Beyond Monoamines: Glutamatergic Function in Mood Disorders

Abstract

The monoamine theory has implicated abnormalities in serotonin and norepinephrine in the pathophysiology of major depression and bipolar illness and contributed greatly to our understanding of mood disorders and their treatment. Nevertheless, some limitations of this model still exist that require researchers and clinicians to seek further explanation and develop novel interventions that reach beyond the confines of the monoaminergic systems. Recent studies have provided strong evidence that glutamate and other amino acid neurotransmitters are involved in the pathophysiology and treatment of mood disorders. Studies employing in vivo magnetic resonance spectroscopy have revealed altered cortical glutamate levels in depressed subjects. Consistent with a model of excessive glutamate-induced excitation in mood disorders, several antiglutamatergic agents, such as riluzole and lamotrigine, have demonstrated potential antidepressant efficacy. Glial cell abnormalities commonly associated with mood disorders may at least partly account for the impairment in glutamate action since glial cells play a primary role in synaptic glutamate removal. A hypothetical model of altered glutamatergic function in mood disorders is proposed in conjunction with potential antidepressant mechanisms of antiglutamatergic agents. Further studies elucidating the role of the glutamatergic system in the pathophysiology of mood and anxiety disorders and studies exploring the efficacy and mechanism of action of antiglutamatergic agents in these disorders, are likely to provide new targets for the development of novel antidepressant agents.

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

“…NMDA antagonists such as MK-801, 4,5 ketamine, 6 amantadine 7 and others 8,9 exhibited antidepressant effects in different animal models. Beside the abovementioned report on D-cycloserine, slight antidepressant effects in humans have also been observed with the NMDA receptor antagonists amantadine 10,11 and ketamine.…”

“…25 The inconsistency of the findings, however, might be due to medication effects, low statistical power and a lack of appropriate control of diagnosis. 9 Support for increased glutamatergic activity in depression comes from magnetic resonance spectroscopy: elevated glutamate levels were found in the occipital cortex of unmedicated subjects with MD. 16 Associated with an increased level of certain neurotransmitter is often a downregulation of the respective receptor.…”

Decreased Glutamate/Glutamine Levels May Mediate Cytidine’s Efficacy in Treating Bipolar Depression: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

“…Given the role of glutamate in the pathophysiology of BD (Krystal et al, 2002;Kugaya and Sanacora, 2005) and potential effects of cytidine on cerebral glutamate levels through mechanisms involving membrane stability and high-energy phosphate restoration (Hurtado et al, 2005), changes in cerebral glutamate/glutamine level were of interest to us.…”

Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

“…Post-mortem brain tissue shows increased glutamate levels in depressed patients compared with controls (Hashimoto et al, 2007). This clinical data has lead to the development of several therapeutic strategies targeting glutamatergic receptors for the treatment of depression (Kugaya and Sanacora, 2005;Paul and Skolnick, 2003). Sub-anesthetic doses of ketamine, an N-methyl-D-aspartate receptor antagonist, have antidepressant effects with immediate onset of action (Maeng and Zarate, 2007;Berman et al, 2000) probably due to its ability to increase synaptogenesis (Li et al, 2010).…”