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New Pharmacologic Approaches to the Treatment of Bipolar Depression

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A Correction to this article was published on 12 February 2024

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Abstract

Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression, with only a handful of atypical anti-psychotics and inconsistent evidence for traditional mood stabilizing agents. There have been few major ‘breakthroughs’ in the treatment of BD depression, and until recently, few agents that work via novel mechanisms of action to exert therapeutic effects. Here, we review treatments for BD depression which are emergent or on the horizon. Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics lumateperone and cariprazine have demonstrated efficacy in large-scale, placebo-controlled, double-blind randomized controlled trials (RCT) in treatment of BD depression. Non-racemic amisulpride showed potential therapeutic benefit in one RCT which requires replication. Three small RCTs examined the efficacy of intravenous ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects after a single infusion. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression to support their use. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation. Further investigation on how these agents may impact specific subgroups of patients will also advance the field.

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  1. Kamyar Keramatian and Trisha Chakrabarty have contributed equally to the manuscript.

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  1. Department of Psychiatry, University of British Columbia, Room 2C7-2255 Wesbrook Mall, Vancouver, BC, V6T 2A1, Canada

    Kamyar Keramatian, Trisha Chakrabarty & Lakshmi N. Yatham

  2. Department of Psychiatry, University of Montréal, 2900 boul. Édouard-Montpetit, Montreal, QC, Canada

    Anais DuBow

  3. Department of Psychiatry, University of Ottawa, 5457-1145 Carling Avenue, Ottawa, ON, Canada

    Gayatri Saraf

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Kamyar Keramatian has served on the scientific advisory board of AbbVie and is also supported by the Vancouver Coastal Health Research Institute Investigator Award. Trisha Chakrabarty has received grant funding from the Michael Smith Foundation and National Research Council-Canada. Anais DuBow and Gayatri Saraf report no conflicts of interest that might be relevant to the contents of this manuscript. Lakshmi N Yatham is a consultant and/or has received speaker fees and/or sits on the advisory board and/or receives research funding from Abbvie, Alkermes, Allergan, Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Institutes of Health Research (CIHR), Dainippon Sumitomo Pharma, Gedeon Richter, GSK, Intracellular Therapies, Lundbeck, Merck, Otsuka, Sanofi and Sunovion over the past 3 years.

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Keramatian, K., Chakrabarty, T., DuBow, A. et al. New Pharmacologic Approaches to the Treatment of Bipolar Depression. Drugs 83, 843–863 (2023). https://doi.org/10.1007/s40265-023-01872-x

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