Intervention: Simvastatin
Trial phase: Phase 2
ATC code: A10BH51 | C10AA01 | C10BA02 | C10BA04 | C10BX01 | C10BX04
SMILES: CCC(C)(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CC(=O)O3)C21
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 4
Group description: Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)

Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.
Eligibility criteria:
Inclusion:

Age 18-65
written informed consent
meets Diagnostic and Statistical Manual - IV (DSM-IV) criteria (by Structured Clinical Interview for DSM-IV (SCID-I/P)) 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 >0.4 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).

Exclusion:

Psychotic features in the current episode, as assessed by YMRS item #8>6
felt by the study clinician to require inpatient hospitalization for adequate management
more than 3 failed pharmacologic interventions in the current major depressive episode, exclusive of primary mood stabilizer
current substance use disorder other than nicotine, by SCID-I/P
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
serious suicide or homicide risk, as assessed by evaluating clinician
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
patients who have taken an investigational psychotropic drug within the last 30 days
patients receiving additional anticonvulsant, antipsychotic, or antidepressant within 1 week prior to study entry
patients requiring continued treatment with excluded medications (see below).

Excluded medications: other statins, which could influence Wnt signaling; any other drug known to interact with simvastatin, including potent inhibitors/inducers of CYP3A4 such as itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, voriconazole, cyclosporine or danazol; gemfibrozil or other lipid-lowering drugs that can cause myopathy when given alone; amiodarone, ranolazine, verapamil, diltiazem, or amlodipine; niacin; digoxin; coumarin anticoagulants; colchicine; nefazodone; protease inhibitors including ritonavir, indinavir, nelfinavir, or saquinavir.

Allowed: benzodiazepines and sedative-hypnotic agents if dosage has been stable for 2 weeks prior to study entry; thyroid or estrogen replacement provided dosage has been stable for 1 month; antidepressants, antipsychotics, and anticonvulsants provided dosage has been stable for 1 week prior to study entry.