This review (2018) examines the neurobiology of depression in light of the rapid fast-acting antidepressant properties of ketamine, with particular regard for the role of inhibitory and excitatory glutamate transmission. It is evident that the primary mechanism of ketamine is the induction of transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to a sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. However, it is unclear whether ketamine’s effects on glutaminergic inhibition via extrasynaptic NMDA) receptors exert rapid or even slow antidepressant effects.

“Abstract: The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission – reviewing the history of the “glutamate inhibition” and “glutamate activation” hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.”

Authors: Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman & John H. Krystal

Summary

Introduction

Serendipity and clinical observations have dominated the path to drug discovery in psychiatry. The first antipsychotic drug was discovered unexpectedly in 1951, and the first tricyclic antidepressant failed as antipsychotic compound in 1899.

The 1950s report of the anti-tuberculosis drug d-cycloserine having antidepressant properties was little noticed for more than four decades, until the late 1990s when ketamine was discovered to have rapid and sustained antidepressant effects in severely depressed patients. Early attempts to treat depression with glutamate release inhibitors and NMDAR antagonists have had limited success, and it is becoming increasingly apparent that these drugs are exerting their effects through glutamate neurotransmission activation, rather than inhibition.

In this perspective paper, we will review the history of the glutamate inhibition and activation hypotheses, propose a synaptic connectivity model of chronic stress pathology, and discuss current challenges and future directions.

Glutamate inhibition or activation? A historical perspective

Early in the 1990s, studies showed that NMDAR antagonists had antidepressant-like effects in rodents, and that chronic stress-related disorders in humans were correlated with dendritic atrophy. Ketamine was thought to inhibit glutamate neurotransmission by blocking NMDARs.

In contrast to the glutamate inhibition model, it has been shown that subanesthetic doses of ketamine transiently activate rather than inhibit glutamate neurotransmission. Moreover, the neurotrophic hypothesis of depression was also supported by evidence, and targeting glutamate neurotransmission offers a novel approach for discovery of new antidepressants.

Synaptic model of chronic stress pathology (CSP)

Trauma and repeated stressors lead to wide spread neuronal remodeling consistent with both reduced and increased synaptic connectivity, depending on the brain region. In the prefrontal cortex, prolonged stress precipitates neuronal synaptic hypoconnectivity, as evident by reduced dendritic length and arborization, and by reduction in synaptic density and strengths.

Acute stress precipitates a prefrontal glutamate surge associated with transient increase in extracellular glutamate, but sustained increase in NMDARs, AMPARs, and synaptic strength. Chronic stress leads to a sustained increase in extracellular glutamate, combined with reduced resting prefrontal glutamate transmission.

Chronic stress leads to increased synaptic connectivity, increased dendritic length and arborization, and increased synaptic density and strength in the NAc. This increase is associated with monoamine dysregulation, and ultimately leads to NAc neuronal hypertrophy.

In preclinical studies, depressive-like behaviors were directly associated with synaptic alterations in the PFC and NAc. Reversal of the synaptic impairment induces antidepressant effects, and both SAADs and RAADs increase PFC, but reduce NAc, synaptic connectivity.

Human MRI studies have shown increased NAc, but reduced hippocampal and PFC volumes in major depression. The NAc gray matter deficits were absent in several human depression studies, and therefore it was proposed that the NAc hypoconnectivity and hyperconnectivity reflect two pathways that may independently precipitate clinical depression.

The synaptic CSP model is not limited to major depression, but is also present in several stress-related disorders, such as posttraumatic stress disorder, generalized anxiety disorder, obsessive compulsive disorder, and bipolar depression.

CSP may be common across many psychiatric disorders and may be a convergent pathway across antidepressants. Furthermore, the location and pattern of the synaptic dysconnectivity, combined with individual characteristics, may be the mechanism through which CSP is associated with distinct clinical presentations and psychopathologies.

Mechanism of action of ketamine and RAADs

Ketamine induces a transient surge in glutamate neurotransmission in the PFC, which leads to a sustained increase in PFC synaptic connectivity within 24 h of treatment.

Ketamine induces transient glutamate neurotransmission activation, which leads to the activity-dependent release of BNDF, activation of mTORC1 signaling, and increase in protein synthesis and synaptic strength. Hence, agents directly targeting postsynaptic glutamate activation may possess RAAD properties.

The role of transient postsynaptic glutamate activation in the RAAD effects of ketamine has been abundantly shown in preclinical studies. This role is further underlined by the fact that the inhibition of postsynaptic glutamate activation using AMPAR antagonists blocks the RAAD effects of ketamine.

Ketamine induces a transient postsynaptic glutamate activation through several mechanisms, including inhibiting NMDARs on a subpopulation of interneurons and increasing eEF2 signaling and BDNF translation, leading to increased protein synthesis and synaptic connectivity. Ketamine, a main metabolite, reaches the brain within 1 min of injection and maintains a brain/ plasma concentration ratio equal to 6.5 for 10 min. Ketamine induces a surge in glutamate transmission and this surge is responsible for its RAAD effects.

Several other RAADs have been shown to be dependent on transient postsynaptic glutamate activation, including scopolamine, rapastinel, the selective NMDAR subtype 2B (GluN2B) antagonist Ro 25-6981, and the mGluR2/3 antagonist LY341495, and the AMPAR potentiator LY392098. Infrequent glutamate activation, such as twice per week administration of ketamine, may provide optimal balance for maintaining the beneficial synaptic connectivity changes.

While evidence supports the SAAD properties of glutamate release inhibitors, these medications do not typically induce RAAD effects. Moreover, chronic administration of these medications may still be increasing glutamate neurotransmission and BDNF, and subsequent normalization of synaptic connectivity. In contrast to synaptic NMDARs, extrasynaptic NMDARs are activated by excessive extracellular levels of glutamate, which leads to an increased calcium influx, activates toxic metabolic processes and triggers cell death. Therefore, selective blockade of extrasynaptic NMDARs may induce synaptogenesis and exert antidepressant effects.

Clinical efficacy of RAADs

There is well replicated evidence showing the RAAD effects of a single ketamine infusion in MDD, but the need for intravenous administration may be a limiting factor. Intranasal administration of ketamine may exert RAAD effects, but the psychotomimetic effects are transient and typically well tolerated.

Other putative RAADs with published clinical trials in MDD include Scopolamine, Traxoprodil, Esketamine, d-cycloserine, Rapastinel, and Lanicemine. However, additional confirmatory clinical trials are still needed to determine the efficacy of these putative RAADs.

The synaptic CSP model predicts that ketamine may have therapeutic effects in many psychiatric disorders with considerable chronic stress component, including depression, PTSD, OCD, GAD, social anxiety disorder, and substance/alcohol use disorders.

Clinical biomarkers of RAADs

Ketamine induces an acute glutamate surge and sustained neuronal remodeling 24 h post treatment.

Several lines of evidence have suggested that ketamine induces a surge in glutamate levels in the prefrontal cortex and that this surge is associated with the psychotomimetic effects of ketamine.

While there is convincing evidence of an acute glutamate surge, most studies were in healthy subjects and do not distinguish between presynaptic glutamate release and postsynaptic activation. Recent data suggests that the psychotomimetic effects of ketamine may be due to the decoupling between presynaptic glutamate release and postsynaptic activation.

Ketamine infusion has been shown to increase PFC global brain connectivity, which parallels the hypothesized glutamate surge. Furthermore, ketamine has been shown to reduce PFC synaptic connectivity in several psychiatric disorders with a strong chronic stress component. Ketamine was found to rapidly normalize PFC GBC abnormalities in MDD patients within 24 h of treatment, and this increase was also associated with treatment response. In addition, ketamine increased hippocampal and reduced NAc volumes in MDD patients within 24 h of treatment.

Current challenges & future directions

Ketamine’s findings generated considerable excitement about the promise of a truly novel class of robust and effective RAADs. However, clinical mechanistic evidence remains lagging.

To date, we do not have a well-established reproducible biomarker of target engagement or target validation for the development of RAADs. This may have been less problematic for the development of monoaminergic drugs, which largely shared the common in vitro detectable pharmacodynamics of serotonin re-uptake inhibition. Determining the in vivo effects of novel RAAD agents on transient glutamate neurotransmission and sustained synaptic connectivity is critical, but currently only possible in animal studies. Ketamine may be a useful tool to establish biomarkers for prefrontal glutamate activation and synaptic connectivity in humans.

Future studies can capitalize on the reversibility of the chronic stress related synaptic hypoconnectivity and the ketamine induced synaptic hyperconnectivity to determine the mechanisms underlying this putative homeostatic stable equilibrium of overall synaptic strength.

Ketamine studies over the past decade have significantly improved our understanding of chronic stress and depression, while unraveling several mechanisms through which transient prefrontal glutamate activation produces rapid restoration of synaptic connectivity along with RAAD effects.