Elucidation of the Mechanisms Underlying the Rapid Antidepressant Actions of Ketamine and Search for Possible Candidates for Novel Rapid-acting Antidepressants

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  • Deyama Satoshi
    Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University

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  • ケタミンの即効性抗うつ作用の機序解明と新規即効性抗うつ薬候補の探索
  • ケタミン ノ ソッコウセイ コウウツ サヨウ ノ キジョ カイメイ ト シンキ ソッコウセイ コウウツヤク コウホ ノ タンサク

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<p>Ketamine, an N-methyl-D-aspartate receptor antagonist, elicits swift antidepressant effects even in subjects with treatment-resistant depression. Nonetheless, owing to the serious adverse effects associated with ketamine, including psychotomimetic effects, the development of safer rapid-acting antidepressants is imperative. The elucidation of the mechanisms underlying the antidepressant effects of ketamine will facilitate the advancement of these alternative treatments. Previous preclinical studies have indicated that the antidepressant properties of ketamine are mediated by the activity-dependent release of brain-derived neurotrophic factor (BDNF) and the subsequent activation of mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC). Our research has demonstrated that ketamine exerts antidepressant-like effects by inducing the release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1) in the mPFC. Furthermore, our recent findings have revealed that resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), which are bioactive lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, exhibit antidepressant-like effects in rodent models. Notably, the antidepressant-like effects of RvD1, RvD2, and RvE1 require mTORC1 activation. Moreover, the intranasal administration of RvE1 elicits rapid antidepressant-like effects through the release of BDNF and VEGF in the mPFC and hippocampal dentate gyrus (DG), as well as mTORC1 activation in the mPFC, albeit not in the DG. These findings strongly suggest that resolvins, particularly RvD1, RvD2, and RvE1, hold promise as prospective candidates for novel, safer, and rapid-acting antidepressants.</p>

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  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 143 (9), 713-720, 2023-09-01

    The Pharmaceutical Society of Japan

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