Pharmacogenomics-assisted schizophrenia management: A hybrid type 2 effectiveness-implementation study protocol to compare the clinical utility, cost-effectiveness, and barriers.

OBJECTIVES: The response to antipsychotic therapy is highly variable. Pharmacogenomic (PGx) factors play a major role in deciding the effectiveness and safety of antipsychotic drugs. A hybrid type 2 effectiveness-implementation research will be conducted to evaluate the clinical utility (safety and efficacy), cost-effectiveness, and facilitators and barriers in implementing PGx-assisted management compared to standard of care in patients with schizophrenia attending a tertiary care hospital in eastern India. METHODS: In part 1, a randomized controlled trial will be conducted. Adult patients with schizophrenia will be randomized (2: 1) to receive PGx-assisted treatment (drug and regimen selection depending on the results of single-nucleotide polymorphisms in genes DRD2, HTR1A, HTR2C, ABCB1, CYP2D6, CYP3A5, and CYP1A2) or the standard of care. Serum drug levels will be measured. The patients will be followed up for 12 weeks. The primary endpoint is the difference in the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale score between the two arms. In part 2, the cost-effectiveness of PGx-assisted treatment will be evaluated. In part 3, the facilitators and barriers to implementing PGx-assisted treatment for schizophrenia will be explored using a qualitative design. EXPECTED OUTCOME: The study findings will help in understanding whether PGx-assisted management has a clinical utility, whether it is cost-effective, and what are the facilitators and barriers to implementing it in the management of schizophrenia. TRIAL REGISTRATION: The study has been registered with the Clinical Trials Registry-India (CTRI/2023/08/056210).

A systematic review of the real-world effectiveness and economic and humanistic outcomes of selected oral antipsychotics among patients with schizophrenia in the United States: Updating the evidence and gaps.

BACKGROUND: Schizophrenia is a chronic, relapsing, and burdensome psychiatric disorder affecting approximately 0.25%-0.6% of the US population. Oral antipsychotic treatment (OAT) remains the cornerstone for managing schizophrenia. However, nonadherence and high treatment failure lead to increased disease burden and medical spending. Cost-effective management of schizophrenia requires understanding the value of current therapies to facilitate better planning of management policies while addressing unmet needs. OBJECTIVE: To review existing evidence and gaps regarding real-world effectiveness and economic and humanistic outcomes of OATs, including asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine/samidorphan, paliperidone, and quetiapine. METHODS: We conducted a literature search using PubMed, American Psychological Association PsycINFO (EBSCOhost), and the Cumulative Index of Nursing and Allied Health Literature from January 2010 to March 2022 as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language articles describing adults with schizophrenia receiving at least 1 of the selected OATs and reporting real-world effectiveness, direct or indirect costs, humanistic outcomes, behavioral outcomes, adherence/persistence patterns, or product switching were identified. RESULTS: We identified 25 studies from a total of 24,190 articles. Real-world effectiveness, cost, and adherence/persistence outcomes were reported for most OATs that were selected. Humanistic outcomes and product switching were reported only for lurasidone. Behavioral outcomes (eg, interpersonal relations and suicide ideation) were not reported for any OAT. The key economic outcomes across studies were incremental cost-effectiveness ratios, cost per quality-adjusted life-years, and health care costs. In studies that compared long-acting injectables (LAIs) with OATs, LAIs had a higher pharmacy and lower medical costs, while total health care cost was similar between LAIs and OATs. Indirect costs associated with presenteeism, absenteeism, or work productivity were not reported for any of the selected OATs. Overall, patients had poor adherence to OATs, ranging between 20% and 61% across studies. Product switching did not impact the all-cause health care costs before and after treatment. CONCLUSIONS: Our findings showed considerable gaps exist for evidence on behavioral outcomes, humanistic outcomes, medication switching, and adherence/persistence across OATs. Our findings also suggest an unmet need regarding treatment nonadherence and lack of persistence among patients receiving OATs. We identified a need for research addressing OATs' behavioral and humanistic outcomes and evaluating the impact of product switching in adults with schizophrenia in the United States, which could assist clinicians in promoting patient-centered care and help payers understand the total value of new antipsychotic drugs.

Variation of Clozapine Use for Treatment of Schizophrenia: Evidence from Pennsylvania Medicaid and Dually Eligible Enrollees.

While clozapine is the most effective antipsychotic treatment for treatment-resistant schizophrenia, it remains underutilized across the United States, warranting a more comprehensive understanding of variation in use at the county level, as well as characterization of existing prescribing patterns. Here, we examined both Medicaid and Medicare databases to (1) characterize temporal and geographic variation in clozapine prescribing and, (2) identify patient-level characteristics associated with clozapine use. We included Medicaid and Fee for Service Medicare data in the state of Pennsylvania from January 1, 2013, through December 31, 2019. We focused on individuals with continuous enrollment, schizophrenia diagnosis, and multiple antipsychotic trials. Geographic variation was examined across counties of Pennsylvania. Regression models were constructed to determine demographic and clinical characteristics associated with clozapine use. Out of 8,255 individuals who may benefit from clozapine, 642 received treatment. We observed high medication burden, overall, including multiple antipsychotic trials. We also identified variation in clozapine use across regions in Pennsylvania with a disproportionate number of prescribers in urban areas and several counties with no identified clozapine prescribers. Finally, demographic, and clinical determinants of clozapine use were observed including less use in people identified as non-Hispanic Black, Hispanic, or with a substance use disorder. In addition, greater medical comorbidity was associated with increased clozapine use. Our work leveraged both Medicaid and Medicare data to characterize and surveil clozapine prescribing. Our findings support efforts monitor disparities and opportunities for the optimization of clozapine within municipalities to enhance clinical outcomes.

One-Year Medication Treatment Patterns, Healthcare Resource Utilization, and Expenditures for Medicaid Patients with Schizophrenia Starting Oral Atypical Antipsychotic Medication.

Oral atypical antipsychotic (OAAP) medications are the most commonly prescribed treatment for the management of schizophrenia symptoms. This retrospective study, using Medicaid claims data (2016-2020), followed patients for 12 months after initiating OAAP therapy. Study outcomes included OAAP adherence, switching, augmentation, healthcare resource utilization (HRU), and expenditures. All-cause and schizophrenia-related HRU and expenditures were compared between adherent and nonadherent cohorts. Among 13,007 included patients (39.1 ± 12.8 years of age, 57.0% male, 36.1% Black, 31.8% White, 9.7% Hispanic), 25.7% were adherent to OAAPs (proportion of days covered [PDC] ≥ 0.8). During the 1-year follow-up period, Black individuals were in possession of an OAAP for an average of 166 days compared to 198 and 202 days for White and Hispanic patients, respectively. Approximately 16% of patients switched OAAP medications and 3.2% augmented therapy with an OAAP added to their index medication. Nearly 40% of patients were hospitalized during follow-up and 68.4% had emergency department (ED) visits. A greater proportion of nonadherent patients had all-cause inpatient (41.7% vs. 34.1%, p < 0.001) and ED visits (71.7% vs. 58.8%, p < 0.001) compared to adherent patients. Annual total healthcare expenditures were $21,020 per patient; $3481 higher for adherent versus nonadherent patients. Inpatient expenditures comprised 44.6% and 30.6% of total expenditures for nonadherent and adherent patients, respectively. Hospitalized patients' total expenditures were $23,261 higher compared to those without a hospitalization. Adherence to OAAP medication is suboptimal and associated with increased utilization of costly hospital and ED resources. Efforts to improve therapies and increase medication adherence could improve clinical and economic outcomes among individuals with schizophrenia.

Out-of-Pocket Costs for Long-Acting Injectable and Oral Antipsychotics Among Medicare Patients With Schizophrenia.

OBJECTIVE: The authors sought to describe out-of-pocket (OOP) costs among beneficiaries with schizophrenia differing in Medicare Part D low-income subsidy (LIS) status. METHODS: National 100% Medicare claims were used to identify all adult fee-for-service Medicare Part D beneficiaries with schizophrenia who used antipsychotics in 2019 (N=283,813). Proportions of patients by LIS status, OOP costs per prescription, and annual OOP costs were reported. Results were stratified by type of antipsychotic received (oral antipsychotic [OAP], first-generation long-acting injectable [FGA-LAI], or second-generation long-acting injectable [SGA-LAI]). RESULTS: In the final sample, 90.3% of beneficiaries had full LIS status, paying minimal copayments (29.6% institutionalized full LIS, paying $0; 42.2% noninstitutionalized full LIS, ≤100% federal poverty level [FPL], paying $1.25-$3.80; and 18.5% noninstitutionalized full LIS, >100% FPL, paying $3.40-$8.50). Only 0.9% of the sample received partial LIS status, and 8.8% had a non-LIS status. Non-LIS beneficiaries had the highest OOP costs, followed by partial LIS beneficiaries. Before entering catastrophic coverage, median OOP costs per prescription for generic OAPs, brand-name OAPs, FGA-LAIs, and SGA-LAIs were $10.85, $171.97, $26.09, and $394.28, respectively, for non-LIS beneficiaries and $3.69, $105.82, $9.35, and $229.20, respectively, for partial LIS beneficiaries. The annual total OOP costs varied substantially by LIS status (full LIS, $0-$130.79; partial LIS, $458.96; non-LIS, $998.81). CONCLUSIONS: Most Medicare beneficiaries with schizophrenia qualified for full LIS and faced minimal OOP costs for both OAPs and LAIs. The remainder (i.e., partial LIS and non-LIS beneficiaries) faced substantial OOP costs, both per prescription and annually, especially for SGA-LAIs.

Cardiac healthcare disparities and electrocardiography (ECG) differences in schizophrenia at end of life.

Schizophrenia is associated with early mortality of 15 to 20 years, and 80 % of deaths are due to cardiovascular disease with a three-times greater risk of sudden-cardiac-death. While lifestyle, medications, genetics, and healthcare disparities are contributing factors, the etiology of this complex process is not fully understood. The aim of this study is to examine cardiac-related healthcare utilization and electrocardiogram (ECG) outcomes in schizophrenia at the end of life (EOL). A cohort of individuals with schizophrenia (SG) (n = 610, ≥50 years) were identified retrospectively from a unified clinical data platform and measures of cardiovascular healthcare utilization were evaluated within a 12-month period prior to death. Similarly, a control group (n = 610) was randomly identified and matched by gender (53 % females) and age of death (72.8 ± 12.4 years). Statistical methods included Cochran-Mantel-Haenszel and mixed-effects logistic & linear regression tests with adjustments for match strata and marital status, race, age, and gender as covariates. Results indicate that SG was more likely to be unmarried, unemployed, or from minority groups (all p < 0.001), and more likely to have diabetes and/or cardiovascular disease (p < 0.001). SG was less likely to receive an ECG (p = 0.001) or cardiac catheterization procedure (p < 0.001). SG had a greater mean QTc (447.2 ms vs. 434.6 ms; p = 0.001) and were twice as likely to have "prolonged QT" on ECG report (p = 0.006). In conclusion, SG had reduced likelihood of cardiac-related healthcare interventions, and despite greater likelihood of prolonged QTc, a recognized biomarker of cardiac risk, ECG was less likely at EOL. Given greater cardiac comorbidity and risk of sudden cardiac death in schizophrenia, improved practice guidelines are needed.

Racial disparities in utilization of first-generation versus second-generation long-acting injectable antipsychotics in Medicaid beneficiaries with schizophrenia.

BACKGROUND: Multiple studies report racial disparities in antipsychotic prescription patterns. This study assessed demographic and clinical factors associated with the utilization of first-generation (FG) versus second-generation (SG) long-acting injectable (LAI) antipsychotics. METHODS: This retrospective, observational cohort analysis used claims data from the IBM MarketScan® Multi-State Medicaid database. The study included adults with an LAI claim between 01-January-2009 and 31-December-2018, an ICD-9-CM or ICD-10-CM diagnosis of schizophrenia, race recorded as Black or White, and ≥12 months of continuous enrollment before the index LAI. Descriptive analysis detailed the relationship between race and FG or SG LAI initiation. Multivariate logistic regression was used to assess potential associations with FG vs. SG LAI initiation, including clinical and demographic factors, comorbidities, and index year. RESULTS: A total of 10,773 patients were included: 6659 (62 %) Black and 4114 (38 %) White. Black patients had a higher utilization of FG LAIs than White patients (46.8 % vs. 38.9 %) over the 10 years analyzed. Black patients were more likely to utilize FG LAIs than White patients (odds ratio: 1.47; 95 % CI: 1.34, 1.62) after controlling for index year and covariates (race, age, gender, insurance plan type, Quan-Charlson Comorbidity index score, comorbidities, prior medications). Significant predictors of FG LAI utilization were older age, type of baseline oral antipsychotic (FG vs SG), type of coverage (managed care vs fee for service), and greater comorbidity burden. CONCLUSION: The utilization of FG LAIs was greater in Black compared to White Medicaid beneficiaries with schizophrenia over a 10-year period. These findings suggest that racial disparities exist in LAI initiation, with implications for differential quality of schizophrenia treatment.

Assessment of interrelationships between cognitive performance, symptomatic manifestation and social functioning in the acute and clinical stability phase of schizophrenia: insights from a network analysis.

BACKGROUND: It has been shown that various aspects of clinical manifestation of schizophrenia are strongly related to social functioning. However, it remains unknown as to whether similar factors predict social functioning at various stages of psychosis. Therefore, the present study aimed to compare the effects of interconnections between various domains of psychopathology and neurocognition on social functioning in people during acute phase of psychosis and those during remission of positive and disorganization symptoms using a network analysis. METHODS: Two independent samples of individuals with schizophrenia spectrum disorders were enrolled (89 inpatients during acute phase and 90 outpatients during remission of positive and disorganization symptoms). Clinical assessment covered the levels of functioning, positive, negative and depressive symptoms. Cognition was recorded using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Data were analyzed by means of the network analysis. Two separate networks of clinical symptoms, social functioning, and cognition (i.e., in patients during acute phase of psychosis and remitted outpatients with schizophrenia) were analyzed and compared with respect to the measures of centrality (betweenness, closeness, strength, and expected influence) and edge weights. RESULTS: In both networks, the majority of centrality metrics (expected influence, strength, and closeness) had the highest values for the RBANS scores of attention (the sum of scores from two tasks, i.e., digit span and coding) and immediate memory. In both networks, social functioning was directly connected to positive, negative and depressive symptoms as well as the RBANS scores of attention and language. Additionally, in remitted patients, social functioning was directly connected to the RBANS score of immediate memory. CONCLUSIONS: Findings from the present study indicate the central role of cognitive deficits, especially those related to attention, processing speed, working and immediate memory in shaping functional impairments regardless of schizophrenia phase. Therapeutic interventions that aim to improve functional capacity need to target these domains of neurocognitive performance.

Comparison of health resource usage and costs associated with first-generation and second-generation long-acting injectable antipsychotics for patients with schizophrenia: A nationwide population-based cohort study.

The aim of this study was to examine psychiatric resource utilization, medical costs and clinical outcomes for patients with schizophrenia who received either first-generation or second-generation long-acting injectable (LAI) antipsychotics. A retrospective cohort study was conducted using data from Taiwan's National Health Insurance Research Database (NHIRD). Patients who began either first-generation or second-generation LAI treatment between 2015 and 2017 were enrolled and followed for three years. The data were evaluated using survival analysis and Cox proportional hazards regression models. Our findings demonstrated that both first- and second-generation LAI therapies led to notable reductions in the frequency of psychiatric hospitalizations and the duration of hospital stays when compared to the initial measurements. Additionally, the second-generation LAI group exhibited significantly lower rates of psychiatric emergencies and hospitalizations, as well as shorter hospital stays, compared to the first-generation LAI group. However, it is worth noting that the second-generation LAI group incurred higher pharmacy fees despite these favorable outcomes. The utilization of both first- and second-generation LAIs can enhance medication adherence and decrease the risk of acute exacerbation in patients with schizophrenia. These findings hold significant implications for schizophrenia management and the efficient allocation of healthcare resources.

Racial and Ethnic Disparities in Long-Acting Injectable Antipsychotic Use in a National Sample of Medicare Beneficiaries With Schizophrenia.

This cross-sectional study assesses the racial and ethnic disparities in long-acting injectable antipsychotic use in a national sample of Medicare beneficiaries with schizophrenia.

The Lifetime Burden of Schizophrenia as Estimated by a Government-Centric Fiscal Analytic Framework.

Objective: To estimate the fiscal consequences of schizophrenia compared to the general US population using a "government perspective" fiscal analytic modeling framework capturing lost tax revenue and broader government costs in 2021.Methods: Schizophrenia was modeled from age 23 using a cohort-based Markov chain with 6-week cycles, simulating the effect of antipsychotic treatment sequences on remission and relapse. Markov states were defined using efficacy and safety outcomes from short- and long-term clinical trials. Mortality was based on US lifetables, schizophrenia-related suicide, and cardiovascular risks. A semi-Markov model with annual cycles simulated the likelihood and costs of incarceration and homelessness in community-based individuals. Lifetime fiscal consequences were estimated conditionally to survival, remission/relapse status, and likelihood of socioeconomic outcomes. Costs and life years were discounted at 3.0% annually. Uncertainty was explored in 1-way and scenario analyses.Results: Unemployment, disability, incarceration, homelessness, health care use, and productivity losses were more common in people living with schizophrenia. Schizophrenia was associated with a $1,540,042 per person lifetime fiscal loss to the government, with $56,707 per life year lived with schizophrenia. Health care costs represented 41.9% of the fiscal losses, 39.4% were due to criminal and homelessness costs, and 17.5% related to foregone tax revenue. Considering a 1.19% prevalence of schizophrenia, the estimated annual fiscal burden in the US was $173.6 billion.Conclusions: The fiscal framework illustrates how schizophrenia influences taxation and government transfer payments over time. These findings can be used to augment cost-effectiveness analyses and inform stakeholders of the fiscal impact of schizophrenia to inform priority interventions.

Cost-effectiveness analysis of monthly, 3-monthly, and 6-monthly long-acting injectable and oral paliperidone in adults with schizophrenia.

BACKGROUND: Paliperidone is among the most cost-effective antipsychotics in adults with schizophrenia, and it has different formulations, including oral paliperidone extended-release (ER) and long-acting injectable (LAI) paliperidone formulations administered every month (PP1M), 3 months (PP3M), or 6 months (PP6M). However, cost-effectiveness analyses comparing different paliperidone formulations were limited. OBJECTIVE: To compare the cost-effectiveness across different paliperidone formulations. METHODS: A Markov model was developed to simulate 1,000 adults aged 40 years with stable schizophrenia transitioning among stable disease-medication adherent, stable disease-medication nonadherent, relapse with hospitalization, relapse with ambulatory care, and death states every 3 months for 5 years. Drug costs were estimated using the prices listed in the Veterans Affairs Federal Supply Schedule, and costs for treating complications were estimated from published studies. All costs were estimated from the US health care system perspective and standardized to 2022 US dollars using the Consumer Price Index Inflation Calculator. Quality-adjusted life-years (QALYs) were estimated using relapse rates from randomized clinical trials and health-related quality of life scores from observational studies. The estimated future costs and QALYs were discounted at 3%. We reported incremental net monetary benefits between alternative formulations at the $50,000 willingness-to-pay (WTP) threshold with a positive value indicating cost-effectiveness. The impact of parameter uncertainty on study outcomes was assessed using 1-way deterministic and probabilistic sensitivity analyses. RESULTS: In adults with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was associated with increased QALY (PP1M = 0.05, PP3M = 0.14, PP6M = 0.15) and increased cost (PP1M = 49,433, PP3M = 26,698, PP6M = 26,147), leading to a negative incremental net monetary benefit (PP1M = -$46,804, PP3M = -$19,508, PP6M = -$18,886) compared with continuing ER. Among LAI formulations, PP6M was cost-saving with the most QALYs gained (cost = $63,277, QALY = 3.731), followed by PP3M (cost = $63,828, QALY = 3.729) and PP1M (cost = $86,563, QALY = 3.638). At the $50,000 WTP threshold, the probabilities for PP1M, PP3M, and PP6M being cost-effective compared with paliperidone ER were 0.4%, 10.2%, and 9.8%, respectively. The probability of PP6M being cost-effective was 92.6% for the PP6M-PP1M pair and 55.2% for the PP6M-PP3M pair, and 91.1% of PP3M use was cost-effective in the PP3M-PP1M pair. The results were generally robust in the sensitivity analyses, even at the $190,000 WTP threshold. CONCLUSIONS: For patients with schizophrenia stabilized with paliperidone ER, switching to LAI formulations was not cost-effective, suggesting the high drug costs for LAI may not justify the improved quality of life within 5 years. Among LAI formulations, PP6M was cost-effective over PP1M and PP3M.

Continuity of care among patients newly initiated on second-generation oral or long-acting injectable antipsychotics during a schizophrenia-related inpatient stay.

BACKGROUND: Maintaining continuity of care after schizophrenia-related hospitalization is challenging for patients and healthcare providers and systems. Prior evidence suggests that second-generation long-acting injectable antipsychotics (SGLAIs) may reduce the risk of treatment nonadherence and readmission versus oral atypical antipsychotics (OAAs). Therefore, quality measures were compared between patients initiated on SGLAIs and OAAs in the United States. METHODS: Adults newly initiated on an SGLAI or OAA during a schizophrenia-related inpatient stay were identified in HealthVerity databases (01/2015-12/2020); the index date was the hospital discharge date. Patients had continuous health insurance coverage for pharmacy and medical services for 6 months pre-admission and post-discharge from the inpatient stay and ≥1 pharmacy or medical claim (i.e. treatment as indicated by the observed insurance claims) for an antipsychotic other than the index SGLAI or OAA in the 6 months pre-admission. Antipsychotic use and adherence, and schizophrenia-related readmissions and outpatient visits were compared during the 6-month period post-discharge. Characteristics between cohorts were balanced using inverse probability weights. RESULTS: Post-discharge, only 36.9% and 40.7% of weighted SGLAI (N = 466) and OAA (N = 517) patients had ≥1 pharmacy or medical claim for the antipsychotic initiated during the inpatient stay, among whom SGLAI patients were 4.4 times more likely to be adherent to that antipsychotic compared to OAA patients (p < .001). Additionally, SGLAI patients were 2.3 and 3.0 times more likely to have a pharmacy or medical claim for and be adherent to any antipsychotic relative to OAA patients (including index antipsychotic; all p < .001). Within 7 and 30 days post-discharge, 1.7% and 13.0% of SGLAI patients and 4.1% and 12.6% of OAA patients had a readmission. Further, SGLAI patients were 51% more likely to have an outpatient visit compared to OAA patients (p = .044). CONCLUSIONS: Less than half of patients initiated on antipsychotics during a schizophrenia-related inpatient stay continued the same treatment post-discharge. However, SGLAI patients were more likely to be adherent to the initiated antipsychotic and to have an outpatient visit, which may suggest improved continuity of care post-discharge relative to OAA patients.

Wireless, noninvasive therapeutic drug monitoring system for saliva measurement toward medication management of schizophrenia.

As an efficient patient management tool of precision medicine, decentralized therapeutic drug monitoring (TDM) provides new vision for therapy adherence and health management of schizophrenia in a convenient manner. To dispense with psychologically burdensome blood sampling and to achieve real-time, noninvasive, and continual circulating tracking of drugs with narrow therapeutic window, we study the temporal metabolism of clozapine, an antipsychotic with severe side effect, in rat saliva by a wireless, integrated and patient-friendly smart lollipop sensing system. Highly sensitive and efficient sensing performance with acceptable anti-biofouling property was realized based on the synergistic effect of electrodeposited reduced graphene oxide and ionic liquids in pretreatment-free saliva with low detection limit and good accuracy cross-validated with conventional method. On this basis, continual salivary drug levels with distinctive pharmacokinetics were found in different routes of drug administration. Pilot experiment reveals a strong correlation between blood and saliva clozapine and a positive relationship between drug dosage and salivary drug level, indicating potential applications presented by noninvasive saliva analysis towards patient-centered and personalized pharmacotherapy and adherence management via proposed smart lollipop system.

Treatment Journey From Diagnosis to the Successful Implementation of a Long-Acting Injectable Antipsychotic Agent in Young Adults With Schizophrenia.

Objective: Long-acting injectable antipsychotic agents (LAIs) are effective in schizophrenia relapse prevention but are often underutilized. This study aims to understand treatment patterns leading to a successful LAI implementation following schizophrenia diagnosis in a large dataset that included commercially insured patients in the United States.Methods: Patients aged 18-40 years with a first schizophrenia diagnosis (per ICD-9 or ICD-10 criteria), successful second-generation LAI implementation (defined a priori as ≥ 90 consecutive days of use), and ≥ 1 second-generation oral antipsychotic agent (OA) were identified from IBM MarketScan Commercial and Medicare Supplemental databases from January 1, 2012, to December 31, 2019. Outcomes were measured descriptively.Results: Of 41,391 patients with newly diagnosed schizophrenia, 1,836 (4%) received ≥ 1 LAI; 202 (< 1%) met eligibility criteria of successful LAI implementation following ≥ 1 second-generation OA. Median (range) time between diagnosis and first LAI was 289.5 (0-2,171) days, time between LAI initiation and successful implementation was 90.0 (90-1,061) days, and time to LAI discontinuation after successful implementation was 166.5 (91-799) days. Before LAI initiation, 58% received ≥ 2 OAs. For 86% with successful LAI implementation, the implementation was accomplished with the first LAI.Conclusions: In this dataset of mainly commercially insured patients, LAI use in early-phase schizophrenia was very low (4%). For the majority for whom a LAI was successfully implemented per a priori definition, the implementation was accomplished with the first LAI and in a short period of time (90 days). However, even when LAIs were used in early-phase schizophrenia, they were generally not the first therapy, as most patients had several prior OA treatments.

Antipsychotic utilization, healthcare resource use and costs, and quality of care among fee-for-service Medicare beneficiaries with schizophrenia in the United States.

BACKGROUND: No research to date has examined antipsychotic (AP) use, healthcare resource use (HRU), costs, and quality of care among those with schizophrenia in the Medicare program despite it serving as the primary payer for half of individuals with schizophrenia in the US. OBJECTIVES: To provide national estimates and assess regional variation in AP treatment utilization, HRU, costs, and quality measures among Medicare beneficiaries with schizophrenia. METHODS: Cross-sectional descriptive analysis of 100% Medicare claims data from 2019. The sample included all adult Medicare beneficiaries with continuous fee-for-service coverage and ≥1 inpatient and/or ≥2 outpatient claims with a diagnosis for schizophrenia in 2019. Summary statistics on AP use; HRU and cost; and quality measures were reported at the national, state, and county levels. Regional variation was measured using the coefficient of variation (CoV). RESULTS: We identified 314,888 beneficiaries with schizophrenia. About 91% used any AP; 20% used any long-acting injectable antipsychotic (LAI); and 14% used atypical LAIs. About 28% of beneficiaries had ≥1 hospitalization and 47% had ≥1 emergency room (ER) visits, the vast majority of which were related to mental health (MH). Total annual all-cause, MH, and schizophrenia-related costs were $23,662, $15,000 and $12,109, respectively. Among those with hospitalizations, 18.4% and 27.3% had readmission within 7 and 30 days and 56% and 67% had a physician visit and AP fill within 30 days post-discharge, respectively. Overall, 81% of beneficiaries were deemed adherent to their AP medications. Larger interstate variations were observed in LAI use than AP use (CoV: 0.21 vs 0.02). County-level variations were larger than state-level variations for all measures. CONCLUSIONS: In this first study examining a national sample of Medicare beneficiaries with schizophrenia, we found low utilization rates of LAIs and high levels of hospital admissions/readmissions and ER visits. State and county-level variations were also found in these measures.

Antipsychotic drug use complicates assessment of gene expression changes associated with schizophrenia.

Recent postmortem transcriptomic studies of schizophrenia (SCZ) have shown hundreds of differentially expressed genes. However, the extent to which these gene expression changes reflect antipsychotic drug (APD) exposure remains uncertain. We compared differential gene expression in the prefrontal cortex of SCZ patients who tested positive for APDs at the time of death with SCZ patients who did not. APD exposure was associated with numerous changes in the brain transcriptome, especially among SCZ patients on atypical APDs. Brain transcriptome data from macaques chronically treated with APDs showed that APDs affect the expression of many functionally relevant genes, some of which show expression changes in the same directions as those observed in SCZ. Co-expression modules enriched for synaptic function showed convergent patterns between SCZ and some of the APD effects, while those associated with inflammation and glucose metabolism exhibited predominantly divergent patterns between SCZ and APD effects. In contrast, major cell-type shifts inferred in SCZ were primarily unaffected by APD use. These results show that APDs may confound SCZ-associated gene expression changes in postmortem brain tissue. Disentangling these effects will help identify causal genes and improve our neurobiological understanding of SCZ.

Assessment of electroencephalography modification by antipsychotic drugs in patients with schizophrenia spectrum disorders using frontier orbital theory: A preliminary study.

AIM: Schizophrenia is characterized by an abnormality in electroencephalography (EEG), which can be affected by antipsychotic drugs. Recently, the mechanism underlying these EEG alterations in schizophrenia patients was reframed from the perspective of redox abnormalities. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) can be calculated using a computational method and may be useful for evaluating the antioxidant/prooxidant effect of antipsychotic drugs. Thus, we examined the association between the effects of antipsychotic monotherapy on quantitative EEG and HOMO/LUMO energy. METHODS: We used medical report data including EEG results of psychiatric patients admitted to Hokkaido University Hospital. We extracted the EEG records of patients diagnosed with a schizophrenia spectrum disorder undergoing antipsychotic monotherapy during the natural course of treatment (n = 37). We evaluated the HOMO/LUMO energy of all antipsychotic drugs using computational methods. Multiple regression analyses were used to examine the relationship between the HOMO/LUMO energy of all antipsychotic drugs and spectral band power in all patients. Statistical significance was set at p < 6.25 × 10-4 adjusted with Bonferroni correction. RESULTS: We showed that the HOMO energy of all antipsychotic drugs had weak positive correlations with delta- and gamma-band power (e.g., standardized ß = 0.617 for delta in the F3 channel, p = 6.6 × 10-5 ; standardized ß = 0.563 for gamma in the O1 channel, p = 5.0 × 10-4 ). CONCLUSION: Although there may be unexpected bias and confounding factors, our findings suggest that the effect of antipsychotic drugs on EEG may be related to their antioxidant actions.

The effects of early initiation of aripiprazole once-monthly on healthcare resource utilization and healthcare costs in individuals with schizophrenia: real-world evidence from US claims data.

AIM: To evaluate the impact of timing of aripiprazole once-monthly (AOM) initiation on healthcare resource utilization (HCRU), risk of hospitalization, and healthcare costs in patients with schizophrenia. METHODS: A retrospective cohort study was conducted using data from the Merative MarketScan database (01/01/2013-12/31/2019). Adults aged ≥18 years with a new episode of care for schizophrenia and an AOM claim were included. Patients were classified into two cohorts based on the time between the first schizophrenia diagnosis and the first AOM claim (early cohort: ≤1 year; late cohort: >1 year). All-cause and psychiatric-specific HCRU, risk of hospitalization, and healthcare costs were evaluated over 1-year post-AOM initiation. The relationship between the timing of AOM initiation and HCRU was evaluated using negative binomial regression, and healthcare costs using generalized linear models (log-link with gamma distribution). Logistic regression was used to estimate the likelihood of hospitalization during the follow up period for both all-cause and psychiatric-specific hospitalization. RESULTS: A total of 945 patients were included (early cohort: n = 525; late cohort: n = 420). At baseline, the early cohort had lower mean age, a greater proportion of males, and a lower mean Charlson Comorbidity Index score than the late cohort (all p < .05). After adjusting for baseline demographic and clinical characteristics, all-cause and psychiatric-specific hospitalization during the 1-year follow-up period were statistically significantly higher for the late cohort versus the early cohort (all-cause: incident rate ratio [IRR] = 1.63, 95% confidence interval [CI]: 1.28-2.07, p < .01; psychiatric-specific: IRR = 1.93, 95% CI: 1.46-2.55, p < .01). The early cohort had statistically significantly lower adjusted all-cause ($21,686 versus $29,033; p = .0002) and psychiatric-specific ($24,414 versus $32,461; p = .0002) healthcare costs versus the late cohort. LIMITATIONS: This study utilized claims data, which are intended for administrative purposes rather than for research. CONCLUSIONS: This analysis extends previous evidence for the benefits of AOM in patients with new episodes of schizophrenia, by demonstrating lower HCRU, risk of hospitalization, and healthcare costs with early AOM initiation compared with later initiation.

Schizophrenia is a costly disease that impacts patients, caregivers, and the healthcare system. Antipsychotic medications are an important component of schizophrenia treatment. These medications reduce symptom severity, improve functioning and reduce costs. Aripiprazole once-monthly (AOM) is a long-acting injectable antipsychotic used to treat schizophrenia. This study evaluates whether starting AOM early in the disease course improves outcomes for people with schizophrenia. Outcomes include healthcare resource utilization, risk of hospitalization, and healthcare costs. The study team found that hospitalization and costs were lower for people who started AOM early in the disease course as opposed to later. This study points to the importance of early treatment to improve outcomes for people with schizophrenia.