Abstract
Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability.
Highlights
As well as being the most prevalent, major depressive disorder is among the most severe and debilitating of the psychiatric illnesses
R-ketamine shows greater potency and longer-lasting antidepressant effects than S-ketamine in the social defeat stress model First, we examined the effects of R-ketamine (10 mg kg − 1) and S-ketamine (10 mg kg − 1) on the social defeat stress model of depression (Figure 1a)
We examined whether the two stereoisomers could affect alterations in the dendritic spines of the prelimbic (PrL) and infralimbic (IL) regions of medial prefrontal cortex (mPFC), shell and core of the nucleus accumbens (NAc), striatum, and CA1, CA3 and dentate gyrus (DG) of the Representative photomicrographs of Golgi–Cox-stained pyramidal neurons in the PrL of mPFC, IL of mPFC, NAc core, NAc shell, striatum, CA1, CA3 and DG of hippocampus from animals of each group
Summary
As well as being the most prevalent, major depressive disorder is among the most severe and debilitating of the psychiatric illnesses. Approximately two-thirds of these patients fail to respond to pharmacotherapy and for those that do, there is a high rate of relapse.[2] This highlights the unmet need for therapeutic agents with a rapid onset of action, for patients who do not respond to current antidepressants, many of whom are at an increased risk of suicide.[3] In this setting, the glutamatergic system represents a promising therapeutic target for major depressive disorder.[4,5,6,7,8,9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
