clinicaltrials.gov Identifier: NCT00870311.

Anxiety, stress, and trauma-related disorders are a major public health concern in the United States. Drugs that target the gamma-aminobutyric acid or serotonergic system, such as benzodiazepines and selective serotonin reuptake inhibitors, respectively, are the most widely prescribed treatments for these disorders. However, the role of glutamate in anxiety disorders is becoming more recognized with the belief that drugs that modulate glutamatergic function through either ionotropic or metabotropic glutamate receptors have the potential to improve the current treatment of these severe and disabling illnesses. Animal models of fear and anxiety have provided a method to study the role of glutamate in anxiety. This research has demonstrated that drugs that alter glutamate transmission have potential anxiolytic action for many different paradigms including fear-potentiated startle, punished responding, and the elevated plus maze. Human clinical drug trials have demonstrated the efficacy of glutamatergic drugs for the treatment of obsessive-compulsive disorder, posttraumatic stress disorder, generalized anxiety disorder, and social phobia. Recent data from magnetic resonance imaging studies provide an additional link between the glutamate system and anxiety. Collectively, the data suggest that future studies on the mechanism of and clinical efficacy of glutamatergic agents in anxiety disorders are appropriately warranted.

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ABSTRACT

Background Although the visual cortex does not typically receive much attention in addiction literature, neuroimaging studies often report significant activity in visual areas when drug users are exposed to drug cues. The purpose of this meta-analysis was to investigate the frequency with which occipital cortex activity is observed during drug cue exposure and to determine its spatial distribution. Methods A comprehensive literature search was performed of human functional neuroimaging studies of drug cue-reactivity. Fifty-five studies were used to determine the frequency with which clusters of significant visual cortex activity during visual drug cues versus non-drug cues were reported. The spatial distribution of visual cortex activations was determined via activation likelihood estimation (ALE; FDR corrected, p<0.01) in a subset of these studies (n=24). Results Eighty-six percent of studies that reported fMRI results for drug versus neutral visual cues within a substance-dependent group showed significant drug-elicited activity in the visual cortex. ALE revealed clusters in the left secondary visual cortex (BA 19) and clusters in the primary visual cortex (BA 17) that were consistently activated by drug cues. Conclusions These data demonstrate that the visual cortex, often overlooked in our discussions of the neural circuitry of addiction, consistently discriminates drug cues from neutral cues in substance dependent populations. While it remains unclear whether drug cue-elicited activation in occipital cortex is related to the rewarding properties of the drug and/or attentional mechanisms, these data support further exploration.

IMPORTANCE Depression is frequently undiagnosed in patients with chronic rhinosinusitis (CRS) and affects quality of life, productivity, and health care use. OBJECTIVE To examine depression-specific outcomes after medical or surgical treatment of CRS. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional, prospective study of patients with refractory CRS treated at tertiary academic rhinology centers was performed from March 1, 2011, to November 1, 2015. Data analysis was performed from October 1, 2015, to November 1, 2015. INTERVENTIONS Patients self-selected to undergo continued medical management or endoscopic sinus surgery for refractory CRS. MAIN OUTCOMES AND MEASURES Patients completed the 22-item Sinonasal Outcome Test (SNOT22), Rhinosinusitis Disability Index (RSDI), Pittsburgh Sleep Quality Index (PSQI), and missed productivity and medication use questionnaires before and at least 6 months after treatment. Computed tomography and endoscopy scoring were performed with reviewers masked to patient-reported data. Depression-specific outcomes were recorded using the 2-item Patient Health Questionnaire (PHQ2). RESULTS Baseline data were available on 685 patients, with 167 (24.4%) having depression according to the PHQ2 scores. The mean (SD) age of the patients was 50.5 (15.0) years, and 332 (48.4%) were male. Revision surgery status was the only baseline factor associated with depression (53.9%vs 38.0%, P < .001). Patients with depression had worse baseline SNOT22 (mean, 64.5 vs 47.6), PSQI (mean, 12.8 vs 8.4), productivity (mean, 22.8 vs 5.2 days missed), and medication use scores for oral antibiotics (mean, 23.8 vs 14.8) and oral corticosteroids (mean, 17.8 vs 9.9) (P < .001 for all). Medical and surgical treatments had similar outcomes for patients with depression with mean improvement in the PHQ2 scores from 3.96 to 1.91 (P < .001), and 110 of 167 patients (65.9%) categorized as having depression at baseline were categorized as not having depression after treatment. Improvements in the PHQ2 scores were associated with improvements in the SNOT22, PSQI, oral antibiotic use, and productivity scores (P ≤ .001 for all). CONCLUSIONS AND RELEVANCE Depression is a common comorbidity in patients with CRS and affects numerous quality-of-life and health care outcomes. There are few objective baseline factors to aid physicians in identifying depression in patients with CRS. Medical and surgical treatments for CRS improve depression and related clinical outcomes.

The high prevalence and comorbidity of anxiety and sleep problems, especially insomnia, suggest an important underlying relationship between these disorders. In this article, we highlight two theoretical models explaining this co-occurrence, provide a brief update on the association between anxiety-insomnia and anxiety-cataplexy in general, and review more specifically sleep problems in generalized anxiety, post-traumatic stress disorder, and panic disorder. We also explore sleep paralysis as an anxiety-sleep event. Our goal with this examination of selective anxiety-sleep problems is to provide clues about diagnostic and treatment approaches and frame strategies for future research.

Recent studies suggest exaggerated responses in the limbic system of patients with generalized social anxiety disorder in response to threat/anxiety-related social situations and aversive conditioning, processes mediated by the glutamatergic system. This single-voxel, high-field 1H-magnetic resonance spectroscopy study examined concentrations of glutamate, and other metabolites, in the anterior cingulate cortex and occipital cortex (control region) of 10 medication-naive patients with generalized social anxiety and 10 matched healthy comparison subjects. Glutamate (relative to creatine) levels were significantly higher in patients than controls in the anterior cingulate, but not occipital, cortex. Anterior cingulate glutamate/creatine levels were also correlated with intensity of social anxiety symptoms. These findings provide new evidence of glutamate's involvement in the neural mechanism underlying social phobia.