Growing evidence has supported rapid and robust antidepressant effects with subanesthetic
doses of intravenous (IV) ketamine for treatment resistant depression (TRD). However, no
completed or ongoing randomized control trials (RCTs) have evaluated the effects of repeated
doses of IV ketamine for a homogenous sample of patients with treatment-resistant bipolar
disorder (TRBD). The primary research goal is to determine the acute antidepressant efficacy,
safety and tolerability of four repeated sub-anesthetic doses of IV ketamine in moderate to
severe TRBD. Secondary aims include evaluating effects of IV ketamine on suicidal ideations,
quality of life, function and duration of effects. Herein, a two-site (University Health
Network and Canadian Rapid Treatment Centre of Excellence), phase II, double-blinded,
midazolam-controlled, two-week RCT evaluating the efficacy, safety and tolerability of four
flexibly-dosed adjunctive ketamine infusions (0.5-0.75mg/kg infused over 40 minutes) for
acute treatment of moderate to severe TRBD (type I & II) is proposed. The primary outcome
will be Montgomery-Åsberg Depression Rating Scale (MADRS) scores, determining the between
group difference in change from baseline to day 14, using analysis of covariance (ANCOVA),
with 14-day MADRS as the outcome and baseline MADRS and stratification variables (sex,
bipolar type) as covariates. Secondary outcomes include evaluating response and remission
rates, safety, tolerability (including treatment-emergent mania), and effects on suicidality,
anxiety, quality of life, function and the duration of effects (to day 28).