Ketamine as treatment for post-traumatic stress disorder: a review

This review (2019) examines the lack of efficient treatment options for patients suffering from PTSD and explores the viability of ketamine for patients who do not respond to conventional treatment. It is thought that ketamine might reverse some of the damage caused by chronic stress, by means of upregulating BDNF and antagonizing NMDA. The review also notes that the deterrent of dissociative side-effects may be less common than previously reported and point to early evidence which supports that ketamine may yield a near-complete resolution of traumatic symptoms, albeit only over a short-term of 1-2 weeks.

Abstract

“Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.”

Authors: Felix Liriano, Candace Hatten & Thomas L. Schwartz

Summary

Abstract

Post-traumatic stress disorder continues to make headlines given multiple military engagements across the world and civilian traumas. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder.

Introduction

Post-traumatic stress disorder (PTSD) is a mental health condition that can be caused by a traumatic event such as death, serious injury, or sexual assault. Patients may also exhibit changes in memory formation and a constellation of symptoms that mirror major depressive disorder (MDD).

PTSD has a prevalence of 8.7% in the United States, with a prevalence of 3.5% during any given 12-month period. It is more common among Latinos, African Americans, and American Indians.

PTSD is associated with high degrees of disability, including poor social and family relationships, excessive absence from work, and lower income, educational, and occupational success.

The Veteran’s Administration/Department of Defense recommends selective serotonin reuptake inhibitors (SSRIs) for use as pharmacotherapy for PTSD, but other drugs may also be used. Ketamine is a novel treatment not typically included in guidelines.

Researchers have found that the symptoms experienced in PTSD may be caused by a loss of synaptic connectivity. The use of ketamine may enhance synaptic connectivity in these circuits, ultimately reversing the effects of stress.

Ketamine pharmacotherapy and mechanism of action

Ketamine produces dissociation between the thalamaco-neocortical and limbic systems, which leads to flaccidity and a slow nystagmus. Minor central nervous system changes have been reported.

Ketamine works as an antagonist at the N-methyl-D-aspartate-type glutamate (NMDA) receptor, which may be a promising drug target to lower PTSD symptoms.

Rationale for use of ketamine

PTSD is a state of hyperarousal plagued by intrusive thoughts, flashbacks, and nightmares. Ketamine has been shown to have some anxiolytic properties in animal studies.

A chronic stress model was created, and the behavior of mice was assessed. The mice that received ketamine had significantly decreased immobility, compared to those who received saline, indicating that ketamine may increase resilience to stress.

Mice that undergo stress response were observed to have a dysregulated HPA axis. Ketamine was able to partially restore the HPA axis, suggesting that ketamine may be useful in environments where stress can be predicted.

In another study, rats were injected with ketamine and then received uncontrollable tail shocks. The rats that received shocks showed increased exploratory behaviors and higher levels of serotonergic (5-HT) in the basolateral amygdala.

Ketamine administration at intervals before IS was able to block the behavioral effects of IS. It was also able to decrease the effects that IS had on JSI.

The rats were restrained for 2 hours, forced to swim for 20 minutes, and then given diethyl ether until they lost consciousness. They were treated with ketamine for 1 week.

Zhang and colleagues ruled out ketamine’s effect on locomotor activity in mice and rats by testing the number of crossing and rearing with lines. They also found that chronic ketamine use allowed for a significant decrease in contextual freezing episodes.

Zhang and colleagues found that chronic administration of ketamine to rats reversed the effect of the traumatic event and increased levels of brain-derived neurotropic factor (BDNF). This is significant because the hippocampus is associated with control of learning, memory, and also links to the HPA.

Another study examined whether ketamine could potentially be used as a prophylactic agent against depressive-like behavior.5 The benefits of using ketamine prophylactically were also highlighted in the study conducted by Brachman and colleagues.

A human double-blind, randomized controlled trial of 41 chronic PTSD patients found that ketamine was significantly better than midazolam at improving PTSD symptoms 24 hours post-infusion. Additionally, ketamine was associated with a decrease in comorbid depressive symptoms as well.

Several case reports have been published, including a 26-year-old combat veteran who received ketamine infusion at a rate of 2 L/min. The patient appeared to acquire a euthymic mood after ketamine, but then relapsed into a dysphoric state.

A 23-year-old veteran with symptoms of PTSD of 6-month duration who had been tried on several medications and treatments failed to improve, was given a 24-hour medication washout and 35 mg IV ketamine over 20 minutes and recovered with only transient nystagmus and visual distortions.

A 7-year-old boy with a history of PTSD, reactive attachment disorder, and disruptive behavior disorder received IV ketamine as part of his anesthesia for tonsillectomy and displayed significant improvements in behavior, including decreased intensity and frequency of aggressive behaviors, and improved ability to control his emotions and behavior.

Another study showed that oral ketamine therapy in an outpatient setting may be beneficial for patients with PTSD. The study showed that there was a significant decrease in both the number of admission and the length of stay in a psychiatric hospital for patients who received oral ketamine.

Safety of ketamine for use in PTSD

Ketamine can create a transient dissociative state and has been thought to either facilitate or worsen PTSD.

One study indicated that patients receiving ketamine had an increased risk of PTSD. The study used 56 accident victims and found that those who received S-ketamine had significantly increased acute symptoms of PTSD, whereas those who received racemic ketamine had only slightly increased acute symptoms.

A study by McGhee and colleagues found that patients receiving ketamine displayed a lower prevalence of PTSD than those who did not. The amount of morphine received did not correlate to PTSD development.

McGhee and colleagues conducted a follow-up study in 2014 on patients at the San Antonio Military Medical Center. They found that patients who received ketamine had greater injuries, longer hospital stays, and greater number of surgeries, but that there was no statistically significant difference in PTSD rates.

Ketamine’s effects on patients with PTSD are important to note. Three patients had to be treated with -adrenergic antagonists due to increased blood pressure, and blurred vision, dry mouth, restlessness, fatigue, nausea/vomiting, poor coordination, and headache were reported.

A retrospective study examined 37 patients receiving long-term oral ketamine for both PTSD and treatment-resistant depression in an outpatient setting. The study found that there were no serious adverse events recorded, and no medical emergencies were noted.

Based on the limited data that exists, ketamine appears to have few side effects and is not associated with any significant drug interactions.

Summary

PTSD is a problematic psychiatric condition that can be difficult to treat. SSRIs are the first-line treatment, but many patients with PTSD are found to be treatment resistant, and atypical antipsychotics are sometimes used clinically to control these symptoms.

Ketamine is a novel treatment for PTSD that has been shown to have similar findings to the use of ketamine in MDD. It is thought that upregulating BDNF and antagonizing NMDA serve to reverse some of the damage caused by chronic stress.