NMDA Antagonists in Bipolar Depression
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Intervention: Standard of Care; Ketamine; D-cycloserine
Intervention description: Quetiapine, olanzapine-fluoxetine, and lurasidone are approved treatments for bipolar depression. Quetiapine dosing will follow the product label(Anon), and will be titrated over the first 4 days to the target dose of 300 mg. Olanzapine-fluoxetine dosing will also follow standard guidelines. Lurasidone will be started at 20 mg, and titrated up to 60 mg daily as clinically indicated. Study physicians will use clinical judgment to choose between standard-of care treatments, and have the option to titrate standard-of-care within approved ranges, and to prescribe adjunctive benztropine and benzodiazepines if clinically indicated.; Ketamine administration will be carried out according to the methods as described by previous studies. Subjects will receive ketamine hydrochloride (0.5 mg/kg) intravenously during 40 minutes. This dosage was selected based on previous trials of ketamine for the treatment of refractory depression and bipolar depression. Vital signs (blood pressure, heart rate) will be closely monitored throughout the time of infusion. Subjects will be evaluated for 2 consecutive days during this phase; i.e. treatment days (day 1) and rating days (day 2). Non-responders to ketamine will not proceed into the DCS phase. Response will be a 25% improvement on the Hamilton Depression Rating Scale (HDRS).; Immediately after the ketamine infusion, subjects will begin an eight-week treatment of DCS adjunctive to standard of care. DCS dosing will begin at 250 mg for three days→500mg (2 capsules)/day for 1 week → 750 mg (3 capsules)/day for 1 week → and 1000 mg (4 capsules)/day for the remainder of the study.
Intervention MeSH terms: Cycloserine; Ketamine; Olanzapine; Quetiapine Fumarate; Fluoxetine
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Bipolar Disorder

Summary:

      The purpose of this study is to test whether ketamine and D-cycloserine can be safely and
      effectively used for the treatment of depression. The investigators hypothesize that ketamine
      will serve as a rapid acting and safe antidepressant in patients with bipolar depression, and
      furthermore, that D-cycloserine will serve as an effective therapy following ketamine
      treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male and female patients with Diagnostic and Statistical Manual, Version 4 (DSM-IV)
             diagnosis of bipolar disorder I or II, current major depressive episode without
             psychotic features, 18-60

          -  Insufficient therapeutic response during the current episode

          -  Medically stable for study participation

          -  Judged clinically not to be at significant suicide or violence risk

          -  Subject is off all psychotropic and other types of drugs likely to interact with
             glutamate for at least 14 days before starting the study. One exception is chloral
             hydrate or short acting benzodiazepines for distressing anxiety or insomnia (up to 72
             hours prior to each MRI scan). In addition, subjects will be off antipsychotics for 1
             month and off fluoxetine for 6 weeks prior to the study.

          -  Subject is likely to be able to tolerate a medication washout. Only subjects who have
             failed their current medication regiment will be washed off medications.

        Exclusion Criteria:

          -  History of chronic psychosis or drug induced psychosis of any kind

          -  Current DSM-IV diagnosis of drug abuse/dependence in the last six months. Subjects
             must have a negative drug screen at baseline.

          -  Women will be excluded if they are pregnant lactating, or not either
             surgically-sterile or using appropriate methods of birth control. Women must agree to
             continue using applicable birth control throughout the trial. All women of
             child-bearing potential must have a negative urine pregnancy test

          -  Taking any medication contraindicated with ketamine or DCS (ethionamide, isoniazid)

          -  History of seizures, renal insufficiency or congestive heart failure

          -  History of clinically significant violence

          -  History of ketamine abuse/dependence or prior clinically significant adverse reaction
             to ketamine

          -  Current alcohol abuse or dependence

          -  Untreated hypertension

          -  Clinically abnormal liver function tests (LFTs), thyroid, renal function or anemia

          -  Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or
             paramagnetic objects contained within the body which may present a risk to the subject
             or interfere with the MR scan.

          -  Medicinal patch, unless removed prior to the MR scan