(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

Overview

Journal Int J Neuropsychopharmacol

Publisher Oxford University Press

Specialty Psychiatry

Date 2023 Aug 14

PMID 37578355

Authors

Szabolcs Koncz

Noemi Papp

Dora Pothorszki

Gyorgy Bagdy

Affiliations

Soon will be listed here.

Abstract

Background: Racemic ketamine consists of two enantiomers, namely (R)-ketamine and (S)-ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)-enantiomer has been approved for the treatment of major depression, whereas (R)-ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of non-REM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects.

Methods: Here, we compared acute effects of the two ketamine enantiomers (15 mg/kg i.p.) on different sleep-wake stages in freely moving, EEG-equipped rats. We also evaluated the antidepressant-like activity of the enantiomers in a chronic restraint stress model of depression.

Results: (S)-ketamine but not (R)-ketamine increased REM sleep latency and decreased REM sleep time at 2 and 3 hours, and increased electroencephalogram delta power during NREM sleep. In addition, only (S)-ketamine increased wakefulness and decreased NREM sleep in the first 2 hours. In the forced swimming test, only (S)-ketamine decreased the immobility time of chronically stressed rats.

Conclusion: Effects of the two ketamine enantiomers on rat sleep-wake architecture and behavior are markedly different when administered in the same dose. (S)-ketamine remarkably affects the sleep-wake cycle and very likely sleep-related neuroplasticity, which may be relevant for its antidepressant efficacy. Our results regarding (R)-ketamine's lack of effect on vigilance and behavior are in line with recent clinical studies.

Citing Articles

Neuroplasticity and Mechanisms of Action of Acute and Chronic Treatment with Antidepressants in Preclinical Studies.

Rosas-Sanchez G, German-Ponciano L, Guillen-Ruiz G, Cueto-Escobedo J, Limon-Vazquez A, Rodriguez-Landa J Biomedicines. 2025; 12(12.

PMID: 39767650 PMC: 11727250. DOI: 10.3390/biomedicines12122744.

Ketamine Reduces Avoidance Responses During Re-Exposition to Aversive Stimulus: Comparison Between ()-Isomer and Racemic Mixture.

Moura C, de Sousa-Silva A, Soares A, de Oliveira Torres C, Belchior H, da Silva Jr E Brain Sci. 2025; 14(12.

PMID: 39766490 PMC: 11674349. DOI: 10.3390/brainsci14121291.

()-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders.

Shafique H, Demers J, Biesiada J, Golani L, Cerne R, Smith J Int J Mol Sci. 2024; 25(12).

PMID: 38928508 PMC: 11203826. DOI: 10.3390/ijms25126804.

Effect of subanesthetic dose of esketamine on postoperative pain in elderly patients undergoing laparoscopic gastrointestinal tumor Surgery:A prospective, double-blind, randomized controlled trial.

Jing Z, Han Y, Li Y, Zeng R, Wu J, Wang Y Heliyon. 2024; 10(5):e27593.

PMID: 38495154 PMC: 10943442. DOI: 10.1016/j.heliyon.2024.e27593.

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats.

Elersic K, Banjac A, Zivin M, Zorovic M PLoS One. 2024; 19(3):e0299379.

PMID: 38427622 PMC: 10906899. DOI: 10.1371/journal.pone.0299379.

References

Kohtala S . Ketamine-50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms. Pharmacol Rep. 2021; 73(2):323-345. PMC: 7994242. DOI: 10.1007/s43440-021-00232-4. View

Wang Y, Melgers M, Meijer J, Deboer T . Comparison of sleep deprivation and a low dose of ketamine on sleep and the electroencephalogram in Brown Norway rats. J Sleep Res. 2023; 32(5):e13863. DOI: 10.1111/jsr.13863. View

Wilson S, Argyropoulos S . Antidepressants and sleep: a qualitative review of the literature. Drugs. 2005; 65(7):927-47. DOI: 10.2165/00003495-200565070-00003. View

Duncan Jr W, Zarate Jr C . Ketamine, sleep, and depression: current status and new questions. Curr Psychiatry Rep. 2013; 15(9):394. PMC: 3827949. DOI: 10.1007/s11920-013-0394-z. View

Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi J, Hashimoto K . Antidepressant Potential of ()-Ketamine in Rodent Models: Comparison with ()-Ketamine. J Pharmacol Exp Ther. 2017; 361(1):9-16. DOI: 10.1124/jpet.116.239228. View

Kohtala S, Theilmann W, Rosenholm M, Penna L, Karabulut G, Uusitalo S . Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses. Mol Neurobiol. 2018; 56(6):4163-4174. PMC: 6505519. DOI: 10.1007/s12035-018-1364-6. View

Vas S, Katai Z, Kostyalik D, Pap D, Molnar E, Petschner P . Differential adaptation of REM sleep latency, intermediate stage and theta power effects of escitalopram after chronic treatment. J Neural Transm (Vienna). 2012; 120(1):169-76. DOI: 10.1007/s00702-012-0847-2. View

Papp N, Vas S, Bogathy E, Katai Z, Kostyalik D, Bagdy G . Acute and chronic escitalopram alter EEG gamma oscillations differently: relevance to therapeutic effects. Eur J Pharm Sci. 2018; 121:347-355. DOI: 10.1016/j.ejps.2018.06.012. View

Feinberg I, Campbell I . Ketamine administration during waking increases delta EEG intensity in rat sleep. Neuropsychopharmacology. 1993; 9(1):41-8. DOI: 10.1038/npp.1993.41. View

10.

Grace K, Horner R . Evaluating the Evidence Surrounding Pontine Cholinergic Involvement in REM Sleep Generation. Front Neurol. 2015; 6:190. PMC: 4555043. DOI: 10.3389/fneur.2015.00190. View

11.

Palagini L, Baglioni C, Ciapparelli A, Gemignani A, Riemann D . REM sleep dysregulation in depression: state of the art. Sleep Med Rev. 2013; 17(5):377-90. DOI: 10.1016/j.smrv.2012.11.001. View

12.

Rafalo-Ulinska A, Palucha-Poniewiera A . The effectiveness of (R)-ketamine and its mechanism of action differ from those of (S)-ketamine in a chronic unpredictable mild stress model of depression in C57BL/6J mice. Behav Brain Res. 2021; 418:113633. DOI: 10.1016/j.bbr.2021.113633. View

13.

Esser S, Hill S, Tononi G . Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. Sleep. 2008; 30(12):1617-30. PMC: 2276134. DOI: 10.1093/sleep/30.12.1617. View

14.

Reus G, Carlessi A, Titus S, Abelaira H, Ignacio Z, da Luz J . A single dose of S-ketamine induces long-term antidepressant effects and decreases oxidative stress in adulthood rats following maternal deprivation. Dev Neurobiol. 2015; 75(11):1268-81. DOI: 10.1002/dneu.22283. View

15.

Johnston J, Henter I, Zarate Jr C . The antidepressant actions of ketamine and its enantiomers. Pharmacol Ther. 2023; 246:108431. PMC: 10213151. DOI: 10.1016/j.pharmthera.2023.108431. View

16.

Jaffe R, Novakovic V, Peselow E . Scopolamine as an antidepressant: a systematic review. Clin Neuropharmacol. 2013; 36(1):24-6. DOI: 10.1097/WNF.0b013e318278b703. View

17.

Steiger A, Kimura M . Wake and sleep EEG provide biomarkers in depression. J Psychiatr Res. 2009; 44(4):242-52. DOI: 10.1016/j.jpsychires.2009.08.013. View

18.

Lu J, Sherman D, Devor M, Saper C . A putative flip-flop switch for control of REM sleep. Nature. 2006; 441(7093):589-94. DOI: 10.1038/nature04767. View

19.

Wichniak A, Wierzbicka A, Walecka M, Jernajczyk W . Effects of Antidepressants on Sleep. Curr Psychiatry Rep. 2017; 19(9):63. PMC: 5548844. DOI: 10.1007/s11920-017-0816-4. View

20.

Ursin R . Serotonin and sleep. Sleep Med Rev. 2003; 6(1):55-69. DOI: 10.1053/smrv.2001.0174. View