Simvastatin Augmentation of Lithium Treatment in Bipolar Depression
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Intervention: Simvastatin; 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 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.; Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin 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. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.
Intervention MeSH terms: Simvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      Primary Aim: To estimate the antidepressant efficacy of simvastatin versus placebo as an
      adjunct to lithium, valproate, and/or other atypical antipsychotic therapy among individuals
      with bipolar I disorder in a nonpsychotic major depressive episode.

      Hypothesis: Simvastatin will be superior to placebo in improvement of depressive symptoms
      assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).
    

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.