An Economic Evaluation of Coordinated Specialty Care (CSC) Services for First-Episode Psychosis in the U.S. Public Sector.

BACKGROUND: Schizophrenia spectrum disorders exert a large and disproportionate economic impact. Early intervention services may be able to alleviate the burden of schizophrenia spectrum disorders on diagnosed individuals, caregivers, and society at large. Economic analyses of observational studies have supported investments in specialized team-based care for early psychosis; however, questions remain regarding the economic viability of first-episode services in the fragmented U.S. healthcare system. The clinic for Specialized Treatment Early in Psychosis (STEP) was established in 2006, to explicitly model a nationally-relevant U.S. public-sector early intervention service. The purpose of this study was to conduct an economic evaluation of STEP, a Coordinated Specialty Care service (CSC) based in a U.S. State-funded community mental health center, relative to usual treatment (UT). METHODS: Eligible patients were within 5 years of psychosis onset and had no more than 12 weeks of lifetime antipsychotic exposure. Participants were randomized to STEP or UT. The annual per-patient cost of the STEP intervention per se was estimated assuming a steady-state caseload of 30 patients. A cost-offset analysis was conducted to estimate the net value of STEP from a third-party payer perspective. Participant healthcare service utilization was evaluated at 6 months and over the entire 12 months post randomization. Generalized linear model multivariable regressions were used to estimate the effect of STEP on healthcare costs over time, and generate predicted mean costs, which were combined with the per-patient cost of STEP. RESULTS: The annual per-patient cost of STEP was $1,984. STEP participants were significantly less likely to have any inpatient or ED visits; among individuals who did use such services in a given period, the associated costs were significantly lower for STEP participants at month 12. We did not observe a similar effect with regard to other healthcare services. The predicted average total costs were lower for STEP than UT, indicating a net benefit for STEP of $1,029 at month 6 and $2,991 at month 12; however, the differences were not statistically significant. CONCLUSIONS: Our findings are promising with regard to the value of STEP to third-party payers.

Investigating the allosteric response of the PICK1 PDZ domain to different ligands with all-atom simulations.

The PDZ family is comprised of small modular domains that play critical roles in the allosteric modulation of many cellular signaling processes by binding to the C-terminal tail of different proteins. As dominant modular proteins that interact with a diverse set of peptides, it is of particular interest to explore how different binding partners induce different allosteric effects on the same PDZ domain. Because the PICK1 PDZ domain can bind different types of ligands, it is an ideal test case to answer this question and explore the network of interactions that give rise to dynamic allostery. Here, we use all-atom molecular dynamics simulations to explore dynamic allostery in the PICK1 PDZ domain by modeling two PICK1 PDZ systems: PICK1 PDZ-DAT and PICK1 PDZ-GluR2. Our results suggest that ligand binding to the PICK1 PDZ domain induces dynamic allostery at the αA helix that is similar to what has been observed in other PDZ domains. We found that the PICK1 PDZ-ligand distance is directly correlated with both dynamic changes of the αA helix and the distance between the αA helix and ßB strand. Furthermore, our work identifies a hydrophobic core between DAT/GluR2 and I35 as a key interaction in inducing such dynamic allostery. Finally, the unique interaction patterns between different binding partners and the PICK1 PDZ domain can induce unique dynamic changes to the PICK1 PDZ domain. We suspect that unique allosteric coupling patterns with different ligands may play a critical role in how PICK1 performs its biological functions in various signaling networks.

Pharmacotherapy for inappropriate sexual behaviors in dementia: a systematic review of literature.

The aim of this study is to systematically review the published literature on pharmacotherapy for inappropriate sexual behaviors in dementia. Literature search of the 5 databases (PubMed, MEDLINE, EMBASE, PsychINFO, and COCHRANE collaboration) and the analysis of the data available for the pharmacotherapeutic treatments of inappropriate sexual behaviors in dementia were carried out. There are no published randomized controlled trials of pharmacotherapy for inappropriate sexual behaviors in dementia, but available data form uncontrolled trials, case series, and individual case reports suggest efficacy for antidepressants, antipsychotics, mood stabilizers, hormonal agents, cimetidine, and pindolol for the treatment of these behaviors. Although there are no controlled data for the treatment of inappropriate sexual behaviors in dementia, available data suggest efficacy for some commonly used pharmacotherapeutic agents.

A novel modelling mechanism of PAEL receptor and GABARAPL2 interaction involved in Parkinson's disease.

Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy. We show that the family of GABARAPs interact with the carboxy terminal (ct) of PAELR and find the cysteine rich region (-CCCCCC-EEC) of ct-PAELR interacts with the GABAA binding site of GABARAPL2. This interaction is modelled by in-slico analysis and confirmed using affinity chromatography, showing Myc-tagged GABARAPL2 is retained by a GST fusion of the ct-PAELR. We also demonstrate that transient transfection of GABARAPL2 in HEK293 cells reduces PAELR expression. This study supports the idea that protein levels of PAELR are likely regulated by a multitude of proteins including parkin, PICK1 and GABARAPL2 via mechanisms that include ubiquitination, proteasomal degradagtion and autophagy.

First-Episode Services for Psychotic Disorders in the U.S. Public Sector: A Pragmatic Randomized Controlled Trial.

OBJECTIVE: This study sought to determine the effectiveness of a comprehensive first-episode service, the clinic for Specialized Treatment Early in Psychosis (STEP), in an urban U.S. community mental health center by comparing it with usual treatment. METHODS: This pragmatic randomized controlled trial enrolled 120 patients with first-episode psychosis within five years of illness onset and 12 weeks of antipsychotic exposure. Referrals were mostly from inpatient psychiatric units, and enrollees were randomly allocated to STEP or usual treatment. Main outcomes included hospital utilization (primary); the ability to work or attend age-appropriate schooling-or to actively seek these opportunities (vocational engagement); and general functioning. Analysis was by modified intent to treat (excluding only three who withdrew consent) for hospitalization; for other outcomes, only data for completers were analyzed. RESULTS: After one year, STEP participants had less inpatient utilization compared with those in usual treatment: no psychiatric hospitalizations, 77% versus 56% (risk ratio [RR]=1.38, 95% confidence interval [CI]=1.08-1.58); mean hospitalizations, .33±.70 versus .68±.92 (p=.02); and mean bed-days, 5.34±13.53 versus 11.51±15.04 (p=.05). For every five patients allocated to STEP versus usual treatment, one additional patient avoided hospitalization over the first year (number needed to treat=5; CI=2.7-26.5). STEP participants also demonstrated better vocational engagement (91.7% versus 66.7%; RR=1.40, CI=1.18-1.48) and showed salutary trends in global functioning measures. CONCLUSIONS: This trial demonstrated the feasibility and effectiveness of a U.S. public-sector model of early intervention for psychotic illnesses. Such services can also support translational research and are a relevant model for other serious mental illnesses.

Cardiovascular mortality in schizophrenia: defining a critical period for prevention.

OBJECTIVE: Better understanding of the temporal development of cardiovascular risk will permit more targeted prevention of premature cardiovascular mortality in schizophrenia. METHODS: The sample for this analysis was drawn from referrals (between 2006 and '11) to an early psychosis clinic based in a U.S. urban community mental health center. 76 individuals with schizophrenia who were young (mean 22.4 years, SD 4.8), early course (median duration of illness 31 weeks) and with minimal prior antipsychotic exposure (median 2 weeks) were compared to age-, gender-, and race-matched peers drawn from the National Health and Nutrition Survey (2007-'08). Measures of cardiovascular risk at baseline, 6 months, and 1 year are reported. RESULTS: While indistinguishable from peers at entry, patients suffered pervasive adverse trajectories of cardiovascular risk factors over the subsequent year. 16 of 44 initial non-smokers became nicotine dependent and none of 32 entering smokers quit. 17 patients transitioned to overweight (BMI 25-29.9, n = 3) or obese (BMI>30, n = 14) categories, while only 24 of 38 (63%) sustained normal weight over one year. Similar adverse trends in blood pressure, lipids, and fasting glucose led to an increase in prevalence of metabolic syndrome (1.31% to 5.26%). 10-year cardiovascular risk estimates showed a small and significant increase although remaining in the low risk (<10%) category. CONCLUSIONS: The early emergence of obesity and smoking in younger schizophrenia samples provides a rational focus for primary prevention of premature cardiovascular mortality. The first year of treatment constitutes the beginning of a critical period for such preventive efforts.

Hoofbeats and zebras: neurodegenerative disorder presenting as a "first episode" of psychosis.

Neurodegenerative disorders can include diverse neuropsychiatric symptoms. Here we present a case referred to a "first-episode" psychosis clinic with socio-occupational decline, auditory hallucinations and paranoid ideation who subsequently exhibited a rapid, severe cognitive and behavioral decline. The brain magnetic resonance imaging findings of the patient have shown a progressive cortical atrophy prominent in the frontal lobes due to a neurodegenerative disorder.

Primary leptomeningeal sarcomatosis; a pathology proven case with challenging MRI and clinical findings.

A 20-year-old male patient admitted with intractable seizures and progressive dementia is presented. Magnetic resonance imaging (MRI) examinations revealed diffuse leptomeningeal thickening, enhancement especially in the basal cisterns and multiple cystic formations in the brain stem, temporal lobes and basal ganglia. The pathologic examination from the right temporal lobe was consistent with leptomeningeal sarcoma. Marked regression of the symptoms and MRI lesions were detected following radiotherapy.