Modulation of NMDA receptor function by inhibition of D-amino acid oxidase in rodent brain.

Observations that N-Methyl-D-Aspartate (NMDA) antagonists produce symptoms in humans that are similar to those seen in schizophrenia have led to the current hypothesis that schizophrenia might result from NMDA receptor hypofunction. Inhibition of D-amino acid oxidase (DAAO), the enzyme responsible for degradation of D-serine, should lead to increased levels of this co-agonist at the NMDA receptor, and thereby provide a therapeutic approach to schizophrenia. We have profiled some of the preclinical biochemical, electrophysiological, and behavioral consequences of administering potent and selective inhibitors of DAAO to rodents to begin to test this hypothesis. Inhibition of DAAO activity resulted in a significant dose and time dependent increase in D-serine only in the cerebellum, although a time delay was observed between peak plasma or brain drug concentration and cerebellum D-serine response. Pharmacokinetic/pharmacodynamic (PK/PD) modeling employing a mechanism-based indirect response model was used to characterize the correlation between free brain drug concentration and D-serine accumulation. DAAO inhibitors had little or no activity in rodent models considered predictive for antipsychotic activity. The inhibitors did, however, affect cortical activity in the Mescaline-Induced Scratching model, produced a modest but significant increase in NMDA receptor-mediated synaptic currents in primary neuronal cultures from rat hippocampus, and resulted in a significant increase in evoked hippocampal theta rhythm, an in vivo electrophysiological model of hippocampal activity. These findings demonstrate that although DAAO inhibition did not cause a measurable increase in D-serine in forebrain, it did affect hippocampal and cortical activity, possibly through augmentation of NMDA receptor-mediated currents.

Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.

3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.

Integrating clinical psychology into primary care settings.

The primary care setting offers a mostly new and exciting opportunity for clinical psychology. Historically, psychology has been relegated to the "back forty," distant and far removed from mainstream medicine in most major hospitals. The primary care integration possibilities for clinical psychology are many. The present article will highlight these opportunities as well as provide the reader with an understanding as to why this conceptual paradigm and practical shift is needed as well as how to integrate clinical psychology services into the primary care setting.

Walter Reed Army Medical Center's mental health response to the Pentagon attack.

The September 11 terrorist attack on the Pentagon captured the attention and concern of America as well as the world. Given the extent of devastation, and the number of deaths at the Pentagon, it was believed that the uniformed mental health services would serve a pivotal role in the recovery and relief efforts. This article provides a synopsis of the complex and multidisciplinary mental health services provided by Walter Reed Army Medical Center in the wake of the September 11 attack on the Pentagon. This article offers an overview of the functions and roles of mental health team members, describes a constellation of services rendered, and describes how missions differed inside and outside of the Pentagon. Additionally, the authors provide the reader with how services were provided at the Family Assistance Center to family members of those killed during the attack. Liaison with civilian medical, mental health, and relief agencies and facilities will be discussed as well. The mental health response was an intensive and complicated experience and has yielded many lesson learned. To this end, the authors will provide the reader with an understanding of how the lessons learned during this mission may assist mental health commanders and leaders in planning and responding to similar deployments in the future.