Ketamine For Post-Traumatic Stress Disorders And Its Possible Therapeutic Mechanism

This review (2021) investigates the possibility of ketamine being used to treat Post-Traumatic Stress Disorder (PTSD).

Abstract

“Posttraumatic stress disorder (PTSD) is a devastating medical illness, for which currently available pharmacotherapies have poor efficacy. Accumulating evidence from clinical and preclinical animal investigations supports that ketamine exhibits a rapid and persistent effect against PTSD, though the underlying molecular mechanism remains to be clarified. In this literature review, we recapitulate the achievements from early ketamine studies to the most up-to-date discoveries, with an effort to discuss an inclusive therapeutic role of ketamine for PTSD treatment and its possible therapeutic mechanism. Ketamine seems to have an inimitable mechanism of action entailing glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity.“

Authors: Muhammad Asim, Wang Bing, Hao Bo & Wang Xiaoguang

Summary

Posttraumatic stress disorder (PTSD) is a devastating medical illness for which currently available pharmacotherapies have poor efficacy. Ketamine appears to have an inimitable mechanism of action entailing glutamate modulation via actions at the NMDA and AMPA receptors.

1. Introduction

Post-traumatic stress disorder (PTSD) is a mental illness that can follow exposure to life-threatening stress. The prevalence of PTSD escalates with trauma severity.

The treatment of PTSD includes pharmacotherapies, psychotherapies, or a combination of both methods. However, the slow onset and limited efficacy shown in SSRIs treatment have labeled a “PTSD pharmacotherapy crisis”, and calls for prioritization of efforts to find new treatment approaches.

2. Animal model of PTSD

Trauma recollection is conditioned learning in which a formerly natural cue was coupled with an aversive occurrence. Extinction learning is the alleviation or withdrawal of a formerly learned response, after lack of association was present.

A fear generalization animal model can be used to study the neuroendocrine and behavioral abnormalities shown in PTSD. The animal model can be used to investigate the neural mechanisms and novel pharmacotherapies for PTSD.

Stress induces structural and functional synaptic plasticity in the brain regions critical to anxiety and fear regulation, including the prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). Moreover, the lesion of IL-mPFC increases the fear generalization in the fear conditioning rats.

Neuroimaging data from PTSD patients showed hyperactivity of the amygdala and hypoactivity of the PFC and hippocampus, which likely underlie the psychopathological presentations of PTSD patients. BDNF Val66Met polymorphism is coupled with a change in neural BDNF release and function correlation with distorted emotional behavior.

Accumulating evidence showed that the glutamatergic system is critical in the pathophysiology of PTSD. A study found that NMDA receptor agonists could help to improve fear extinction among individuals diagnosed with PTSD, but other studies failed to find a difference.

3. Ketamine

Ketamine, a glutamate NMDA receptor antagonist, has been shown to reduce fear memory in rodents and to reduce symptom severity in individuals with chronic PTSD. It has also been shown to stimulate neurogenesis in the hippocampus, amygdala, and PFC.

Ketamine has been shown to decrease the incidence of PTSD in combat veterans and improve the symptoms of acute stress disorder and PTSD in accident victims. However, the effect of ketamine on chronic PTSD is much more promising.

3.1. Preclinical and clinical data in support of a dose-dependent response of ketamine

Ketamine has been shown to have dose-dependent effects on PTSD and depressive-like behavior. Ketamine with a dose of 30 mg/kg attenuates depressive behavior in mice, however, 10 mg/kg, or 90 mg/kg did not reduce, and 30 mg/kg ketamine also buffered the fear memory when injected 1-week before contextual fear conditioning in mice.

Ketamine dose-dependently inhibited fear generalization by modulating GluN2B-BDNF signaling in mice, and decreased dendritic spine density, synaptic transmission in hippocampal CA1, and impaired learning and memory in mice. However, ketamine showed some adverse or psychotic effects dose-dependently.

3.2. NMDA receptors and BDNF mediating effect of ketamine

Ketamine and lanicemine, NMDA receptors antagonists, activate the mechanistic target of the rapamycin (mTOR) singling pathway and increase the expression of synaptic signaling protein and the formation of new synapses in the prefrontal cortex, which may be involved in the pathophysiology of mood disorders.

Ketamine administration increased the expression of NMDA receptors in the hippocampus and decreased the expression of BDNF. Moreover, ketamine regulates fear generalization through GluN2B/BDNF signaling.

Ketamine induces a focal increase in the activity of the prefrontal cortex in healthy volunteers, presumably via inhibition of NMDARs at GABAergic neurons. Ketamine also shows an acute antidepressant effect in vivo, but the long-lasting effect is still unknown.

Ketamine blocks the NMDARs at GABAergic interneurons, which release glutamate, which triggers the release of BDNF, which leads to protein synthesis.

3.3. mGluR mediating effect of ketamine

Metabotropic glutamate receptors (mGluR) are present both at pre and postsynaptic neurons. Ketamine also targets mGluR2 to induce antidepressant response, but the mechanism of this effect is still unclear.

3.4. Cholecystokinin mediating effect of ketamine

Cholecystokinin (CCK) is the most abundant neuropeptide in the brain and is a critical modulator of neuroplasticity. It has been found that a lack of the CCK gene results in the impairment of spatial memory and decreased anxiety and depressive behavior. CCK-4 infusion induces acute panic attacks in patients with panic disorders and PTSD, and triggers trauma-related flashbacks in PTSD patients. CCK-4 may be involved in the etiology of both PTSD and Panic disorders.

Ketamine shows an acute antidepressant effect by blocking the LHb glutamate burst firing and LTP formation at the lateral entorhinal cortex-dentate gyrus synapse. Ketamine preferentially blocks the release of CCK which could lead to blockage of LTP formation.

4. Conclusion and future perspectives

Although many studies have been performed on the effect of ketamine against stress-related disorders, the underlying molecular mechanism, and possible side effects remain to be carefully defined. Detailed investigation of ketamine effect on PTSD using specific assay protocol will no doubt reveal more insight. Ketamine could have a time and dose-dependent effect on PTSD. It is important to examine the effect of ketamine on PTSD with a dose-dependent response at a specific time window.