Journal
BIOLOGICAL PSYCHIATRY-COGNITIVE NEUROSCIENCE AND NEUROIMAGING
Volume 2, Issue 7, Pages 566-574Publisher
ELSEVIER
DOI: 10.1016/j.bpsc.2017.04.006
Keywords
Functional MRI; Global brain connectivity; Glutamate; Ketamine; Rapid-acting antidepressants; Treatment-resistant depression
Categories
Funding
- National Institute of Mental Health [K23MH101498, R01MH081870]
- Veterans Affairs National Center for PTSD
- Veterans Affairs Research Career Development Award
- Brain & Behavior Foundation (National Alliance for Research on Schizophrenia and Depression)
- Patterson Trust Award
- GlaxoSmithKline
- Johnson Family Chair for Research
- Michael E. Debakey Veterans Affairs Medical Center, Houston, TX [VHA 5I01CX000994]
- Janssen Research Development
Ask authors/readers for more resources
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 postadministration, while ketamine increased medial prefrontal GBCr during infusion. Lannotrigine 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available