Ketamine has two enantiomers known as esketamine and arketamine. Arketamine seems to be more potent and long-lasting antidepressant effects.
Ketamine, an anaesthetic medication, has gained popularity due to its promising effects in the treatment of resistant depression, bipolar disorders, anxiety disorders, and PTSD. Previously, it has been mainly used as an anesthetic medication since its approval by FDA in 1970. Recent advances in research studies indicate ketamine can treat mental health disorders resistant to traditional medications.
Ketamine has two enantiomers known as S-Ketamine and R-Ketamine. R in R-Ketamine refers to right-sided and S in S-Ketamine refers to left-sided.
Racemic Ketamine consists of both enantiomers S-Ketamine and R-Ketamine in equal doses (1:1). It is interesting to know that intravenous infusion of ketamine contains both of these enantiomers.
Racemic Ketamine and enantiomers of ketamine show distinct psychological functions. Antidepressant effects of ketamine may depend on the extent of psychological effects produced by different enantiomers.
In a randomized double-blinded placebo-controlled trial Torsten Passie et al. compared the effects of (R/S)-ketamine and (S)-ketamine on the state of consciousness, psychopathology, and neurocognitive performance in healthy volunteers. After the initial bolus, (R/S)-Racemic Ketamine and S-Ketamine or placebo were administered intravenously to 3 groups of 10 healthy male volunteers. No significant difference in effects of (R/S)-Racemic Ketamine and S-Ketamine was observed.
Moreover, this study indicated negatively experienced psychopathology with S-ketamine. It opens new questions about the protective effects of R-ketamine against the psychotomimetic effects of S-Ketamine. So, R-Ketamine may be ideal for the treatment of patients with depression. Preclinical data shows R-Ketamine is more potent and exerts long-lasting effects in the treatment of depression.
In a non-human clinical study by Sr Edward et Al. It was suggested that S-ketamine is more potent than R-Ketamine. Moreover, S-Ketamine has a higher clearance rate and therapeutic index than R-Ketamine. Metabolism of ketamine and its uptake in body tissues is enantioselective.
A clinical study by HA Adams suggests that, In comparison to R-Ketamine and racemic ketamine, S-Ketamine has greater analgesic and anesthetic potency (Approximately twofold higher). Reduced drug load and rapid recovery are distinct features of S-Ketamine when used alone.
Ketamine acts as an antagonist to NMDA receptors. S-Ketamine has a fourfold increased affinity to NMDA receptors as compared to R-Ketamine, which contributes to greater anaesthetic potency of ketamine.
PF White et Al. studied the clinical and electroencephalographic (EEG) effects of isomers of ketamine in surgical patients. As a result, S-Ketamine showed fewer adverse effects, less agitated behaviour, and better amnesia (intraoperative) and analgesia.
Although both enantiomers of ketamine, R-Ketamine and S-Ketamine show antidepressant effects, Robson et Al. observed that R-Ketamine has greater and long-lasting antidepressant effects as compared to S-Ketamine. It was supposed that the long-term antidepressant effect of ketamine may be due to the possible interaction of R-Ketamine with systems other than NMDA receptors. Robson and colleagues found that R-Ketamine has an affinity for σ1 receptor chaperones.
C Yang et al. observed the antidepressant effects of S-Ketamine and R-Ketamine. As a result, R-Ketamine shows more neuroplasticity than S-Ketamine. It is more effective in correcting the neuro-histological correlates of mental health disorders like treatment-resistant depression, bipolar disorders, PTSD, and MDD. Moreover, neuroplasticity contributes to the long-term antidepressant effects of R-Ketamine.
Racemic Ketamine contains equal quantities of R-Ketamine and S-Ketamine. While discussing analgesic and anesthetic properties, S-Ketamine is more potent and safe with lower psychotomimetic and other risks than R-ketamine. Few studies indicate R-Ketamine has long-term antidepressant effects and is more potent.
However, intravenous and intranasal S-Ketamine has shown beneficial effects in the treatment of treatment-resistant depression, however, the size of the evidence base of S-Ketamine efficacy in TRD is small. Until now, there are no clinical data that directly compares the effects of R-Ketamine, S-Ketamine, and racemic ketamine.
Moreover, it's interesting to know that S-ketamine performs better in patients who experience adverse effects with racemic ketamine. S-ketamine has better tolerability without compromising antidepressant effects.
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