Targeting Glutamatergic Signaling for the Development of Novel Therapeutics for Mood Disorders

Abstract

There have been no recent advances in drug development for mood disorders in terms of identifying drug targets that are mechanistically distinct from existing ones. As a result, existing antidepressants are based on decades-old notions of which targets are relevant to the mechanisms of antidepressant action. Low rates of remission, a delay of onset of therapeutic effects, continual residual depressive symptoms, relapses, and poor quality of life are unfortunately common in patients with mood disorders. Offering alternative options is requisite in order to reduce the individual and societal burden of these diseases. The glutamatergic system is a promising area of research in mood disorders, and likely to offer new possibilities in therapeutics. There is increasing evidence that mood disorders are associated with impairments in neuroplasticity and cellular resilience, and alterations of the glutamatergic system are known to play a major role in cellular plasticity and resilience. Existing antidepressants and mood stabilizers have prominent effects on the glutamate system, and modulating glutamatergic ionotropic or metabotropic receptors results in antidepressant-like properties in animal models. Several glutamatergic modulators targeting various glutamate components are currently being studied in the treatment of mood disorders, including release inhibitors of glutamate, N-methyl-D-aspartate (NMDA) antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput enhancers, and glutamate transporter enhancers. This paper reviews the currently available knowledge regarding the role of the glutamatergic system in the etiopathogenesis of mood disorders and putative glutamate modulators.

Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

“…ketamine, another glutamatergic agent, in MDD patients, which may be relevant to OCD based on high comorbidity with MDD [104]. In fact, a recent case study showed effectiveness of ketamine in treatment-resistant OCD [105].…”

Is depression associated with an increased risk of treatment-resistant epilepsy? Research strategies to investigate this question

“…For example, using the forced swim test (FST), trials with NMDA and metabotropic antagonists (including MK-801, ketamine, mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the mGluR2/3 antagonists LY341495 and MGS0039) yielded a dose-dependent reduction in immobility time [66,67]. Likewise, an antidepressant effect of NMDA receptor antagonists has been suggested in patients with treatment-resistant MDD in three double-blind placebo-controlled trials, two with ketamine [68,69] and one with the NR2B subunitselective N-methyl-D-aspartate receptor antagonist CP-101,606 (Traxoprodil) [70]. Furthermore, antidepressants of the TCA, SSRI, and SNRI families are known to downregulate glutamatergic receptors of the NMDA family and potentiate glutamatergic receptors of the AMPA family [71].…”

Memantine and Catatonia

“…While memantine itself has not been shown to be generally useful for mood disorders in the preliminary studies I will describe later, reports such as that by Obregon and colleagues on catatonic depression provide a signal that the glutaminergic approach may one day be quite important. Before discussing the case, I will give a brief overview of this topic, derived from excellent recent reviews by Zarate, Machado-Vieira, and their colleagues at the National Institutes of Mental Health 68,69 and by Sancorra at Yale. 70,71 Glutamate, the most abundant excitatory neurotransmitter in the brain, has been suspected of involvement in mood disorders for many years, yet only in the past decade has it become a target for investigation of new therapeutics.…”