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).

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.“

Authors: Chadi G. Abdallah, Christopher L. Averill, Ramiro Salas, Lynnette A. Averill, Philip R. Baldwin, John H.Krystal, Sanjay J. Mathew & Daniel H. Mathalon

Summary

Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

Prefrontal global brain connectivity with global signal regression (GBCr) was investigated in treatment-resistant depression and healthy subjects.

HHS Public Access Author manuscript Biol Psychiatry Cogn Neurosci Neuroimaging. Author manuscript; available in PMC 2018 October 01. Published in final edited form as:

Results – TRD patients showed reduced GBCr in the dorsomedial and dorsolateral prefrontal clusters compared to healthy control, and increased GBCr 24h following ketamine, but not midazolam. Lamotrigine reduced the ketamine-induced GBCr surge.

Introduction

Major depressive disorder (MDD) is a disabling mental illness with poorly understood pathophysiology and high rates of inadequate treatment response. Ketamine, a glutamate modulator, induces rapid acting antidepressant effects in MDD and healthy subjects, and this link may be related to underlying glutamate neurotransmission.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that induces a glutamate neurotransmission surge leading to increased synaptogenesis and reversal of depression-related glutamate synaptic deficits. Two models have been proposed for the mechanisms through which ketamine induces glutamate neurotransmission. Proton magnetic resonance spectroscopy has been used to provide indirect evidence that ketamine stimulates glutamate, but there are inconsistencies that may affect the potential utility of this method as a robust biomarker for drug development.

Global brain connectivity values (GBCr) are used to identify major brain networks, are used to predict cognitive functioning and intelligence, and are shown to significantly correlate with regional cerebral blood flow. Depressive features and chronic stress-induced glutamate alterations are found in the PFC and are reversed by ketamine treatment.

Ketamine normalized glutamate synaptic transmission 24h post-ketamine administration in models of depression, suggesting that glutamate neurotransmission plays a crucial role in TRD and raising the question of whether ketamine-induced increases in synaptic glutamate neurotransmission is causally related to fMRI measure of GBCr.

We first compared PFC GBCr between TRD and healthy controls, and then examined the effects of lamotrigine, an inhibitor of glutamate neurotransmission, on PFC GBCr. We hypothesized that lamotrigine would significantly reduce ketamine-induced PFC GBCr changes.

All subjects completed an informed consent process prior to participation in the study. The studies were approved by institutional review boards.

Cohort A included 22 TRD and 29 HC. Of the 22 TRD, 20 were randomized to ketamine or to active placebo midazolam and 17 completed fMRI scans at 24h following treatment.

Cohort B included 18 males between the ages of 22 and 36. Ketamine was administered as a bolus (0.23 mg/kg in 2 min) followed by 0.58 mg/kg over approximately 70 min, a well-validated infusion regimen to maintain a steady-state level of ketamine during fMRI acquisition and subsequent clinical assessments.

Neuroimaging

In Cohort A, fMRI scans were completed at baseline for all subjects, and 24h following ketamine and midazolam infusions in TRD participants. In Cohort B, fMRI scans were completed while subjects performed a visual oddball task, and functional connectivity measures were computed.

Statistical Analyses

We conducted voxel-wise paired t-tests to examine the effects of lamotrigine and ketamine on GBCr in the PFC. We also conducted a pairwise paired t-test to examine the effects of lamotrigine on the ketamine-induced GBCr changes.

The clinical characteristics of TRD participants were well matched to the parent trial, and there was a significant reduction in MADRS severity in the ketamine group compared to placebo.

GBCr in TRD & Post-ketamine

A voxel-wise analysis showed lower GBCr in TRD in three PFC clusters, which overlapped with the Ventral Attention and Frontoparietal networks.

The average GBCr in the altered clusters significantly increased following ketamine treatment, but no significant changes were found in the placebo group. There was no correlation between baseline GBCr and MADRS or IDS severity.

In Cohort B, lamotrigine significantly reduced GBCr in the bilateral rostral anterior cingulate and medial PFC, and ketamine significantly increased GBCr in two clusters located in the bilateral dorsomedial and left frontolateral PFC.

Ketamine significantly increased BPRS and CADSS scores, but lamotrigine had no effect. Follow-up analysis showed ketamine-induced increases in BPRS Positive and Negative symptoms.

PFC Limbic Network

The vPFC limbic area plays a critical role in the pathophysiology of depression, and previous reports have associated this brain area with TRD and ketamine infusion. However, ketamine treatment did not significantly reduce vPFC GBCr in TRD subjects.

GBCr & Treatment Response

Exploratory analyses were conducted to examine whether baseline GBCr predicted the antidepressant effects of ketamine or placebo. We found that baseline GBCr predicted improvement in MADRS but not improvement in IDS.

Discussion

This study affirmed its primary objectives and demonstrated that reduced PFC GBCr is present in treatment resistant MDD patients. Furthermore, ketamine-induced increases in PFC GBCr were paralleled by robust increases in mPFC GBCr, which supports a direct link between increased cortical glutamate transmission and GBCr.

The ROI analysis showed higher levels of vPFC GBCr in TRD compared to HC, and subjects with a history of more severe treatment failures had higher levels of vPFC GBCr. Intriguingly, subjects with more prominent baseline vPFC GBCr abnormalities showed an enhanced response to ketamine, but poor response to placebo.

The level of GBCr abnormalities was not associated with the baseline severity of depression. Our current working model of depression speculates that certain GBCr abnormalities would be most pronounced in the Glutamate-Based Depression (GBD) subgroup.

The GBD model of depression is based on the synaptic hypothesis of depression, and predicts that patients with MDD will have reduced gray matter integrity and altered amino acid neurotransmitters in the PFC and hippocampus. However, not all MDD patients have these abnormalities, and ketamine treatment can normalize them.

Lamotrigine did not block the psychotomimetic effects of ketamine in depressed subjects, in contrast to previous reports. This finding highlights the need for robust biomarkers with high sensitivity for drug development.

The limitations of the current study include the small number of subjects who received ketamine and post-treatment scans, the lack of an appropriate non-active placebo control, and the lack of human evidence directly showing blockade of ketamine-induced glutamate neurotransmission by lamotrigine.

The current report builds on the discovery of ketamine-induced rapid acting antidepressant effects and attempts to provide evidence of a direct link between large scale networks and underlying molecular alterations in depression.

Ketamine increased the GBCr in the PFC of patients with treatment-resistant depression, relative to healthy controls, in three clusters.

Lamotrigine significantly inhibited the ketamine-induced GBCr surge, and ketamine significantly increased GBCr when lamotrigine was added to the ketamine infusion.

The ventral prefrontal cortex (vPFC) had higher global brain connectivity than the control group, and ketamine reduced global brain connectivity in the vPFC in 7 of 10 treatment-resistant depression patients, but this reduction was not statistically significant.