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R-Ketamine vs. S-Ketamine

(R,S)-ketamine is a N-methyl-ᴅ-aspartate (NMDA) receptor antagonist and a commonly used anesthetic agent worldwide. In the late 1990s, studies and case reports began highlighting this drug’s rapid-acting and sustained antidepressant effects, a major discovery in the research of mood disorders [1]. (R,S)-ketamine is a mixture of the two enantiomers R- and S-ketamine, which predominantly differ in their binding properties [2]. S-ketamine has an approximately fourfold greater affinity for the phencyclidine site of the NMDA receptor than R-ketamine as well as strong anti-depressant effects but also strong psychomimetic side effects such as confusion, euphoria, perceptual difficulties, or mood elevation. On the other hand, R-ketamine is generally associated with a milder but longer-lasting antidepressant effect [2,3].

In 2017, a PET study on conscious monkeys found a reduction of dopamine D2/3 binding potential in the striatum following S-ketamine administration, but not R-ketamine [4]. In 2000, a research team in Japan used monkey brains and found [11C] raclopride could be used in PET to detect release of endogenous dopamine from presynaptic terminals [5]. Applying this finding, researchers at the Central Research Laboratory in Japan (2017) found marked radioactivity in the striatum of S-ketamine-treated animals, suggesting S-ketamine causes significant release of dopamine but prevents it from binding to its receptors [4]. The excessive dopamine may also be the cause of the psychosis and dissociation associated with chronic S-ketamine administration. In healthy subjects, an infusion of S-ketamine produced a dissociative state, changes in mood and sensory perception, difficulty in reality appraisal, and ego inflation [6]. Despite an increasing number of studies arguing in favor of ketamine’s role in treating depressive disorders, the drug’s abuse potential is its greatest limitation. The conditioned place preference test (CPP) is a widely used behavioral model designed to assess a drug’s rewarding, aversive, or addicting effects [7].  A 2015 preclinical study found ketamine (the racemic combination) increased scores on the CPP test, suggesting ketamine itself is rewarding [8]. Another preclinical study used the same assessment and found similar increases after S-ketamine administration, but not R-ketamine, indicating potential abuse liability of S-ketamine in particular [9].

Parvalbumin (PV) positive cells are GABAergic interneurons that rely on Ca2+ binding for proper functioning [10]. A reduction in PV-neurotransmission is associated with neuropsychiatric disorders such as Alzheimer’s Disease, autism spectrum disorder, schizophrenia, and substance use disorder. In 2016, a research team in Japan used PV-immunohistochemistry to assess the effect of intermittent ketamine administration. They observed a significant decrease in PV-immunoreactivity in the prelimbic and infralimbic areas of the prefrontal cortex, as well as the CA1, CA3, and dentate gyrus of the hippocampus after intermittent administrations of S-ketamine, but not R-ketamine [11]. These results correlate with earlier findings using the same methods but with single-dose administrations of the respective drugs [8].  These studies suggest S-ketamine plays a role in the loss of PV-positive cells, which is associated with psychiatric presentations [11].

S-ketamine is metabolized to its major metabolite, S-norketamine, by cytochrome P450 enzymes. Like S-ketamine, S-norketamine induces strong antidepressant effects in murine models of depression. S-norketamine significantly attenuated the reduced dendritic spine density in the prelimbic area, the CA3, and the dentate gyrus in mice exposed to chronic social defeat stress. In the same regions, S-norketamine also improved reduced levels of BDNF protein, a marker of neuroplasticity [12]. Unlike S-ketamine, its metabolite does not show psychomimetic effects such as increased locomotion, hyperactivity, or increased scores on the conditioned place preference test. S-norketamine also had no effect on the proportion of PV-positive cells in the prefrontal cortex [9,12]. These results suggest that S-norketamine may be a more promising therapeutic approach, if it can be successfully stabilized and administered.

Although the US and Europe approved an S-ketamine based nasal spray for treatment-resistant depression, several concerns have been raised, including its safety for pediatric patients and its numerous side effects [13,14]. A recent pilot study demonstrated R-ketamine produced sustained antidepressant effects without side effects such as dissociation [9,15]. With ketamine’s different enantiomers and metabolites, more research on their effects and applications is warranted. 

References

  1. Abdallah, C. G., Sanacora, G., Duman, R. S., & Krystal, J. H. (2018). The Neurobiology of Depression, Ketamine and Rapid-acting Antidepressants: Is it Glutamate Inhibition or Activation? Pharmacology & Therapeutics, 190, 148–158. https://doi.org/10.1016/j.pharmthera.2018.05.010
  2. Paul, R., Schaaff, N., Padberg, F., Möller, H.-J., & Frodl, T. (2009). Comparison of Racemic Ketamine and S-ketamine in Treatment-resistant Major Depression: Report of Two Cases. The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry, 10(3), 241–244. https://doi.org/10.1080/15622970701714370
  3. Zhang, J., Li, S., & Hashimoto, K. (2014). R(−)Ketamine shows Greater Potency and Longer Lasting Antidepressant Effects than S (+)Ketamine. Pharmacology Biochemistry and Behavior, 116, 137–141. https://doi.org/10.1016/j.pbb.2013.11.033
  4. Hashimoto, K., Kakiuchi, T., Ohba, H., Nishiyama, S., & Tsukada, H. (2017). Reduction of Dopamine D2/3 Receptor Binding in the Striatum after a Single Administration of Esketamine, but not R-Ketamine: A PET study in Conscious Monkeys. European Archives of Psychiatry and Clinical Neuroscience, 267(2), 173–176. https://doi.org/10.1007/s00406-016-0692-7
  5. Tsukada, H., Harada, N., Nishiyama, S., Ohba, H., & Kakiuchi, T. (2000). Cholinergic Neuronal Modulation Alters Dopamine D2 Receptor Availability in vivo by Regulating Receptor Affinity Induced by Facilitated Synaptic Dopamine Turnover: Positron Emission Tomography Studies with Micro-dialysis in the Conscious Monkey Brain. Journal of Neuroscience, 20(18), 7067–7073. https://doi.org/10.1523/JNEUROSCI.20-18-07067.2000
  6. Vollenweider, F. X., Leenders, K. L., Øye, I., Hell, D., & Angst, J. (1997). Differential Psychopathology and Patterns of Cerebral Glucose Utilization Produced by (S)- and (R)-ketamine in Healthy Volunteers using Positron Emission Tomography (PET). European Neuropsychopharmacology, 7(1), 25–38. https://doi.org/10.1016/S0924-977X(96)00042-9
  7. Prus, A. J., James, J. R., & Rosecrans, J. A. (2009). Conditioned Place Preference. In J. J. Buccafusco (Ed.), Methods of Behavior Analysis in Neuroscience (2nd ed.). CRC Press/Taylor & Francis. http://www.ncbi.nlm.nih.gov/books/NBK5229/
  8. Yang, C., Shirayama, Y., Zhang, J. -c, Ren, Q., Yao, W., Ma, M., Dong, C., & Hashimoto, K. (2015). R-Ketamine: A Rapid-onset and Sustained Antidepressant Without Psychotomimetic Side Effects. Translational Psychiatry, 5(9), e632–e632. https://doi.org/10.1038/tp.2015.13
  9. Hashimoto, K. (2020). Molecular Mechanisms of the Rapid-acting and Long-lasting Antidepressant Actions of (R)-ketamine. Biochemical Pharmacology, 177, 113935. https://doi.org/10.1016/j.bcp.2020.113935
  10. Nahar, L., Delacroix, B. M., & Nam, H. W. (2021). The Role of Parvalbumin Interneurons in Neurotransmitter Balance and Neurological Disease. Frontiers in Psychiatry, 12. https://www.frontiersin.org/article/10.3389/fpsyt.2021.679960
  11. Yang, C., Han, M., Zhang, J., Ren, Q., & Hashimoto, K. (2016). Loss of Parvalbumin-Immunoreactivity in Mouse Brain Regions After Repeated Intermittent Administration of Esketamine, but not R-ketamine. Psychiatry Research, 239, 281–283. https://doi.org/10.1016/j.psychres.2016.03.034
  12. Yang, C., Kobayashi, S., Nakao, K., Dong, C., Han, M., Qu, Y., Ren, Q., Zhang, J., Ma, M., Toki, H., Yamaguchi, J., Chaki, S., Shirayama, Y., Nakazawa, K., Manabe, T., & Hashimoto, K. (2018). AMPA Receptor Activation–Independent Antidepressant Actions of Ketamine Metabolite (S)-norketamine. Biological Psychiatry, 84(8), 591–600. https://doi.org/10.1016/j.biopsych.2018.05.007 
  13. Zimmermann, K. S., Richardson, R., & Baker, K. D. (2020). Esketamine as a Treatment for Pediatric Depression: Questions of Safety and Efficacy. The Lancet Psychiatry, 7(10), 827–829. https://doi.org/10.1016/S2215-0366(19)30521-8
  14. Turner, E. H. (2019). Esketamine for Treatment-resistant Depression: Seven Concerns about Efficacy and FDA Approval. The Lancet Psychiatry, 6(12), 977–979. https://doi.org/10.1016/S2215-0366(19)30394-3
  15. Leal, G. C., Bandeira, I. D., Correia-Melo, F. S., Telles, M., Mello, R. P., Vieira, F., Lima, C. S., Jesus-Nunes, A. P., Guerreiro-Costa, L. N. F., Marback, R. F., Caliman-Fontes, A. T., Marques, B. L. S., Bezerra, M. L. O., Dias-Neto, A. L., Silva, S. S., Sampaio, A. S., Sanacora, G., Turecki, G., Loo, C., … Quarantini, L. C. (2021). Intravenous Arketamine for Treatment-resistant Depression: Open-label Pilot Study. European Archives of Psychiatry and Clinical Neuroscience, 271(3), 577–582. https://doi.org/10.1007/s00406-020-01110-5