Adjunctive Isradipine for the Treatment of Bipolar Depression

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).

Inclusion Criteria:

- Age 18-65

- written informed consent

- meets DSM-IV criteria (by SCID-I/P) for bipolar I disorder, current episode depressed

- MADRS score of at least 20 (i.e., moderate depression) and no greater than 34 (i.e.,
severe depression) at screen and baseline visit

- 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 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.