Ketamine as a promising prototype for a new generation of rapid-acting antidepressants

This review (2015) summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action that may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets, and directions for future research.

Abstract

“Review: The discovery of ketamine’s rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild to moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment is not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action that may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that can continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders.”

Authors: Chadi G. Abdallah, Lynnette A. Averill, & John H. Krystal

Summary

Ketamine’s rapid and robust antidepressant effects opened a window into a new generation of antidepressants. It has been generally well tolerated across patient groups, but the optimal dosing and route of administration are not fully known.

Introduction

Depressive disorders are a leading cause of disability, often causing chronic recurrent symptoms, increased morbidity, heightened risk of suicide, poor functional outcomes, and profound socioeconomic burden. However, the past five decades of research focusing on antidepressant development have unfortunately seen little success in creating fundamentally novel psychopharmacologic interventions.

Ketamine is a glutamate N-methyl-D-aspartate receptor (NMDA-R) antagonist that can be administered intravenously, intramuscularly, intranasally, intrarectally, and orally. It has been shown to have profound and rapid effects on depressive symptoms, and has been suggested as a prototype for a new generation of antidepressants.

Robust and rapid antidepressant effects

Researchers found that NMDA-R antagonists showed promising antidepressant qualities, and that ketamine had striking, robust, rapid antidepressant effects within 4 h of intravenous administration. Ketamine showed efficacy in rapidly reducing suicidal ideation within hours of administration.

Ketamine has rapid antidepressant effects and is sustained for 3 – 7 days, with a response rate of approximately 25% to 85% within 24 h and 14% to 70% at 72 h post-infusion.

Three meta-analyses have been published that consistently confirm the efficacy of ketamine’s antidepressant effects. These meta-analyses also highlight the need for further research into optimal dosing, route of administration, and treatment schedules. Ketamine trials are short, have short durations, and lack complete blinding to treatment status. However, the true biological effect of ketamine is supported by the relatively consistent time curve of response to ketamine across studies.

Posttraumatic stress disorder

Ketamine has been shown to be effective in treating PTSD symptoms, which are often highly comorbid with depressive disorders. Ketamine is well tolerated and has shown no evidence of worsening in PTSD symptoms.

Feder and colleagues found that ketamine improved PTSD symptoms in patients when compared to midazolam. The dissociative symptoms occurred during infusion, peaked at 40 min, and subsided within 80 min.

Neurocognitive functioning

Ketamine’s antagonism of the glutamatergic NMDA-R produces enhanced activity in excitatory networks and marked changes in synaptic plasticity and strength, which may translate into enhanced cognition 24 h post-treatment.

Ketamine studies have consistently demonstrated transient cognitive deficits during infusion, but the hypothesized pro-cognitive effects of ketamine 24 h post-treatment are not fully studied. However, low baseline cognitive processing speed uniquely predicts depression improvement at 24 h post-ketamine.

Ketamine is generally well tolerated and produces only mild to moderate adverse side effects, such as dizziness, nausea, and mild increases in blood pressure and heart rate.

Studies have shown that a single infusion of ketamine is safe and effective, but the optimal dose, route of administration, and the safety of repeated or chronic treatment are still not fully known.

Mechanism of action

Convergent evidence implicates synaptic plasticity in the pathophysiology of depression. Ketamine is believed to exert its rapid antidepressant effect by increasing brain-derived neurotrophic factor (BDNF) function and activating mTOR signaling.

Ketamine inhibits overall NMDA-R activities, leading to sedation and reduced glutamate signaling. However, low doses of ketamine increase glutamate release, which plays a critical role in the antidepressant effects of ketamine.

Ketamine exerts its antidepressant effect through two pathways: at-rest inhibition of the NMDAR and stimulation of synaptic glutamate receptors. This leads to an increase in BDNF function and mTOR signaling, which promotes synaptogenesis.

Clinical biomarkers

Ketamine treatment is associated with increased prefrontal excitability, synaptic strength, connectivity between the medial PFC and amygdala, and low pre-treatment mPFC (glutamate + glutamine)/glutamate ratio. However, not all studies have demonstrated a relationship between peripheral BDNF and response to ketamine treatment.

Conclusions

Ketamine’s rapid antidepressant effects opened a window into a new generation of antidepressants and a better understanding of the biological underpinnings of depression. Ketamine remains an investigational drug with abuse liability.

Exciting new research has been done in the field of depression over the past decade. However, several questions remain unanswered, including the optimal dose and route of administration, and the relationship between cognitive function and ketamine treatment.

Figure 2.

Ketamine’s antidepressant-like effects are mediated by changes in the GluR1 subunit of the AMPA receptor, eEF2k, BDNF, pmTOR, and GSK3.