Current Evidence for the Role of Rapid-Acting Antidepressants in Bipolar Depression: A Perspective and Plan for Action
Jonathan Repple, Maximilian Bayas, Chiara Möser, Nene F Kobayashi, Andreas Reif
Biological Psychiatry March 8, 2025 DOI: 10.1016/j.biopsych.2025.02.903 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression |
| Keywords | #bipolardisorder manic depression Bipolar affective disorder #ketamine ketamine therapy Nmda antagonist Rapid antidepressant #glutamatepathways gluta Bipolar disorder Rapid-acting antidepressant |
| Citations | 8 |
| Key findings | Despite the established efficacy and safety of (es)ketamine for bipolar depression, research on other rapid-acting antidepressants in this context remains scarce, highlighting an urgent need for well-controlled clinical studies. |
Abstract
After decades of limited progress in depression treatment, recent advancements have sparked renewed interest in developing novel antidepressants, particularly rapid-acting antidepressants (RAADs). Despite these promising developments, there remains a significant gap in research on bipolar depression. While several antipsychotics have been investigated for their efficacy in bipolar depression due to the reduced risk of mania induction, research on RAADs, such as (es)ketamine, remains scarce despite their demonstrated safety and effectiveness. In this review, we give an overview of current developments in RAADs in the context of bipolar disorder. Both published studies as well as phase II, III, and IV studies on bipolar depression (based on ClinicalTrials.gov) are reviewed in this work. The following RAAD substance classes have been or are currently being investigated as possible treatments for bipolar depression: NMDA antagonists and indirect AMPA agonists (ketamine, esketamine, riluzole, felbamate), GABAA (gamma-aminobutyric acid A) activators or positive allosteric modulators (zuranolone, pregnenolone, PEA), psychedelics (psilocybin, 5-MeO-DMT), muscarine receptor antagonists (scopolamine), and kappa opioid receptor antagonists (navacaprant). Other than the well-established efficacy and safety of (es)ketamine in treating bipolar depression, there has been little research effort in the treatment of bipolar depression. Recent research into RAADs demonstrates the growing field of novel mechanisms of action in the pharmacological treatment of bipolar depression. However, there is an urgent need for well-controlled clinical studies on RAADs in bipolar depression to expand treatment options and improve outcomes for millions of affected individuals worldwide.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 2
Cites 36
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- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 31 more in the library