Considering the lengthy history of pharmacological treatment of schizophrenia, the development of novel antipsychotic agents targeting the glutamatergic system is relatively new. A glutamatergic deficit has been proposed to underlie many of the symptoms typically observed in schizophrenia, particularly the negative and cognitive symptoms (which are less likely to respond to current treatments). D-serine is an important coagonist of the glutamate NMDA receptor, and accumulating evidence suggests that D-serine levels and/or activity may be dysfunctional in schizophrenia and that facilitation of D-serine transmission could provide a significant therapeutic breakthrough, especially where conventional treatments have fallen short. A summary of the relevant animal data, as well as genetic studies and clinical trials examining D-serine as an adjunct to standard antipsychotic therapy, is provided in this article. Together, the evidence suggests that research on the next generation of antipsychotic agents should include studies on increasing brain levels of D-serine or mimicking its action on the NMDA receptor.

Paroxetine is widely prescribed because it has the indication for multiple psychiatric disorders. Our objective was to assess the effect of short-term administration of paroxetine on low-density lipoprotein cholesterol (LDL-C) levels in both healthy controls (HCs) and in patients with panic disorder (PD). Blood samples for measurement of LDL-C were collected atbaseline, after 8 weeks of paroxetine administration and post-discontinuation in 24 male HCs and nine male patients suffering from PD, for a total of 33 subjects. Paroxetine treatment, both in HCs and PD patients, induced a mean 9% increase per subject in LDL-C that normalized post-discontinuation, suggesting causality. The National Cholesterol Education Program (NCEP) guidelines suggest that this paroxetine-induced increase in LDL-C is clinically significant but would not warrant therapeutic intervention in this population selected to be at low cardiovascular risk. However, the increase in LDL-C levels raised above the threshold of 2.7 mmol/L (100 mg/dL) in 36% of our low-risk subjects. The LDL-C increase in this subgroup would be associated with a minor increase in coronary heart disease (CHD) risk. A similar 9% paroxetine-induced increase in LDL-C observed in the large number of psychiatric patients suffering from comorbid established CHD would be detrimental from a cardiovascular perspective and would oppose the new NCEP therapeutic goals of decreasing LDL-C levels by 30-40% in high and moderately high-risk patients. It is possible that longer treatment duration and use of higher doses of paroxetine would lead to a greater increase in LDL-C.

The herpes simplex virus virion host shutoff protein (vhs) is an mRNA-specific RNase that contributes to shutoff of host protein synthesis. We show here that vhs-induced mRNA decay proceeds 5 to 3 in an in vitro assay system derived from rabbit reticulocyte lysate.The herpes simplex virus (HSV) virion host shutoff protein (vhs) encoded by gene UL41 triggers accelerated turnover of cellular and viral mRNAs, thereby contributing to shutoff of host protein synthesis and timely transitions between the successive phases of viral gene expression (reviewed in reference 15). Although vhs is dispensable for virus replication in established cell lines in tissue culture, vhs mutants are severely impaired in mouse models of HSV infection (17, 18). Mounting evidence indicates that the attenuated phenotype of vhs mutants stems (at least in part) from an impaired ability to disarm elements of the host innate immune response including the type I interferon system (3,11,13,19). Thus, vhs is a key determinant of HSV virulence. vhs displays extensive amino acid sequence similarity to a family of cellular nucleases that are involved in DNA replication and repair (2, 7), and Everly and coworkers have provided compelling genetic and biochemical evidence that vhs has inherent RNase activity (7). It therefore seems plausible that most or all of the effects of vhs on cellular and viral gene expression stem from its RNase activity on target mRNAs. Thus, the mode of RNA decay induced by vhs is of considerable interest.Previous studies have shown that vhs-induced RNA degradation involves endoribonucleolytic cleavage of the target RNA, at least in in vitro assay systems (4,5,21). Remarkably, vhs preferentially targets mRNAs over other cytoplasmic RNA species in vivo (10,14). Some evidence suggests that this selectivity stems from interactions with the host translation initiation machinery: vhs initially targets the 5Ј region and sequences immediately downstream of picornavirus internal ribosome entry sites (IRES elements) on several mRNAs in an in vitro translation system (4, 5), and it renders the 5Ј end of HSV tk mRNA less abundant than the 3Ј end in vivo (9). In addition, vhs binds host translation initiation factors 4B (eIF4B) and eIF4H (1,8). Taken in combination, these observations have led to the hypothesis that vhs is initially delivered to mRNAs during the process of translation initiation (8) and then degrades the transcript in an overall 5Ј to 3Ј direction (9). However, it is important to note that the foregoing studies have not examined the mode of vhs-induced decay in detail beyond mapping the initial cleavage events. In addition, Taddeo and colleagues and Esclatine and colleagues have recently presented evidence that vhs-induced decay of some mRNAs bearing AU-rich instability elements initiates at or close to the 3Ј end of the transcript (6,20). Whether the subsequent decay of these AU-rich mRNAs displays directionality remains to be determined.To gain further insight into the overall pattern of mRNA decay induced by vhs, we c...

LDL-C levels are directly affected by the occurrence of a PA in males. These findings, in association with previous reports of increased cholesterol levels in PD patients, suggest that a chronic increase in LDL-C as a result of frequent PAs may be one of the mechanisms that contributes, at least in male patients, to previously reported increased CV risk in patients with PD. The gender difference and the temporal association between PAs and increased LDL-C may explain the inconsistency in the findings of previous investigations of cholesterol levels in PD patients.

Panic disorder has been associated with both an increased risk of coronary events as well as an increased risk of stroke. Hemoconcentration, with both a decrease in plasma volume and an increase in plasma viscosity, is a possible contributor to the risk of acute ischemic events. Our objectives were to demonstrate the process of hemoconcentration in response to induced panic symptoms and to assess the effect of pretreatment with ethinyl estradiol on panic-induced hemoconcentration. Fifteen male patients with panic disorder and 10 male healthy volunteers were included in a double-blind cross-over placebo-controlled design consisting of two injections of pentagastrin following randomized pretreatment with placebo and ethinyl estradiol. Plasma levels of hematocrit and hemoglobin were assessed at baseline and post-injections, and used to calculate an indirect estimation of the change in plasma volume. Pentagastrin-induced panic symptoms were associated with a mean decrease in plasma volume of 4.8% in the placebo pretreatment condition. Pretreatment with ethinyl estradiol attenuated this effect. The acute hemoconcentration observed in relation to pentagastrin-induced panic symptoms may be relevant to the increased risk of stroke and acute coronary events found in patients with panic disorder.