Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine

This review (2017) examines ketamine’s rapid antidepressant efficacy with respect to evidence that it can neurochemical/physiological disturbances, such as abnormalities in excitatory and/or inhibitory neurotransmission in association with altered brain levels of glutamate and gamma-aminobutyric acid. It highlights neuroimaging studies to support the notion that glutamatergic modulation may be a viable biomarker for investigating depression in future studies.

Abstract

“In patients with major depressive disorder (MDD) or bipolar disorder (BD), abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic dose ketamine has led to a collection of studies that have examined neurochemical (e.g. glutamatergic and GABA-ergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.”

Authors: Marc S. Lener, Mark J. Niciu, Elizabeth D. Ballard, Minkyung Park, Lawrence T. Park, Allison C. Nugent & Carlos A. Zarate

Summary

Patients with major depressive disorder or bipolar disorder may have aberrant functional connectivity patterns within large brain networks, which may be mediated by altered brain levels of glutamate and gamma-aminobutyric acid.

In rodent studies, alterations in cortical glutamate and gamma-aminobutyric acid levels were associated with depressive-like behaviors, and in clinical studies, alterations in Glu and GABA levels were identified. These findings suggest that dysfunction in excitatory and/or inhibitory neurotransmitter signaling mechanisms may play a critical role in depression.

Ketamine, an NMDA receptor antagonist, may be the best available molecular tool to probe the impact of glutamatergic modulation on excitatory/inhibitory neural circuitry dynamics in healthy and depressed subjects with MDD or BD.

DYSREGULATION OF GLUTAMATERGIC AND GABAERGIC NEUROTRANSMISSION IN DEPRESSION

Proton MRS is used to image neurochemicals in vivo, including N-acetylaspartate, GABA, Glu, glutamine (Gln), and a combination of Glu/Gln with a minor contribution from GABA (known as Glx). Glu is produced in neurons from glucose-derived tricarboxylic acid cycle intermediates and branched-chain amino acids.

In patients with MDD, abnormal amino acid neurotransmitter levels measured by 1H-MRS have been found in the dorsolateral prefrontal cortex (PFC) and other PFC areas, as well as the anterior cingulate cortex (ACC) and occipital cortex (OCC). This may be related to abnormal mitochondrial energy production in glutamatergic neurons.

Ketamine affects glutamatergic and GABAergic metabolism and neurotransmission by antagonizing NMDA receptors on GABAergic inter- neurons and on postsynaptic neurons, and increasing synthesis of brain-derived neurotrophic factor (BDNF). Ketamine also increases activity of mammalian target of rapamycin (mTOR) and stabilizes nitrergic Rheb.

Researchers found that reductions in synaptic strength may contribute to reduced energy production within glutamatergic neurons, and may also reduce Glu neurotransmission over successive episodes of depression.

Neurochemical studies in patients with BD have shown mixed results. Some studies found no differences in Glu between patients with BD and healthy subjects, while others noted increased Glx in the PFC and ACC in depressed states. Studies of patients with BD are confounded by wide and overlapping ranges of mood and neurocognitive states, as well as by concurrent use of medications, which can alter Glu and GABA levels in the brain.

PET imaging provides complementary information to MRS studies regarding neurotransmitter signaling mechanisms. Reduced mGluR5 density in patients with MDD was observed in two clinical PET studies that used an mGluR5-specific radioligand, and animal studies showed antidepressant-like effects associated with mGluR5-specific antagonists.

In 1H-MRS studies of patients with MDD, lower GABA levels were reported in the PFC, ACC, and OCC compared with healthy subjects, and these changes may be more pronounced in association with melancholia. However, in studies of euthymic patients with BD, decreased and increased GABA levels have been observed.

Researchers believe that a deficiency of excitatory neurotransmission or an imbalance of excitatory/inhibitory neurotransmission characterizes a subset of depressed patients. Despite the clinical efficacy of GABAergic medications in BD, inconsistent reports of GABA levels associated with BD do not support an isolated deficiency in GABA in depression.

FUNCTIONAL CIRCUITRY ABNORMALITIES IN DEPRESSION

Neural circuitry is the complex array of interconnected neurons in the brain from which simultaneous and coordinated information processing is refined and reorganized by experience-related synaptic changes. Functional imaging studies can identify abnormal neural circuitry and respond to behavioral or neurochemical interventions.

Patients with MDD have abnormalities in resting-state functional connectivity patterns in large brain networks, including the default mode network (DMN), which deactivates during cognitive tasks and is associated with introspection or self-referential thought when not actively recruited in task performance.

BD patients show abnormalities in functional connectivity between the mPFC and ACC with limbic-striatal regions, and show stronger functional connectivity within the dorsolateral PFC and ventrolateral PFC compared with MDD patients.

Functional connectivity patterns derived from resting-state fMRI studies and MEG studies across multiple frequency bands were similar in healthy subjects and patients with MDD. These results support the role of the sgACC and other cortical and subcortical regions in impaired cognitive control, psychomotor retardation, and other symptom clusters in depression.

KETAMINE IN DEPRESSION

Ketamine’s antidepressant effects were demonstrated over a decade ago in a double-blind, placebo-controlled clinical study of eight depressed patients. Ketamine’s antidepressant effects were replicated in both MDD and BD patients across single and repeated administrations under various study designs.

Ketamine antagonizes NMDA receptors on GABAergic interneurons and on postsynaptic neurons, increases synthesis of intracellular growth factors, and activates mammalian target of rapamycin. These effects have led to the development of Glu-based treatments for depressive disorders.

ANTIDEPRESSANT RESPONSE TO KETAMINE AND GLU/GABA NEUROTRANSMISSION

Five 1H-MRS studies have examined Glu, Gln, Glx, and/or GABA levels before and after intravenous ketamine infusion; all were conducted in healthy subjects. In one study, elevated Glu levels were observed in the ACC 2 hours after infusion, correlating with psychotomimetic symptoms.

Ketamine administration is not associated with changes in Glx, Glu, or GABA levels in the mPFC/ACC 40 minutes after infusion. However, consistent with the “glutamate surge” hypothesis, Glu levels increase during ketamine infusion, leading to psychotomimetic effects. DeLorenzo etal. (40) found that ketamine increased mGluR5 binding in the ACC, mPFC, orbital PFC, ventral striatum, parietal lobe, dorsal putamen, dorsal caudate, amygdala, and hippocampus in healthy control subjects after intravenous ketamine infusion.

Three studies examined ketamine’s effect on Glu, Glx, and/or GABA in patients with MDD, but found inconsistent results. One study observed improved depressive symptoms in association with increased pretreatment Glx/Glu ratio in the dorsomedial PFC/dorsal anterolateral PFC, but no association with baseline levels or change in any amino acid neurometabolite.

KETAMINE AND FUNCTIONAL NEURAL CIRCUITRY IN DEPRESSION

The rostral ACC is associated with increased neural activity and increased antidepressant response in healthy subjects, patients with MDD, and patients with bipolar disorder. Ketamine may also increase glucose metabolism in the rostral ACC and putamen, which may predict antidepressant response to treatment.

Specific electrophysiological measures may be used to infer excitatory/inhibitory neurotransmitter imbalances, such as oscillations in the gamma-frequency band. These oscillations may be attributed to interactions between superficial excitatory pyramidal cells and inhibitory GABAergic interneurons, and may be associated with abnormalities in functional connectivity and disruptions in neuronal plasticity. A MEG study in healthy volunteers found that ketamine increased anterior theta and gamma power but decreased posterior theta, delta, and alpha power. Ketamine also reduced NMDA- and AMPA-mediated frontoparietal connectivity.

Ketamine administration causes changes in frontoparietal electrophysiological synchrony and power, but it is unclear whether these changes are similar in depressed patients.

KETAMINE AS A FUNCTIONAL NEUROCIRCUITRY MODULATOR: FUTURE DIRECTIONS

In depressed patients, alterations in Glu-related excitatory neurotransmission may exist, and an imbalance of Glu over GABA neurotransmission may manifest as network connectivity perturbations in BD and MDD. Ketamine’s antidepressant efficacy may be associated with specific Glu and/or GABA levels.

Pharmacodynamic fMRI studies conducted in healthy volunteers have established test-retest reliability and specificity in association with ketamine infusions, thus supporting the use of this technique in future ketamine studies.

MDD is a complex disorder with wide variability of treatment response. Neuroimaging techniques, in conjunction with other illness biomarkers, may be required to diagnose and treat psychiatric disorders.

Figure 2 shows the proposed regions of interest for identifying alterations in glutamate/gamma-aminobutyric acid and abnormalities in functional connectivity.

The authors thank the 7SE research unit and staff for their support, and Ms. Ioline Henter for invaluable editorial assistance. CAZ is listed as a co-inventor on a patent application for ketamine.

Authors

Authors associated with this publication with profiles on Blossom

Mark Niciu
Mark Niciu is an Assistant Professor of Psychiatry at the University of Iowa. Mark and his team are interested in the therapeutic effects of ketamine.

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