Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

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.

Acute change in anterior cingulate cortex GABA, but not glutamine/glutamate, mediates antidepressant response to citalopram

“…Substantial evidence implicates abnormal glutamatergic neurotransmission in MDD, and glutamate-modulating interventions show promising antidepressant effects (Lener et al, 2016). Several classes of antidepressant treatments, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and electroconvulsive therapy (ECT), have been shown to affect the glutamate system (Skolnick et al, 1996).…”

GABAergic Influence in the Antidepressant Effect of Fluoxetine in Unstressed and Stressed Mice

“…Also the altered levels of GABA had been reported in the patients of depression (Gold et al, 1980;Price et al, 2009). Further the network dysfunction in association with altered brain levels of glutamate and GABA have been identified in both animal and human studies of depression (Lener et al, 2016). Thus the dysfunction of the GABAergic system is associated with major depression (Sanacora et al, 1999) and therefore the treatment with the GABAergic agents or GABA modulating drugs may exerts the beneficial effects (Birkenhäger et al, 1995).…”

“…SSRIs treatment increases the cortical GABA levels in the depressed patients and suggest that this results from an action of SSRIs on GABA neurons rather than as a secondary consequence of mood improvement (Bhagwagar et al, 2004). SSRIs thus act in part to restore the disrupted GABAergic activity (Licata et al, 2014). Preclinical studies demonstrate that GABA modulating agents are active in commonly used rodent behavioral models of antidepressant activity, and that chronic administration of antidepressant drugs induces marked changes in GABAergic function (Sanacora and Saricicek, 2007).…”

“…oral administration of fluoxetine (5 mg/kg) for 21 days elevated the CSF GABA levels by approximately 2-fold (P < 0.05) (Gören et al, 2007); also the chronic treatment with fluoxetine administered in drinking water normalizes GABA release in mice (Begenisic et al, 2014). SSRIs treatment known to increase the cortical GABA concentration in the depressed patients and therefore SSRIs act in part to restore the disrupted GABAergic activity (Licata et al, 2014).…”

“…GABA A receptor is the principal inhibitory neurotransmitter receptor in the mammalian brain (Kleingoor et al, 1993) and the altered expression or function of these receptors is increasingly implicated in the etiology of anxiety and depressive disorders (Merali et al, 2004;Sanacora et al, 2004;Bhagwagar et al, 2008;Poulter et al, 2008;Sequeira et al, 2009;Craddock et al, 2010;Klempan et al, 2009;Levinson et al, 2010).…”