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Cited by 18Treatment of Major DepressionFunctional Brain Connectivity StudiesTranscranial Magnetic Stimulation Studies

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·2020·Advances in Pharmacology
DOI 10.1016/bs.apha.2020.04.003
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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.

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  • In animals, chronic stress results in prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex, and functional impairment of the PFC.

    “In animals, chronic stress results in the prolonged release of glucocorticoids and leads to hypertrophy of the amygdala and nucleus accumbens, atrophy of the hippocampus and prefrontal cortex (PFC), and functional impairment of the PFC (44–55).”

    From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [44]

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Authors
Averill, L. A., Fouda, S., Murrough, J. W., & Abdallah, C. G.
Affiliations
  • United States Department of Veterans Affairs (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Lynnette A. Averill
ORCID
Venue
Advances in Pharmacology
Publisher
Elsevier
Published
2020
Volume
89
Pages
163-194
ISSN
1054-3589 (ISSN-L)
DOI
10.1016/bs.apha.2020.04.003
OpenAlex
W3024442905
Cited by
18
References
140
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 2
FWCI
4.71
Type
book chapter
Language
en
Open access
closed
Licence
Locations
  • Advances in pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Boehringer Ingelheim
  • National Institute of Mental Health
  • Sage Therapeutics
  • Robert E. Leet and Clara Guthrie Patterson Trust
  • Avanir Pharmaceuticals
  • Novartis
  • Allergan
  • Janssen Research and Development
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
Keywords
ketamine, major depressive disorder, functional connectivity, treatment-resistant depression, glutamatergic neurotransmission, synaptic loss, prefrontal cortex, anterior cingulate cortex, striatum, treatment response biomarkers, early life stress, sex differences
MeSH terms
Antidepressive Agents, Chronic Disease, Depressive Disorder, Major, Major Depressive Disorder, Humans, Ketamine, Nerve Net, Stress, Psychological

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