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Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

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

ABSTRACT 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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    • "A recent active placebo controlled trial demonstrated fast-acting, but transient effects of ketamine in treatment-resistant depression patients (Murrough et al., 2013). Ketamine's antidepressant properties have been demonstrated in several animal models of antidepressant efficacy (reviewed in Browne and Lucki, 2013) as well as in some treatment-resistant depression models. In BDNF heterozygous null mice, where imipramine had no effect in the FST, ketamine produced a robust antidepressant-like response at 50 mg/kg (Lindholm et al., 2012). "
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    ABSTRACT: Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment- resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants. Copyright © 2014. Published by Elsevier B.V.
    European Journal of Pharmacology 11/2014; 753. DOI:10.1016/j.ejphar.2014.10.063 · 2.68 Impact Factor
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    • "First of all, ketamine administration blocks NMDAR. In all the cases, the protracted antidepressant effect is mediated by the consequent neuroplastic alterations (see Browne and Lucki, 2013; Hayley and Litteljohn, 2014). "
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    Frontiers in Behavioral Neuroscience 04/2014; 8:130. DOI:10.3389/fnbeh.2014.00130 · 4.16 Impact Factor
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    • ", 2013 ) . However , evaluation of antidepressant response showed that not all patients respond to ketamine treatment and that the duration of the antidepressant effect varies across studies ( Browne and Lucki , 2013 ; Sos et al . , 2013 ; Gálvez et al . "
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