Review
Novel glutamatergic agents for major depressive disorder and bipolar disorder

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Abstract

Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BPD) are common, chronic, recurrent mental illnesses that affect the lives and functioning of millions of individuals worldwide. Growing evidence suggests that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of mood disorders as well as the efficacy of glutamatergic agents as novel therapeutics.

Highlights

ā–ŗ Mood disorders affect the lives and functioning of millions of individuals worldwide. ā–ŗ The glutamatergic system is central to the pathophysiology of mood disorders. ā–ŗ We review the efficacy of glutamatergic agents as novel therapeutics for mood disorders.

Introduction

Mood disordersā€”major depressive disorder (MDD) and bipolar disorder (BPD)ā€”are serious, debilitating, life-shortening illnesses that affect millions of individuals worldwide. The World Health Organization (WHO) predicted that, by 2020, MDD would be the second leading cause of disability worldwide (Murray and Lopez, 1996). Although most patients with mood disorders receive some benefit from available treatments (Rush et al., 2006, Trivedi et al., 2006), the largest open label study examining the effectiveness of pharmacological treatment of MDD conducted to date (STAR*D) (Trivedi et al., 2006) found that less than one third of patients achieved remission with an adequate trial of a standard antidepressant after up to 14Ā weeks of treatment. Furthermore, half of the patients with MDD in the STAR*D study did not achieve remission until they had completed two antidepressant trials and nearly 24Ā weeks. Similarly, many patients with BPD do not respond to existing medications (Judd et al., 2002), particularly during depressive episodes (Nierenberg et al., 2006, Rush et al., 2006).

Thus, therapeutic options for these devastating disorders are still far from adequate for treating acute illness episodes, relapses, and recurrences, as well as for restoring premorbid functioning (Insel and Scolnick, 2006, Machado-Vieira et al., 2008), and the development of new therapies is essential. Such treatments would be expected to be more effective for more patients, be better tolerated, and act more rapidly than currently available therapeutics. In this context, considerable research has taken place over the last decade regarding the role of the glutamatergic system in the pathophysiology of mood disorders. Furthermore, findings from diverse studies suggest the relevance of the glutamatergic system in the development of novel agents to treat mood disorders. In this article, we highlight the promising nature of some of these recent advances, with a special focus on human studies.

Section snippets

The functional tripartite glutamatergic system

Glutamate is the most abundant excitatory neurotransmitter in the brain, and acts in three different cell compartmentsā€”the pre- and postsynaptic neurons and gliaā€”that together characterize the ā€œtripartite glutamatergic synapseā€ (Machado-Vieira et al., 2009a). Physiological activity in the glialā€“neuronal glutamateā€“glutamine cycle includes the uptake and inactivation of glutamate after its actions as a neurotransmitter have been completed, an effect that aims to prevent toxic effects secondary to

Tripartite glutamatergic synapse dysfunction in mood disorders

Synaptic levels of glutamate can rise to excitotoxic concentrations rapidly after an insult (e.g., trauma, ischemia) or when glutamate transporter function is decreased, which may involve direct changes in glutamate packaging, release, and reuptake. Diverse pathophysiological mechanisms have been described. For example, inhibition of astrocytic reuptake of glutamate rapidly decreases glutamate uptake, which can lead to a hyperglutamatergic state and neural toxicity due to increased

Mood disorders: therapeutic targets and new agents that act through the tripartite glutamatergic synapse

Many studies have provided important insights regarding the role of the glutamatergic system in the pathophysiology and therapeutics of psychiatric and neurological illnesses. Indeed, glutamatergic system dysfunction has been implicated in the pathophysiology of many different disorders including amyotrophic lateral sclerosis (ALS), Huntington's chorea, epilepsy, Alzheimer's disease, schizophrenia, and anxiety disorders. Thus, dysfunction of glutamatergic neurotransmission may be a common

Riluzole

Riluzole (2-amino-6-trifluoromethoxy benzothiazole), which has both neuroprotective and anticonvulsant properties, is a glutamatergic modulator approved by the FDA for the treatment of ALS. Although riluzole induces no known direct effects on NMDARs or KARs (Debono et al., 1993), it inhibits glutamate release by inhibiting voltage-dependent sodium channels in neurons, its best known mechanism; riluzole also enhances AMPA trafficking and membrane insertion of GluR1 and GluR2 and increases

Conclusions

Glutamate is the main excitatory neurotransmitter in the human brain. Based on this fact alone, one might expect agents that act on the glutamatergic system to have therapeutic efficacy in some psychiatric disorders. Glutamate controls synaptic excitability and plasticity in most brain circuits, including limbic pathways involved in plasticity and mood disorders. Thus, drugs that target glutamate neuronal transmission offer significant novel approaches for the treatment of mood disorders.

Acknowledgments and disclosure

The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, National Institutes of Health (IRP-NIMH-NIH). Dr. Zarate is listed among the inventors on a patent application submitted for the use of ketamine in depression. He has assigned his rights on the patent to the US government. The authors have no conflict of interest to disclose, financial or otherwise.

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