Journal
BIOCHEMICAL PHARMACOLOGY
Volume 198, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.114963
Keywords
Treatment resistant depression; Racemic ketamine; (S)-ketamine; (R)-ketamine; Ketamine enantiomers; Neuroplasticity
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Funding
- CNPq [302382/2019-4]
- FIPE-HCPA GPPG [2019-0745]
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Ketamine is a rapid-acting antidepressant that is effective in patients with treatment-resistant depression due to its strong synaptogenic-modulatory effect. This review summarizes the mechanisms involved in the modulation of neurotransmission, neuroplasticity, and neural network activity, as well as discusses the side effects of ketamine and its enantiomers.
Approximately one-third of individuals with major depressive disorder are resistant to conventional antidepressants (i.e., monoamine-based therapies), and, even among respondents, a proper therapeutic effect may require weeks of treatment. Ketamine, a racemic mixture of the two enantiomers, (R)-ketamine and (S)-ketamine, is an N-methyl-d-aspartate receptor (NMDAR) antagonist and has been shown to have rapid-acting antidepressant properties in patients with treatment-resistant depression (TRD). Although (R)-ketamine has a lower affinity for NMDAR, it presents greater potency and longer-lasting antidepressant properties, with no major side effects, than racemic ketamine or (S)-ketamine in preclinical findings. Thereby, ketamine and its enantiomers have not only an antagonistic effect on NMDAR but also a strong synaptogenic-modulatory effect, which is impaired in TRD pathophysiology. In this review, we summarize the current evidence regarding the modulation of neurotransmission, neuroplasticity, and neural network activity as putative mechanisms of these rapid-acting antidepressants, highlighting differences on intracellular signaling pathways of synaptic proteins such as mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK) and brain-derived neurotrophic factor (BDNF). In addition, we discuss probable mechanisms involved in the side effects of ketamine and its enantiomers.
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