Glutamate is the most abundant excitatory neurotransmitter in the brain. It acts on three different cell compartments—presynaptic neurons, postsynaptic neurons, and glia—that characterize the “tripartite glutamatergic synapse”11
(see ). This integrated, neuronal-glial synapse is complex and directly involves the release, up-take, and inactivation of glutamate by different glutamate receptors (see text box) and other targets with potential clinical relevance, such as voltage-dependent ion channels and amino acid transporters.
Figure 1 The tripartite glutamatergic synapse in mood disorders. The glutamate-glutamine cycle plays a key role in the regulation of pre- and postsynaptic ionic and metabotropic glutamate receptors that have been implicated in the pathophysiology of mood disorders. (more ...)
Since the initial identification of glutamate as a neuro-transmitter in 1959, many studies have provided important insights into the role of the glutamatergic system in the pathophysiology and therapeutics of psychiatric disorders. The involvement of the glutamatergic system in mood disorders was first proposed based on preclinical data with N-methyl-d
-aspartate (NMDA) antagonists.12
Early studies showed altered glutamate levels in serum and cerebrospinal fluid from patients with mood disorders (reviewed in Machado-Vieira R et al.).13
In the last decade, accumulating evidence from diverse studies suggests that the glutamatergic system plays a critical role in both MDD and BPD. Postmortem studies describe altered glutamate levels in diverse brain areas in individuals with mood disorders.14,15
In addition, elevated glutamate levels in the occipital cortex and decreased levels in the anterior cingulate cortex appear to be the most consistent findings in nuclear magnetic resonance spectroscopy studies of individuals with mood disorders.16–18
It is important to note that dysfunctions in glutamate levels and regulation are more complex than the simplistic view of either increased or decreased levels associated with mood disorders; indeed, both higher and lower levels have been described in different brain areas by imaging studies.16,17
Recently, magnetic resonance spectroscopy data evaluating gluta-mate/glutamine levels—which indirectly assess activity of the neuronal-glial cycle—have also provided important new insights into its dynamic regulation in mood disorders. Notably, the glutamate-glutamine cycle plays a critical role in the regulation of synaptic plasticity, learning, and memory.19
Broadly, synaptic plasticity
refers to the cellular process that results in lasting changes in the efficacy of neuro-transmission. More specifically, it refers to the variability of the strength of a signal transmitted through a synapse.20 Neuroplasticity
is a broader term that includes changes in intracellular signaling cascades and gene regulation,21
modifications of synaptic number and strength, variations in neurotransmitter release, modeling of axonal and dendritic architecture, and, in some areas of the central nervous system, the generation of new neurons. In recent years, research has linked mood disorders with structural and functional impairments related to neuroplasticity in various regions of the central nervous system.22
Thus, agents capable of increasing cellular resilience within the complex and interconnected dynamics between glutamate release and uptake in the tripartite glutamatergic synapse, while concomitantly targeting downstream signaling pathways involved in neuroplasticity, are promising novel therapeutics for the treatment of mood disorders. Here, we describe recent findings regarding glutamatergic-based novel therapeutics for mood disorders; these treatments target glutamate receptors, ionic channels, transporters, and postsynaptic proteins that regulate intra- and intercellular glutamate dynamics ().
Excitatory Amino Acid Transporters and Vesicular Glutamate Transporters
Glutamate clearance from the extracellular space takes place mostly through the high-affinity excitatory amino acid transporters (EAATs). Decreased expression of diverse EAATs has been observed in postmortem studies of subjects with mood disorders (),23,24
and increased expression of these transporters (e.g., as induced by ß-lactam antibiotics) has been found to induce antidepressant-like effects.25–27
Mood stabilizers such as valproate and lamotrigine also similarly upregulate EAAT activity,28,29
albeit through a potentially different mechanism. In contrast, EAAT antagonism induced depressive effects and altered circadian activity in preclinical models.26,30
Regarding the role of vesicular glutamate transporters (VGLUTs) in mood disorders, a recent postmortem study noted significantly decreased VGLUT1 mRNA expression in both MDD and BPD patients.31
Similarly, reduced VGLUT1 expression has been associated with increased anxiety, depressive-like behaviors, and impaired long-term memory.32
Preclinical studies have found that diverse antidepressants increase VGLUT expression in the limbic system,32,33
and a similar effect was observed after lithium treatment34
—a mechanism that may be involved in lithium's protective effects against glutamate-induced excitotoxicity.35
Diverse compounds that target VGLUTs are now in development.36
This novel class of compounds is expected to induce therapeutic effects by buffering increased glutamatergic release.
Ionotropic Glutamate Receptors
Several studies have shown that ionotropic glutamate receptors play an important role in mood regulation. The NMDA receptors (NMDARs) have a slower and more prolonged postsynaptic current than the α
-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate receptors, but all ionotropic glutamate receptors exhibit fast receptor deactivation and dissociation of glutamate. These cellular effects may underlie the specific therapeutic profile of AMPA and NMDA modulators, mostly characterized by their rapid antidepressant effects.4
It has recently been proposed that both NMDA antagonism and AMPA receptor (AMPAR) activation are involved in ketamine's rapid antidepressant effects (see below for a more detailed discussion). Given the ability of AMPARs to induce a more rapid dissociation of glutamate, the proper balance in this dynamic and complex turnover may account for ketamine's unique therapeutic effects.
With regard to dysregulation of AMPARs, decreased levels of AMPAR subunits (glutamate receptor [GluR] 1, GluR2, and GluR3; see text box) have been reported in the prefrontal cortex and striatum of subjects with mood disorders.14,15,37,38
Also, abnormal metabotropic (m) GluR3 expression has been reported in suicidal subjects with BPD—a finding that was not replicated in a subsequent study.39,40
In line with these results, transgenic animals with lower GluR1 expression exhibit increased depressive-like behaviors.41
Therapeutically, AMPAR potentiators have been tested in various neuropsychiatric disorders and are a promising new class of agents for the treatment of mood disorders.42
AMPAR potentiators include benzothiazides (e.g., cyclothiazide), benzoylpiperidines (e.g., CX-516), and birylpropylsulfonamides (e.g., LY392098).43,44
These agents play a key role in modulating activity-dependent synaptic strength and behavioral plasticity.45
Furthermore, several preclinical studies found that the antidepressant-like effects of some AMPAR potentiators were also associated with improved cognitive functioning (reviewed in Miu et al.,43
and O'Neill et al.).48
In contrast to the antidepressant-like properties seen with AMPAR potentiators, AMPAR antagonists (e.g., the anticonvulsant talam-panel) are believed to have antimanic properties. To date, no placebo-controlled clinical trials with AMPAR potentiators for the treatment of depression or AMPA antagonists for the treatment of mania have been published.
Regarding the role of NMDARs in mood disorders, a series of elegant studies conducted over a decade ago used tricyclic antidepressants to demonstrate that NMDARs may represent a final common pathway of antidepressant action, one that is particularly associated with faster onset.49,50
Building on these findings, studies have described altered NMDAR binding and expression in individuals with MDD and BPD.23,24,37,51–53
Also, polymorphisms of GRIN1
, and GRIN2B
(see text box) have been shown to confer susceptibility to BPD,54–56
further supporting a role for these targets in the pathophysiology of this disorder.
Diverse preclinical and clinical studies have found that NMDA antagonists produce rapid antidepressant effects.57–61
For instance, one preclinical study observed antidepressant-like effects with a selective NMDAR-2B antagonist,57
and other brain-penetrant NMDAR-2B antagonists are currently in development.62,63
These pre-clinical findings are supported by a recent, double-blind, randomized, placebo-controlled clinical trial evaluating the NMDAR-2B subunit−selective antagonist CP-101,606, which induced significant and relatively rapid antidepressant effects (by day 5) in patients with treatment-resistant MDD, but with evidence of psychomimetic properties.64
Additional clinical studies with NMDR-2A and -2B antagonists in MDD are under way.
It is important to mention that while dramatic clinical therapeutic effects were observed with the high-affinity NMDA antagonist ketamine in MDD (see below), a placebo-controlled study of the low-to-moderate affinity, noncompetitive NMDA antagonist memantine (oral dosing) found no antidepressant effects.65
These findings suggest that high affinity and IV administration may be key factors for achieving rapid antidepressant effects with this class of agents.
Kainate receptors activate postsynaptic inhibitory neurotransmission. These effects play a crucial role in calcium metabolism, synaptic strength, and oxidative stress, all of which are associated with the pathophysiology of MDD and BPD.11,66
A recent, large, family-based association study evaluating the kainate GRIK3
gene described linkage disequilibrium in MDD.67
Likewise, elevated GRIK3
DNA-copy number was observed in individuals with BPD;68
relatedly, a common variant in the 3'UTR GRIK4
gene was found to protect against BPD.69
Interestingly, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) and Munich Antidepressant Response Signature (MARS) projects described an association between treatment-emergent suicidal ideation and the glutamate system via the involvement of the GRIA3
A recent study also found that individuals with MDD who had a GRIK4
gene polymorphism (rs1954787) were more likely to respond to treatment with the antidepressant citalopram.72
In preclinical studies, GluR6 knockout mice displayed increased risk-taking and aggressive behaviors, as well as hyperactivity, in response to amphetamine—manic-like behaviors that decreased after chronic lithium treatment.73
These promising findings have led to increased interest in developing kainite receptor modulators, but, to date, no such compounds have been evaluated in the treatment of mood disorders.
Metabotropic Glutamate Receptors
Genetically-induced decreases in expression of mGluRs and agents that target mGluRs—especially Group II and III mGluR modulators—have consistently been found to induce anxiolytic, antidepressant, and neuroprotective effects in preclinical models.74–80
In particular, Group I and II mGluR antagonists such as MPEP (2-methyl-6-[phenylethynyl]-pyridine) and MGS-0039 had antidepressant-like and neuroprotective effects in animal models.81–84
Similar effects were observed with selective Group III mGluR agonists.77,79,85
Several compounds that modulate mGluRs are currently under development for treating MDD.
Postsynaptic Density Proteins
Other potentially relevant targets involving the glutamatergic synapse include the postsynaptic density (PSD) proteins. These proteins (PSD95, SAP102, and others), which interact with ionotropic glutamate receptors at the synaptic membrane, modulate receptor activity and signal transduction. For instance, NMDAR activation interacts directly with PSD95, thereby playing a critical role in the regulation of membrane trafficking, clustering, and downstream signaling events. In mood disorders, decreased PSD95 levels were observed in the dentate gyrus of individuals with BPD.53
In individuals with MDD, PSD95 levels were found to be significantly increased in the limbic system.86
SAP102, which interacts primarily with the NMDAR-2B subunit, has been shown to decrease NMDAR-2B subunit expression in individuals with mood disorders, a finding that was correlated with decreased expression of NMDAR subunits in the limbic system.24,87,88
While these findings suggest that PSD proteins may interact with NMDARs in the pathophysiology of mood disorders, currently no compounds specifically targeting PSD proteins have been developed.