Glutamatergic Treatments: Randomized Controlled Trials
In this double-blind, randomized, crossover study, Zarate et al. (pages 939–946) sought to replicate prior findings of a rapid antidepressant response to ketamine in bipolar depression. They administered a single intravenous infusion of ketamine or placebo to individuals with bipolar depression who were also receiving either lithium or valproate. Within 40 minutes, depressive symptoms and suicidal ideation significantly improved in subjects receiving ketamine compared to placebo; this improvement remained significant through day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial.
Glutamatergic pathway abnormalities and a chronic redox imbalance have both been linked to autism, suggesting that N-acetylcysteine (NAC) may serve as a potentially successful treatment. In a double-blind randomized study, Hardan et al. (pages 956–961) evaluated the effectiveness of NAC in the treatment of irritability in children with autism. Compared to placebo, oral NAC resulted in significant improvements in irritability. Limited side effects were observed and NAC was well-tolerated.
D-cycloserine (DCS) has shown promising effects as a pharmacological supplement to exposure therapy. In a double-blind randomized trial, de Kleine et al. (pages 962–968) examined the effects of DCS on exposure treatment for posttraumatic stress disorder. The exposure treatment program effectively reduced symptoms regardless of whether patients received placebo or DCS. However, they found preliminary support for the use of DCS in a subgroup of patients with more severe symptoms needing longer treatment.
Treatment Effects and Mechanisms
Lessening conditioned responses elicited by drug-related cues may be a valuable component of addiction treatment. Myers and Carlezon (pages 947–955) review evidence that DCS, an N-methyl-D-aspartate (NMDA) receptor partial agonist, facilitates extinction of conditioned responses to drug-related cues. While the beneficial effects of DCS seem clear in animal models, the approaches used in clinical studies often make null effects difficult to interpret. They propose designs for future studies that may mitigate these limitations to provide a clearer indication of the therapeutic potential of DCS.
In healthy adults, NMDA antagonist ketamine induces behavioral, cognitive and electrophysiological changes similar to those observed in schizophrenia. In animals, NAC reverses the effects of NMDA antagonist phencyclidine, by stimulating the cystine-glutamate exchanger. Gunduz-Bruce et al. (pages 969–977) investigated whether NAC pretreatment attenuates ketamine-induced changes in healthy adults. Overall, NAC pretreatment did not reduce ketamine's effects, but when given alone, it significantly enhanced P300 amplitudes, suggesting a potential beneficial effect on cognition that merits further study.
NAC has been shown to inhibit cocaine seeking by elevating extrasynaptic glutamate levels in the nucleus accumbens. Using a cocaine extinction and reinstatement paradigm in rats, Kupchik et al. (pages 978–986) found that NAC-mediated stimulation produced opposite effects on glutamate transmission, inhibiting metabotropic glutamate receptors (mGluR) 2/3 but enhancing mGluR5. They also found that mGluR5 blockade augments the capacity of NAC to inhibit cocaine seeking. These findings suggest that efficacy of NAC treatment for addiction could potentially be enhanced by balancing the stimulation of mGluRs.
NMDA receptor (NMDA-R) antagonists elicit psychotic symptoms in humans and schizophrenia-like behavior in rodents, including an increase in cortical gamma activity. Kocsis (pages 987–995) measured changes in gamma power in freely moving rats after administration of NMDA-R antagonists with different subunit selectivity. Nonselective and NR2A subunit-blocking NMDA-R antagonists induced strong increases in gamma power, whereas blockade of other subunit receptors had only minor effects. This study provides evidence that NR2A receptors display preferential involvement in acute aberrant gamma activation after NMDA-R blockade.
Brain-derived neurotrophic factor is essential for synaptogenesis, the formation of synaptic spines that mediate the transmission of excitatory impulses. Ketamine has been found to stimulate synaptogenesis in prefrontal cortex. Liu et al. (pages 996–1005) now show that expression of the brain-derived neurotrophic factor Met allele in mice results in basal synaptic deficits and blocks synaptogenic and antidepressant actions of ketamine in prefrontal cortex, suggesting that the therapeutic response to this drug may be attenuated or blocked in depressed patients who carry the loss of function Met allele.
Redox-dysregulation, due to glutathione impairments, is a risk factor for schizophrenia. das Neves Duarte et al. (pages 1006–1014) used magnetic resonance spectroscopy (MRS) to quantify neurochemical concentrations in the anterior cortex of wild-type and GCLM knockout mice, which display chronic glutathione deficiencies. They observed changes in knockout mice that resemble, in part, those observed in the brains of schizophrenia patients. Alterations such as elevated glutamine, glutamate and glutamine/glutamate occurred primarily at prepubertal ages and were normalized with NAC treatment.
To examine the physiological mechanisms associated with ketamine's psychotomimetic and rapid-onset antidepressant actions, Chowdhury et al. (pages 1022–1025) employed MRS studies in rats to evaluate its effects on glutamate and γ-aminobutyric acid neurotransmitter cycling. They report that a subanesthetic dose of ketamine, but not an anesthetic dose, induces a rapid increase in amino acid neurotransmitter metabolism in the medial prefrontal cortex. Similar effects were not found in the hippocampus at either dose. These results provide supportive evidence that acutely increased levels of glutamatergic activity may be involved in ketamine's antidepressant effects.
Elevated Glutamate During Alcohol Withdrawal
Enhanced glutamatergic transmission has been implicated in acute withdrawal syndrome, but most work has been conducted preclinically. In their MRS study, Hermann et al. (pages 1015–1021) found increased glutamate levels during detoxification in corresponding prefrontal brain regions of both alcohol-dependent humans and rats compared to their respective control groups. These findings indicate that metabolic alterations related to glutamatergic neurotransmission may represent a biomarker for monitoring disease progression or treatment response in alcoholism.
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© 2012 Published by Elsevier Inc. All rights reserved.
