Exploiting N-Methyl-D-Aspartate Channel Blockade for a Rapid Antidepressant Response in Major Depressive Disorder

University of Ottawa Institute of Mental Health Research, Mood Disorders Research, Ottawa, Canada. Electronic address: .
Biological psychiatry (Impact Factor: 10.26). 08/2013; 74(4):238-9. DOI: 10.1016/j.biopsych.2013.05.029
Source: PubMed
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    • "The first line treatment for attention deficit hyperactivity disorders consists of psychostimulants, such as methylphenidate (MPH). MPH exerts blockade of dopamine and norepinephrine synaptic transporters [1] "

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    • "This differs from current drug development approaches to produce high-affinity agents that engage and occupy the target-binding site for extended time periods. This possibility is supported by anecdotal evidence using low doses of ketamine and bolus vs slow infusions.61 "
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    ABSTRACT: Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.
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    ABSTRACT: This literature review begins with a rationale for the development of new therapeutic approaches for the treatment of depressive disorder. In the following sections the history of the finding of ketamine‘s antidepressant effect, its pharmacological properties and application routes are summarized. The following is an overview of the existing scientific evidence of ketamine’s efficacy in patients with unipolar and bipolar depression, suicidality and the adjuvant use in electroconvulsive therapy. Finally, the author discusses acute and chronic side effects, safety of repeated administration of ketamine and possibilities of extending the antidepressant effect. The last section summarizes recent findings on the mechanism of the antidepressant effect of ketamine on the molecular level and its effect on neuronal plasticity.
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