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Recent systematic reviews have encouraged the psychiatric research community to reevaluate the contours of schizophrenia epidemiology. This paper provides a concise overview of three related systematic reviews on the incidence, prevalence, and mortality associated with schizophrenia. The reviews shared key methodological features regarding search strategies, analysis of the distribution of the frequency estimates, and exploration of the influence of key variables (sex, migrant status, urbanicity, secular trend, economic status, and latitude). Contrary to previous interpretations, the incidence of schizophrenia shows prominent variation between sites. The median incidence of schizophrenia was 15.2/100,000 persons, and the central 80% of estimates varied over a fivefold range (7.7-43.0/100,000). The rate ratio for males:females was 1.4:1. Prevalence estimates also show prominent variation. The median lifetime morbid risk for schizophrenia was 7.2/1,000 persons. On the basis of the standardized mortality ratio, people with schizophrenia have a two- to threefold increased risk of dying (median standardized mortality ratio = 2.6 for all-cause mortality), and this differential gap in mortality has increased over recent decades. Compared with native-born individuals, migrants have an increased incidence and prevalence of schizophrenia. Exposures related to urbanicity, economic status, and latitude are also associated with various frequency measures. In conclusion, the epidemiology of schizophrenia is characterized by prominent variability and gradients that can help guide future research.
Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known about the inactivation of 2-AG, which can be hydrolyzed by multiple enzymes in vitro, including FAAH and monoacylglycerol lipase (MAGL). Here, we have taken a functional proteomic approach to comprehensively map 2-AG hydrolases in the mouse brain. Our data reveal that approximately 85% of brain 2-AG hydrolase activity can be ascribed to MAGL, and that the remaining 15% is mostly catalyzed by two uncharacterized enzymes, ABHD6 and ABHD12. Interestingly, MAGL, ABHD6, and ABHD12 display distinct subcellular distributions, suggesting that they may control different pools of 2-AG in the nervous system.
Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.
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