPFQ, mean (SD) −1.4 (4.3) −0.6 (3.6) t(10)=−0.32 0.75
SDS total score change, mean (SD) 3.8 (10.0) 0.2 (3.5) z=−0.37 0.71
SDS work score change, mean (SD) 1.5 (4.1) 0.0 (1.4) z=−0.37 0.71
SDS social life score change, mean (SD) 1.3 (3.7) −0.6 (1.4) z=−1.00 0.32
SDS family life score change, mean (SD) 0.4 (2.1) 0.8 (1.7) z=−0.76 0.45
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a

Fisher’s exact test.

CGI-I, Clinical Global Impressions-Improvement; CPFQ, Cognitive and Physical Functioning Questionnaire; IDS-SR, Inventory of Depressive Symptomatology Self Report; LOCF, Last observation carried forward; MADRS, Montgomery-Asberg Depression Rating Scale; n.a., Not available; PBO-R, Placebo responder; RIL-R, Riluzole responder; SD, Standard deviation; SDS, Sheehan Disability Scale

Figure 2. Time to Non-response in Acute Phase Responders.

Figure 2.

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No statistically significant differences were found between the RIL-R group and PBO-R group (Log-rank statistic=0.24, p=0.62).

PBO-R, Placebo responder; RIL-R, Riluzole responder

Similarly, out of 30 patients in the RIL-NR group, 6 patients were responders at 12 weeks of the extension phase, 13 patients were still non-responders, and 11 patients had dropped out. Out of 24 patients in the PBO-NR group, 7 patients were responders at 12 weeks of the extension phase, 13 patients were still non-responders, and 4 patients were lost to follow-up. Response rates did not differ significantly between the RIL-NR group and PBO-NR group (20.0%- vs. 29.2%, χ2(1)=0.61, p=0.43) (Table 3). No statistically significant differences were found in any of the secondary outcome measures (MADRS, CGI-I, IDS-SR, CPFQ, and SDS) between the RIL-NR and PBO-NR groups.

Table 3.

Outcome Measures in Acute Phase Non-responders (LOCF)

Characteristics RIL-NR PBO-NR Statistics P-value
Response rate, % 20.0% (6/30) 29.2% (7/24) χ2(1)=0.61 0.43
MADRS score change, mean (SD) −4.8 (7.3) −6.8 (7.6) z=−0.86 0.39
CGI-I, mean (SD) 3.2 (1.2) 3.0 (1.1) z=−0.71 0.48
Rate of those who score ≤2 on the CGI-I, % 33.3% (10/30) 33.3% (8/24) χ2(1)=0.00 1.00
IDS-SR score change, mean (SD) −7.0 (9.1) −7.6 (13.9) t(33)=0.16 0.88
CPFQ, mean (SD) −4.0 (5.2) −2.1 (6.2) z=−1.11 0.27
SDS total score change, mean (SD) −3.3 (4.7) −3.8 (6.4) z=−0.17 0.86
SDS work score change, mean (SD) −0.9 (1.6) −1.4 (1.8) z=−0.98 0.33
SDS social life score change, mean (SD) −1.4 (2.2) −1.4 (2.3) z=−0.10 0.92
SDS family life score change, mean (SD) −0.9 (1.7) −1.0 (3.1) z=−0.53 0.59
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CGI-I, Clinical Global Impressions-Improvement; CPFQ: Cognitive and Physical Functioning Questionnaire; IDS-SR, Inventory of Depressive Symptomatology Self Report; LOCF, Last observation carried forward; MADRS, Montgomery-Asberg Depression Rating Scale; PBO-NR, Placebo non-responder; RIL-NR, Riluzole non-responder; SD, Standard deviation; SDS, Sheehan Disability Scale

Per the SPCD design, the RIL-R group comprised subjects who received 4 weeks of riluzole treatment in the acute phase and those who received 8 weeks of riluzole treatment. In comparing these two subgroups, there were no statistically significant differences in any outcome measures (maintained response rate, relapse rate, MADRS, CGI-I, IDS-SR, CPFQ, and SDS) between the patients in the 4-week vs. 8-week treatment schedules (data not shown). In the RIL-NR group, no statistically significant differences were found in any of the outcome measures between the patients who received 4 weeks of riluzole in the acute phase and those who received 8 weeks, other than SDS work score change (−1.7±1.7 vs. 0.0±1.0, z=−2.54, p=0.01) (other data not shown).

Adverse Events

The most commonly reported adverse events in this extension phase were fatigue (9.1%), vivid dreams or nightmares (6.1%), nausea (6.1%), and nasal congestion (6.1%). One patient in the PBO-NR group discontinued riluzole at week 8 due to vomiting and global amnesia. The patient was hospitalized but fully recovered within a week; this event was judged by investigators to probably be related to riluzole. One patient in the RIL-R group was hospitalized overnight due to observation for shortness of breath in the context of acute bronchitis and was discontinued from the study at week 6. It was judged by the investigators that this was not related to riluzole administration. One patient in the PBO-NR group was discontinued from the study at week 12 since he attempted to kill himself from car exhaust fumes. He immediately aborted suicide attempt and denied any suicidal ideation, intent or behaviors after that. It was judged by the investigators that this was not related to riluzole administration. There was no significant abnormality of liver function tests. No patients required dose reduction due to side effects.

Discussion

To our knowledge, this is the first study to examine the longer-term outcome of adjunctive riluzole in patients with TRD. Our analysis suggests that adjunctive riluzole is relatively well tolerated and could be helpful for some patients, despite the non-superiority of riluzole to placebo in overall efficacy over 8 weeks of treatment as reported in the parent study (Mathew et al., 2017). More notably, 60% to 70% of patients who had been responders to acute phase treatment at 8 weeks maintained response during the 12 week follow-up period while 8% of those patients relapsed. Furthermore, 20% to 30% patients who had not responded to acute phase treatment were responders at 12 weeks of follow-up. These outcomes might be at a similar level to that of atypical antipsychotic augmentation in patients with TRD (Fava et al., 2012; Papakostas et al., 2015; Brunner et al., 2014).

There are several limitations to be noted in the present study. First, this is an analysis of an open-label extension phase of a double-blind randomized placebo-controlled trial, and placebo effects cannot be ruled out. Second, the sample size was relatively small, particularly with regard to acute phase responders, which limits our power to detect differences between the groups. Among 85 acute phase completers, 19 patients dropped out from the study before start of the extension phase. Finally, 18 out of 66 patients dropped out during the extension phase.

Patients may be likely to have higher positive expectations during the early phase of a clinical trial, which may encourage them to stay in the study, and also contribute to placebo effects. In fact, in our review of 13 clinical trials comparing antidepressants vs. placebo, we showed that the majority of improvement during antidepressant and placebo treatment occurred in the first half of the antidepressant trial regardless of the duration (Yang et al., 2005). However, the findings of this study indicate that patients might still have the possibility to show improvement by continuing to take riluzole. Even modest response rates in the range of 20% to 30% as seen in the two acute phase non-responder groups are encouraging, in view of the fact that this study sample represented treatment-resistant patients.

As mentioned in the introduction to this paper, riluzole has several mechanisms of action associated with the glutamatergic system (Zarate and Manji, 2008). Notably, not only is riluzole thought to be a neuroprotective agent that inhibits excitotoxic effects of extracellular glutamate by increasing EAAT2 expression and function, it also increases hippocampal BDNF expression in animals. Furthermore, BDNF contributes to the cellular processes underlying neuronal plasticity and restoration/enhancement of neural connectivity mechanisms (Manji et al., 2003). A small pilot study from the same clinical trial sample found that lower serum and plasma BDNF at baseline was associated with riluzole response (Wilkinson ST et al., 2018). Thus, riluzole has been shown to have neuroprotective properties in animal models of Parkinson’s disease, dementia, brain ischemia, traumatic brain injury, spinal cord injury, post-traumatic peripheral neuropathy, and acute noise-induced hearing loss (Zarate and Manji, 2008; Manji et al., 2003). Considering the potential changes in protein expression and reduced excitation of extrasynaptic glutamate receptors, longer-term treatment of riluzole might be necessary to show the significant antidepressant-like effect.

In conclusion, the present study has evaluated the longer-term outcome of adjunctive riluzole for the treatment of TRD. While the effectiveness of riluzole in randomized placebo-controlled trials for depression lasting up to 8 weeks has been inconsistent, tolerability appears relatively good. Our findings suggest that riluzole may be beneficial for a certain number of patients with TRD, and its use warrants further investigation.

HIGHLIGHTS.

  • Longer-term riluzole augmentation in treatment-resistant depression was examined.

  • The 12-week maintained response rate was 66.7% in acute phase responders.

  • The response rate at 12 weeks was 24.1% in acute phase non-responders.

  • Longer-term tolerability of adjunctive riluzole was relatively good.

  • Riluzole may be beneficial for some patients with treatment-resistant depression.

Acknowledgments:

The authors thank the members of the study Steering Committee: Thomas Kosten, John H. Krystal, Andrew Nierenberg, Carlos A. Zarate, Jr., and the Data Safety and Monitoring Board of the NIMH for oversight of the study. The authors also thank Satoko Sakurai for their continuous support.

Role of Funding:

This work was supported by the National Institute of Mental Health (R01MH085055, R01MH085054, R01MH085050). This work was also supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, TX, the Connecticut Department of Mental Health and Addiction Services, the West Haven VA PTSD Center, and the Agency for Healthcare Research and Quality (AHRQ, K12HS023000, STW). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the National Institutes of Health, the AHRQ, Department of Veterans Affairs or the United States government. Sanofi S.A. donated a supply of riluzole and matching placebo for the study.

Footnotes

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Declarations of interest:

Dr. Sakurai has received manuscript or speaker’s honoraria from Dainippon Sumitomo, Eli Lilly, Meiji-Seika Pharma, Otsuka Pharmaceutical, Tanabe Mitsubishi Pharma, and Yoshitomi Yakuhin within the past three years. He also receives support from the Japanese Society of Clinical Neuropsychopharmacology. Dr. Chang had stock of Abbott and Shire Pharmaceuticals and received support from an NIDDK career development award. Dr. Wilkinson reports research funding and consulting fees from Janssen. He also receives support from the Agency for Healthcare Research and Quality (K12HS023000) and from the Brain and Behavioral Research Foundation (formerly NARSAD), the Robert E. Leet and Clara Guthrie Patterson Trust, and the American Foundation for Suicide Prevention. Dr. Mathew is supported by the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Tx. He has served as a consultant to Alkermes, Bracket, Clexio, Janssen, Perception, and Sage Therapeutics. He has received research support from Biohaven, NeuroRx, and Vistagen. Dr. Mischoulon has received research support from Nordic Naturals. He has provided unpaid consulting for Pharmavite LLC and Gnosis USA, Inc. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, Blackmores, and PeerPoint Medical Education Institute, LLC. He has received royalties from Lippincott Williams & Wilkins for published book “Natural Medications for Psychiatric Disorders: Considering the Alternatives.” Dr. Fava reports 3-year disclosures as below: all lifetime disclosures can be view on line at: http://mghcme.org/faculty/faculty-detail/maurizio_fava; research support: Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; Biohaven; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clarus Funds; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM);National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Organon Pharmaceuticals; Otsuka Pharmaceutical Development, Inc.; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceuticals; Tal Medical; VistaGen; Wyeth-Ayerst Laboratories; advisory board/ consultant: Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; Boehringer Ingelheim; Boston Pharmaceuticals; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; Marinus Pharmaceuticals; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Navitor Pharmaceuticals, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Praxis Precision Medicines; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Purdue Pharma; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Relmada Therapeutics, Inc.; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceuticals; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex; Teva Pharmaceuticals; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Usona Institute,Inc.; Vanda Pharmaceuticals, Inc.; Versant Venture Management, LLC; VistaGen; speaking/publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories.; equity holdings: Compellis; PsyBrain, Inc.; royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd. Dr Cusin has received speaking and consulting fees from Janssen, Takeda, Boehringer, Alkermes. –Equity: None. –Royalty/patent: PCT/US15/56192; 070919.00032 Acyclic cucurbit[N]uril type molecular containers to treat intoxication and substance abuse. Dr. Dording has nothing to declare. Dr. Yeung has nothing to declare. Dr. Foster has nothing to declare. Dr. Jain has nothing to declare. Dr. Trinh has nothing to declare. Mr. Bernard has nothing to declare. Mr. Boyden has nothing to declare. Dr. Iqbal has nothing to declare.

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