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.
Highlights
Major depressive disorder (MDD) is a serious public health problem and one of the most common psychiatric disorders, with a lifetime prevalence of 17% in the United States (Kessler et al, 2005)
It has been demonstrated that the NMDA receptor antagonist ketamine has rapid-acting and transient antidepressant effects in patients that are treatment resistant (Mathew et al, 2012)
Reversal of chronic mild stress (CMS)-induced depressive-like phenotypes measured using the mouse FORCED SWIM TEST (FST), NOVELTY SUPPRESSED FEEDING (NSF), and SUCROSE PREFERENCE TEST (SPT) has been reported by ketamine in the absence of any drug effect in stress naïve mice (Autry et al, 2011)
Summary
Major depressive disorder (MDD) is a serious public health problem and one of the most common psychiatric disorders, with a lifetime prevalence of 17% in the United States (Kessler et al, 2005). Ketamine reduces immobility levels in mice acutely, with studies reporting reductions in immobility time at 30 min (Mantovani et al, 2003; Rosa et al, 2003; Cruz et al, 2009; Koike et al, 2011a) and 24 h (Koike et al, 2011b) following a single injection of ketamine. This table outlines studies that have assessed the antidepressant-like effects of ketamine at 30 min to 24 h post-administration in commonly used behavioral tests.
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