Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial
This double-blind, randomised study (n=48) involving patients with treatment-resistant depression (TRD) and suicidal ideation (SI) evaluated the effects of a single infusion of 35mg/70kg ketamine or 3.15mg/70kg midazolam. Using positron emission tomography-magnetic resonance imaging, the study observed a small but significant volumetric reduction in the right dorsolateral prefrontal cortex (DLPFC) in the ketamine group compared to the midazolam group, and a greater reduction in depressive symptoms was associated with smaller decreases in right DLPFC volumes.
Authors
- Tung-Ping Su
- Mu-Hong Chen
Published
Abstract
Background
Evidence has shown a rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression (TRD) and prominent suicidal ideation (SI). The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in the TRD pathomechanisms.
Objective
Whether the structural and functional changes of the DLPFC, particularly Brodmann area 46, are associated with the antidepressant and antisuicidal effects of ketamine infusion among such patients is unknown.
Methods
We randomized 48 patients with TRD and SI into groups receiving a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale were used to assess symptoms. Positron emission tomography (PET)-magnetic resonance imaging was conducted prior to infusion and on Day 3 postinfusion. We performed longitudinal voxel-based morphometry (VBM) analysis to evaluate the gray matter (GM) volume changes of the DLPFC. The standardized uptake value ratio (SUVr) of 18F-fluorodeoxyglucose PET images was calculated using the SUV of the cerebellum as a reference region.
Results
The VBM analysis revealed a small but significant volumetric reduction in the right DLPFC in the ketamine group compared with that in the midazolam group. A greater reduction in depressive symptoms was associated with a smaller decrease in right DLPFC volumes (p = 0.025). However, we found no SUVr changes of the DLPFC between baseline and post-Day 3 ketamine infusion.
Discussion
The optimal modulation of the right DLPFC GM volumes may play an essential role in the antidepressant neuromechanisms of low-dose ketamine.
Research Summary of 'Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial'
Introduction
Low-dose ketamine infusion has been shown to produce rapid antidepressant and antisuicidal effects in treatment-resistant depression (TRD), but response varies considerably across patients. Earlier research, including a meta-analysis of 2,050 TRD cases, reported a response rate near 45% to low-dose ketamine, and several neuroimaging studies have implicated the dorsolateral prefrontal cortex (DLPFC) in the neuropathology of TRD. Prior structural work has reported reduced DLPFC gray matter (GM) in TRD, and functional imaging has documented acute prefrontal activation after ketamine; nevertheless, whether ketamine induces short-term structural or metabolic changes in the DLPFC—particularly Brodmann area 46—and whether such changes relate to clinical improvement remains unclear. Li and colleagues set out to test whether a single low dose of ketamine (0.5 mg/kg) alters GM volume and glucose metabolism in the bilateral DLPFC and whether those changes are associated with reductions in depressive and suicidal symptoms. They randomised 48 adults with unipolar TRD and prominent suicidal ideation to ketamine or an active control (midazolam) and performed PET–MRI before infusion and on Day 3 postinfusion to examine voxel-based morphometry (VBM) and 18F‑FDG uptake in BA46. The authors hypothesised increases in DLPFC GM volume and glucose metabolism after ketamine and predicted that such neuroimaging changes would correlate with clinical benefit.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- Authors
- APA Citation
Li, W., Chen, L., Su, T., Li, C., Lin, W., Wu, H., Tsai, S., Bai, Y., Tu, P., & Chen, M. (2023). Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial. Journal of Affective Disorders, 335, 105-110. https://doi.org/10.1016/j.jad.2023.05.024
References (5)
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, L. A., Collins, K. A. et al. · Neuropsychopharmacology (2016)
Alnefeesi, Y., Chen-Li, D., Jawad, M. Y. et al. · Journal of Psychiatric Research (2022)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Li, C. T., Chen, M. H., Lin, W. C. et al. · Human Brain Mapping (2016)
Su, T. P., Chen, M. H., Li, C. T. et al. · Neuropsychopharmacology (2017)
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