Intervention: Isradipine
Trial phase: Phase 2
ATC code: C08CA03
SMILES: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 2
Group description: 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.
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.