Efficacy and Tolerability of Riluzole in Treatment Resistant Depression

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.

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