Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment
This cohort study (n=51) found evidence for the hypothesis that ketamine normalizes prefrontal dysconnectivity. The first part of the study showed an increase in activity in the prefrontal global signal regression after ketamine (35mg/70kg) administration (which was lower in those with depression).
Authors
- Sanjay Mathew
- John Krystal
- Lauren Averill
Published
Abstract
Background
Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr.
Methods
In the cohort A study, we used functional magnetic resonance imaging to compare GBCr between 22 patients with TRD and 29 healthy control subjects. Then, we examined the effects of ketamine and midazolam on GBCr in patients with TRD 24 hours posttreatment. In the cohort B study, we acquired repeated functional magnetic resonance imaging in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction.
Results
In the cohort A study, patients with TRD showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared with healthy control subjects. In patients with TRD, GBCr in the altered clusters significantly increased 24 hours following ketamine (effect size = 1.0, confidence interval = 0.3 to 1.8) but not following midazolam (effect size = 0.5, confidence interval = −0.6 to 1.3). In the cohort B study, oral lamotrigine reduced GBCr 2 hours post administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects.
Conclusions
This study provides the first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.
Research Summary of 'Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment'
Introduction
Major depressive disorder is characterised by poorly understood pathophysiology and high rates of inadequate treatment response. Over the past two decades, accumulating evidence has strongly implicated glutamate neurotransmission in both the pathophysiology of depression and the mechanism of ketamine's rapid antidepressant effects. However, with the notable exception of ketamine, the translation of glutamate-targeting strategies from preclinical to clinical settings has been largely unsuccessful, hindering the development of novel rapidly acting antidepressants. This study aimed to characterise the role of prefrontal global brain connectivity — a measure of regional functional coupling — in treatment-resistant depression (TRD) and to investigate how glutamate modulation by ketamine (a positive modulator) and lamotrigine (an inhibitor of glutamate release) differentially affects prefrontal connectivity, using a pharmacoimaging approach.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Abdallah, C. G., Averill, C. L., Salas, R., Averill, L. A., Baldwin, P. R., Krystal, J. H., Mathew, S. J., & Mathalon, D. H. (2017). Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2(7), 566-574. https://doi.org/10.1016/j.bpsc.2017.04.006
References (8)
Papers cited by this study that are also in Blossom
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Abdallah, C. G., Averill, L. A., Krystal, J. H. · Annals of the New York Academy of Sciences (2015)
Bobo, W. V., Vande Voort, J. L., Croarkin, P. E. et al. · Depression and Anxiety (2016)
Newport, D. J., Carpenter, L. L., Mcdonald, W. M. et al. · American Journal of Psychiatry (2015)
Abdallah, C. G., Averill, L. A., Collins, K. A. et al. · Neuropsychopharmacology (2016)
Ari, A., Abdallah, C. G., Sanacora, G. et al. · Annual Review of Medicine (2014)
William Deakin, J. F., Lees, J., McKie, S. et al. · JAMA Psychiatry (2008)
Abdallah, C. G., Jackowski, A., Salas, R. et al. · Neuropsychopharmacology (2017)
Cited By (5)
Papers in Blossom that reference this study
Zhou, Y-L., Wang, C., Lan, X-F. et al. · Frontiers in Psychiatry (2022)
Wilkowska, A., Wiglusz, M. S., Cubała, W. J. et al. · Frontiers in Psychiatry (2021)
Veraart, J. K. E., Smith-Apeldoorn, S. Y., Bakker, I. M. et al. · International Journal of Neuropsychopharmacology (2021)
Abdallah, C. G., Sanacora, G., Duman, R. S. et al. · Chronic Stress (2018)
Jones, J. L., Mateus, C. F., Malcolm, R. J. et al. · Frontiers in Psychiatry (2018)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.