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Repeated Dosing of Ketamine in the Forced Swim Test: Are Multiple Shots Better Than One?

Ridge G. Weston, Paul J. Fitzgerald, Brendon O. Watson

Frontiers in Psychiatry May 11, 2021 DOI: 10.3389/fpsyt.2021.659052 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Peer reviewed
Population Rodents
Intervention Ketamine
Dose 50 or 100 mg/kg
Topics Anxiety Depression Ketamine Serotonin Esketamine
Keywords Monoaminergic Dosing Antidepressant Behavioural despair test Psychopharmacology Drug Mood Receptor
Citations 19
Key findings Repeated ketamine dosing in rodents can produce both paradoxical increases in immobility at high doses and more effective, longer-lasting decreases in immobility compared to a single dose in the forced swim test.

Abstract

The anesthetic drug ketamine has been successfully repurposed as an antidepressant in human subjects. This represents a breakthrough for clinical psychopharmacology, because unlike monoaminergic antidepressants, ketamine has rapid onset, including in Major Depressive Disorder (MDD) that is resistant to conventional pharmacotherapy. This rapid therapeutic onset suggests a unique mechanism of action, which continues to be investigated in reverse translational studies in rodents. A large fraction of rodent and human studies of ketamine have focused on the effects of only a single administration of ketamine, which presents a problem because MDD is typically a persistent illness that may require ongoing treatment with this drug to prevent relapse. Here we review behavioral studies in rodents that used repeated dosing of ketamine in the forced swim test (FST), with an eye toward eventual mechanistic studies. A subset of these studies carried out additional experiments with only a single injection of ketamine for comparison, and several studies used chronic psychosocial stress, where stress is a known causative factor in some cases of MDD. We find that repeated ketamine can in some cases paradoxically produce increases in immobility in the FST, especially at high doses such as 50 or 100 mg/kg. Several studies however provide evidence that repeated dosing is more effective than a single dose at decreasing immobility, including behavioral effects that last longer. Collectively, this growing literature suggests that repeated dosing of ketamine has prominent depression-related effects in rodents, and further investigation may help optimize the use of this drug in humans experiencing MDD.

Comparable studies

Other preclinical and animal studies on ketamine for anxiety, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats Wistar rats 2018 Experimental study n = 40
Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Rodents 2024 Review
Sexually Dimorphic Behavioral Profile in a Transgenic Model Enabling Targeted Recombination in Active Neurons in Response to Ketamine and (2R,6R)-Hydroxynorketamine Administration Arc-CreERT2 × CAG-Sun1/sfGFP mice 2020 Experimental study
Psychedelics Improve the Mental Health of Rats Male Wistar-Kyoto (WKY) rats 2019 Controlled experiment n = 42

Citations in the library

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Anxiety Depression Ketamine Serotonin Esketamine

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