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

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.

Exploring pharmacological options for adolescent depression: a preclinical evaluation with a sex perspective

“…Moreover, when evaluating the impact that sex induced on the sustained effects of ketamine on resilience to chronic stress, a recent report in adult mice showed that while ketamine prevented chronic stress-induced changes in affective-like behaviors in males, it did not protect females [ 33 ]. Furthermore, the drop in ketamine’s efficacy after re-exposure in adulthood could be mediated by the emerging differences driven by age [ 36 , 25 ] and/or be dose-related [ 40 – 43 ]. Our data suggested a great antidepressant-like potential for ketamine in adolescence, while also demonstrated that maternal deprivation interacted with ketamine treatment to modulate its effects in female rats.…”

“…In this context, ketamine, an NMDA receptor antagonist, was recently approved by the FDA for treatment-resistant depression and suicidality in adults [ 22 ], and while its use in younger populations is currently limited to anesthetic and analgesic purposes [ 23 ], an increasing number of clinical reports [ 24 – 26 ] suggested a potential use for this drug in adolescent depression, although special caution is still needed in terms of safety and long-term potential concerns in addiction-liability [ 27 , 28 ]. In this context, recent studies are centered in evaluating the differential effects of ketamine as influenced by sex (some studies showed improved responses in rodents for females [ 29 – 32 ] or males [ 33 ], while others even showed no sex differences in humans [ 34 , 35 ]), by age [ 36 , 25 ] and prior stress exposure (e.g., [ 32 , 36 – 39 ]), as well as the potential dose-related molecular actions behind these disparities [ 40 – 43 ]. Another good candidate to be further explored as a potential antidepressant for adolescent depression is cannabidiol [ 44 – 46 ], a non-psychotomimetic active compound extracted from the plant Cannabis Sativa .…”

Pharmacogenetic and drug interaction aspects on ketamine safety in its use as antidepressant ‐ implications for precision dosing in a global perspective

“…Antidepressant effects of ketamine may be influenced by individual dose, frequency and route of administration 44,45 . Ketamine can be administered via multiple routes including epidural, intramuscular, oral, intravenous, intranasal and rectal administration 46 .…”

“…Antidepressant effects of ketamine may be influenced by individual dose, frequency and route of administration. 44,45 Ketamine can be administered via multiple routes including epidural, intramuscular, oral, intravenous, intranasal and rectal administration. 46 Oral ketamine administration yields the lowest bioavailability and lowest systemic exposure due to the extensive hepatic first-pass metabolism.…”

“…For instance, a larger reduction in Hamilton Depression Rating Scale was observed in patients who received 0.5 mg kg −1 compared to those who received 0.2 mg kg −1 of ketamine 44 . Furthermore, repeated dosing has been associated with stronger and longer lasting behavioural effects in a force swim test in mice 45 . In TRD patients repeated intravenous infusion (0.5 mg kg −1 , 3 times daily for 12 d) of ketamine led to improvement of depression in the long‐term 49 .…”