These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.

No abstract

The purpose of this retrospective, multivariate analysis is to examine how medical conditions and demographic characteristics affect the costs of treating individuals diagnosed with anxiety. Data from MarketScan Databases [The MEDSTAT Group, 2000] were used to identify individuals with new episodes of anxiety. Multivariate analysis was used, with the dependent variable being the log of total medical costs. This analysis controlled for demographic characteristics, medical comorbidities, anxiety diagnosis, and prior resource utilization. A smearing estimate is used to calculate the total medical costs for patients with any anxiety disorder. The mean estimated total medical cost for individuals diagnosed with any anxiety disorder was $6,475. The multivariate model indicates that controlling for demographics and other disease states, generalized anxiety disorder (GAD), panic disorders, and posttraumatic stress disorder (PTSD) are associated with a $2,138, $1,603, and $3,940 increase, respectively, in the total medical cost (P < .0001). The incremental impact of depression, other anxiety disorders, and prior mental health diagnoses on the total medical costs were $1,945, $1,900, and $1,515, respectively (P < .0001). Individuals with the highest costs, and therefore the greatest need for intervention, are anxious patients with depression, individuals diagnosed with PTSD or GAD, and individuals diagnosed with both anxiety and a comorbid medical condition such as an acute myocardial infarction or diabetes.

These results suggest that LY354740 has an anxiolytic profile in humans without being sedative.