Ketamine: A Review for Clinicians

Abstract

A growing series of clinical trials and case series now suggest that ketamine-originally used as an anesthetic agent-potentially offers an exciting new treatment option for severe depression. Increasing numbers of studies show that ketamine can provide prompt relief for many depressed patients, including those with severe treatment-refractory depression. Although the effects of a single treatment are commonly short-lived, multiple infusion protocols may offer sustained relief. The uniquely rapid onset of antidepressant action raises the potential for ketamine use in a variety of clinical situations, including the prevention or shortening of hospital stays, the treatment of acute suicidal ideation, and the facilitation of medication crossovers. Ketamine, in combination with other multimodal treatment approaches, including psychotherapy, may further augment response effect and duration. Promises of efficacy have led to increasingly unbridled use to treat a variety of psychiatric disorders, with diverse approaches and treatment environments, despite inadequate data demonstrating the true clinical efficacy and safety of the various protocols or a thorough understanding of mechanisms of action. This article briefly reviews the history of ketamine's development as a potential antidepressant, current hypotheses related to its mechanisms of action, and existing evidence for its safety and efficacy with a focus on clinicians' interests.

Keywords: Antidepressants; Drug treatment/psychopharmacology; Mood Disorders-Unipolar.

FIGURE 1.

Models of Ketamine’s Mechanism of Action^{a a}A: Glutamate surge model of the absence of ketamine. Under normal physiological conditions, activation of NMDA receptors on inhibitory GABAergic interneurons (1) tonically inhibits release of presynaptic glutamate (2), resulting in minimal activation of postsynaptic AMPA receptors (3), low levels of BDNF expression, and mTOR activation to drive baseline local protein synthesis. Under the desuppression-of-translation model, low levels of spontaneous stimulation of postsynaptic NMDA receptors cause an activation of elongation factor 2 kinase (5) and subsequent phosphorylation of elongation factor 2, resulting in inhibition of local protein synthesis, including BDNF expression (6). B: Glutamate surge model of the presence of subanesthetic doses of ketamine. This model proposes that subanesthetic doses of ketamine selectively block NMDA receptor function on inhibitory GABAergic interneurons (1), thus causing a surge in glutamate release (2) and an increased phasic activation of the postsynaptic AMPA receptors (3) that results in increased local protein and BDNF expression (4). This is believed to result in further AMPA activation and local increases in neuroplasticity and synaptogenesis (5). The desuppression model suggests that subanesthetic doses of ketamine are selectively blocking the function of NMDA receptors at rest, responding to spontaneous glutamate release (6). This response results in decreased activation of elongation factor 2 kinase, dephosphorylation and activation of elongation factor 2 (7), and increased levels of local protein synthesis, including BDNF (4). This would result in an increased insertion of AMPA receptors and generate the same downstream effects as proposed above on BDNF, local protein synthesis and synaptogenesis (3–5). More recently, data generated with hydroxynorketamine and other novel compounds suggest that NMDA receptor blockade may not be necessary to achieve the cellular response associated with ketamine. Instead, this model proposes that the effects of these drugs are produced by either non-NMDA–mediated stimulated release of presynaptic glutamate (2) or direct activation of the postsynaptic AMPA receptors (3) that then initiate the same downstream cascade of events leading to increased neuroplasticity (4 and 5). Abbreviations: BDNF, brain-derived neurotrophic factor; mTOR, mechanistic target of rapamycin; eEF2, eukaryotic elongation factor 2; eEF-2K, eukaryotic elongation factor 2 kinase; HNK, hydroxynorketamine