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Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions

Motohiro Okada, Yasuhiro Kawano, Kouji Fukuyama, Eishi Motomura, Takashi Shiroyama

International Journal of Molecular Sciences October 26, 2020 DOI: 10.3390/ijms21217951 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Topics Anxiety Ketamine Serotonin Esketamine
Keywords Monoaminergic Dissociative Antidepressant Schizophrenia object-oriented programming Anhedonia Nmda receptor Adverse effect Psychotomimetic Pharmacology
Citations 31
Key findings Ketamine's antidepressant and schizophrenia-like effects occur at similar doses, with psychotropic effects preceding antidepressant effects, and repeated use risks abuse and memory deficits.

Abstract

Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.

Comparable studies

Other narrative reviews on ketamine for anxiety, most cited first.

Study Year Design Participants
A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders 2017 Review and consensus statement
KETAMINE'S MECHANISM OF ACTION: A PATH TO RAPID‐ACTING ANTIDEPRESSANTS 2016 Review
Eradicating Suicide at Its Roots: Preclinical Bases and Clinical Evidence of the Efficacy of Ketamine in the Treatment of Suicidal Behaviors 2018 Review
Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder Patients with treatment-resistant depressive symptoms as part of major depressive... 2018 Narrative review
Ketamine as a Fast Acting Antidepressant: Current Knowledge and Open Questions 2013 Review

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