Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4: 161

Frontiers in Pharmacology (Impact Factor: 3.8). 12/2013; 4:161. DOI: 10.3389/fphar.2013.00161
Source: PubMed


Newer antidepressants are needed for the many individuals with major depressive disorder (MDD) that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine's effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse potential of ketamine.

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Available from: Caroline Ann Browne, Jan 17, 2014
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    • "first these neuroadaptative mechanisms and, second, potentials common features with the molecular pathways and neural circuits to those shown to be involved in ketamine rapid-onset anti-depressant effects (Browne and Lucki 2013). "
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    ABSTRACT: Background: Recreational ketamine use may be modulated by factors such as ketamine infusion patterns, associated conditioned stimuli and spatial-temporal contexts. Our aim was to study the pharmacological and non-pharmacological factors that regulate the acquisition of ketamine use. Methods: In experiment 1, four groups of male rats were trained to self-administer ketamine during nine 1-h daily sessions, under four reinforcement schedules: i) pre-session ketamine priming (Priming-[KET]), ii) conditioned stimulus (CS) paired to the ketamine infusions ([KET + CS]), iii) neither priming nor CS ([KET]), iv) combination of both (Priming-[KET + CS]). In experiment 2, two groups of male rats were trained to self-administer ketamine during nine 1-h daily or weekly sessions, under the Priming-[KET + CS] schedule. Lever pressing was then extinguished by saline substitution for ketamine infusion. Afterwards, ketamine was made available again upon responding under the same schedule. Results: The Priming-[KET + CS] schedule of reinforcement showed a significant increase in the number of ketamine reinforcements and a significant discrimination between active vs. inactive levers. The same schedule allowed the establishment of ketamine self-administration on a weekly basis. During the extinction phase, rate of responding significantly dropped in both weekly and daily groups although it was twofold longer in the former, which showed a lack of reacquisition. Conclusions: Both pre-session ketamine priming and a conditioned stimulus paired to the ketamine infusions are required for the acquisition of ketamine self-administration. The longer extinction and the lack of reacquisition in the weekly group could be due to changes in temporal context that might affect the conditioning process.
    Psychopharmacology 09/2015; DOI:10.1007/s00213-015-4077-9 · 3.88 Impact Factor
    • "A major drawback of monoamine-based antidepressant medications that are currently in clinical use is that they require sustained treatment of several weeks or longer before therapeutic benefits are achieved (Rush et al., 2006). The ineffectiveness of acute FLX administration in the 24-hour FST and LH paradigms markedly contrasts with the actions of ketamine, which have been documented in recent animal studies (Maeng et al., 2008; Li et al., 2010; Autry et al., 2011; Browne and Lucki, 2013). "
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    ABSTRACT: Currently approved antidepressant drug treatment typically takes several weeks to be effective. The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment for depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor by the selective full antagonist 7-Cl-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-Cl-kynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely-moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pre-treatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression and indicate that the prodrug approach using 4-Cl-KYN holds promise for use in humans, without the negative side effects seen with ketamine or other channel blocking NMDA receptor antagonists. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 08/2015; 355(1). DOI:10.1124/jpet.115.225664 · 3.97 Impact Factor
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    • "). A wide range of ketamine doses (1–100 mg/kg) has been reported to effectively produce antidepressant-like effects in various mouse strains (Mantovani et al., 2003; Hayase et al., 2006; Kos et al., 2006; Popik et al., 2008; Browne and Lucki, 2013). We thus performed a dose response test in our CD-1 mouse model of stress and found that the minimum dose for ketamine to suppress immobility time in the FST was 50 mg/ "
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    ABSTRACT: Evidence suggests that mammalian target of rapamycin (mTOR) activation mediates ketamine's rapid but transient antidepressant effects, and that glycogen synthase kinase-3β (GSK-3β) inhibits this pathway. However, ketamine has associated psychotomimetic effects and a high risk of abuse. The mood stabilizer lithium is a GSK-3 inhibitor with strong anti-suicidal properties. Here, we used a mouse stress model to investigate whether adjunct lithium treatment would potentiate ketamine's antidepressant-like effects. Mice received chronic restraint stress and long-term pre- or post-ketamine lithium treatment in drinking water. The effects of lithium on ketamine-induced antidepressant-like effects, activation of the mTOR/brain-derived neurotrophic factor (BDNF) signaling pathways, oxidative stress, and dendritic spine density in the brain of mice were investigated. Sub-therapeutic (600 mg/L) lithium-pretreated mice exhibited an antidepressant-like response to an ineffective ketamine (2.5 mg/kg, i.p.) challenge in the forced swim test. Both the antidepressant-like effects and restoration of dendritic spine density in the medial prefrontal cortex (PFC) of stressed mice induced by a single ketamine (50 mg/kg) injection were sustained by post-ketamine treatment with 1200 mg/L of lithium for at least two weeks. These benefits of lithium treatments were associated with activation of the mTOR/BDNF signaling pathways in the PFC. Acute ketamine (50 mg/kg) injection also significantly increased lipid peroxidation, catalase activity, and oxidized glutathione levels in stressed mice. Notably, these oxidative stress markers were completely abolished by pretreatment with 1200 mg/L of lithium. Our results suggest a novel therapeutic strategy and justify the use of lithium in patients who benefit from ketamine. Published by Oxford University Press on behalf of CINP 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    The International Journal of Neuropsychopharmacology 12/2014; 18(6). DOI:10.1093/ijnp/pyu102 · 4.01 Impact Factor
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