Which is more effective against depression, r-ketamine or s-ketamine?
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Comparative Efficacy of R-Ketamine and S-Ketamine in Treating Depression
Introduction to Ketamine Enantiomers in Depression Treatment
Ketamine, a well-known anesthetic, has gained attention for its rapid and sustained antidepressant effects, particularly in treatment-resistant depression. Ketamine exists as a racemic mixture containing equal parts of two enantiomers: R-ketamine (arketamine) and S-ketamine (esketamine). Recent research has focused on comparing the efficacy and side effects of these two enantiomers to determine which is more effective and safer for treating depression.
Antidepressant Potency and Duration
R-Ketamine's Superior Efficacy
Multiple studies have demonstrated that R-ketamine exhibits greater potency and longer-lasting antidepressant effects compared to S-ketamine. In animal models of depression, R-ketamine has shown a more significant and sustained reduction in depressive behaviors than S-ketamine . For instance, in the social defeat stress and learned helplessness models, R-ketamine produced a more potent and longer-lasting antidepressant effect than S-ketamine. Additionally, R-ketamine maintained its antidepressant effects in the tail suspension and forced swimming tests for a longer duration than S-ketamine .
Mechanisms of Action
The superior efficacy of R-ketamine is attributed to its effects on brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) signaling, as well as synaptogenesis in key brain regions such as the prefrontal cortex (PFC) and hippocampus . These molecular mechanisms are crucial for the antidepressant effects of ketamine and its enantiomers, with R-ketamine showing a more pronounced impact on these pathways .
Side Effects and Safety Profile
Reduced Psychotomimetic Effects with R-Ketamine
One of the significant advantages of R-ketamine over S-ketamine is its lower propensity to induce psychotomimetic side effects. S-ketamine is associated with behavioral abnormalities such as hyperlocomotion, prepulse inhibition deficits, and rewarding effects, which are not observed with R-ketamine . Furthermore, S-ketamine, but not R-ketamine, has been shown to cause a loss of parvalbumin-positive cells in the prelimbic region of the medial PFC and dentate gyrus, which could be linked to its psychotomimetic effects .
Abuse Potential
R-ketamine also appears to have a lower abuse potential compared to S-ketamine. In conditioned place preference tests, S-ketamine increased preference scores, indicating a higher potential for abuse, whereas R-ketamine did not. This suggests that R-ketamine may be a safer option for long-term use in treating depression.
Clinical Implications and Future Directions
Current Approvals and Ongoing Research
While S-ketamine has been approved by the US Food and Drug Administration (FDA) for treatment-resistant depression, ongoing research and clinical trials are exploring the potential of R-ketamine as a more effective and safer alternative . The promising preclinical data on R-ketamine's efficacy and safety profile support its potential as a novel antidepressant with fewer side effects and lower abuse liability.
Conclusion
In summary, R-ketamine demonstrates greater antidepressant efficacy and a more favorable safety profile compared to S-ketamine. Its longer-lasting effects and reduced risk of psychotomimetic side effects and abuse make it a promising candidate for treating depression, particularly in patients who are resistant to traditional antidepressants. Further clinical studies are warranted to confirm these findings and potentially pave the way for the approval of R-ketamine as a new treatment option for depression.
Sources and full results
Most relevant research papers on this topic
R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects
Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine.
A historical review of antidepressant effects of ketamine and its enantiomers
R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine
An update on ketamine and its two enantiomers as rapid-acting antidepressants
Letter to the Editor: R-ketamine: a rapid-onset and sustained antidepressant without risk of brain toxicity
Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine
Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective
Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine
Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review
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