Bipolar Disorder
Conditions
Keywords
Riluzole, Neuroprotective, Open-Label Study, Glutamate Dysfunction, Bipolar Mood Disorder, Bipolar Disorder, Mood Disorder
Brief summary
This study examines if Riluzole, FDA approved for ALS, will improve symptoms of depression in Bipolar Disorder. Purpose: This study will examine the safety and effectiveness of riluzole (Rilutek trademark) for short-term treatment of depression symptoms, such as depressed mood, psychomotor retardation, and excessive sleeping in patients with bipolar disease. Riluzole is approved by the Food and Drug Administration (FDA) to treat amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease). Preliminary findings of a study using riluzole to treat acute depression in patients with unipolar depression indicate that it may have antidepressant properties in some patients. Patients between 18 and 70 years of age with bipolar I or II disorder without psychosis may be eligible for this 8-week study. Candidates must be currently depressed, must have had at least one previous major depressive episode, and must have failed to improve with prior treatment with at least one antidepressant. They will be screened with a medical history, physical examination, electrocardiogram (EKG), blood and urine tests, and psychiatric evaluation. A blood or urine sample will be analyzed for illegal drugs. Women of childbearing potential will have a pregnancy test. Participants will begin an 8-week course of treatment, starting with a placebo (a sugar pill formulated to look like the active drug) and, at some point, switching to riluzole. In addition to drug treatment, participants will undergo the following procedures: Physical examination and electrocardiogram (EKG) at the beginning and end of the study; Weekly check of vital signs (temperature, blood pressure and heart rate); Weekly 1-hour interviews consisting of psychiatric and psychomotor rating scales to assess treatment response; Weekly blood tests to measure blood levels of riluzole and evaluate drug side effects. At the end of the study, participants' psychiatric status will be reassessed and appropriate long-term psychiatric treatment arranged. Atendemos pacientes de habla hispana. We enroll eligible participants locally and from around the country. Travel arrangements are provided and costs covered by the National Institute of Mental Health (NIMH). (Arrangements vary by distance and by specific study.) After completing the study participants receive short-term follow-up care while transitioning back to a provider.
Detailed description
The treatments for acute unipolar depression have been extensively researched. However, despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of depressed patients fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Very few studies have examined the efficacy of somatic treatments for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Clinical data suggests that lamotrigine an inhibitor of glutamate release and the N-methyl-D-aspartate (NMDA) antagonist ketamine may have antidepressant effects. Finally, our group recently found in two separate studies that the glutamate modulating agent riluzole was effective in treatment-resistant unipolar and bipolar depression (Zarate et al 2004). Together, these data suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants. In this study, we propose to extend our findings from open-label studies with riluzole in treatment-resistant depression by investigating its efficacy in a double-blind placebo-controlled study in bipolar depression. Patients, ages 18 to 70 years with a diagnosis of bipolar disorder I or II current episode depressed (without psychotic features), will be randomized to double-blind treated to receive either riluzole (50-200 mg/day) or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 78 patients with acute bipolar depression will be enrolled in this study.
Interventions
DRUGRiluzole
Riluzole
DRUGPlacebo
Placebo
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Male or female subjects, 18-70 years of age. Female subjects of childbearing potential must be using a medically accepted means of contraception. Each subject must have a level of understanding sufficient to agree to all required tests and examinations. Each subject must understand the nature of the study and must sign an informed consent document. Subjects must fulfill the criteria bipolar I or II disorder, current episode depressed without psychotic features as defined in the Diagnostic and Statistical Manual (DSM-IV) based on clinical assessment and confirmed by the Structured Clinical Interview for DSM (SCID-P). Subjects must have an initial score at Visit 1 and Visit 2 of at least 20 on the MADRS. Current duration of depressive episode should be at least 4 weeks. Subjects must have experienced, in the opinion of the investigator, at least one previous major depressive episode as defined in DSM-IV (not including the current major depressive episode).
Exclusion criteria
Presence of psychotic features. Female subjects who are either pregnant or nursing. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease. Subjects with uncorrected hypothyroidism or hyperthyroidism. Clinically significant abnormal laboratory tests. Current or past blood dyscrasia. Documented history of hypersensitivity or intolerance to riluzole. DSM-IV substance abuse or dependence within the past 90 days. No alcohol or recreational drug use will be permitted during the study. Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections prior to visit 2. Treatment with a reversible monoamine oxidase inhibitor (MAOI), guanethidine, or guanadrel within 1 week or with fluoxetine within 5 weeks prior to Visit 2. Treatment with any other concomitant medication with primarily central nervous system (CNS) activity, other than specified in Appendix A. Treatment with clozapine or electroconvulsive therapy (ECT) within 4 weeks prior to Visit 2. Current diagnosis of schizophrenia or other psychotic disorder as defined in the DSM-IV. Current Axis I Anxiety Disorder that is clinically significant. Judged clinically to be at serious suicidal risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Scale | 8 weeks | The Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated assessment of depression symptoms. Patients were rated weekly on 10 symptoms on a scale of 0 to 6 for each item, where 0 indicated no symptoms and 6 indicated the highest severity of that symptom. Total scores range from 0 to 60, where a moderate severity of depression would be present with a score of at least 20. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Riluzole Riluzole was dispensed either once or twice a day as 50 mg tablets. Riluzole dosing began at 50 mg twice per day by mouth and was increased on a weekly basis by 50 mg, as tolerated, to achieve a dose of 200 mg/day. Dose escalations continued until at least a 50% reduction in depression (MADRS) scores, intolerable side effects, or study completion. Dose was raised on a weekly basis by 50 mg until the dose of 200 mg was achieved unless precluded by an adverse event. If significant side effects occurred, titration was slowed and doses were reduced under double-blind conditions. The maximum permitted dose of riluzole was be 200 mg/day. Those subjects not tolerating a dosage of 50 mg/day were removed from the study. | 8 |
| Placebo Placebo pills resembling 50 mg riluzole tables were dispensed either once or twice a day. Dosing began at 50 mg twice per day by mouth and was increased on a weekly basis by 50 mg, as tolerated, to achieve a dose of 200 mg/day. Dose escalations continued until at least a 50% reduction in depression (MADRS) scores, intolerable side effects, or study completion. Dose was raised on a weekly basis by 50 mg until the dose of 200 mg was achieved unless precluded by an adverse event. If significant side effects occurred, titration was slowed and doses were reduced under double-blind conditions. The maximum permitted dose of riluzole was be 200 mg/day. Those subjects not tolerating a dosage of 50 mg/day were removed from the study. | 11 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lack of Efficacy | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Riluzole | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 47.29 Years STANDARD_DEVIATION 15 | 48.73 Years STANDARD_DEVIATION 11.29 | 48.08 Years STANDARD_DEVIATION 12.74 |
| Region of Enrollment United States | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 8 / 11 |
| serious Total, serious adverse events | 0 / 8 | 0 / 11 |
Outcome results
Primary
Montgomery-Asberg Depression Rating Scale
The Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated assessment of depression symptoms. Patients were rated weekly on 10 symptoms on a scale of 0 to 6 for each item, where 0 indicated no symptoms and 6 indicated the highest severity of that symptom. Total scores range from 0 to 60, where a moderate severity of depression would be present with a score of at least 20.
Time frame: 8 weeks
Population: Data from all patients were included in the analysis, except for one riluzole patient with missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Riluzole | Montgomery-Asberg Depression Rating Scale | 29.551 Units on a scale | Standard Error 2.481 |
| Placebo | Montgomery-Asberg Depression Rating Scale | 23.723 Units on a scale | Standard Error 1.916 |
Comparison: The primary intent of this study was to compare the efficacy of riluzole to placebo in the treatment of overall depressive symptomatology of bipolar disorder subjects who were acutely depressed. Data from 8 riluzole and 11 placebo participants were analyzed due to missing data for one riluzole patient.p-value: 0.08695% CI: [-12.59, 0.934]Mixed Models Analysis