In the past 12 months, there has been substantial progress in our understanding of molecular processes related to the pathogenesis of major psychiatric and substance use disorders, and impressive translation of this knowledge toward developing better treatment. For example, our basic understanding of brain glutamate systems has yielded tremendous advances. Glutamate is the major excitatory neurotransmitter in the brain.1 It is involved in the neuro-circuitry of memory, emotions, and cognition and is implicated in myriad psychiatric conditions, including depression, anxiety, schizophrenia, drug addiction, and neuropsychiatric disorders.
This article reviews the recent knowledge about glutamate in different psychiatric conditions based on research published in the past year.
Stress is an important risk factor in the genesis of anxiety disorder. Animal studies have shown that stress precipitates glutamate release in limbic regions that may in part act to stimulate the hypothalamus-pituitary-adrenal axis and contribute to glucocorticoid-induced neurotoxicity.2 Recent studies have found dendritic remodeling, synaptic spine reductions, glial loss, and possibly volumetric reductions from glutamate excess following stress.1 Therefore, new drugs that target glutamatergic neurotransmission may be promising candidates for pharmacological treatments for patients who have stress-related anxiety disorders.
Work by Riaza Bermudo-Soriano and colleagues3 suggests that N-methyl-D-aspartate receptor (NMDA-R) antagonists (memantine), NMDA-R partial agonists (D-cycloserine), and metabotropic glutamate receptors 2 and 3 (mGluR2/3) allosteric modulators (LY354740 and LY544344) may be candidates for the treatment of anxiety disorders. In preliminary human studies, presynaptic autoreceptor mGluR2/3 agonists seem to be associated with clinical efficacy.4
The monoamine hypothesis for mood disorders has been the dominant model since the 1960s.5 This has been challenged because monoamine antidepressants are only effective in 50% to 60% of depressed patients, and only about 70% respond after 4 acute treatment steps based on STAR*D algorithms.6 There is now evidence that glutamate dysfunction is involved in the limbic and prefrontal circuits of depressed individuals. For example, there is an increase of extracellular glutamate during acute and chronic stress and during depression.1
Animal and human studies have indicated that targeting the glutamate system may hasten onset of action of antidepressant treatment.1 There is a growing interest in ketamine(Drug information on ketamine)—a nonselective NMDA-R antagonist. Subanesthetic doses appear to enhance the strength of cortical synapses through NMDA-R– and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-dependent and neurotrophic mechanisms and may rapidly reverse prefrontal cortex–based deficits in depression at the neurocircuitry level. The result may be the amelioration of clinical symptoms.2
Zarate and colleagues7 replicated their previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response and a rapid diminution in suicidal ideation. Limitations included a small sample (N = 15) and short duration (2 weeks); also, improvement remained significant over placebo for only 3 days.
A recent review by Covvey and colleagues8 concluded that for depressive symptoms in treatment-resistant depression, ketamine produced rapid reductions in depressive symptoms and had a relatively benign adverse-effect profile. However, the sustainability effect remains unknown. Testing the safety and tolerability of repeated-dose ketamine remains a high priority of future investigations.9