Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine, a glutamate-based antidepressant, can rapidly alleviate depression within hours of treatment. Replicated evidence shows its rapid and potent effects in treatment-resistant depression. Preclinical and biomarker studies have begun to explain the mechanism behind these rapid effects, offering new insights into depression's biology and identifying potential treatment targets. This article discusses ketamine's efficacy, safety, and tolerability, summarizes depression's neurobiology, reviews the mechanisms of ketamine's rapid antidepressant effects, and considers prospects for next-generation rapid-acting antidepressants.
Depression and Anxiety
April 6, 2016
Chadi G. Abdallah, Thomas G. Adams, Benjamin Kelmendi et al.
204 citations
Major depressive disorder is a common psychiatric condition that often responds poorly to traditional antidepressants, which can take weeks to work. Over the past two decades, the NMDA receptor antagonist ketamine has attracted attention because a single low dose produces rapid antidepressant effects in people with treatment-resistant depression. Evidence from animal and human studies suggests that ketamine triggers a surge of glutamate, initiating a cascade that promotes synaptogenesis and reverses stress-related damage, especially in the prefrontal cortex. This review covers the neurobiology of stress-related depression, the safety and efficacy of ketamine, its mechanism of action, and predictors of treatment response, along with research limitations and future directions.
Annals of the New York Academy of Sciences
February 27, 2015
Chadi G. Abdallah, Lynnette A. Averill, John H. Krystal
117 citations
Ketamine produces rapid and robust antidepressant effects in patient populations that often show little or no response to traditional antidepressants, and it is generally well tolerated with only transient mild-to-moderate adverse effects during infusion. However, the optimal dosing, route of administration, and safety of chronic treatment remain uncertain. This review describes ketamine's clinical effects, its neurobiological mechanisms, and how these may illuminate the neurobiology of depression, relevant biomarkers, and treatment targets. The authors also suggest directions for future research to improve psychopharmacologic interventions for depressive and trauma-related disorders.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Therapeutic Advances in Psychopharmacology
January 1, 2023
Anya Ragnhildstveit, Jeremy Roscoe, Lisa C. Bass et al.
49 citations
PTSD has few effective pharmacological treatments, and trauma-focused psychotherapies are limited by provider shortages and low patient engagement, often leading to chronic illness and reduced quality of life. Ketamine, an NMDA receptor antagonist already indicated for major depression with rapid antidepressant effects, shows transdiagnostic potential. A synthesis of clinical evidence—including case reports, chart reviews, open-label studies, and randomized trials—reveals high heterogeneity in presentation and treatment approach but encouraging signals of safety, efficacy, and durability. Future research directions are discussed.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2024
Ruth H Asch, Chadi G. Abdallah, Richard E Carson et al.
11 citations
A review describes the development of PET radiotracers targeting the synaptic vesicle glycoprotein 2A (SV2A), which allows measurement of synaptic density in living brains. In depression, lower SV2A density is found in people with significant depressive symptoms. A ketamine challenge was used to examine synaptogenesis in vivo. The authors stress the value of combining clinical imaging with animal model studies, presenting preliminary findings from chronic stress models. Methodological challenges and future directions for SV2A imaging, possibly alongside other neural markers, are discussed.
European Journal of Psychotraumatology
August 29, 2023
Lihong Jiang, Amanda J. F. Tamman, Christopher L. Averill et al.
8 citations
Early trauma is linked to stronger glutamatergic synaptic strength in people with PTSD, measured via a novel in vivo marker called energy per cycle (EPC). In a sample of 34 adults (16 with PTSD, 18 healthy controls), higher early trauma correlated with higher EPC only in the PTSD group. Greater synaptic strength was associated with reduced behavioral inhibition, and EPC mediated stronger links between reward responsiveness and early trauma. These findings suggest that trauma-induced changes in synaptic plasticity may underlie psychiatric risk and point to potential targets for treatments like ketamine and psilocybin.
Psychiatric Annals
February 1, 2020
Lynnette A. Averill, Christopher L. Averill, Chadi G. Abdallah
6 citations
Ketamine's discovery as a rapid antidepressant has transformed drug development and understanding of chronic stress pathology. This review covers the history of NMDA receptor modulators leading to ketamine's psychiatric use, its rapid antidepressant and antisuicidal effects, a model of synaptic loss and dysconnectivity underlying chronic stress pathology, clinically relevant biomarkers and mechanisms, and how ketamine may both reverse chronic stress pathology and serve as a research tool. The authors discuss outstanding questions and the ongoing debate between optimism and concern about ketamine's widespread use.
iScience
January 16, 2026
Amir Valizadeh, John D Roache, Xinyu Zhang et al.
2 citations
Post-traumatic stress disorder varies greatly in its clinical and biological features, making treatment difficult. The largest randomized trial of ketamine for PTSD found no overall benefit over placebo, highlighting the need to identify which patients might respond. Using pre-treatment blood DNA methylation profiles and clinical data from that trial, machine learning models predicted treatment response. A model based on 1,208 methylation sites outperformed models using only clinical variables, and combining both data types improved accuracy further. The methylation-derived score identified responders with 92.9% accuracy. Predictive methylation sites were near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci, suggesting peripheral DNA methylation patterns can guide precision pharmacotherapy for PTSD.
medRxiv Preprint Server
April 10, 2020
Chadi G. Abdallah, Kyung-Heup Ahn, Lynnette A. Averill et al.
1 citation
preprint
A robust and reproducible brain connectivity fingerprint (CFP) was identified during ketamine infusion in healthy participants, characterized by reduced connectivity within primary cortices and the executive network, but increased connectivity between the executive network and the rest of the brain. This same CFP measured one week after treatment in major depressive disorder patients predicted response to eight weeks of sertraline, but not placebo. The findings suggest a brain network biomarker that links ketamine's acute effects to the mechanisms of conventional antidepressants.