Contribution of the opioid system to depression and to the therapeutic effects of classical antidepressants and ketamine.
Miroslav Adzic, Iva Lukic, Milos Mitic, Emilija Glavonic, N. Dragičević, Sanja Ivkovic
Life Science May 1, 2023 DOI: 10.1016/j.lfs.2023.121803 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Esketamine Ketamine |
| Key findings | Argues that opioid receptor signaling is dysregulated in depression and that modulating mu, kappa, delta, and nociceptin/orphanin FQ receptors may serve as an adjuvant or alternative to classical monoaminergic antidepressants. Contends that some classical antidepressants require opioid receptor modulation for their effects, and that ketamine mediates its antidepressant effects via the endogenous opioid system. Concludes that further research is needed to clarify benefits and weaknesses. |
Abstract
Major depressive disorder (MDD) afflicts approximately 5 % of the world population, and about 30-50 % of patients who receive classical antidepressant medications do not achieve complete remission (treatment resistant depressive patients). Emerging evidence suggests that targeting opioid receptors mu (MOP), kappa (KOP), delta (DOP), and the nociceptin/orphanin FQ receptor (NOP) may yield effective therapeutics for stress-related psychiatric disorders. As depression and pain exhibit significant overlap in their clinical manifestations and molecular mechanisms involved, it is not a surprise that opioids, historically used to alleviate pain, emerged as promising and effective therapeutic options in the treatment of depression. The opioid signaling is dysregulated in depression and numerous preclinical studies and clinical trials strongly suggest that opioid modulation can serve as either an adjuvant or even an alternative to classical monoaminergic antidepressants. Importantly, some classical antidepressants require the opioid receptor modulation to exert their antidepressant effects. Finally, ketamine, a well-known anesthetic whose extremely efficient antidepressant effects were recently discovered, was shown to mediate its antidepressant effects via the endogenous opioid system. Thus, although opioid system modulation is a promising therapeutical venue in the treatment of depression further research is warranted to fully understand the benefits and weaknesses of such approach.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 8
- Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors. Molecular Pharmacology October 17, 2024
- Demographic and clinical predictors of response and remission in the treatment of major depressive disorder with ketamine and esketamine: A systematic review. Psychiatry Research March 1, 2025
- Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences December 20, 2024
- Is the antidepressant effect of ketamine separate from its psychotomimetic effect? A review of rodent models. Neuropharmacology November 1, 2024
- Adjunctive ketamine vs. buprenorphine in co-occurring major depressive disorder and opioid use disorder: a randomized, double-blind clinical trial assessing anxiety symptom severity and craving intensity. Trials April 17, 2025
and 3 more in the library
Cites 22
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
and 17 more in the library