Clinical trial NCT01204918: Efficacy and Tolerability of Riluzole in Treatment Resistant Depression
Official title: Efficacy and Tolerability of Riluzole in Treatment Resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Depression
Keywords: MDD
Depression
Treatment refractory
Glutamate
Riluzole
Major depressive disorder
psychopharmacology
rilutek
Lead sponsor: Yale University
Sponsor class: OTHER
First posted: 2010-09-17
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Group A inclusion/exclusion

Inclusion Criteria:

1. Age 18-65
2. Written informed consent
3. Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current
4. Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of \> 20 at screening, baseline and start of double-blind phase (Phase 2)
5. 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.
6. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline and start of Phase 2.

Exclusion Criteria:

1. 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)
2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit
3. Patients who demonstrate \> 50% decrease in depressive symptoms as reflected by the IDS-SR total score from screen to baseline
4. 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.
5. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease
6. 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)
7. History of a seizure disorder or clinical evidence of untreated hypothyroidism
8. Patients requiring excluded medications (see Table 3 for details)
9. Psychotic features in the current episode or a history of psychotic features, as assessed by SCID
10. Any investigational psychotropic drug within the last 3 months
11. Have failed 3 or more adequate antidepressant trials during the current Major Depressive Episode by MGH-ATRQ criteria.
12. Patients with a history of antidepressant-induced hypomania.
13. 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.
14. Axis II personality disorders that are the primary purpose of treatment, or would interfere with a patient's safety or compliance.
15. Patients currently being treated for a respiratory disorder (including asthma or COPD)
16. Any subject who scores a 5 or higher on item #10 of the MADRS

Group B inclusion/exclusion

Inclusion criteria:

1. Age 18-65
2. Written informed consent
3. Meets DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current
4. Inventory of Depressive Symptomatology - Self-Rated (IDS-SR30) score of \> 20 at screening and baseline visits, that is at the start of Phase 2
5. 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.
6. Montgomery Asberg Depression Rating Scale (MADRS) score of 18 or higher at baseline and start of Phase 2.

Exclusion Criteria

1. 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)
2. Patients who no longer meet DSM-IV criteria for MDD during the baseline visit
3. 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.
4. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease
5. 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)
6. History of a seizure disorder or clinical evidence of untreated hypothyroidism;
7. Patients requiring excluded medications (see Table 3 for details)
8. Psychotic features in the current episode or a history of psychotic features, as assessed by SCID
9. Any investigational psychotropic drug within the last 3 months
10. Have failed 3 or more adequate antidepressant trials during the current Major Depressive Episode by MGH-ATRQ criteria.
11. Patients with a history of antidepressant-induced hypomania.
12. 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.
13. Axis II personality disorders that are the primary purpose of treatment, or would interfere with a patients safety or compliance.
14. Patients currently being treated for a respiratory disorder (including asthma or COPD)
15. Any subject who scores a 5 or higher on item #10 of the MADRS

Primary outcomes:
measure: Change in Montgomery and Asberg Depression Rating Scale (MADRS)
timeFrame: 4 weeks of therapy (baseline to week 4)
measure: Change in Montgomery and Asberg Depression Rating Scale (MADRS)
timeFrame: 4 weeks of therapy (week 4 to week 8)
Secondary outcomes:
measure: Responders Having at Least a 50% Improvement in MADRS Compared to the Baseline
timeFrame: 8 weeks therapy
measure: Systematic Assessment for Treatment Emergent Events (SAFTEE-SI)
timeFrame: 8 weeks
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University, Yale Depression Research Program
state: Connecticut
city: Boston
country: United States
facility: Massachussettes General Hospital, Depression Clinical and Research Center
state: Massachusetts
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
Study officials:
affiliation: Yale University
name: Gerard Sanacora, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusettes General Hospital
name: Maurizio Fava, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: Sanjay Matthew, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: National Institute of Mental Health (NIMH)
name: Carlos Zarate, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sanacora G, Kendell SF, Levin Y, Simen AA, Fenton LR, Coric V, Krystal JH. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007 Mar 15;61(6):822-5. doi: 10.1016/j.biopsych.2006.08.037. Epub 2006 Dec 4.
citation: Zarate CA Jr, Payne JL, Quiroz J, Sporn J, Denicoff KK, Luckenbaugh D, Charney DS, Manji HK. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry. 2004 Jan;161(1):171-4. doi: 10.1176/appi.ajp.161.1.171.
citation: Hejazi NS, Farmer CA, Oppenheimer M, Falodun TB, Park LT, Duncan WC Jr, Zarate CA Jr. The relationship between the HDRS insomnia items and polysomnographic (PSG) measures in individuals with treatment-resistant depression. J Psychiatr Res. 2022 Apr;148:27-33. doi: 10.1016/j.jpsychires.2022.01.022. Epub 2022 Jan 11.