NMDA Antagonists in Bipolar Depression
Condition: Bipolar Disorder
MeSH terms: Bipolar Disorder
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Bipolar disorder affects 2% of the population in the United States and the depressive phase
      contributes disproportionally to morbidity and mortality. At present, few approved treatments
      for bipolar depression are available, and have primarily depended on manipulations of brain
      monoaminergic systems. In contrast, recent studies suggest that the N-methyl-D-aspartate
      glutamate-receptor (NMDAR) antagonist, ketamine, may provide near-immediate relief for
      treatment resistant depression. Its utility during long-term treatment, however, is limited
      by its psychotomimetic potency and the need for repeated IV infusions. D-cycloserine (DCS) is
      an approved oral antibiotic for tuberculosis drug and a well-studied mixed agonist/antagonist
      at the NMDAR/glycine binding site. DCS showed preliminary evidence of efficacy in a pilot
      study. DCS would thus be practical from both a safety and route of administration
      perspective. The present study will explore the feasibility and safety of DCS for maintenance
      treatments, as measured by magnetic resonance spectroscopy (MRS).
    

Intervention name(s): Standard of Care; Ketamine; D-cycloserine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Quetiapine; Olanzapine; fluoxetine; Ketamine Hydrochloride; DCS
Intervention MeSH terms: Cycloserine; Ketamine; Olanzapine; Quetiapine Fumarate; Fluoxetine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Bipolar Disorder