Summary of IV Ketamine Research in the Treatment of Chronic Depression

This post may feel a bit “dry” but is a succinct summary of the current research regarding IV ketamine in TRD (treatment resistant depression). Would love to hear your comments and questions!

Introduction

Depression is a common mental health disorder that affects millions of people worldwide. Despite the availability of various treatment options, a significant proportion of individuals with depression do not respond to conventional antidepressant medications. Such individuals are said to have treatment-resistant depression (TRD). Recently, ketamine has emerged as a potential alternative treatment option for TRD. Ketamine is a dissociative anesthetic that has been used for several years in anesthesia and pain management. In this article, we summarize the current research findings on the use of intravenous ketamine for TRD.

Ketamine MOA (mechanism of action)

Ketamine is primarily a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. It also has agonist effects on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These receptor interactions lead to an increase in glutamate release and activation of downstream signaling pathways that promote synaptic plasticity and neurogenesis. It is thought that these effects of ketamine may underlie its antidepressant effects. 

Clinical trials

Several randomized controlled trials (RCTs) have evaluated the efficacy of intravenous ketamine for TRD. In a meta-analysis of 11 RCTs, Caddy et al. (2015) found that ketamine was significantly more effective than placebo in reducing depressive symptoms in individuals with TRD. The effect size was moderate to large, and the antidepressant effects were rapid, with significant improvement observed within hours of administration. The duration of the antidepressant effects varied between studies, ranging from a few days to several weeks. In a subsequent meta-analysis of 20 RCTs, Zheng et al. (2020) also found that ketamine was more effective than placebo in reducing depressive symptoms in individuals with TRD. The effect size was large, and the antidepressant effects were rapid, with significant improvement observed within 24 hours of administration. The duration of the antidepressant effects varied between studies, ranging from a few days to several weeks. In addition to RCTs, several open-label studies and case series have also reported positive results with intravenous ketamine for TRD (Murrough et al., 2013; Phillips et al., 2014; Wilkinson et al., 2018). These studies have also reported rapid and sustained antidepressant effects with ketamine.

Safety of Therapeutic Ketamine

The safety and tolerability of intravenous ketamine for TRD have also been evaluated in several studies. In general, ketamine was well-tolerated, with the most common side effects being dissociative and cognitive effects. These effects were usually transient and resolved within hours of administration. Other side effects reported included nausea, dizziness, and headache. However, there have been concerns about the potential for abuse and dependence with ketamine. To address these concerns, several studies have evaluated the abuse potential and cognitive effects of ketamine in individuals with a history of substance abuse. In a study by Morgan et al. (2010), ketamine was found to have low abuse potential and did not produce significant cognitive impairment in individuals with a history of substance abuse.

Limitations

Despite the promising results, there are several limitations to the current research on ketamine for TRD. First, most studies have been conducted in small sample sizes, which limits the generalizability of the findings. Second, the optimal dosing and frequency of ketamine administration for TRD are not well-established. Finally, the long-term safety and efficacy of ketamine for TRD are not known.

Conclusion

Intravenous ketamine has emerged as a important potential alternative treatment option for TRD. The antidepressant effects of ketamine are rapid and sustained, with a large effect size. Ketamine is generally well-tolerated by patients.