Depression afflicts approximately 16% of the world population. Although antidepressant medications are available, many patients remain treatment-refractory, and currently used drugs take several weeks to be effective. A recent finding is that the non-competitive NMDA receptor antagonist ketamine has rapid antidepressant efficacy in treatment-resistant patients. Despite these promising results, ketamine's potential as a long-term antidepressant medication is limited due to its addictive nature, anesthetic properties, and capacity to produce dissociative effects even at low doses. Similar to many existing psychotropic drugs, the full clinical actions of ketamine may be due to more than one target. Ketamine is rapidly and stereospecifically metabolized to various metabolites that have distinct biological activities. These metabolites may be responsible for either the therapeutic or the side effects of ketamine when it is utilized as an antidepressant. Our preliminary data indicate that some metabolites exert antidepressant-like actions and increase AMPA excitatory post-synaptic current frequency in stratum radiatum interneurons, indicative of increases in glutamate release from CA3 Schaffer collateral inputs. The central hypothesis guiding the proposed studies is that a ketamine metabolite or metabolites independently exert clinically relevant actions that substantially explain ketamine's clinical profile. Here, we will use mice to test the antidepressant-like properties and the side effect profile of these compounds. We will first, in Specific Aim #1, define the range of ketamine metabolite's actions on ketamine-sensitive tests related to depression. In addition to utilizing tests to predict rapid and sustained therapeutic antidepressant action in both male and female mice, these studies will assess different endophenotypes associated with depression including helplessness and anhedonia. Quantifying plasma and brain levels at time points relevant to our behavioral studies will permit us to determine the extent to which ketamine's behavioral effects are associated with brain concentrations of its metabolites.
In Specific Aim #2, we will assess whether ketamine metabolites account for the side effects of ketamine. We will determine the effects of metabolites in behavioral tests that predict stimulant effects, as well as abuse and psychotomimetic potential.
In Specific Aim #3, we will determine the pharmacological activity of ketamine metabolites relevant to their antidepressant actions. We will use whole-cell patch-clamp electrophysiology to determine the cellular mechanisms that underlie the antidepressant actions of ketamine metabolites. Using behavioral approaches we will assess the contribution of identified mechanisms. A comprehensive understanding of how the therapeutic actions of ketamine are exerted is imperative for the development of improved pharmacotherapies that will effectively reproduce the therapeutic benefit of ketamine, but without the unwanted side effects. Completion of the proposed experiments will provide a strong scientific framework to better understand these properties.

Public Health Relevance

Ketamine has efficacy as a fast-acting antidepressant in treatment refractory major depression patients; however, its potential as a long-term antidepressant treatment is limited due to its addictive nature, anesthetic properties, and capacity to produce dissociative effects. Ketamine is rapidly and stereospecifically metabolized to a number of biologically active metabolites that are pharmacologically distinct from ketamine. We propose to utilize rodent behavioral models and electrophysiological characterization of brain circuit function to determine the relevant antidepressant and side-effect actions of ketamine's metabolites, which may lead to important insights and discovery of relevant mechanisms important for the development of a next generation of fast- acting antidepressant compounds.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Winsky, Lois M
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University of Maryland Baltimore
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Zanos, P; Gould, T D (2018) Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23:801-811
Zanos, Panos; Gould, Todd D (2018) Intracellular Signaling Pathways Involved in (S)- and (R)-Ketamine Antidepressant Actions. Biol Psychiatry 83:2-4
Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2018) Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev 70:621-660
Zanos, Panos; Thompson, Scott M; Duman, Ronald S et al. (2018) Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS Drugs 32:197-227
Brown, P Leon; Zanos, Panos; Wang, Leiming et al. (2018) Isoflurane but not Halothane Prevents and Reverses Helpless Behavior: A Role for EEG Burst Suppression? Int J Neuropsychopharmacol :
Nugent, Allison C; Ballard, Elizabeth D; Gould, Todd D et al. (2018) Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry :
Zanos, Panos; Nelson, Mackenzie E; Highland, Jaclyn N et al. (2017) A Negative Allosteric Modulator for ?5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice. eNeuro 4:
Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2017) Reply to: Antidepressant Actions of Ketamine Versus Hydroxynorketamine. Biol Psychiatry 81:e69-e71
Zanos, Panos; Moaddel, Ruin; Morris, Patrick J et al. (2017) Zanos et al. reply. Nature 546:E4-E5
Morris, Patrick J; Moaddel, Ruin; Zanos, Panos et al. (2017) Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites. Org Lett 19:4572-4575

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