Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment.
Chadi G. Abdallah, Christopher L. Averill, Ramiro Salas, Lynnette A. Averill, Philip R Baldwin, John H. Krystal, Sanjay J. Mathew, Daniel H. Mathalon
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging October 2017 DOI: 10.1016/j.bpsc.2017.04.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pharmacological challenge functional MRI study (two-part: case-control comparison and repeated-measures drug challenge) Peer reviewed |
|---|---|
| Sample size | 69 |
| Population | 22 patients with treatment-resistant depression and 29 healthy controls in study A; 18 healthy subjects in study B |
| Interventions | Ketamine Midazolam Lamotrigine |
| Duration | GBCr assessed 24 hours post-treatment in TRD patients; GBCr assessed 2 hours post-lamotrigine and during ketamine infusion in healthy subjects |
| Measures | Global brain connectivity with global signal regression (GBCr), functional magnetic resonance imaging (fMRI) |
| Topics | Ketamine Depression Esketamine |
| Keywords | Treatment resistant depression Functional MRI Global brain connectivity Glutamate Rapid acting antidepressants |
| Key findings | Prefrontal GBCr was reduced in treatment-resistant depression and increased 24 hours after ketamine but not midazolam. In healthy subjects, lamotrigine reduced GBCr and blunted the ketamine-induced GBCr increase, which the authors interpret as indirect evidence that ketamine's effects on prefrontal connectivity may involve enhanced glutamate neurotransmission. |
Abstract
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. In study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. In study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [-0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h 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. This study provides 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.
Comparable studies
Other observational and cohort studies on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
| Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... | 2017 | Observational cohort | n = 59 |
| Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... | 2014 | Post hoc analysis of pooled data from four studies | n = 108 |
| An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder | 2011 | Observational cohort | n = 14 |
| Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... | 2019 | Observational cohort | n = 25 |
Citations in the library
Cited by 36
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers Therapeutic Advances in Psychopharmacology 2020
- Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments The International Journal of Neuropsychopharmacology November 14, 2018
- Brain Changes Associated With Long-Term Ketamine Abuse, A Systematic Review Frontiers in Neuroanatomy March 18, 2022
- An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. Frontiers in Psychiatry November 24, 2021
and 31 more in the library
Cites 18
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
and 13 more in the library