Novel drug developmental strategies for treatment‐resistant depression
Éva Borbély, Mária Simon, Eberhard Fuchs, Ove Wiborg, Boldizsár Czéh, Zsuzsanna Helyes
British Journal of Pharmacology November 25, 2021 DOI: 10.1111/bph.15753 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression |
| Keywords | Depression economics Drug Pharmacology |
| Citations | 103 |
| Key findings | The most promising novel drug targets for treatment-resistant depression are NMDA and mGlu5 receptor antagonists, κ receptor antagonists, and hallucinogenic tryptamine derivates, with S-ketamine being the only registered drug for TRD. |
Abstract
Major depressive disorder is a leading cause of disability worldwide. Because conventional therapies are ineffective in many patients, novel strategies are needed to overcome treatment‐resistant depression (TRD). Limiting factors of successful drug development in the last decades were the lack of (1) knowledge of pathophysiology, (2) translational animal models and (3) objective diagnostic biomarkers. Here, we review novel drug targets and drug candidates currently investigated in Phase I–III clinical trials. The most promising approaches are inhibition of glutamatergic neurotransmission by NMDA and mGlu 5 receptor antagonists, modulation of the opioidergic system by κ receptor antagonists, and hallucinogenic tryptamine derivates. The only registered drug for TRD is the NMDA receptor antagonist, S ‐ketamine, but add‐on therapies with second‐generation antipsychotics, certain nutritive, anti‐inflammatory and neuroprotective agents seem to be effective. Currently, there is an intense research focus on large‐scale, high‐throughput omics and neuroimaging studies. These results might provide new insights into molecular mechanisms and potential novel therapeutic strategies.
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 16
- Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review Frontiers in Psychiatry May 26, 2022
- Trends in research on novel antidepressant treatments. Frontiers in Pharmacology 2025
- Esketamine Combined With SSRI or SNRI for Treatment-Resistant Depression. JAMA Psychiatry April 2, 2025
- Ketamine's mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine's antidepressant effects? Molecular Psychiatry September 1, 2024
- Efficacy and Safety of Esketamine Combined with Antidepressants for Treatment-Resistant Depression: A Meta-Analysis Neuropsychiatric Disease and Treatment December 1, 2022
and 11 more in the library
Cites 30
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Global Street Food: la cocina de la calle Diseño interior 2009
and 25 more in the library