Skip to content

Ketamine and electroconvulsive therapy pairing in depression and mood disorders

S. Kose, M. Çetin

April 3, 2017 DOI: 10.1080/24750573.2017.1332513 (opens in new tab)

Read Full Text
Relevant Not relevant

Study at a glance

AI-extracted from the abstract
Characteristics Review Double-blind Open-label
Intervention Ketamine
Dose 0.5 mg/kg of body weight
Duration 15-day assessment period; twice weekly treatment regimen administered for 4–6 weeks
Topics Depression Esketamine Ketamine
Key findings Ketamine, an NMDA receptor antagonist, appears to produce rapid and sustained antidepressant effects in treatment-resistant depression, with a multicenter double-blind study showing intravenous ketamine at 0.5 mg/kg two or three times weekly was comparably effective over 15 days, and the authors suggest a twice-weekly regimen for 4–6 weeks could induce and maintain robust antidepressant effect. The authors caution that dissociative and cognitive effects, abuse potential, and neurotoxicity concerns warrant cautious use.

Abstract

Although a number of medications are available for treatment of depressive disorders, one of the major limitations of all present antidepressants is delayed onset of action [1]. In addition, despite recent advances in the pharmacological and non-pharmacological treatment of major depressive disorder, almost one third of patients fail to respond to any treatments [2]. In recent years, one of the efforts to overcome the current limitations in treatment of depression has been to administer intravenous ketamine. Studies showing a rapid-onset antidepressant effect for the anesthetic agent ketamine, N-methyl-Daspartate (NMDA) glutamate receptor antagonist, in patients with treatment-resistant depression (TRD), have stimulated a new wave of pre-clinical and clinical research focused on the glutamate system and the NMDA receptor complex in mechanisms in major depressive disorder. A series of studies showed that chronicbut not acute, administration of several antidepressants, including imipramine, the serotonin-selective reuptake inhibitor citalopram and electroconvulsive therapy (ECT) in rats produced dose-dependent and persistent changes in the binding profile of NMDA receptors [2]. These findings suggested that adaptive changes in NMDA receptors might be a final common pathway for antidepressant action [2]. Studies in mice has linked enhanced AMPA signaling with increased synaptic plasticity [3]. Previously, Li et al. reported that ketamine rapidly activates the mammalian target of rapamycin (mTOR) intracellular signaling pathway, resulting in increased amounts of synapse-related proteins as well as an increased number and function of new spine synapses in the prefrontal cortex of rats [4]. Blockade of mTOR signaling in rats prevented the ketamine-induced synaptogenesis and antidepressant behavioral responses. These findings provided a key link between neurotrophicand plasticity-related theories of depression and the mechanism of action in NMDA receptor antagonists, suggesting that compounds that enhance neurotrophic support or activate the mTOR pathway directly may have had antidepressant activity. Li et al. [4] also showed that the synaptic and antidepressant effects of ketamine in animals were blocked by administration of an antagonist of the glutamate α-amino-3hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor. Taken together, these findings supported a model where ketamine may have decreased NMDA receptor signaling and enhance AMPA receptor signaling, with a net effect of increased synaptic plasticity and neuronal growth, which was postulated as the basis for the observed antidepressant effects. Relapse prevention strategies in depression regarding ketamine use are worth noting. Encouraging results showed how repeated administration of low-dose ketamine three days a week for two weeks in patients with TRD, similar to an ECT, produced a sustained antidepressant response up to 3 months [5]. In an effort to reduce cognitive side effects related to NMDA receptor antagonists, compounds selective for the NR2B subunit of the NMDA receptor were investigated. An initial study of an NR2B-selective NMDA receptor antagonist showed acute antidepressant effects in 30 patients with TRD as adjunctive treatment to a stable dose of paroxetine [6]. Concerns regarding unique dissociative and other neurocognitive effects of ketamine, abuse potential, and neurotoxic effects of NMDA receptor antagonists shown in rats [7] require a cautious approach to the use of ketamine treatment for treatment-resistant depressed patients. Nonetheless, more than almost 60 years of clinical experience with ketamine use suggested that ketamine had been overall very safe and well-tolerated medication [8]. While the transient cognitiveand dissociative effects of ketamine might limit its widespread use in depression treatment, it certainly represents a crucial addition to the armamentarium of therapeutic interventions for TRD cases, similar to ECT. Recently, Singh et al., in a multicenter, double-blind study, reported that ketamine, when administered intravenously at 0.5 mg/kg of body weight either two or three times weekly, appeared comparably effective in both achieving rapid onset and maintaining antidepressant efficacy in patients with TRD across the 15-day period of assessment [9]. The improvement was similar in the two frequency groups. As less frequent treatment administration is usually preferred in order to reduce the patient and clinic burden and costs, this result, taken together with other data acquired during the double-blind and open-label phases, suggests that the twice weekly treatment regimen administered for 4–6 weeks could induce and maintain a robust antidepressant effect in thetreatment-resistant depressed patients. Furthermore, both treatment regimens were found generally tolerable, with significant attenuation of dissociative adverse events across repeated infusions. The use of ECT in depression is limited by concerns about its cognitive adverse effects. The neurotransmitter glutamate has a central role in cognition, especially in learning and memory, through its effects on synaptic plasticity and the signaling pathway involved in longterm potentiation in the hippocampus [10]. Memory

Comparable studies

Other narrative reviews on ketamine for depression, most cited first.

Study Year Design Participants
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression 2021 Review
Ketamine: a paradigm shift for depression research and treatment 2019 Review
Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective 2019 Review
Ketamine: A tale of two enantiomers 2020 Review
Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor 2021 Review

Citations in the library

Cites 7

and 2 more in the library

Related reading

Explore topics

Depression Esketamine Ketamine Addiction Neuroplasticity Serotonin

By condition and practice

Ketamine for depression