Targeting glutamate signalling in depression: progress and prospects

This review (2017) examines the history, rationale, and efficacy of glutamate-modulating agents in treating depression. Ketamine has emerged as the prototypical fast-acting antidepressant and has yielded compelling hypotheses about the role of glutamate, although the role of its effects on NMDA receptor inhibition still remains unclear as to whether it alleviates depression. Preliminary evidence also suggests that ketamine-like drugs exert antidepressant properties by regulating monoamine signaling, opioid signaling, inflammatory systems, or even epigenetic mechanisms.

Abstract

“Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N‑methyl-d‑aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose–response relationships and therapeutic mechanisms.”

Authors: James W. Murrough, Chadi G. Abdallah, and Sanjay J. Mathew

Summary

Major depressive disorder is among the most disabling medical illnesses worldwide and ranks first among all mental health, substance and neurological disorders in terms of disability-adjusted life years. Many patients with MDD do not respond to current treatments, and the peak efficacy of first-line antidepressants is delayed.

The glutamate system is incredibly complex and poses numerous obstacles for drug discovery efforts. However, several early-stage clinical neuropsychiatric programmes have been initiated for compounds that target different components of the glutamate system.

The NMDAR-blocking agent ketamine, which has been available for human use since the 1960s, was reported to induce profound clinical improvements in the core symptoms of depression within several hours of treatment. This discovery triggered vigorous research in both industry and academia to understand the role of glutamate signalling in depression.

Glutamate signalling in health and disease

Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), and regulates second-messenger systems, membrane-bound receptors, nuclear gene expression and translation. AMPARs and NMDARs are both Na+-permeable and have major roles in activity-dependent synaptic plasticity, whereas NMDARs have a uniquely high permeability to Ca2+.

NMDAR signalling promotes cell survival and neurotrophic functions, while abnormally elevated or misappropriated NMDAR signalling leads to deleterious effects on neurons.

Glutamate dysfunction in depression

Several lines of evidence implicate the glutamate system in pathophysiological processes that are relevant to depressive disorders, including elevated glutamate levels in the plasma, cerebrospinal fluid and the brains of patients with depression.

Glial cells have several important roles in glutamate signalling, including the production of trophic factors and the release of EAATs.

Glutamate (Glu) is the most abundant excitatory neurotransmitter in the brain and is crucial for information processing, memory and neuronal plasticity. There are several types of Glu receptors, including ionotropic receptors, kainate receptors and amino3hydroxy5methyl4isoxazole propionic acid receptors. The mGluRs are transmembrane G proteincoupled receptors (GPCRs) that are divided into group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7 and mGluR8). NMDAR and AMPAR activation leads to synaptogenesis. Glial cells regulate intrasynaptic concentrations of Glu through excitatory amino acid transporters and Gly transporters, and release Glu in the extrasynaptic space. There are several changes in glutamatergic signalling that could potentially be targeted by modulators in depression. These include reducing GABAergic inhibitory tone, increasing presynaptic release of Glu, increasing presynaptic vesicular Glu release, and enhancing EAAT function. Ketamine and other NMDAR antagonists are believed to exert neuroprotective effects by blocking extrasynaptic NMDARs. mGluR5 negative allosteric modulators or antagonists may also exert neuroprotective effects by potentiating the mechanistic target of rapamycin complex 1.

Chronic stress leads to neuronal atrophy and decreased synaptic functioning in the PFC and hippocampus of animal models of depression, and these changes are believed to underlie several gross abnormalities found in the brains of individuals with MDD.

Human neuroimaging approaches have implicated the glutamate system in depression. Proton magnetic resonance spectroscopy (1H-MRS) studies have found reduced Glx levels in the PFC, reduced GABA levels in the PFC and occipital cortex, and elevated glutamate levels in the occipital cortex.

Ketamine as an antidepressant

Ketamine is a non-competitive antagonist at the NMDAR, and also interacts with opioid and cholinergic receptors. It is commonly used in the treatment of depression, and has a favourable therapeutic and safety profile compared with the racemic mix and the (S)enantiomer.

In a small study, patients with depression received a single low-dose intravenous (i.v.) infusion of ketamine or placebo (saline). Ketamine produced acute mental status changes, including psychosis-like effects, dissociation and a self-reported feeling of a ‘high’, which disappeared rapidly, whereas reductions in the core symptoms of depression occurred separately, hours to days after infusion.

In RCTs comparing ketamine with a control condition, ketamine has been shown to have a significant antidepressant effect in treatment-resistant unipolar and bipolar samples, although the evidence is limited by risk of bias and small samples.

Several studies have examined the effect of repeated administration of ketamine over 2 weeks or more. A recent RCT found that a single dose of ketamine can have an enduring effect on depression severity.

There are several areas of active investigation concerning the use of ketamine for depression, including intranasal, oral, sublingual, intramuscular and transdermal administration. The effects of ketamine on specific symptom dimensions within depression, and on specific underlying neurobehavioral constructs, represent an important research direction.

A recent study found rapid antidepressant efficacy of a 40-minute i.v. infusion of (S)-ketamine in 30 patients with TRD. No data concerning the tolerability or efficacy of (R)-ketamine in humans have been published to date.

Mechanisms of glutamate modulators

There is strong evidence that ketamine and other NMDAR antagonists show antidepressant properties in animal models. However, the mechanism of action of these agents is complex, and there is some evidence that ketamine may trigger an antidepressant effect through an active metabolite that acts in an NMDAR-independent manner.

Findings from preclinical studies

Studies show that NMDAR antagonists, including ketamine, exert antidepressant behavioural effects in animal depression models, and that ketamine increases BDNF expression and synaptic formation, whereas memantine has no effect on hippocampal BDNF and no antidepressant behavioural effects.

Ketamine and its metabolite (2S,6S;2R,6R)-hydroxynorketamine (HNK)49 are both capable of triggering an antidepressant effect independently of the NMDAR, suggesting that directly targeting the NMDAR may not be required.

Rapidly acting antidepressants have been shown to directly or indirectly activate intrasynaptic AMPAR and NMDAR signalling, and associated intracellular cascades. AMPAR activation is required for NMDAR activation, and AMPAR antagonism can block the beneficial effects of ketamine and other putative rapid-acting antidepressants.

Neuroplasticity pathways are altered in depression, and synaptic plasticity can occur locally (as in long-term depression) or globally (as in synaptic scaling). Synaptic scaling may be particularly relevant to depression pathophysiology.

Ketamine increases the translation of synaptic proteins through a BDNF – TRKB – AKT – mTORC1 pathway that is dependent on AMPAR activation. The mechanism linking ketamine to the activation of synaptic plasticity pathways remains incompletely understood.

Ketamine inhibits glycogen synthase kinase 3 (GSK3) function and thus may disinhibit pro-plasticity pathways. It also synergizes with lithium and other GSK3 inhibitors in animal depression models and may regulate immune cell signalling.

Findings from human studies

Animal studies have revealed the molecular events underpinning the antidepressant mechanisms of ketamine and other glutamate modulators. Translational and clinical studies will be required to validate these results in humans.

Biomarkers related to the immediate effects of ketamine.

Ketamine increases synaptic glutamate concentrations in the PFC of individuals with MDD, and this increase is crucial to activity dependent stimulation of neuroplasticity pathways. Elevated glutamate release has similarly been linked to the dissociative or psychotomimetic effects of ketamine.

Biomarkers related to the sustained effects of ketamine.

Ketamine increases the glutamine/ glutamate ratio within the perigenual ACC, normalizes the caudate response to positive emotional stimuli, and blunts the amygdala response to negative and neutral affective stimuli in healthy volunteers. The PFC of patients with depression shows reduced functional connectivity, which is partially reversed 24 hours after ketamine treatment.

Recent studies of in vivo metabolism in participants with mood disorders paint a mixed picture. Ketamine treatment may trigger antidepressant effects partly through changes in brain metabolism within prefrontal and medial temporal regions.

NMDAR modulators promote the effects of glutamate signalling and inhibit the negative consequences of toxic glutamate signalling through two main pathways: activation of ERK, AKT and mTORC1 and suppression of eEF2 kinase. Chronic mild stress reduces neurotrophic support and BDNF signalling within cortical and hippocampal glutamatergic synapses, and lowdose ketamine rapidly reverses this reduction through a number of processes, including inhibition of NMDAR on a subpopulation of interneurons, activation of intrasynaptic NMDARs and AMPARs, and increased BDNF release. Ketamine has been shown to robustly modulate both the promotion and the inhibition of Glu signalling. Other NMDAR antagonists and modulators may have morerestricted effects, possibly explaining the variability of their efficacy and onset of action compared with ketamine.

Several studies have shown that BDNF plays a role in the antidepressant effects of ketamine in humans, although the link between BDNF function and the mechanism of action of ketamine in humans remains tentative.

Other glutamate modulators in development

d-Cycloserine (DCS) is an antituberculosis drug that has antidepressant-like effects at high doses. It has been shown to have superior benefit over placebo in patients with treatment-resistant bipolar depression.

GLYX‑13 and NRX‑1074

GLYX-13 is a tetrapeptide that enhances LTP in vitro and has concentration-dependent effects on NMDAR currents. It has antidepressant-like activity in several preclinical behavioural assays.

A recent company-sponsored RCT reported promising effects of GLYX-13 on MDD, although the lowest and highest doses had no significant antidepressant effect. The compound was well tolerated and did not show any evidence of increasing psychotomimetic symptoms.

A proof-of-concept study of the oral NR2B-selective antagonist MK-0657 in patients with TRD126 showed favourable tolerability but a mixed efficacy profile. A randomized, double-blind placebo-controlled trial is being conducted to evaluate the adjunctive antidepressant effects of CERC-301.

7-Chlorokynurenic acid, a potent antagonist at the obligatory glycine-binding site on NMDAR NR1 subunits, has been used to probe NMDAR function. It has been shown to have antidepressant-like effects in several mouse models.

Dextromethorphan‑containing compounds

Dextromethorphan is an NMDAR antagonist and the active ingredient in several over-the-counter cough suppressants. A combination product containing dextromethorphan plus quinidine was approved for the treatment of pseudobulbar affect, and a phase II programme for MDD was launched in 2014.

Sarcosine (N‑methylglycine)

Sarcosine, a naturally occurring GlyT1 inhibitor, raised synaptic glycine levels and increased NMDAR activity in a small RCT, and led to superior reductions in depressive symptoms compared with citalopram.

AMPAR modulators

AMPARs play a key role in synaptic plasticity and the antidepressant-like effects of ketamine have been identified as an obligatory component of AMPAR signalling. Several studies have investigated the potential of AMPAR potentiators in the treatment of depression.

Metabotropic glutamate receptor modulators

Antidepressant drug development focusing on mGluRs is in relatively early stages, but has demonstrated rapid, ketamine-like antidepressant effects in preclinical models. Although a phase I study of the mGluR2/3 antagonist BCI-632 has completed, data had not been published at the time of writing.

Patient selection

Studies that involve mechanistically novel agents for depression may not effectively constrain heterogeneity, because treatment outcome may vary as a function of demographic and symptom characteristics, history of trauma, neurocircuit function and genotype.

Dosing and clinical trial design

All clinical trials of parenteral ketamine in depression have used 0.5 mg per kg infused over 40 minutes. A less well-studied but equally crucial component of dose optimization concerns dosing frequency, as some NMDAR modulators might be more optimally administered intermittently rather than daily.

Standard outcome scales for conventional antidepressant trials may lack sensitivity for detecting rapid changes in mood, and shorter versions may be more sensitive.

Safety

Ketamine has a favourable safety profile in well-controlled medical settings, but it is neurotoxic at high doses and for prolonged periods. It is recreationally abused as a club drug and is listed in Schedule 3 by the FDA.

A review of three clinical trials of ketamine for depression found no evidence of negative psychological or medical sequelae, or substance abuse-related emergencies, although high doses and long courses of the drug may cause hypertension, tachycardia and cystitis.

Conclusions

Ketamine has been identified as a prototype rapid-acting antidepressant, but there is a near absence of studies that examine its safety or efficacy beyond a single treatment administration. This gap in the literature represents a crucial unmet research need.

Many challenges remain for the development of glutamate modulators for the treatment of depression, including a lack of definitive diagnostic and treatment-related biomarkers, and a paucity of data on long-term outcomes.

There are several studies on the global burden of mental and substance use disorders, including the Global Burden of Disease Study 2010 and the Clinical, Economic, and Societal Burden of Treatment-Resistant Depression Study. Papakostas, G. I., Ionescu, D. F., Mathew, S. J., Berman, R. M. et al. have reviewed the latest research on new mechanisms for treatment-resistant major depressive disorder, including treatments targeting the glutamate system, the opioid system, inflammatory signalling systems and others.

Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. The activation of synaptic NMDA receptors leads to upregulation of BDNF expression and the activation of extrasynaptic NMDA receptors leads to downregulation of BDNF expression. The glutamate system is involved in several mood disorders, including PTSD, depression and anxiety disorders. The genetics of stress-related disorders is also discussed, as well as the role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death.

The NR1 subunit of the glutamate/NMDA receptor is increased in schizophrenia and affective disorders, and the NR2C subunit is increased in depression.

Chandley, M. J. et al. found elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression.

The loss of glial cells within the prefrontal cortex of patients with mood disorders is consistent with the hypothesized glutamate abnormalities in these disorders.

A comprehensive review summarizes the diverse mechanisms by which glutamate signalling is influenced by stress and by the functioning of the glucocorticoid system, and a meta-analysis of resting-state functional connectivity alterations reported in patients with depression.

Ketamine has several mechanisms of action, including the metabolism of racemic ketamine to (2R,6R)-HNK, which shows antidepressant-like effects in mice that seem to be independent of the NMDAR. Ketamine and other glutamatergic NMDA antagonists have been shown to have an antidepressant effect in patients with treatment-resistant major depression.

In patients with treatment-resistant depression, repeated ketamine dosing over up to 4 weeks showed comparable efficacy that was superior to placebo. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression is currently underway. Hu, Y. D., Lapidus, K. A., Loo, C. K., Schoevers, R. A., Chaves, T. V., Balukova, S. M., Rot, M. A. & Kortekaas, R. used ketamine to treat depression. Ketamine has been shown to have anti-anhedonic effects in treatment-resistant bipolar depression and major depressive disorder, as well as anti-fatigue effects in bipolar disorder. Ketamine has been shown to reduce suicidal ideation and to improve implicit cognitive measures in treatment-resistant depression, and to improve antidepressant response. Ketamine may also have procognitive effects.

Ketamine’s antidepressant effects are dependent on the activation of the mTOR pathway and increased number and function of new spine synapses in the PFC of rats. Ketamine and other NMDAR antagonists produce fast-acting antidepressant-like effects in mouse models that depend on the rapid synthesis of BDNF. Ketamine and striatal FosB overexpression reduce social defeat stress-induced anhedonia in mice, and increased glutamate cycling in the prefrontal cortex is associated with rapid onset of antidepressant-like effects in rats. Scopolamine increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Ketamine’s antidepressant effects may be due to the inhibition of glycogen synthase kinase-3, which in turn contributes to the augmentation of AMPA receptor signaling. Serum interleukin-6 may be a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression.

Ketamine induces changes in immune markers in serum and protein kinases/phosphatases in the brain. These changes are not associated with rapid antidepressant response. A pilot 1H-MRS study demonstrated that ketamine administration is associated with a transient rise in Glx and GABA levels in patients with depression. Ketamine affects brain GABA and glutamate levels with 1H-MRS and may mediate its antidepressant effects. Ketamine safety and tolerability in clinical trials for treatment-resistant depression is discussed. Ketamine treatment reduces amygdalo-hippocampal reactivity to emotional stimulation, reduces global functional connectivity of the medial prefrontal cortex in major depressive disorder, and increases brain-derived neurotrophic factor in treatment-resistant unipolar depression and bipolar disorder. Ketamine can improve depression by increasing brain derived neurotrophic factor (BDNF) levels and improving sleep quality. The NR2B subunit selective N-methyl-d-aspartate can also improve depression by increasing sleep quality.

Lanicemine, a low-trapping NMDA channel blocker, produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. D-cycloserine, a glycine site partial agonist, enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in the hippocampus. Several studies have shown that NMDA receptor glycine site partial agonists induce antidepressant-like effects without ketamine-like side effects, and that NR2B antagonists are effective in treating treatment-resistant major depressive disorder. Nations, K. R. et al., examined the effects of Org 26576, an AMPA receptor positive allosteric modulator, in healthy volunteers and depressed patients, and Dwyer, J. M., Lepack, A. E. & Duman, R. S. investigated the effects of mGluR2/3 blockade in patients with major depressive disorder.

Miller, S. et al., Williams, L. M. et al., Breitenstein, B. et al., Zarate, C. A. Jr. et al., conducted a randomized trial of a low-trapping nonselective N-methyl-d-aspartate channel blocker in major depression.

Ketamine may attenuate inflammation and glutamate hypotheses of depression by targeting the kynurenine pathway. Ketamine also may produce antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats.

Functional antagonists at the NMDA receptor complex exhibit antidepressant actions, and inescapable versus escapable shock modulates long-term potentiation in the rat hippocampus.