Bipolar Disorder
Conditions
Keywords
Bipolar Disorder, Depression, Lithium, Valproate, Isradipine
Brief summary
This study investigates the medication isradipine, which is currently approved by the FDA to treat high blood pressure, in the treatment of depression in bipolar disorder. Isradipine or placebo (contains no active medication) will be used as an add-on to lithium, valproate, and/or atypical antipsychotics for individuals currently experiencing a major depressive episode. Our hypothesis is that isradipine will be superior to placebo in improving depressive symptoms.
Detailed description
Primary Aim: To estimate the antidepressant efficacy of isradipine versus placebo as an adjunct to lithium, valproate, and/or other atypical antipsychotics among individuals with bipolar I disorder in a nonpsychotic major depressive episode. Hypothesis: Isradipine will be superior to placebo in improvement of depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).
Interventions
DRUGIsradipine
The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to isradipine versus placebo add-on for 4 weeks, with the placebo nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the isradipine treatment effect. Subjects who respond in phase 1, and all subjects who receive isradipine in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed.
DRUGPlacebo
Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to isradipine vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed.
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-65 * written informed consent * meets Diagnostic and Statistical Manual-IV (DSM-IV) criteria (by Structured Clinical Interview for Diagnostic and Statistical Manual - IV -I/P (SCID)) for bipolar I disorder, current episode depressed * Montgomery-Asberg Depression Scale (MADRS) score of at least 20 (i.e., moderate depression) and no greater than 34 (i.e., severe depression) at screen and baseline visit * Young Mania Rating Scale (YMRS) score \< 12 at screen and baseline visit * currently treated with a lithium preparation (carbonate or citrate) at stable dose for at least 4 wks with level \>0.6 and \<1.0; and/or valproate at stable dose for at least 4 wks at level \>60 and \<110; and/or other atypical antipsychotic at stable dose for at least 4 weeks (at least minimum FDA-labeled dose) * Caucasian by self-report - please see discussion below
Exclusion criteria
* Psychotic features in the current episode, as assessed by YMRS item #8 \> 6 \[where treatment guidelines urge use of antipsychotics that may confound isradipine results\] * felt by the study clinician to require inpatient hospitalization for adequate management (to include serious suicide or homicide risk, as assessed by evaluating clinician) * 3 or more failed pharmacologic interventions in the current major depressive episode, excluding lithium/valproate/other atypical antipsychotic \[response rates for these subjects is likely to be extremely low and would require a substantially larger-scale study to identify treatment effects\] * obsessive-compulsive disorder, or any diagnosis of a DSM-IV anxiety disorder where the anxiety disorder and not bipolar disorder is the primary focus of clinical attention * current substance use disorder other than nicotine, by SCID-I/P * a primary clinical diagnosis of a personality disorder, or comorbid diagnosis of antisocial or borderline personality disorder * 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) * women who are breastfeeding * other unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, neurological, or hematological disease, based on review of medical history, physical examination, and screening laboratory tests (this will include any clinical or laboratory evidence of hypothyroidism; if maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1) * history of hypertension or current treatment for hypertension * current use of isradipine or history of anaphylactic reaction or intolerance to isradipine or any component of the preparation * ECG abnormalities at entry: prolonged QTC interval or complete or incomplete bundle branch block * patients who have taken an investigational psychotropic drug within the last 3 months * patients receiving other excluded antipsychotics or antidepressants within 2 weeks prior to study entry * patients requiring continued treatment with excluded medications (see below). Excluded medications: antidepressants, antipsychotics, and anticonvulsants (other than valproate), which could influence calcium signaling or impact mood; other calcium channel blockers; any other antihypertensive because of the risk of cause hypotension; any other drug known to interact with isradipine. Benzodiazepines or other sedative-hypnotic agents (e.g., zolpidem) may not be initiated after study entry; subjects requiring these agents will be removed from the study. Allowed: Sedative-hypnotic agents if dosage has been stable for 4 weeks prior to study entry; thyroid or estrogen replacement provided dosage has been stable for 3 months. Acceptable anticonvulsants include lamotrigine, valproate, gabapentin, topiramate, oxcarbazepine, carbamazepine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in MADRS (4 Weeks) | Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4) | Change in Montgomery-Asberg Depression Rating Scale (MADRS) in isradipine-treated epochs versus placebo-treated epochs. These scores represent total scores, and on the MADRS total scores range from 0-60. A higher score indicates increased depression severity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Isradipine-Isradipine Subjects will receive isradipine in phase 1 (4 weeks) and phase 2 (4 weeks)
Isradipine: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to isradipine versus placebo add-on for 4 weeks, with the placebo nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the isradipine treatment effect. Subjects who respond in phase 1, and all subjects who receive isradipine in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. | 1 |
| Placebo -> Isradipine Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or isradipine for the next 4 weeks
Isradipine: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to isradipine versus placebo add-on for 4 weeks, with the placebo nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the isradipine treatment effect. Subjects who respond in phase 1, and all subjects who receive isradipine in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed.
Placebo: Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to isradipine vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. | 0 |
| Placebo-Placebo Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or isradipine for the subsequent 4 weeks
Placebo: Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to isradipine vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. | 1 |
| Total | 2 |
Baseline characteristics
| Characteristic | Placebo -> Isradipine | Isradipine-Isradipine | Placebo-Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Age, Continuous | — | 56 years | 44 years | 50 years |
| Region of Enrollment United States | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 1 | 0 / 0 | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 0 | 0 / 1 |
Outcome results
Primary
Change in MADRS (4 Weeks)
Change in Montgomery-Asberg Depression Rating Scale (MADRS) in isradipine-treated epochs versus placebo-treated epochs. These scores represent total scores, and on the MADRS total scores range from 0-60. A higher score indicates increased depression severity.
Time frame: Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Isradipine-Isradipine | Change in MADRS (4 Weeks) | -9 scores on a scale |
| Placebo-Placebo | Change in MADRS (4 Weeks) | 0 scores on a scale |