Elsevier

Current Opinion in Pharmacology

Volume 20, February 2015, Pages 35-39
Current Opinion in Pharmacology

How does ketamine elicit a rapid antidepressant response?

https://doi.org/10.1016/j.coph.2014.11.005Get rights and content

Highlights

  • Ketamine triggers a rapid antidepressant response in patients with major depression.

  • Ketamine elicits rapid translation of brain-derived neurotrophic factor (BDNF).

  • Rapid BDNF translation requires deactivation of eukaryotic elongation factor2 kinase.

  • Ketamine, but not memantine, blocks resting NMDAR-mediated neurotransmission in Mg2+.

  • Block of resting NMDAR-mediated synaptic responses is essential for ketamine action.

A single sub-psychotomimetic dose of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist, produces a fast-acting antidepressant response in patients suffering from major depressive disorder. Depressed patients report alleviation of core symptoms within 2 h of a single low-dose intravenous infusion of ketamine with effects lasting up to 2 weeks. The rapidity of ketamine action implies that major symptoms of depression can be alleviated without substantial structural plasticity or circuit rewiring. Therefore, the ability of ketamine to exert a rapid effect provides a unique opportunity to elucidate the types of acute synaptic plasticity changes that can be recruited to counter depression symptoms.

Introduction

In the last decade, clinical studies have demonstrated that intravenous administration of a low dose of ketamine triggers a rapid antidepressant response in patients with major depression [1, 2, 3] including treatment resistant depression [2, 3] and bipolar depression [4, 5]. These studies have bolstered the hope that patients that do not respond to traditional antidepressants, which target monoaminergic neurotransmission and typically take several weeks to show efficacy, can be treated rapidly with ketamine. Antidepressants with a rapid onset of action are particularly needed for patients at increased risk for suicide, as the long time frame required for the efficacy of classical antidepressants limits their use in emergency circumstances.

Ketamine is a non-competitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist that binds to the open channel pore. Recent studies demonstrated that the antidepressant-like action of ketamine could be modeled in animals [6, 7, 8]. These studies also showed that similar to classical antidepressants, ketamine requires expression of brain-derived neurotrophic factor (BDNF) [6, 9]. However, while ketamine triggered acute translation of BDNF protein was essential for its rapid antidepressant effects [6], ketamine action was not sensitive to inhibition of transcription and ketamine administration did not elicit an increase in transcription of BDNF mRNA arguing against the role of transcription dependent processes [6].

Classical antidepressants take several weeks to show efficacy. To explain their mechanism of action, there has been significant interest in long-term processes that rewire neuronal circuits. There is some evidence that such long-term circuit level reorganization may require neurogenesis and depend on transcriptional alterations as well as chromatin remodeling [10, 11, 12]. In contrast, ketamine exerts its action within hours, shortly after its clearance, thus pointing towards a fundamentally different mechanism that may nevertheless require BDNF signaling albeit in a much faster time frame. Therefore, the ability of ketamine to exert a rapid effect indicates that major symptoms of depression can be alleviated without any requirement of substantial circuit rewiring. This basic aspect of ketamine action provides a unique opportunity to elucidate the types of acute synaptic plasticity changes that can be recruited to counter depression symptoms. In addition, the NMDA receptor blocking action of ketamine is a biophysically well-characterized process, which makes it possible to identify specific signal transduction events that link NMDA receptor blockade by ketamine to subsequent elevation in BDNF levels.

Section snippets

How does blockade of NMDA receptors elicit plasticity?

Ketamine as well as other NMDA receptor antagonists produce rapid antidepressant-like effects in mouse behavioral models that are dependent on rapid protein synthesis of BDNF [6]. This study demonstrated that rapid synthesis of BDNF requires deactivation of eukaryotic elongation factor 2 (eEF2) kinase and decreased phosphorylation of eukaryotic elongation factor (eEF2). Experiments in animal models showed that ketamine-mediated blockade of NMDA receptors at rest deactivates eEF2 kinase,

Synaptic circuits that mediate the antidepressant action of ketamine

The increasing number of studies focused on elucidating ketamine's action on synaptic transmission present significant opportunities for conceptual advance by delineating the molecular basis of rapid antidepressant responses. In addition, clinical studies that assess the impact of alternative NMDA receptor blockers as well as other means of altering glutamatergic signaling on triggering antidepressant responses provide promising directions for new treatments [27, 28, 29]. However, the exact

Synaptic mechanisms that may underlie long term antidepressant efficacy

Recent preclinical studies on ketamine action did not only address how ketamine may trigger an antidepressant effect but also provided clues on potential mechanisms that may maintain this effect in the long term. Ketamine mediated suppression of spontaneous NMDA receptor mediated neurotransmission results in a transient elevation in BDNF levels that returns to baseline within 24 h after ketamine administration [6]. However, in patients as well as in animal models antidepressant responses remain

Conclusion

Recent studies on rapid antidepressant action presented a productive merger of basic studies on synaptic transmission and plasticity with reverse translational approaches to uncover mechanisms of action for clinically validated rapid antidepressants. Identification of synaptic substrates that mediate an antidepressant response will offer new leads toward the development of robust, reliable fast acting antidepressants. The initial insight from this work suggests that acute alterations in

Conflict of interest

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by National Institutes of Health Grants MH070727 (to L.M.M.) and MH066198 (to E.T.K.), as well as awards from the Brain and Behavior Research Foundation (to E.T.K. and L.M.M.) and the International Mental Health Research Organization (to L.M.M.).

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