Ketamine and other potential glutamate antidepressants

This review (2015) examined molecular mechanisms underlying the antidepressant efficacy of ketamine and other glutamate drugs in humans. Although antidepressant effects are partially mediated through glutamate release onto non-NMDA receptors including AMPA and metabotropic receptors, there are also reported effects on 5-HT, dopamine, and intracellular effects on the mTOR pathway in animal studies that are yet to be elucidated.

Abstract

“The need for rapid acting antidepressants is widely recognised. There has been much interest in glutamate mechanisms in major depressive disorder (MDD) as a promising target for the development of new antidepressants. A single intravenous infusion of ketamine, a N-methyl-d-aspartate (NMDA) receptor antagonist anaesthetic agent, can alleviate depressive symptoms in patients within hours of administration. The mechanism of action appears to be in part through glutamate release onto non-NMDA receptors including α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors. However these are also reported effects on 5-HT, dopamine and intracellular effects on the mammalian target of rapamycin (mTOR) pathway. The effects of SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants may also involve alterations in NMDA function. The article reviews the effect of current antidepressants on NMDA and examines the efficacy and mechanism of ketamine. Response to ketamine is also discussed and comparison with other glutamate drugs including lamotrigine, amantadine, riluzole, memantine, traxoprodil, GLYX-13, MK-0657, RO4917523, AZD2066 and Coluracetam. Future studies need to link the rapid antidepressant effects seen with ketamine to inflammatory theories in MDD.”

Authors: Arpan Dutta, Shane McKie & J. F. William Deakin

Summary

Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist anaesthetic agent, alleviates depressive symptoms in patients within hours of administration. Its mechanism of action is in part through glutamate release onto non-NMDA receptors including -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and metabotropic receptors.

1. Introduction

The need for rapid acting antidepressants is widely recognised, but response rates have not improved beyond approximately 60%. New targets for antidepressant action include neurokinin, corticotrophin releasing factor, intracellular signalling cascades and modulation of glucocorticoid, cytokine, opioid and cannabinoid receptors.

Interest in glutamate in depression goes back to the late 1980s, when studies showed that tricyclic antidepressants had zinc-like functional effects on the NMDA receptor. In 1990, Trullas and Skolnick demonstrated that functional antagonists at the NMDA receptor had antidepressant-like behavioural effects in animals.

2.1. Methodology of studies

Most studies used ketamine 0.5 mg/kg by intravenous infusion over 40 minutes, but some used lower dosages. Some studies allowed the use of concomitant medications including other antidepressants, and some had MDD patients with comorbid anxiety disorders.

Studies of depression treatment have used the MADRS or HAM-D as primary outcome measures, but these scales may have limited validity when used more frequently than weekly.

The studies had small sample sizes, statistically significant differences in patient characteristics between controls and depressives, and were read from graphical data in the papers which may have led to errors.

2.2. Response to ketamine infusion

Ketamine has an antidepressant effect that begins within 24 hours of a single intravenous infusion and can last up to 14 days. There is some variability in the response to ketamine, however, and lower response rates were noted in bipolar depression than in MDD.

Eight studies examined whether repeated doses of ketamine cause a more sustained effect than single dosage. The results showed that repeated ketamine infusions improved mean reductions in MADRS scores compared to single ketamine infusion and that remission was maintained for at least 12 months.

2.3. Biomarkers of response to ketamine

Ketamine response has been associated with increases in brain derived neurotrophic factor (BDNF) and slow wave EEG sleep activity on the night of ketamine infusion in one study of treatment resistant MDD patients, and with decreased MADRS scores following ketamine infusion in another study.

Ketamine responders have lower D- and L-serine plasma concentrations compared to non-responders, and have higher Clinician Administered Dissociative States Scale (CADSS) scores. This is opposite to the findings of a previous study of standard antidepressants.

There are pre-treatment predictor effects observed in patients with MDD, including increased rostral anterior cingulate cortex activity measured by magnetoencephalographic recordings (MEG), and increased -band responses in the somatosensory cortex using MEG.

Pre-treatment neurotransmitter and metabolic abnormalities have been reported. These findings suggest that ketamine responders may be identified by the effects in the ACC and PFC.

Several studies have found biological predictors of ketamine response, including family history of alcohol dependence and increased peripheral vitamin B12 levels. However, these biomarkers are not currently practical for clinical usage.

2.4. Trials to identify mechanisms of ketamine effects

Eight mechanistic trials using i.v. ketamine have been carried out. Lamotrigine and riluzole failed to attenuate psychotomimetic symptoms produced by ketamine or enhance its antidepressant effects, and riluzole did not sustain response in those patients that had responded to i.v. ketamine infusion.

Two open-label case studies investigated the S-isomer of ketamine, which has a higher affinity for the phencyclidine site of the NMDA receptor site and a higher frequency of psychotomimetic side effects in humans. The S-ketamine treatment improved HAM-D in 43% of patients.

Alternative routes of administration for ketamine have recently been examined. Intranasal ketamine produced similar reductions in HAM-D to i.v. ketamine in MDD.

Ketamine has dissociative effects, which make it hard to evaluate studies. Its use in clinical practice is also problematic because of its short-lasting effects.

2.5. Mechanisms of action of ketamine

Ketamine works by blocking the NMDA receptor-associated ion-channel, which increases glutamate release, which can act on non-NMDA glutamate receptors. This increases the effects of ketamine-like drugs in animals.

Ketamine subunit selectivity for GluN1/GluN2A and GluN2B has been discovered in an animal drug discrimination model utilising using compounds to mimic the behavioural effects of ketamine. Ketamine increases extra-cellular dopamine and serotonin levels in the medial prefrontal cortex in rats when given acutely.

Ketamine reduces immobility in the forced swim test, onset of behavioural despair and anhedonia in rats and increases the expression of several proteins in the prefrontal cortex, including mTOR, 4E-BP1, P70S6 kinase, ERK and protein kinase B. These proteins are associated with antidepressant behavioural actions with ketamine, but not conventional antidepressants.

Ketamine increases glutamate release in humans and this effect was blocked by lamotrigine. However, euphoria was not attenuated by lamotrigine and this suggests that ketamine’s immediate effects on mood may be mediated directly by NMDA blockade and not by the secondary effect of increased glutamate release.

3.1.1. Lamotrigine

A multicentre double-blind randomized controlled trial of lamotrigine in 192 outpatients demonstrated significant improvement in the Clinical Global Impression, HAM-D and MADRS. However, rashes, headaches and a small proportion manic or hypomanic episodes were noted.

3.1.2. Riluzole

Riluzole is an inhibitor of glutamate release that enhances synaptic AMPA receptor expression and blocks NMDA receptor activation. It has been shown to improve MADRS scores in patients with treatment resistant MDD.

Riluzole did not maintain the acute antidepressant effects of ketamine in Mathew et al. (2010), but Brennan et al. (2010) reported significant improvements in bipolar disorder depression scores using riluzole 100 – 200 mg.

3.2.1. Memantine

Memantine is a derivative of amantadine, an NMDA receptor antagonist, and may have agonist activity at dopamine D2 receptors. It was used in the treatment of moderate to severe Alzheimer’s dementia, but the evidence for its antidepressant effect is not clear.

3.2.2. Amantadine

Amantadine is an NMDA antagonist that has been used for the treatment of Parkinson’s disease and has been shown to improve mood in humans with “chronic depressive syndrome”. However, there is no RCT evidence to support its efficacy in depression.

3.2.3. Traxoprodil (CP-101,606)

CP-101,606 is an GluN2B subunit selective NMDA receptor antagonist that has been studied as adjunctive therapy to paroxetine. It produced a 60% response rate versus 20% for placebo on the HAM-D and was maintained in 42% of patients till 15 days after.

3.2.4. GLYX-13

GLYX-13, a novel NMDA receptor glycine site functional partial agonist, was reported to have antidepressant effects within 24 hours.

3.2.5. MK-0657

Ibrahim et al. (2012a) investigated MK-0657, a GluN2B antagonist, in treatment resistant MDD patients for 12 days. No significant improvement was noted on MADRS, although significant improvement was noted on BDI and HAM-D.

3.3.1. RO4917523/AZD2066/Coluracetam

There are several novel compounds which have been recently trialled, including the mGLU5 antagonists RO4917523 and AZD2066, as well as Coluracetam (BCI-540).

4. Conclusions and need for future studies

The current theory of NMDA antagonist’s antidepressant effect is summarised with evidence in Table 2. However, there is no evidence that glutamate is an important mechanism of action of antidepressant drugs, and no glutamate or other risk genes have yet been identified from large scale genome-wide association studies.

Studies have shown that astroglial cells are reduced in number and function in post-mortem brain, which may allow glutamate to spill over onto extrasynaptic dendritic NMDA receptors and inhibit glutamate release. NMDA antagonists may reverse the deficient glutamate release and block the toxic stimulation of extrasynaptic NMDA receptors.

Ketamine works through glutamate release onto AMPA receptors, riluzole may also increase synaptic AMPA expression, and lamotrigine may reduce the psychotomimetic effects of ketamine. None of the above seems to offer the rapid antidepressant effect of ketamine. Although changes in synaptic cascade have been noted, citalopram, fluoxetine, imipramine and amitriptyline have all shown effects at blocking NMDA induced currents. However, a recent study showed no change in glutamate or glutamine despite improvement in HAMD scores.

Ketamine has been reported to have an antidepressant effect on mood rating scales. However, the evidence is unreliable due to inadequate sample sizes, lack of control groups and randomisation and differences in patient group characteristics.

There are no reliable biomarkers of glutamate function in patients with depression, but phMRI evidence of prolonged deactivation of the subgenual cingulate with ketamine and prolonged activation with citalopram has been noted.

Ketamine acts in part through glutamate release onto non-NMDA receptors, but also has effects on 5-HT, dopamine and the mTOR pathway. It is also reported to have a neuroprotective and antidepressant effect in animal models.