Inpatient antipsychotic medication switching and rehospitalization risk among patients with schizophrenia-spectrum disorders.

OBJECTIVE: To describe patterns of antipsychotic switching among patients hospitalized for schizophrenia and to correlate antipsychotic switching with hospital readmission risk. METHODS: We identified 3295 patients with index hospitalizations for schizophrenia or schizoaffective disorder from New York State Medicaid claims 2017-2018 who had filled at least one prescription for an antipsychotic in both the 44 days (one month +14 day grace period) prior to and after their admission. We identified patients who had kept or switched any of their antipsychotic medication between the pre- and post-periods surrounding their index hospitalization. We compared the kept and switched any groups, adjusting for patient characteristics. RESULTS: Of patients who had filled antipsychotic prescriptions in both the 44 days prior to and after their hospitalization, 1599 (48.6 %) had switched at least one antipsychotic and 1215 (36.8 %) had switched their primary antipsychotic. Switching any antipsychotic was associated with increased hazards of readmission, HR = 1.21, 95%CI 1.09-1.35, which was slightly concentrated during the first 90 days after hospital discharge. CONCLUSIONS: Switching antipsychotic medications during hospitalization occurs commonly and is associated with higher rehospitalization risk following hospital discharge.

Retrospective State Medicaid Claims Analysis of Children and Adults With Obsessive-Compulsive Disorder.

OBJECTIVE: With a lifetime U.S. prevalence of 2.3%, obsessive-compulsive disorder (OCD) is a chronic condition often producing reduced quality of life and disability when left untreated. Little is known about the prevalence or treatment of diagnosed OCD in public behavioral health systems. METHODS: Using a claims analysis of 2019 New York State Medicaid data (N=2,245,084 children; N=4,274,100 adults), the authors investigated the prevalence and characteristics of children and adults with OCD. The authors also examined whether these individuals received treatment with medication or psychotherapy. RESULTS: The prevalence of OCD was 0.2% among children and 0.3% among adults. Fewer than half of children (40.0%) and adults (37.5%) received U.S. Food and Drug Administration-approved medications (with or without psychotherapy); another 19.4% of children and 11.0% of adults received 45- or 60-minute psychotherapy alone. CONCLUSIONS: These data demonstrate the need for public behavioral health systems to increase their capacity to identify and treat OCD.

Prediction Tool for Individual Outcome Trajectories Across the Next Year in First-Episode Psychosis in Coordinated Specialty Care.

Importance: In coordinated specialty care (CSC) settings for people with a first episode of psychosis, the development of reliable, validated individual-level prediction tools for key outcomes may be informative for shared clinician and client decision-making. Objective: To develop an individual-level prediction tool using machine-learning methods that predicts a trajectory of education/work status or psychiatric hospitalization outcomes over a client's next year of quarterly follow-up assessments. Additionally, to visualize these predictions in a way that is informative to clinicians and clients. Design, Setting, and Participants: Individual-level data were collected for all patients enrolled in the OnTrackNY program at enrollment and at quarterly follow-ups using standardized forms. The OnTrackNY program, a network of CSC sites in New York State, provides person-centered, recovery-oriented, and evidence-based psychosocial and pharmaceutical interventions to individuals aged 16 to 30 years with recent-onset (<2 years) nonaffective psychosis. Although data collection is ongoing, data for this study were collected from October 2013 to December 2018, and the time frame for analysis was July 2020 to May 2021. Data were separated into a training/cross-validation set to perform internally validated model development and a separate holdout test set (~20% of the sample) for external validation. Random probability forest models were developed to predict individual-level trajectories of outcomes. Exposures: Forty-three individual-level demographic and clinical features collected at enrollment in OnTrackNY, 25 of which were time-varying and updated at quarterly follow-up assessments, and 13 site-level demographic and economic census variables. Main Outcomes and Measures: Individual-level education and/or employment status and psychiatric hospitalization trajectories at quarterly follow-up periods across the first 2 years of CSC. Results: The total study sample consists of 1298 individuals aged 16 to 30 years and included 341 women (26.3%), 949 men (73.1%), and 8 (<1%) with another gender. Prediction models performed well for 1-year trajectories of education/work across all validation sets, with areas under the receiver operating characteristic curve (AUCs) ranging from 0.68 (95% CI, 0.63-0.74) to 0.88 (95% CI, 0.81-0.96). Predictive accuracy for psychiatric hospitalization 3 months ahead reached AUC above 0.70; moreover, predictions of future psychiatric hospitalizations at 6 months and beyond were consistently poor, with AUCs below 0.60. Given the good externally validated performance for predicting education/work, a prototype interactive visualization tool displaying individual-level education/work trajectories and related features was developed. Conclusions and Relevance: This study suggests that accurate prediction tools can be developed for outcomes in people with first-episode psychosis, which may help inform shared clinician/client decision-making. Future work should study the effectiveness of its deployment, including proper communication to inform shared clinician/client decision-making in the context of a learning health care system. At present, more work is needed to develop better performing prediction models for future psychiatric hospitalizations before any tool is recommended for this outcome.

Rates of Inpatient and Emergency Room Use Before and After Discharge Among Medicaid Enrollees in OnTrackNY.

OBJECTIVE: This study examined hospital and emergency room (ER) use among Medicaid enrollees before and after discharge from OnTrackNY, a coordinated specialty care program for recent-onset psychosis. METHODS: Medicaid claims data were linked to program data. Inpatient hospitalization, inpatient days, and ER visits were assessed in the 6 months prior to OnTrackNY enrollment and 6 months prior to and after discharge. The sample consisted of 138 participants with continuous Medicaid enrollment during the study. RESULTS: Inpatient visits significantly declined from the pre-OnTrackNY enrollment period to the predischarge period (ß=-1.23, standard error [SE]=0.22, p<0.001), did not significantly change in the first 6 months after discharge (ß=0.19, SE=0.26, p=0.48), and remained significantly lower than before OnTrackNY enrollment (ß=-1.05, SE=0.20, p<0.001). Similar patterns were observed for inpatient days and ER use. CONCLUSIONS: ER and hospital use declined during OnTrackNY participation and did not significantly change in the first 6 months after discharge.

A New Method for Estimating Incidence of First Psychotic Diagnosis in a Medicaid Population.

OBJECTIVE: Early intervention programs for first-episode psychosis (FEP) require population-based methods to identify individuals with FEP. This study adapted a previously published method to estimate incidence of first psychotic diagnosis in a state Medicaid program. Secondary aims were to examine demographic and service patterns associated with a first psychotic diagnosis in Medicaid. METHODS: A retrospective, population-based study of New York State Medicaid data was conducted to identify first occurrence of psychotic diagnosis among persons ages 15-35 between January 1, 2013, and December 31, 2017 (N=31,606). Age-stratified incidence rates (IRs) were calculated by demographic characteristics, first-diagnosis type, and service-related characteristics. Review of charts from OnTrackNY and Medicaid managed care organizations (MCOs) was conducted to confirm identified cases. Initial IRs and confirmation rates were used to estimate adjusted IRs. RESULTS: Age-stratified IRs varied by demographic, diagnostic, and service-related characteristic. IRs of FEP were higher for persons ages 15 to 25 relative to persons ages 26-35 if the first provider was an acute behavioral health emergency or inpatient setting (rate ratio=1.286; 95% confidence interval=1.24-1.33). Case confirmation rates were 90% for OnTrack NY and 53% for the MCOs. Adjusted annual IR of first diagnosis of psychosis was 272 per 100,000. CONCLUSIONS: Incidence of first psychotic diagnosis in this Medicaid population was higher than previously found in insured populations. Future work will focus on algorithm refinements and piloting outreach. Administrative data algorithms may be useful to providers, Medicaid MCOs, and state Medicaid authorities to support case finding and early intervention.

Results of a Coordinated Specialty Care Program for Early Psychosis and Predictors of Outcomes.

OBJECTIVE: This study prospectively evaluated outcomes of OnTrackNY, a statewide coordinated specialty care (CSC) program for treatment of early psychosis in community settings, as well as predictors of outcomes. METHODS: The sample included 325 individuals ages 16-30 with recent-onset nonaffective psychosis who were enrolled in OnTrackNY and who had at least one three-month follow-up. Clinicians provided data at baseline and quarterly up to one year. Domains assessed included demographic and clinical characteristics, social and occupational functioning, medications, suicidality and violence, hospitalization, and time to intervention. Primary outcomes included the symptoms, occupational functioning, and social functioning scales of the Global Assessment of Functioning (GAF), as adapted by the U.S. Department of Veterans Affairs Mental Illness Research, Education and Clinical Center; education and employment status; and psychiatric hospitalization rate. RESULTS: Education and employment rates increased from 40% to 80% by six months, hospitalization rates decreased from 70% to 10% by three months, and improvement in GAF scores continued for 12 months. Female gender, non-Hispanic white race-ethnicity, and more education at baseline predicted better education and employment status at follow-up. CONCLUSIONS: Individuals with early psychosis receiving CSC achieved significant improvements in education and employment and experienced a decrease in hospitalization rate. Demographic variables and baseline education predicted education and employment outcomes. CSC teams should make particular effort to support the occupational goals of individuals at increased risk of not engaging in work or school, including male participants and participants from racial and ethnic minority groups.

Zebrafish Larvae Model of Dilated Cardiomyopathy Induced by Terfenadine.

BACKGROUND AND OBJECTIVES: Dilated cardiomyopathy can be the end-stage of severe cardiac disorders and directly affects the cardiac muscle, inducing cardiomegaly and heart failure (HF). Although a wide variety of animal models are available to study dilated cardiomyopathy, there is no model to assess dilated cardiomyopathy with non-invasive, simple, and large screening methods. METHODS: We developed a dilated cardiomyopathy model in zebrafish larvae using short duration terfenadine, a known cardiotoxic drug that induces ventricular size dilation. Fractional shortening of zebrafish hearts was calculated. RESULTS: We treated zebrafish with 5 to 10 µM terfenadine for 24 hours. In terfenadine-treated zebrafish, blood frequently pooled and clotted in the chamber, and circulation was remarkably reduced. Atria and ventricles were swollen, and fluid was deposited around the heart, mimicking edema. Cardiac contractility was significantly reduced, and ventricular area was significantly enlarged. Heart rate was markedly reduced even after terfenadine withdrawal. Acridine orange staining also showed that terfenadine increased cardiomyocyte apoptosis. A significant increase of natriuretic peptide B (NPPB) mRNA was found in terfenadine-treated zebrafish. A low dose of terfenadine (5-10 µM) did not show mortality in short-term treatment (24 hours). However, moderate dose (35-45 µM) terfenadine treatment reduced zebrafish survival within 1 hour. CONCLUSION: With advantages of rapid sample preparation procedure and transparent observation of the live heart, this model can potentially be applied to large-scale drug screening and toxicity assays for non-ischemic HF.

OnTrackNY: The Development of a Coordinated Specialty Care Program for Individuals Experiencing Early Psychosis.

OnTrackNY is a coordinated specialty care program that delivers early intervention services to youths experiencing a first episode of nonaffective psychosis. Treatment aims to help individuals improve their mental health and achieve personal goals related to work, school, and social relationships. This column describes OnTrackNY's progression from a research project to real-world implementation. The authors describe the treatment model, approach to training and dissemination, and procedures for collecting and sharing data with OnTrackNY teams and provide data on client characteristics and selected outcomes.

Suppression of Toll-Like Receptor 4 Dimerization by 1-[5-Methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine.

Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS) and triggers the activation of myeloid differention factor 88 (MyD88) and the Toll/interleukin-1 receptor domain-containing adapter, inducing interferon-ß (TRIF)-dependent major downstream signaling pathways. To evaluate the therapeutic potential of 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. Here, we investigated whether MNP modulates the TLR4 signaling pathways and which anti-inflammatory target in TLR4 signaling is regulated by MNP. MNP inhibited the activation of nuclear factor-κB (NF-κB) induced by LPS (TLR4 agonist), and it also inhibited the expression of cyclooxygenase-2 and inducible nitric oxide synthase. MNP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization in addition to IKKß. These results suggest that MNP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression.

Suppression of TLRs signaling pathways by 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine.

Toll-like receptors (TLRs) play significant roles in recognizing the pathogen-associated molecular patterns that induce innate immunity, and subsequently, acquired immunity. In general, TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-ß (TRIF)-dependent pathways, which lead to the activation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP) has been previously synthesized in our laboratory. To evaluate the therapeutic potential of MNP, its effect on signal transduction via the TLR signaling pathways was examined. MNP was shown to inhibit the activation of NF-κB and IRF3 induced by TLR agonists, as well as to inhibit the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. MNP also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the MyD88- or TRIF-dependent signaling pathways. These results suggest that MNP can modulate MyD88- and TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression.

1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine Suppresses Toll-Like Receptor 4 Dimerization Induced by Lipopolysaccharide.

Toll-like receptor 4 (TLR4) recognizes LPS and triggers the activation of the myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter, inducing interferon-ß (TRIF)-dependent major downstream signaling pathways. Previously, we presented biochemical evidence that 1-[4-Fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), which was synthesized in our laboratory, inhibits NF-κB activation induced by LPS. Here, we investigated whether FPP modulates the TLR4 downstream signaling pathways and what anti-inflammatory target in TLR4 signaling is regulated by FPP. FPP inhibited LPS-induced NF-κB activation by targeting TLR4 dimerization. These results suggest that FPP can modulate the TLR4 signaling pathway at the receptor level to decrease inflammatory gene expression.

An Initiative to Improve Clozapine Prescribing in New York State.

Clozapine remains the only medication approved for treatment-resistant schizophrenia. But underuse is the norm. In 2010, the New York State Office of Mental Health began a multifaceted initiative to promote the evidence-based use of clozapine. From 2009 to 2013, in the absence of a well-funded pharmaceutical marketing campaign, the proportion of new clozapine trials among all new outpatient antipsychotic trials increased 40% among adult New York Medicaid recipients with a diagnosis of schizophrenia. The largest gains occurred in state-operated clinics. New York's experience demonstrates the feasibility of making clozapine more accessible to patients who stand to benefit most.

Suppression of the TRIF-dependent signaling pathway of Toll-like receptor by CDr10b in RAW264.7 macrophages.

Toll-like receptors (TLRs) recognize distinct pathogen-associated molecular patterns and play a critical role in innate immune responses. TLR signaling pathways can be largely classified as either myeloid differential factor 88 (MyD88)- or toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. Compound of Designation red 10 binding (CDr10b) was synthesized to investigate its role in neuroinflammatory diseases. This study was conducted to determine whether CDr10b can affect TLR signaling pathways. CDr10b suppressed NF-κB activation as well as COX-2 and iNOS expression induced by TLR3 or TLR4 agonists. CDr10b also suppressed the activation of interferon regulatory factor 3 (IRF3) and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. These results indicate that CDr10b can modulate the TRIF-dependent pathway of TLRs and has the potential to become a new therapeutic drug for chronic inflammatory diseases.

Suppressive effects of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine on the Toll-like receptor signaling pathways.

When various pathogens invade a host, toll-like receptors (TLRs) play a significant role in recognizing the pathogen-associated molecular patterns carried by the pathogens to induce innate immune reaction, followed by acquired immunity reaction. TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent pathways. To evaluate the therapeutic potential of 1-[4-fluoro-2-(2-nitrovinyl)phenyl]pyrrolidine (FPP), previously synthesized in our laboratory, its effect on signal transduction via the TLR signaling pathways was examined. FPP inhibited the activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) induced by TLR agonists, as well as inhibited the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. FPP also inhibited the activation of NF-κB and IRF3 when induced by the overexpression of downstream signaling components of the TLRs. As a result, FPP has potential to become a new therapeutic drug for many inflammatory diseases.

CDr10b inhibits the expression of cyclooxygenase-2 and inducible nitric oxide synthase induced by lipopolysaccharide.

The pathophysiological processes of inflammation can lead to a host of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. The dysregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activation play important roles in the development of certain inflammatory diseases. Here, we investigated the effects of CDr10b which is originally developed for a microglia staining probe on inflammation, by modulating NF-κB activation and iNOS and COX-2 expression induced by lipopolysaccharide (LPS) in murine macrophages. The CDr10b suppressed NF-κB activation and iNOS and COX-2 expression induced by LPS. All the results suggest that CDr10b is a promising novel agent for the treatment of inflammatory diseases.

Suppression of TRIF-dependent signaling pathway of toll-like receptors by (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine.

Toll-like receptors (TLRs) play an important role in the recognition of microbial pathogens and induce innate immune responses. The recognition of microbial components by TLRs triggers the activation of myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent downstream signaling pathways. Previously, we synthesized (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine (NVPP), which contains a nitrovinyl-phenyl and pyrrolidine. To evaluate the therapeutic potential of NVPP, its effect on signal transduction via the TRIF-dependent pathway of TLRs induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly[I:C]) was examined. NVPP inhibited LPS or poly[I:C]-induced activation of nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), and the phosphorylation of IRF3, as well as inhibiting the activation of interferon-inducible genes such as interferon inducible protein-10 (IP-10). These results suggest that NVPP can modulate TRIF-dependent signaling pathways of TLRs, potentially resulting in effective therapeutics for chronic inflammatory diseases.

Suppression of inducible nitric oxide synthase expression induced by Toll-like receptor agonists by (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine.

Toll-like receptors (TLRs) recognize many pathogen-associated molecular patterns and induce innate immunity. TLR signaling pathways induce the activation of various transcription factors, such as nuclear factor-κB (NF-κB), leading to the induction of pro-inflammatory gene products, such as inducible nitric oxide synthase (iNOS). Here, we investigated the effect of an (E)-1-(2-(2-nitrovinyl)phenyl)pyrrolidine (NVPP), previously synthesized in our laboratory, on inflammation by modulating NF-κB activation and iNOS expression induced by TLR agonists in murine macrophages. NVPP suppressed NF-κB activation and iNOS expression induced by lipopolysaccharide (TLR4 agonist), polyriboinosinic polyribocytidylic acid (TLR3 agonist), and macrophage-activating lipopeptide 2kDa (TLR2 and TLR6 agonist). All the results suggest that NVPP is suitable for development as a new anti-inflammatory drug.

Phenethyl isothiocyanate regulates inflammation through suppression of the TRIF-dependent signaling pathway of Toll-like receptors.

AIMS: The aim of this study was to evaluate the therapeutic potential of the phenethyl isothiocyanate (PEITC) in Toll-like receptor (TLR) signaling pathways. MAIN METHODS: To evaluate the cytotoxic nature of PEITC in RAW 264.7 cells, cytotoxicity was determined using the MTS cell viability assay. RAW264.7 cells were transfected with a nuclear factor-κB (NF-κB), interferon ß (IFNß) PRDIII-I, or interferon inducible protein-10 (IP-10) luciferase plasmid and then luciferase enzyme activities were determined by luciferase assay. The expression of inducible nitric oxide synthase (iNOS) and phosphorylation of interferon regulatory factor 3 (IRF3) were determined by Western blotting. The levels of IP-10 were determined with culture medium by using an IP-10 enzyme-linked immunosorbent assay (ELISA) kit. KEY FINDINGS: PEITC suppressed the activation of IRF3 and the expression of IP-10 induced by lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly[I:C]). SIGNIFICANCE: TLRs play an important role in the induction of innate immune responses for host defense against invading microbial pathogens. PEITC found in cruciferous vegetables has an effect on treatment of many chronic diseases. Our results suggest that beneficial effects of PEITC on chronic inflammatory diseases are mediated through modulation of Toll-interleukin-1 receptor domain-containing adapter inducing interferon-ß (TRIF)-dependent signaling pathway of TLRs.