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R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects.

C Yang1, Y Shirayama1,2, J-c Zhang1

  • 1Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.

Translational Psychiatry
|September 2, 2015
PubMed
Summary

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R-ketamine demonstrates superior antidepressant effects compared to S-ketamine (esketamine) by enhancing brain-derived neurotrophic factor (BDNF) signaling and synaptogenesis. R-ketamine offers a safer alternative with fewer side effects and reduced abuse potential.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Psychiatry

Background:

  • Ketamine shows antidepressant efficacy but has limitations due to side effects and abuse potential.
  • Understanding the distinct properties of ketamine stereoisomers is crucial for developing safer antidepressants.
  • Racemic ketamine's antidepressant effects are well-documented, but its clinical use is restricted.

Purpose of the Study:

  • To compare the antidepressant efficacy and side-effect profiles of R-ketamine and S-ketamine (esketamine).
  • To investigate the underlying neurobiological mechanisms, including BDNF-TrkB signaling and synaptogenesis, of ketamine stereoisomers.
  • To evaluate the safety and therapeutic potential of R-ketamine as a novel antidepressant.

Main Methods:

  • Administered R-ketamine and S-ketamine to mouse models of depression (social defeat stress, learned helplessness).

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  • Assessed antidepressant-like behavior, dendritic spine density, BDNF-TrkB signaling, and synaptogenesis in key brain regions (PFC, hippocampus).
  • Evaluated behavioral side effects (locomotion, prepulse inhibition, reward) and neurochemical changes (parvalbumin-positive cells).

    • Main Results:

    • R-ketamine exhibited more potent and sustained antidepressant effects than S-ketamine in behavioral models.
    • R-ketamine significantly increased BDNF-TrkB signaling and synaptogenesis in the PFC and hippocampus, unlike S-ketamine.
    • S-ketamine, but not R-ketamine, induced psychotomimetic side effects and reduced parvalbumin-positive cells in specific brain areas.

    Conclusions:

    • R-ketamine provides sustained antidepressant effects mediated by enhanced neuroplasticity in the PFC and hippocampus.
    • R-ketamine demonstrates a favorable safety profile, lacking the psychotomimetic and abuse liabilities associated with S-ketamine.
    • R-ketamine represents a promising candidate for a potent, long-lasting, and safe antidepressant treatment.