Pharmacology, Biochemistry and Behavior
December 9, 2019
Satoshi Deyama, R. Duman
181 citations
Depression is linked to reduced levels of neurotrophic factors like BDNF and VEGF, which contribute to neuronal atrophy in brain regions such as the prefrontal cortex and hippocampus, and to decreased adult neurogenesis. Conventional antidepressants partially reverse these deficits by inducing BDNF or VEGF but have limitations, including a delayed therapeutic response and low efficacy. Ketamine, an NMDA receptor antagonist, produces rapid (within hours) and sustained (up to a week) antidepressant effects in treatment-resistant depression and rodent models. In rodents, ketamine quickly increases BDNF and VEGF release in the medial prefrontal cortex and hippocampus, boosting spine synapses and hippocampal neurogenesis. These neurotrophic actions appear to underlie ketamine's rapid and sustained antidepressant effects, pointing toward development of faster-acting antidepressants with fewer side effects.
Pharmacology, Biochemistry and Behavior
June 1, 2019
Lijia Chang, Kai Zhang, Yaoyu Pu et al.
174 citations
In a mouse model of chronic social defeat stress, a single intranasal dose of (R)-ketamine produced stronger antidepressant effects than (R,S)-ketamine or (S)-ketamine. Conversely, (S)-ketamine caused the greatest increase in locomotor activity and deficits in prepulse inhibition, followed by (R,S)-ketamine, while (R)-ketamine showed the least. In conditioned place preference tests, repeated intranasal (S)-ketamine and (R,S)-ketamine increased preference scores dose-dependently, indicating abuse liability, whereas (R)-ketamine did not. These findings suggest intranasal (R)-ketamine may be a safer antidepressant option.
Pharmacology, Biochemistry and Behavior
February 5, 2020
Yan Wei, Lijia Chang, K. Hashimoto
157 citations
The antidepressant effects of (R,S)-ketamine, a mixture of (R)-ketamine and (S)-ketamine, are a major advance in mood research. Off-label use for treatment-resistant depression has grown in the US, and in 2019 the FDA and European authorities approved (S)-ketamine nasal spray for this condition, but only in certified medical settings. Preclinical evidence indicates that (R)-ketamine may be more potent and longer-lasting as an antidepressant than (S)-ketamine, with fewer side effects. Clinical trials of (R)-ketamine in humans are now underway. This article reviews the history of these compounds and discusses the mechanisms behind ketamine's antidepressant actions.
Pharmacology, Biochemistry and Behavior
April 22, 2020
J. Witkin, J. Kranzler, K. Kaniecki et al.
33 citations
The (R)-ketamine enantiomer may offer a safer treatment for substance abuse disorder by reducing withdrawal symptoms and drug-seeking behavior without causing negative mood or anhedonia. In experiments with morphine-dependent rats, (R)-ketamine alleviated withdrawal signs and blocked morphine-induced place preference in mice without producing place preference itself. Unlike S-ketamine, (R)-ketamine did not induce anhedonia in rats. These findings suggest (R)-ketamine could dampen withdrawal and drug liking without the dissociative or mood-related side effects that limit current therapies, supporting further preclinical and clinical investigation.
Pharmacology, Biochemistry and Behavior
August 1, 2022
A. Pałucha-poniewiera
Combining a low, subeffective dose of ketamine or its enantiomer (R)-ketamine with an mGlu2/3 receptor antagonist produces antidepressant-like effects in animal models of depression without the undesirable side effects seen with higher doses of ketamine or (S)-ketamine, such as psychostimulatory effects. The antidepressant effect of ketamine appears linked to mGlu2 receptor activity and may be reduced by mGlu2 agonists. This strategy aims to enhance ketamine's therapeutic effect while lowering its dose to reduce side effects, which are particularly concerning in patients with treatment-resistant depression. Further research is needed to confirm effectiveness in humans.
Pharmacology, Biochemistry and Behavior
January 12, 2021
Tianhao Gao, Rongjun Ni, Shasha Liu et al.
Pretreatment with lithium moderates the effects of a single dose of ketamine on mania-like behavior and c-Fos expression in the mouse forebrain. Ketamine increased movement and induced higher c-Fos expression in several forebrain regions, including the lateral septal nucleus, hypothalamus, amygdala, and hippocampus. Chronic lithium treatment attenuated the ketamine-induced increase in movement and inhibited the rise in c-Fos-immunoreactive neurons in the dentate gyrus, CA1, dorsal and ventral subiculum, and amygdaloid nuclei. These findings may help understand mania episodes related to ketamine treatment for major depressive disorder and bipolar disorder.
Pharmacology, Biochemistry and Behavior
November 13, 2019
Taro Kato, R. Duman
Ketamine produces rapid (within hours) and long-lasting (7 to 10 days) antidepressant effects by blocking NMDA receptor channels. Rapastinel, a novel glutamatergic compound that acts as an NMDAR partial agonist, also produces rapid antidepressant actions in depressed patients and preclinical rodent models without ketamine-like side effects such as cognitive impairment and psychotomimetic symptoms. Despite recent negative clinical trials, rapastinel may still prove effective as an alternative rapid-acting antidepressant with reduced side effects. This review discusses rapastinel's pharmacological profile and the molecular and cellular mechanisms underlying its rapid and sustained antidepressant actions.
Pharmacology, Biochemistry and Behavior
September 1, 1997
S. Heishman, K. Arasteh, M. Stitzer
Alcohol and marijuana produced similar dose-related changes in subjective drug effects and comparable impairment on digit-symbol substitution and word recall tests, but neither affected time perception or reaction time. Alcohol slightly impaired performance on a number recognition test, while marijuana did not. Ratings of perceived impairment were identical for the high doses of both drugs. The study used controlled puffing and inhalation technology to deliver alcohol (0.25, 0.5, or 1.0 g/kg) and marijuana (4, 8, or 16 puffs of 3.55% THC) to five male volunteers with moderate drug use histories.