Efficacy and Tolerability of Riluzole in Treatment Resistant Depression

• ClinicalTrials.gov Identifier: NCT01204918
• Recruitment Status: Completed
• First Posted: September 17, 2010
• Results First Posted: February 8, 2018
• Last Update Posted: March 6, 2020
• Sponsor: Yale University
• Information provided by (Responsible Party): Yale University

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Depression	Drug: Riluzole; Drug: placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy and Tolerability of Riluzole in Treatment Resistant Depression
• Study Start Date: June 2011
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: August 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Riluzole addition to SSRI antidepressant; Riluzole 100mg added to ongoing SSRI or SNRI antidepressant for 8 weeks	Drug: Riluzole; Riluzole 100mg PO; Other Name: Rilutek
Placebo Comparator: Placebo addition to standard SSRI antidepressant; Placebo will be added to ongoing SSRI or SNRI antidepressant treatment for 8 weeks	Drug: placebo; placebo
Experimental: Riluzole/Placebo addition to SSRI antidepressant; 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; Riluzole 100mg PO; Other Name: Rilutek; Drug: placebo; placebo

Outcome Measures

Primary Outcome Measures :

1. Change in Montgomery and Asberg Depression Rating Scale (MADRS) [ Time Frame: 4 weeks of therapy (baseline to week 4) ]

   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

2. Change in Montgomery and Asberg Depression Rating Scale (MADRS) [ Time Frame: 4 weeks of therapy (week 4 to week 8) ]

   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

Secondary Outcome Measures :

1. Responders Having at Least a 50% Improvement in MADRS Compared to the Baseline [ Time Frame: 8 weeks therapy ]
   Responders having at least a 50% improvement in MADRS compared to the baseline in the sequential parallel design
2. Systematic Assessment for Treatment Emergent Events (SAFTEE-SI) [ Time Frame: 8 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Connecticut

Yale University, Yale Depression Research Program

New Haven, Connecticut, United States, 06511

United States, Massachusetts

Massachussettes General Hospital, Depression Clinical and Research Center

Boston, Massachusetts, United States, 02114

United States, Texas

Baylor College of Medicine

Houston, Texas, United States, 77030

Sponsors and Collaborators

Yale University

Investigators

• Principal Investigator: Gerard Sanacora, MD PhD; Yale University
• Principal Investigator: Maurizio Fava, MD; Massachusettes General Hospital
• Principal Investigator: Sanjay Matthew, MD; Baylor College of Medicine
• Principal Investigator: Carlos Zarate, MD; National Institute of Mental Health (NIMH)

More Information

Publications:

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. Epub 2006 Dec 4.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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 Jan 11;148:27-33. doi: 10.1016/j.jpsychires.2022.01.022. [Epub ahead of print]

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT01204918
• Obsolete Identifiers: NCT01298427
• Other Study ID Numbers: 0903004917; 137889 ( Other Identifier: Other )
• First Posted: September 17, 2010
• Results First Posted: February 8, 2018
• Last Update Posted: March 6, 2020
• Last Verified: March 2020

Keywords provided by Yale University:

MDD; Depression; Treatment refractory; Glutamate; Riluzole; Major depressive disorder; psychopharmacology; rilutek

Additional relevant MeSH terms:

Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Behavioral Symptoms; Mood Disorders; Mental Disorders; Riluzole; Anticonvulsants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Neuroprotective Agents; Protective Agents