Glutamate Systems in DSM-5 Anxiety Disorders: Their Role and a Review of Glutamate and GABA Psychopharmacology

Abstract

Serotonin reuptake inhibitors and benzodiazepines are evidence-based pharmacological treatments for Anxiety Disorders targeting serotonin and GABAergic systems, respectively. Although clearly effective, these medications fail to improve anxiety symptoms in a significant proportion of patients. New insights into the glutamate system have directed attention toward drugs that modulate glutamate as potential alternative treatments for anxiety disorders. Here we summarize the current understanding of the potential role of glutamate neurotransmission in anxiety disorders and highlight specific glutamate receptors that are potential targets for novel anxiety disorder treatments. We also review clinical trials of medications targeting the glutamate system in DSM-5 anxiety disorders. Understanding the role of the glutamate system in the pathophysiology of anxiety disorder may aid in developing novel pharmacological agents that are effective in treating anxiety disorders.

Keywords: anxiety; clinical trials; glutamate; pharmacology; preclinical trials; psychiatry.

Figure 1

Glutamate is the biological precursor for GABA. Glutamate is synthesized from the nonessential amino acid glutamine, and glutamate is converted into GABA by the enzyme glutamate decarboxylase.

Figure 2

Depicts glutaminergic synapse and the receptors that are the site of action of glutaminergic drugs. Glutamate is packed into vesicles by vesicular glutamate transporter (vGluT). It binds to both ionotropic receptors and metabotropic receptors. Glial cells play a primary role in glutamate reuptake thus terminating the glutamate synaptic signal. Steady-state extra synaptic glutamate levels are also regulated by the glial cystine-glutamate antiporter (XC-).