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R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

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      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.

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      Most cited references 60

      • Record: found
      • Abstract: found
      • Article: not found

      Physiology and neurobiology of stress and adaptation: central role of the brain.

       B McEwen (2007)
      The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.
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        • Record: found
        • Abstract: found
        • Article: not found

        A neurotrophic model for stress-related mood disorders.

        There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
          Bookmark
          • Record: found
          • Abstract: found
          • Article: not found

          A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

          Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant). After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.
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            Author and article information

            Affiliations
            [1 ]Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health , Chiba, Japan
            [2 ]Department of Psychiatry, Teikyo University Chiba Medical Center , Ichihara, Japan
            Author notes
            [* ]Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health , 1-8-1 Inohana, Chiba 260-8670, Japan. E-mail: hashimoto@ 123456faculty.chiba-u.jp
            Journal
            Transl Psychiatry
            Transl Psychiatry
            Translational Psychiatry
            Nature Publishing Group
            2158-3188
            September 2015
            01 September 2015
            1 September 2015
            : 5
            : 9
            : e632
            26327690
            5068814
            tp2015136
            10.1038/tp.2015.136
            Copyright © 2015 Macmillan Publishers Limited

            This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

            Categories
            Original Article

            Clinical Psychology & Psychiatry

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