Efficacy and Tolerability of Riluzole in Treatment Resistant Depression

Study Overview
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Brief Summary
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This study aims to examine the antidepressant efficacy of riluzole, employing a randomized, double-blind, placebo-controlled, adjunctive trial in treatment-resistant major depressive disorder (TRD).

Detailed Description
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This study aims to examine the antidepressant efficacy of riluzole, employing a randomized, double-blind, placebo-controlled, 8 week trial of adjunctive trial in treatment-resistant major depressive disorder (TRD). Preclinical studies have shown riluzole to modulate Glu release and clearance, and to have potent neuroprotective properties, promoting neuro-resiliency. Other preclinical data now also show the drug to have antidepressant-like effects in rodent models used to screen for antidepressant activity. In addition, several small open-label clinical studies further suggest riluzole has antidepressant and anxiolytic properties, even in patients who do not respond to standard monoaminergic antidepressant and anxiolytic medications.

Official Title
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Efficacy and Tolerability of Riluzole in Treatment Resistant Depression

Conditions
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Depression

Intervention / Treatment
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* Drug: Riluzole
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Group A inclusion/exclusion Inclusion Criteria: Age 18-65 Written informed consent Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of > 20 at screening, baseline and start of double-blind phase (Phase 2) May have a history of failure to respond to up to two FDA-approved antidepressants at adequate doses during the current episode for at least 8 weeks, and for inclusion into the Phase 2 subjects must have failed the 8-week prospective citalopram treatment. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline and start of Phase 2. Exclusion Criteria: Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy) Patients who no longer meet DSM-IV criteria for MDD during the baseline visit Patients who demonstrate > 50% decrease in depressive symptoms as reflected by the IDS-SR total score from screen to baseline Serious suicide or homicide risk, as assessed by evaluating clinician A serious suicide risk will be considered an inability to control suicide attempts, imminent risk of suicide in the investigator's judgment, or a history of serious suicidal behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS) as either (1) one or more actual suicide attempts in the 3 years before study entry with the lethality rated at 3 or higher, or (2) one or more interrupted suicide attempts with a potential lethality judged to result in serious injury or death. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past) History of a seizure disorder or clinical evidence of untreated hypothyroidism Patients requiring excluded medications (see Table 3 for details) Psychotic features in the current episode or a history of psychotic features, as assessed by SCID Any investigational psychotropic drug within the last 3 months Have failed 3 or more adequate antidepressant trials during the current Major Depressive Episode by MGH-ATRQ criteria. Patients with a history of antidepressant-induced hypomania. Patients with any evidence of clinically significant liver abnormalities, or any liver transaminase level >1.5 X ULN at initial screening, or >5 x ULN during Phase 2 treatment. Axis II personality disorders that are the primary purpose of treatment, or would interfere with a patient's safety or compliance. Patients currently being treated for a respiratory disorder (including asthma or COPD) Any subject who scores a 5 or higher on item #10 of the MADRS Group B inclusion/exclusion Inclusion criteria: Age 18-65 Written informed consent Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of > 20 at screening and baseline visits, that is at the start of Phase 2 Has a history of failure to respond to 1, 2, or 3 FDA-approved antidepressants at adequate doses during the current episode for at least 8 weeks, as defined by the MGH Antidepressant Treatment Response Questionnaire (MGH-ATRQ), and must be currently on the failed SSRI for at least 8 weeks and on a stable dose for at least 4 weeks. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline and start of Phase 2. Exclusion Criteria Pregnant women or women of child bearing potential who are not using a medically accepted means of contraception (to include oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy) Patients who no longer meet DSM-IV criteria for MDD during the baseline visit Serious suicide or homicide risk, as assessed by evaluating clinician A serious suicide risk will be considered an inability to control suicide attempts, imminent risk of suicide in the investigator's judgment, or a history of serious suicidal behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS) as either (1) one or more actual suicide attempts in the 3 years before study entry with the lethality rated at 3 or higher, or (2) one or more interrupted suicide attempts with a potential lethality judged to result in serious injury or death. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease The following DSM-IV diagnoses: substance use disorders active within the last six months, any bipolar disorder (current or past), any psychotic disorder (current or past) History of a seizure disorder or clinical evidence of untreated hypothyroidism; Patients requiring excluded medications (see Table 3 for details) Psychotic features in the current episode or a history of psychotic features, as assessed by SCID Any investigational psychotropic drug within the last 3 months Have failed 3 or more adequate antidepressant trials during the current Major Depressive Episode by MGH-ATRQ criteria. Patients with a history of antidepressant-induced hypomania. Patients with any evidence of clinically significant liver abnormalities, or any liver transaminase level >2 X ULN at initial screening, or >5 x ULN during Phase 2 treatment. Axis II personality disorders that are the primary purpose of treatment, or would interfere with a patients safety or compliance. Patients currently being treated for a respiratory disorder (including asthma or COPD) Any subject who scores a 5 or higher on item #10 of the MADRS

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Riluzole addition to SSRI antidepressant<br>Riluzole 100mg added to ongoing SSRI or SNRI antidepressant for 8 weeks | Drug: Riluzole<br>* Riluzole 100mg PO<br>* Other names: Rilutek;|
| Placebo Comparator: Placebo addition to standard SSRI antidepressant<br>Placebo will be added to ongoing SSRI or SNRI antidepressant treatment for 8 weeks | Drug: placebo<br>* placebo<br>|
| Experimental: Riluzole/Placebo addition to SSRI antidepressant<br>Riluzole 100mg added to ongoing SSRI or SNRI antidepressant for 4 weeks and placebo will added to ongoing SSRI or SNRI antidepressant treatment for 4 weeks | Drug: Riluzole<br>* Riluzole 100mg PO<br>* Other names: Rilutek;Drug: placebo<br>* placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Montgomery and Asberg Depression Rating Scale (MADRS) | This 10 item instrument is completed by the clinician by using a structured interview and defined anchor points, and aims to quantify the degree of depression over the past 7 days. The MADRS is a widely studied instrument for depression, and its reliability and validity are high. This instrument is administered at every study visit during the double-blind RCT, and at the screening, and baseline. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Usual cutoff points are: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression | 4 weeks of therapy (baseline to week 4) | 
| Change in Montgomery and Asberg Depression Rating Scale (MADRS) | This 10 item instrument is completed by the clinician by using a structured interview and defined anchor points, and aims to quantify the degree of depression over the past 7 days. The MADRS is a widely studied instrument for depression, and its reliability and validity are high. This instrument is administered at every study visit during the double-blind RCT, and at the screening, and baseline. Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Usual cutoff points are: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression | 4 weeks of therapy (week 4 to week 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responders Having at Least a 50% Improvement in MADRS Compared to the Baseline | Responders having at least a 50% improvement in MADRS compared to the baseline in the sequential parallel design | 8 weeks therapy | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE-SI) | A commonly used instrument originally developed by NIMH and adapted into a self-report instrument. The version of the scale that we plan to use examines in a systematic fashion all possible treatment-emergent side effects and probes specific adverse symptoms, including suicidal thoughts and behaviors, and self-injurious behavior. Presented below are counts of people that had experienced the event by 8 weeks. | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, Depression, Treatment refractory, Glutamate, Riluzole, Major depressive disorder, psychopharmacology, rilutek