Ketamine for Adults With Treatment-Resistant Depression or Post-Traumatic Stress Disorder
Authors: Tran Khai , Mahood Quenby 
Published: April 2022

Two randomized controlled trials reported mixed evidence on the efficacy of repeated IV ketamine infusions for improving post-traumatic stress disorder. One randomized controlled trial with small sample size found that repeated IV ketamine infusions significantly improved post-traumatic stress disorder symptoms compared with midazolam in civilian population, while the other randomized controlled trial with larger sample size could not demonstrate a significant efficacy on post-traumatic stress disorder symptoms compared with placebo in military population. The antidepressant effects of ketamine were rapid, but the effects were not sustained after few weeks of post-treatment follow-up.

One randomized controlled trial comparing IV ketamine with IV esketamine found both treatments had comparable acute antidepressant effects for treatment-resistant depression 24 hours following infusion.

Two randomized controlled trials provided mixed evidence on the efficacy of single infusion of IV ketamine that was used as anesthetic agent for electroconvulsive therapy for treatment-resistant depression. One randomized controlled trial involving military population showed that patients undergoing electroconvulsive therapy for treatment-resistant depression with ketamine anesthesia had similar improvement of depression when compared with patients undergoing electroconvulsive therapy with methohexital anesthesia. However, in other randomized controlled trial comparing with propofol-based anesthesia in a civilian population, ketamine-based anesthesia provided faster improvement in depressive symptoms and fewer electroconvulsive therapy treatments to achieve disease remission.

In a small randomized controlled trial, alternate infusions of subanesthetic dose of ketamine or midazolam with alternate electroconvulsive therapy showed no significant difference in antidepressant effects between groups.

The efficacy of oral ketamine was demonstrated in 1 randomized controlled trial that repeated administration of oral ketamine significantly reduced depressive symptoms compared with placebo.

A small retrospective chart review study showed that repeated administration of intramuscular ketamine had no significant differences in the improvement of depressive and anxiety symptoms compared with repeated transcranial magnetic stimulation.

Findings suggest overall safety and tolerability of ketamine for treatment of post-traumatic stress disorder or treatment-resistant depression. Most frequent side effects associated with ketamine were dissociative symptoms and cardiovascular changes such as increased blood pressure and heart rate, but these effects were transient.

The Danish guideline recommend against the use of IV ketamine in patients with treatment-resistant depression, due to low quality and insufficient evidence regarding the lack of long-term efficacy and the risk of abuse of ketamine. Likewise, the Canadian guideline recommends IV ketamine be considered as third-line treatment for adults with TRD, because of the short-lived efficacy of ketamine, its side effects, and the lack of strategies for relapse prevention after ketamine infusions.