Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

This review (2014) examines ketamine as a prospective treatment option for patients with depression and provides an overview of its role within the glutamate system, its antidepressant mechanisms of action, safety profile, and evidence from clinical studies that investigated the efficacy of single or multiple infusions. Furthermore, it compares alternative modes of ketamine administration and highlights fundamental research on other types of NMDA agonists that may have less psychotomimetic effects.

Abstract

“Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.”

Authors: Nicolas D. Iadarola, Mark J. Niciu, Erica M. Richards, Jennifer L. Vande Voort, Elizabeth D. Ballard, Nancy B. Lundin, Allison C. Nugent, Rodrigo Machado-Vieira & Carlos A. Zarate

Summary

Introduction

Transient mood reactivity often accompanies both rewarding and stressful life events. However, severe mood and behavioral dysregulation over a prolonged period can be maladaptive to the individual and result in major depressive episodes and suicidal ideation and behaviors.

More than 60 years ago, tricyclic antidepressants and monoamine oxidase inhibitors were discovered. These medications altered the reuptake, degradation or receptor pharmacodynamics of biogenic amines, leading to the discovery of newer atypical antidepressants.

Preclinical studies with NMDA receptor antagonists suggested that the glutamate system might be a novel experimental therapeutic approach to depression, and ketamine was a reasonable translational candidate due to decades of safety and tolerability in the fields of anesthesia and neurology.

This article will review glutamatergic neurotransmission, clinical data supporting ketamine’s antidepressant efficacy, and reverse translational research into ketamine’s mechanism of action in preclinical models of depression.

The glutamate system

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, and the NMDA receptor and AMPA receptor are important in regulating glutamatergic neurotransmission. The AMPA receptor causes a faster influx of sodium ions and a refractory desensitization, reducing the strength of membrane depolarization upon subsequent glutamate binding.

Single infusion studies

Berman and colleagues reported the first ketamine depression study in 2000, and Zarate et al. (2006) replicated this finding in a larger sample of treatment-resistant MDD patients. The antidepressant efficacy abated over time, but 35% still met response criteria a week after a single infusion.

In 2013, Murrough and colleagues published a two-site randomized controlled trial of ketamine in treatment-resistant MDD. Ketamine had greater antidepressant efficacy at the primary outcome than midazolam.

Ketamine has been shown to have antidepressant efficacy in treatment-resistant unipolar depression and treatment-resistant bipolar depression. However, some of the nonspecific psychotomimetic effects of ketamine may be difficult to distinguish from the activating effects of monoaminergic antidepressants when given to patients with bipolar depression.

Multiple infusion studies

The efficacy of repeated-dose ketamine infusions for treatment-resistant depression was investigated in a small trial, and a larger trial included subjects with TRD. The response rate was 70.8%, with a high positive predictive value of 4 h response predicting end-of-trial response. In a repeated-dose ketamine study, 10 patients with TRD received 0.3 mg/kg ketamine infused over 100 min twice weekly until either remission was achieved or the subject received four total infusions. Three and five patients were responders and remitters, respectively. A study of 28 medicated treatment-resistant patients with unipolar and BDep used repeated-dose ketamine administration for 3 weeks. Eight patients responded and four patients remitted without cognitive impairment.

There are several case reports of patients with TRD who received repeated subanesthetic dose ketamine administration, but there are currently insufficient data to recommend long-term off-label use in a nonresearch milieu.

Alternative modes of administration

While more work is needed to explore repeated dosing, other studies have examined alternative methods of delivery, including oral, intramuscular, sublingual, and intranasal.

Oral

Oral ketamine has much lower bioavailability (20%) compared to nonparenteral forms, but has shown significant antidepressant and anxiolytic efficacy in a hospice/palliative care setting. Side effects were minor and relatively rare, for example, diarrhea, insomnia and akathisia.

Intramuscular

Intramuscular ketamine has similar bioavailability to intravenous ketamine, and has been shown to have a higher peak exposure. It has also been shown to have an antidepressant effect, and has an expected side-effect profile without the medical sequelae seen in ketamine abusers, for example, cystitis.

Sublingual

Sublingual ketamine has a slightly improved bioavailability compared with oral ketamine and is well tolerated. It has antidepressant efficacy in 20 outpatients with current unipolar and bipolar depression.

Intranasal

In a trial with 20 patients with major depression, intranasal ketamine showed significant antidepressant effects. It was associated with only minor changes in hemodynamic, dissociative and psychotomimetic parameters.

Antisuicidal effects

Ketamine has been reported to have antisuicidal properties. In 33 subjects with TRD, suicidal thinking was reduced within 40 min and maintained for up to 4 h post infusion, and in 108 patients with treatment-resistant major depression, suicidal thinking was partially related to improvements in neuropsychiatric symptoms.

Studies investigating the use of ketamine for the treatment of suicidality have been conducted in both chronic and acute settings, but these studies are likely investigating chronic as opposed to acute suicidal ideation with greater potential for suicidal behaviors.

Safety and tolerability

Ketamine has been used safely and effectively as a dissociative anesthetic since its introduction in the 1960s. Two Yale groups reported two cases of next-day dysphoria, anxiety and suicidal ideation in subjects with treatment-resistant obsessive – compulsive disorder who received open-label subanesthetic dose ketamine for the treatment of OCD.

Mt Sinai and Baylor reported that 97 patients with MDD received 205 intravenous ketamine infusions between 2006 and 2012. No patients reported any long-term problems from ketamine research participation, and the majority of patients considered ketamine infusions at least ‘somewhat acceptable’.

Pharmacology

Ketamine is a synthetic derivative of phencyclidine (PCP), and has moderate affinity for the NMDA receptor as a noncompetitive antagonist. It also has opioidergic properties, which may be critical for its antidepressant and anxiolytic efficacy.

Preclinical studies

Ketamine’s mechanism of action involves NMDA receptor blockade on cortical -aminobutyric acid(GABA)ergic interneurons, which releases the tonic inhibition on major output neurons, and increases acute synaptic glutamate release/cycling, increased AMPA to NMDA postsynaptic throughput, and activation of second messenger/signal transduction cascades.

Ketamine stimulates translation of the neurotrophin BDNF in dendritic spines of hippocampal pyramidal neurons, which is necessary for ketamine’s rapid antidepressant-like effects in rodents. Ketamine inhibits eEF-2K activity, which results in greater local BDNF translation in dendritic spines.

Ketamine activates mammalian target of rapamycin (mTOR), a critical hub of cellular growth and proliferation, in preclinical models of despair. Ketamine increases mTOR phosphorylation and other downstream molecular targets critical for transcriptional activation within 1 hour of administration.

Ketamine inhibits glycogen synthase kinase-3 (GSK-3) by increasing serine phosphorylation, and this phosphorylation is necessary for antidepressant-like effects in model rodents. Ketamine also potentiates the antidepressant, synaptogenic and electrophysiological effects of lithium.

Clinical predictors

We analyzed data from 108 patients with major depression and found that increased body mass index, a family history of an alcohol use disorder and no lifetime personal history of suicide attempt were associated with ketamine’s antidepressant action.

Ketamine-induced dissociative or psychotomimetic side effects may be a critical component in predicting eventual antidepressant response, although hemodynamic and psychotomimetic side effects did not correlate with ketamine’s antidepressant efficacy at any of the aforementioned time points.

Peripheral measures

Our group and others have examined several candidate peripheral measures as potential correlates of ketamine’s antidepressant response. However, baseline peripheral vitamin B12 levels did not correlate with antidepressant efficacy.

D-serine, a glial-derived partial agonist at the NMDA receptor glycine site, has antidepressant-like effects in a depression model in rodents and augments antidepressant effects in TRD but only at higher doses.

Several studies have reported an association between baseline serum BDNF and ketamine’s antidepressant activity. In a sample of 22 subjects with TRD from the ketamine-midazolam study, plasma BDNF levels at 240 minutes were associated with greater antidepressant improvement at the same time point.

SHANK3, a postsynaptic density protein that interacts with NMDA receptors, predicted increased ketamine antidepressant efficacy in treatment-resistant BDep.

Ketamine neuroimaging reports in depression have shown that lower baseline left hippocampal volume is a positive predictor of ketamine’s antidepressant improvement in 13 medication-free patients with MDD, and increased subgenual anterior cingulate cortical rMRGlu is a potential treatment response biomarker. Ketamine’s antianhedonic effects were independent of depression improvement, and correlated with increased dorsal anterior cingulate cortex and putamen rMRGlu. However, ketamine’s antianhedonic effects in BDep did not correlate with rMRGlu change in the ventral striatum.

Ketamine-associated plasma metabolomic profiles may identify novel associations not previously hypothesized to exist, such as increased mitochondrial oxidation of fatty acids and increased BMI in lithium-maintained ketamine responders.

Other NMDA receptor antagonists in depression

Ketamine has acute dissociative and psychotomimetic side effects and potential abuse liability, so other NMDA receptor antagonists have been studied in depression. Memantine showed preliminary antidepressant-like effects in rodent models of despair. Memantine has been studied in bipolar depression. In an 8-week randomized, placebo-controlled study, escalating-dose memantine had better antidepressant success compared with placebo at 4 weeks, but this effect was not sustained at trial endpoint.

AZD6765 is a noncompetitive NMDA receptor antagonist with a Ki similar to ketamine, but lower trapping. It has lower response rates, lower remission rates, and a shorter duration of effect than ketamine, but failed to separate from placebo in a phase IIb study.

Subtype-specific NMDA receptor antagonists may also have less dissociative and other undesirable adverse effects than nontrapping antagonists. A small, randomized, double-blind, placebo-controlled, crossover study of an oral NR2B antagonist in treatment-resistant MDD demonstrated rapid antidepressant action as early as day 5.

2012 was a record year for new drug approvals, yet most of these drugs were in the area of oncology. Furthermore, mental illnesses and suicidality have not seen significant reductions in morbidity and mortality.

Ketamine depression research is ongoing and many exciting unanswered clinical questions remain. Some interesting avenues include continued studies of alternative/nonparenteral modes of administration and ketamine augmentation.

A multisite study will attempt to address the lack of an antidepressant dose – response curve by using parallel-group, repeated-dose infusions of the psychoactive placebo midazolam and four doses of ketamine.

Our group is interested in translating preclinical findings to patients with depression by developing treatment response biomarkers and other surrogate endpoints.

Conflict of interest statement

Dr. Zarate has assigned his rights to a patent to the US Government and will share in any royalties received.