Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.

Aim: To compare exenatide and sitagliptin glucose and glucoregulatory measures in subjects with type 2 diabetes.Methods: An 8-week, double-blind, randomized, crossover, single-centre study. Eighty-six subjects (58% female, body mass index 35 ± 5 kg/m2, haemoglobin A1c 8.3 ± 1.0%) received either exenatide 10 µg (subcutaneous) twice daily or sitagliptin 100 mg (oral) daily for 4 weeks and crossed to the other therapy for an additional 4 weeks. Main outcome was time-averaged glucose during the 24-h inpatient visits.Results: Both treatments decreased average 24-h glucose, but exenatide had a greater effect [between-group difference: −0.67 mmol/l, 95% confidence interval (CI): −0.9 to −0.4 mmol/l]. Both treatments decreased 2-h postprandial glucose (PPG), area under the curve of glucose above 7.8 mmol/l (140 mg/dl) and 11 mmol/l (200 mg/dl) and increased the time spent with glucose between 3.9 and 7.8 mmol/l (70 and 140 mg/dl) during 24 h, but exenatide had a significantly greater effect (p < 0.05). Both treatments decreased postprandial serum glucagon, with exenatide having a greater effect (p < 0.005). Both treatments decreased fasting blood glucose to a similar degree (p = 0.766). Sitagliptin increased, while exenatide decreased, postprandial intact glucagon-like peptide-1. Both drugs improved homeostasis model assessment of β-cell function (HOMA-B), with exenatide having a significantly greater effect (p = 0.005). Both exenatide and sitagliptin decreased 24-h caloric intake, with exenatide having a greater effect (p < 0.001). There was no episode of major hypoglycaemia. Adverse events were mild to moderate and mostly gastrointestinal in nature with exenatide. No study withdrawals were due to an adverse event.Conclusion: Compared to sitagliptin, exenatide showed significantly lower average 24-h glucose, 2-h PPG, glucagon, caloric intake and improved HOMA-B.

AimsTransient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide.MethodsA single subcutaneous dose (10 μg) of exenatide was administered to 120 healthy subjects (19–65 years, BMI 23–35 kg/m2). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax) of plasma exenatide concentrations over 8 h post-dose were compared.ResultsAmong all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m2 (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P-value < 0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and Cmax of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups.ConclusionAdministration of oral anti-emetics before a single 10-μg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment.

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Frege's puzzle is a fundamental challenge for accounts of mental and linguistic representation. This piece surveys a family of recent approaches to the puzzle that posit representational relations. I identify the central commitments of relational approaches and present several arguments for them. I also distinguish two kinds of relationism-semantic relationism and formal relationism-corresponding to two conceptions of representational relations. I briefly discuss the consequences of relational approaches for foundational questions about propositional attitudes, intentional explanation, and compositionality.