Chronic stress pathology and ketamine-induced alterations in functional connectivity in major depressive disorder: An abridged review of the clinical evidence.
Lynnette A. Averill, Samar Fouda, James W. Murrough, Chadi G. Abdallah
Advances in pharmacology (San Diego, Calif.) 2020 DOI: 10.1016/bs.apha.2020.04.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Clinical trial Functional connectivity MRI Neurobiology Neuroimaging Resting state Stress |
| Key findings | The authors propose that chronic stress pathology involves synaptic loss and functional dysconnectivity, and that ketamine's rapid antidepressant effects may work by normalizing these alterations in prefrontal, striatal, and anterior cingulate cortex connectivity. They suggest ketamine can serve both as a treatment and as a tool for studying biomarkers of chronic stress and treatment response. |
Abstract
A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 8
- Psychedelics and Other Psychoplastogens for Treating Mental Illness Frontiers in Psychiatry October 4, 2021
- The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence. Therapeutic Advances in Psychopharmacology 2023
- Functional activity and connectivity signatures of ketamine and lamotrigine during negative emotional processing: a double-blind randomized controlled fMRI study. Translational Psychiatry October 14, 2024
- Ketamine Assisted EMDR Therapy™ for PTSD: investigating the synergistic effects of pharmacotherapy and psychotherapy European Journal of Psychotraumatology November 4, 2025
- Mechanisms of Action and Change in Psychedelic-Assisted Therapies: A Holistic Framework for Ethical, Competent Clinical Care FOCUS: The Journal of Lifelong Learning in Psychiatry July 1, 2026
and 3 more in the library
Cites 39
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
- Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder JAMA Psychiatry April 16, 2014
- A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders JAMA Psychiatry March 1, 2017
and 34 more in the library