Efficacy and Tolerability of Riluzole and Biomarker of Treatment Response in Treatment-Resistant Depression

Objective: This collaborative R01 investigates the safety and efficacy of the
glutamate-modulating and neuroprotective agent riluzole in a randomized double-blind
placebo-controlled clinical trial (RCT) in patients with treatment resistant depression
(TRD). The recent findings of the STAR*D study highlight the fact that our current
armamentarium of antidepressant medications, developed out of the monoamine hypothesis, has
serious limitations. There is now emerging evidence that amino acid neurotransmitter (AANt)
systems may also contribute to the pathophysiology of major depressive disorder (MDD), and
that drugs targeting these systems may have potent antidepressant properties. Riluzole is
currently approved by the US FDA for the treatment of amyotrophic lateral sclerosis (ALS).
It has been shown to have a variety of neurobiological effects on glutamatergic function
associated with the drug's neuroprotective and plasticity-enhancing properties. There have
now been two recent open-label studies showing riluzole to be effective in TRD as well as
several reports demonstrating riluzole's efficacy in bipolar depression, generalized anxiety
disorder, and obsessive-compulsive disorder. However, no RCT has been performed in TRD.

Study Population: Treatment-resistant major depression.

Design: This randomized, double-blind, placebo-controlled trial, using a sequential parallel
comparison design, evaluates the efficacy and safety of riluzole augmentation of the
selective serotonin reuptake inhibitor citalopram in outpatients ages 18-65 years with
moderate TRD. Significance to Public Health: In this unique 5-year proposal, investigators
from four institutions [Yale, Baylor, MGH and NIMH (ETPB)] will conduct a RCT to examine the
efficacy, safety and tolerability of adjunctive riluzole treatment in TRD.

Demonstration of riluzole's benefit would represent a major advance for patients with
difficult-to-treat depression, and may help elucidate our understanding of the
pathophysiology of MDD and the mechanism of antidepressant action. Most immediately, since
riluzole is already a FDA-approved medication that has been safely prescribed to thousands
of patients with ALS, positive findings from this study could rapidly disseminate into
clinical practice and would encourage further investigation of this strategy. Demonstrating
riluzole's efficacy in TRD would open the door to the discovery of future medications
targeting the glutamatergic system that could be used to fight this common and devastating
disorder.

Outcome measures: The primary efficacy endpoint is the mean change in Montgomery-Asberg
Depression Rating Scale (MADRS) total score from the end of the prospective open-label
citalopram treatment to the end of the double-blind adjunctive treatment with riluzole or
placebo. Response and remission rates are secondary outcome measures.

- INCLUSION CRITERIA:

Group A subjects:

- Age 18-65;

- Able to understand the procedures in this study and can provide own voluntary
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 > 24 at
screening, baseline and start of double-blind phase (Phase 2);

- May have a history of failure to respond to 0-2 FDA-approved antidepressants,
including citalopram, at adequate doses during the current episode for at least 8
weeks, and for inclusion into 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.

Group B subjects:

- 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-SR(30)) score of > 24 at
screening and baseline visits, that is at the start of Phase 2;

- Has a history of failure to respond to at least one but no more than 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, including citalopram, 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:

Group A subjects:

- Pregnant women or women of child bearing potential who are not using a medically
accepted means of contraception (to include oral, injectible, or implant birth
control, condom, diaphragm with spermicide, intrauterine devices (IUD), tubal
ligation, abstinence or partner with vasectomy);

- Patients who do not have the capacity to provide voluntary informed consent.

- Patients who no longer meet DSM-IV criteria for MDD during the baseline visit;

- Patients who demonstrate > 50 percent 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

- 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 more than 2 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 times the ULN at initial screening, or > 5 times the
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

- Patients with a previous adverse reaction to citalopram

Group B subjects:

- 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

- 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 4 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 times the ULN at initial screening, or > 5 times the
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