Adjunctive Isradipine for the Treatment of Bipolar Depression
Condition: Bipolar Disorder
MeSH terms: Depression; Bipolar Disorder
Intervention: Isradipine; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Isradipine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Bipolar Disorder; Depression; Lithium; Valproate; Isradipine

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.
    

Eligibility criteria:

        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.