The concept and management of acute episodes of treatment-resistant bipolar disorder: a systematic review and exploratory meta-analysis of randomized controlled trials

•Treatment-resistance carries significant burden in BD.•The existing definitions for resistant mania or bipolar depression are inconsistent.•Ketamine and ECT represent promising avenues in the management of resistant BD. The definitions of treatment-resistant bipolar disorder (TRBD) have varied across studies. Additionally, its management is clinically challenging. An updated synthesis and appraisal of the available evidence is needed. A systematic search of major electronic databases from inception up to May 25th, 2020, was conducted to identify randomized controlled trials (RCTs) of pharmacological and non-pharmacological interventions for the management of TRBD. When sufficient evidence was available, a meta-analysis was conducted. Seventeen studies (n = 928 patients) were included in the qualitative synthesis. Fourteen studies (n = 803) assessed treatment-resistant acute bipolar depression (TRBD-De), including five neuromodulatory and nine pharmacological trials. Rapid- vs. standard up-titration of clozapine showed promising efficacy for TRBD mania, without significant adverse events. Electroconvulsive therapy (ECT) was confirmed to be similarly effective for TRBD-De as for treatment-resistant unipolar depression: odd ratio, OR = 0.919 (95%C.I. = 0.44–1.917), I2 = 13.98, p = .822. TRBD-De patients exposed to ketamine at day one post-infusion had high odds of response: OR = 10.682 (95%C.I. = 2.142–53.272), I2 = 0, p =