Characteristics and Healthcare Burden of Patients with Schizophrenia Treated in a US Integrated Healthcare System.

BACKGROUND: Schizophrenia is one of 15 major causes of disability worldwide and is responsible for more than USD 150 billion in annual healthcare costs in the United States. Although the burden of schizophrenia as measured by healthcare resource utilization (HRU) is known to be considerable, data generally come from claims databases or healthcare systems/payors representing only a subset of patients, such as Medicare/Medicaid recipients. A broader understanding of HRU across the schizophrenia patient population would help identify underserved groups and inform strategies for improving healthcare delivery. AIMS OF THE STUDY: This observational study examined overall HRU and the influence of sociodemographic factors in adult patients with schizophrenia receiving care in a US integrated healthcare system. METHODS: A retrospective cohort study was conducted using data from electronic medical records (EMRs). Patients were required to have at least two diagnostic codes for schizophrenia recorded in the EMR within a 12-month period from January 2009 to June 2018, and to have received active care (≥ 1 in-system healthcare visit every six months) for at least 12 months before and after the index date (the earlier of the schizophrenia diagnosis dates). Patients were followed until no longer receiving active care or the end of the study. Patient characteristics were assessed during the 12-month pre-index period, and inpatient, readmission, emergency room (ER), and outpatient visits and antipsychotic prescriptions were described during follow-up. Findings were reported overall and in subgroups by race/ethnicity, age, and sex. RESULTS: The study cohort included 2,941 patients (mean age, 48.3 years; 54.5% male, 51.8% black, 45.8% with Medicare). During the follow-up period (mean, 4.6 years), inpatient hospital stays were common, with at least one all-cause, mental health-related, or schizophrenia-related inpatient visit occurring for 48.7%, 47.3%, and 38.8% of patients, respectively. Hospital readmissions within 30 days of an all-cause inpatient visit occurred in 20.4% of patients, with 14.5% of patients readmitted within 30 days of a schizophrenia-related inpatient visit. More than two-thirds of patients had ER visits, and 40.7% had schizophrenia-related ER visits. Only 46.7% of patients with a schizophrenia-related inpatient visit and 58.5% of patients with a mental health-related inpatient visit had a 30-day outpatient follow-up visit. Subgroup analyses revealed that a larger proportion of non-Hispanic black vs non-Hispanic white patients had 30-day outpatient follow-up visits, ER visits, mental health specialist visits, and antipsychotic prescriptions. Moreover, older age was associated with fewer ER and mental health specialist visits and less use of injectable and second-generation antipsychotics, and women were less likely than men to receive antipsychotic therapy, particularly injectable medications. DISCUSSION: Patients with schizophrenia receiving care in a US integrated healthcare system had considerable acute HRU and suboptimal rates of routine and follow-up care. Inequities in schizophrenia burden and care were observed in demographic subgroups. IMPLICATIONS FOR HEALTH POLICIES: Population health management strategies focusing on efficient resource allocation and improving healthcare quality are needed to reduce the burden of schizophrenia. Differential findings by race/ethnicity, age, and sex indicate the need for optimizing approaches to care in these subgroups.

The Impact of Once-Monthly Paliperidone Palmitate on Healthcare Utilization Among Patients With Schizophrenia Treated in an Integrated Healthcare System: A Retrospective Mirror-Image Study.

INTRODUCTION: Previous evidence demonstrated that patients with schizophrenia consumed substantial healthcare resources in an integrated healthcare system. This study evaluated the impact of initiating once-monthly paliperidone palmitate (PP1M) on healthcare resource utilization (HRU) among patients with schizophrenia treated in a US integrated healthcare system. METHODS: This retrospective study used electronic medical records from Atrium Health. Adults with at least two diagnoses of schizophrenia who received an initial PP1M dose between September 2009 and April 2019 (the corresponding date defined the index date) and at least one subsequent dose within 90 days were included. Additionally, patients were required to have received active care (at least one healthcare visit every 6 months) during 12-month pre- and post-index periods and at least one oral antipsychotic prescription during the 12-month pre-index period. Inpatient, emergency room (ER), and outpatient visits were compared over 12-month pre- versus post-index periods within the same cohort using McNemar's and Wilcoxon signed rank tests. Findings were reported for all patients and separately in patients with at least one schizophrenia relapse (schizophrenia-related inpatient or ER visit) during the 12-month pre-index period. RESULTS: The study cohort included 210 patients (mean age 34.2 years, 69.5% male, 39.1% had Medicaid). From the 12-month pre- to post-index period, the proportion of patients with visits and mean number of visits reduced for all-cause inpatient (67.6% to 22.4%, 1.2 to 0.4), 30-day readmission (12.4% to 2.4%, 0.2 to 0.1), and ER (68.6% to 45.7%, 2.3 to 1.2) visits, whereas the mean number of outpatient visits increased (8.7 to 11.6) (all P < 0.05). Similar trends were observed for mental health- and schizophrenia-related HRU. The trends in HRU in patients with prior relapse were similar with a higher extent of reduction in inpatient and ER use compared to the overall cohort. CONCLUSION: Initiation of PP1M was associated with reduced acute HRU in patients with schizophrenia, indicating potential clinical and economic benefits, especially in patients with prior relapse.

Development of a Behavioral Health Stigma Measure and Application of Machine Learning for Classification.

Objective: Given the growing public health importance of measuring the change in mental health stigma over time, the goal of this study was to demonstrate the potential for using machine learning as a tool to analyze patterns of social stigma as a complement to traditional research methods. Methods: A total of 1,904 participants were recruited through Sona Systems, Ltd (Tallinn, Estonia), an experiment management system for online research, to complete a self-reported survey. The collected data were used to develop a new measure of mental (behavioral) health stigma. To build a classification predictive model of stigma, a decision tree was used as the data mining tool, wherein a set of classification rules was generated and tested for its ability to examine the prevalence of stigma. Results: A three-factor stigma model was supported and confirmed. Results indicate that the measure is content-valid and internally consistent. Performance evaluation of the machine learning-based classification algorithm revealed a sufficient inter-rater reliability with a predictive accuracy of 92.4 percent. Conclusion: This study illustrates the potential for applying machine learning to derive a data-driven understanding of the extent to which stigma is prevalent in society. It establishes a framework for the development of an index to track stigma over time and to assist healthcare decision-makers with improving the health of populations and the experience of care for patients.

Conducting clinical research in community mental health settings: Opportunities and challenges.

Tremendous progress has been made in the past decade surrounding the underlying mechanisms and treatment of neuropsychiatric disease. Technological advancements and a broadened research paradigm have contributed to the understanding of the neurochemistry, brain function and brain circuitry involved in neuropsychiatric disorders. The predominant area of unmet medical need in the United States is major psychiatric disorders, and major depressive disorder is the leading cause of disability for ages 15-44. Total spending on research and development by the pharmaceutical industry has grown exponentially during the past decade, but fewer new molecular entities (NME) for the treatment of major psychiatric disorders have received regulatory approvals compared to other therapeutic areas. Though significant expansion has occurred during the "decade of the brain", the translation of clinical trials outcomes into the community mental health setting is deficient. Randomized controlled trials (RCTs) have been the standard approach to clinical evaluation of the safety and efficacy of NMEs for the past 60 years; however, there are significant barriers and skepticism in the implementation of evidence-based outcomes into clinical practice. Recruitment of patients, shortages of experienced clinical researchers, regulatory requirements and later translation of outcomes into clinical practice are ever growing problems faced by investigators. The community mental health setting presents particular barriers in the replication of therapeutic outcomes from RCTs. The diagnostic complexity of major psychiatric diseases and the highly selective patient populations involved in clinical trials lend to the gap in translation from the "bench to the bedside". The community mental health setting lends to a diverse patient population with numerous co-morbidities and environmental factors that are unaccounted in the average RCT. While we acknowledge the enormous complexity in developing novel and innovative treatments for major psychiatric disorders, we must continue to improve the translatability of clinical trials to real world settings. Progress has been rather slow but as the gap in treatment effectiveness is reduced, so will costs and barriers in community mental health.

Targeting cognitive deficits in schizophrenia: a review of the development of a new class of medicines from the perspective of community mental health researchers.

INTRODUCTION: Schizophrenia is a chronic disorder associated with positive and negative symptoms and wide-ranging deficits in neurocognitive function. Neurocognitive deficits are considered to be the core pathophysiological symptoms of the illness. Neurocognitive deficits are also closely associated with functional outcome. At present, cognitive deficits remain one of the most important unmet therapeutic needs in schizophrenia. AREAS COVERED: Neuroscientific discoveries over the past decades have enriched our understanding of the neurobiological mechanism underlying cognitive deficits in schizophrenia. This research has identified new molecular mechanisms and processes as promising pharmacological targets. However, in spite of extensive efforts to develop a new class of cognitive-enhancing medicines for the treatment of schizophrenia over the past 5 years, no novel pharmacological agents have received the regulatory approvals required by the Food and Drug Administration. The efficacy and safety outcomes from selective Phase II clinical trials are reviewed. EXPERT OPINION: The evolving concept of neurocognition and the current guidelines for the design and methodology of clinical trials of cognitive-enhancing drugs for the treatment of individuals with schizophrenia are critically examined. The future directions in the development of cognitive-enhancing medicines for the treatment of schizophrenia from the perspective of clinicians and researchers from community mental health settings are discussed.

Once-daily medications for the pharmacological management of ADHD in adults.

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children and adolescents. Symptoms of ADHD often persist beyond childhood and present significant challenges to adults. Pharmacotherapy is a first-line treatment option for ADHD across all age groups. The current review's goals are (a) to critically examine the current state of knowledge regarding once-daily formulations of pharmacotherapies for treatment of adults with ADHD and (b) to provide clinicians with evidence-based information regarding the safety, efficacy and tolerability of once-daily medications for adult ADHD. The reviewed body of evidence strongly supports the use of pharmacotherapy as a first-line therapeutic option for the treatment of adults with ADHD. The once-daily pharmacological agents are effective therapeutic options for the treatment of adults with ADHD. In the US, based on the available evidence, once-daily medications are currently underutilized in adults with ADHD compared to pediatric population.

Is quetiapine a drug of abuse? Reexamining the issue of addiction.

BACKGROUND: The abuse and diversion of pharmacological agents with CNS mechanisms of action is an important concern from governmental, regulatory, public health and safety perspectives. In recent years, there have been an increased number of reports concerning the abuse and diversion of quetiapine in forensic population and in individuals with histories of substance abuse. OBJECTIVE: To better understand this surging pattern the available body of evidence was critically examined. METHODS: A literature search from January 1991 to July 2008 restricting papers to English and using PUBMED and PsychInfo was performed. RESULTS: Nine papers were identified. The content of these papers is discussed in light of recent research on drug abuse.

Pharmacotherapy of adult attention deficit/hyperactivity disorder: review of evidence-based practices and future directions.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children and adolescents with well-known clinical consequences and functional outcomes that affect individuals throughout their lifespan. The diagnosis of adult ADHD is often a clinical diagnosis made on the basis of behavioral symptoms that begin early in life, and persist over time across different settings. OBJECTIVE: Although pharmacotherapy is a first-line treatment option for ADHD across all age groups, there is a relative paucity of well-designed and well-controlled studies evaluating the treatment outcomes in adult ADHD. In this review, evidence-based pharmacotherapy of adult ADHD and directions of future research are critically examined. METHODS: A literature search from 1980 to 2007, restricting papers to English, using PUBMED and PsychInfo was performed. Studies were examined based on empirically derived criteria. RESULTS: The reviewed body of evidence strongly supports the use of pharmacotherapy as a first-line therapeutic option for the treatment of adults with ADHD.

Effects of acute tiagabine administration on aggressive responses of adult male parolees.

Experimental and clinical studies have supported a relationship between gamma-aminobutyric acid (GABA) and aggressive behavior in non-humans and humans. Tiagabine is a GABA uptake inhibitor that has been shown to produce acute behavioral effects in animals. In addition, tiagabine has been shown to decrease aggression in agitated patients when administered chronically. The present study was designed to investigate the effects of acute administration of tiagabine on aggressive responding on a laboratory task in adult humans. Ten adult males participated in experimental sessions on the Point Subtraction Aggression Paradigm (PSAP), which provided subjects with aggressive, escape, and monetary-reinforced response options. All subjects received four acute oral doses of Tiagabine (4, 8, 12 and 16 mg) separated by placebo sessions. Tiagabine decreased aggression at doses that either did not affect, or affected to a lesser extent, monetary-reinforced responding. The results are consistent with some prior research using the PSAP showing a possible unique role for GABA in the regulation of human aggression. A possible behavioral mechanism for the rate-decreasing effects on aggressive responding produced in the present study is that tiagabine may modify aggressive responding by suppressing reactions to aversive stimuli.

Human proactive aggression: association with personality disorders and psychopathy.

Aggressive behaviors can be divided into two categories: reactive and proactive. Reactive aggressive behaviors occur in response to a stimulus or provocation. Proactive aggressive behaviors occur without provocation and are goal directed. A number of findings have suggested that individuals displaying proactive aggression may be discerned from individuals not displaying proactive aggression on measures of personality, psychopathology and psychopathy as well as in aggressive histories and type and severity of aggressive behaviors committed. In this study, subjects were recruited from a large urban community and classified as proactive (n = 20), reactive-only (n = 20) or nonaggressive (n = 10) based on laboratory behavioral testing. Subjects were administered a battery of questionnaires and structured interviews pertaining to personality disorders and psychopathy. It was hypothesized that proactive aggressive subjects would show greater numbers of personality disorders and have greater psychopathy relative to reactive-only and nonaggressive subjects. These hypotheses were supported. These results suggest that proactive aggression may be identified in a laboratory-based task, and differences between proactive and reactive-only aggressors can be detected.

Response perseveration and adaptation in heavy marijuana-smoking adolescents.

The present study examined two behavioral processes - response perseveration and response adaptation - in adolescents who were heavy marijuana smokers and control adolescents. Testing took place in a controlled laboratory setting, using customized software and either a computer keyboard or a custom built response panel for response input. Adolescents age 14-18 were recruited into a heavy smoking (near daily) group (N=22) or a control group (N=31) with <15 lifetime uses of marijuana and no history of substance abuse or dependence. Marijuana use was verified by daily quantification of urinary cannabinoids and self-reports. Participants completed laboratory tasks designed to measure response perseveration (Wisconsin Card Sort Task, WCST) and response adaptation (concurrent variable-ratio reinforcement schedule with changing contingencies). Data were analyzed via ANOVA, controlling for multiple factors including: gender, age, nicotine use, presence of conduct disorder, and subscales of the Youth Self Report. After controlling for these compared to controls marijuana-using participants made significantly more perseverative and total errors on the WCST and showed significantly impaired (e.g., less adaptive) response allocation to the changing reinforcement contingencies on the concurrent-reinforcement task. Within the constraints of the study's limitations in controlling for alternative sources of between-subject variability, the data suggest that individuals who regularly smoke marijuana during adolescence show measurable perturbations in important basic behavioral processes. The data are also consistent with a previous laboratory study demonstrating reduced motivation in marijuana-smoking adolescents versus controls [Lane, S.D., Cherek, D.R., Pietras, C.J., and Steinberg, J.L. (2005). Performance of heavy marijuana-smoking adolescents on a laboratory measure of motivation. Addictive Behaviors, 30, 815-828].

Pharmacological aspects of the treatment of conduct disorder in children and adolescents.

In recent years, the rates of psychosocial disorders in children and adolescents have increased, with behavioural manifestations of conduct disorder being one of the most common reasons for referrals to community psychiatrists. Childhood conduct problems are associated with a variety of psychiatric disorders in adult life that extend beyond antisocial behaviour. An increased awareness of the costs of conduct disorder to individuals, families and society has led to advancements in the pharmacological and nonpharmacological therapeutic modalities for this disorder. Despite this, patients with conduct disorder are difficult to treat as the patterns of maladaptive behaviours they exhibit are diverse and can vary as a function of age and sex. A multidisciplinary approach to the treatment of conduct disorder, which includes behavioural parent training, interpersonal skills training, family therapy and the use of psychotropic agents targeted at a particular cluster of symptoms, can increase the overall effectiveness of each of the applied interventions. Aggression, hyperactivity, impulsivity and mood symptoms are the most sensitive proximal targets. Evidence suggests that antipsychotics, antidepressants, mood stabilisers, antiepileptic drugs, stimulants and adrenergic drugs can be well tolerated and effective therapeutic options for individuals with conduct disorder and comorbid psychiatric conditions. However, the most successful therapeutic outcomes are likely to be achieved by combining the current advances in psychopharmacology with behavioural and psychosocial interventions, aimed at modifying the excessive patterns of maladaptive behaviours observed in conduct disorder.

Effects of marijuana on temporal discriminations in humans.

Marijuana has been reported to alter the discrimination of time. The present study used a psychophysical approach to examine the effects of marijuana on temporal discrimination in humans. Research participants were required to push one of two buttons depending on the duration of a conditional stimulus (a blue square on a computer monitor). Correct choices ('C' button after a 2-s stimulus; 'A' button after a 4-s stimulus) resulted in an increase in session earnings of 0.12 dollars. Intermediate durations (probe stimuli between 2 and 4 s) were also presented. Psychophysical functions relating the probability of judging a duration as 'long' (4 s) as a function of actual stimulus durations were characterized by a logistic function fitted to the data. Administration of both low (1/2 placebo and 1/2 2.2% Delta (9)-tetrahydrocannabinol cigarette) and high (3.89% Delta(9)-tetrahydrocannabinol) potency marijuana cigarettes produced a bias of judging intervals as long, consistent with an interpretation that subjective time passes more quickly when an individual is intoxicated by marijuana. Deliberation time, operationally defined as response latency, peaked on trials with sample durations that corresponded to the measure of central tendency, and shifted in a similar manner after marijuana administration. The data are consistent with other studies on the effects of marijuana on time estimation.

Individual differences in aggressive responding to intravenous flumazenil administration in adult male parolees.

Nonhuman and human studies have shown that benzodiazepine (BZD) receptor agonists can modify aggressive behaviour. However, it is unknown whether flumazenil, a BZD receptor antagonist, enhances or inhibits aggressive behaviour. The present study was designed to investigate the effects of acute administrations of flumazenil on aggressive responding in adult humans. Six adult males with histories of childhood conduct disorder (DSM IV R) participated in experimental sessions. Aggression was measured using the Point Subtraction Aggression Paradigm (PSAP; Cherek 1992), which provided subjects with aggressive and monetary-reinforced response options. Acute doses of flumazenil (2 and 3mg) did not produce statistically significant changes in either monetary-reinforced responding or aggressive responding. The analysis of individual subjects data revealed that aggressive responses varied across subjects. The results are discussed in terms of individual differences based on the previous history of BZD abuse. Additional laboratory research is needed to better clarify the behavioural mechanisms by which BZD receptor antagonists modify human aggressive responding.

Pharmacotherapy of postpartum depression: current practice and future directions.

Postpartum depression has well-documented consequences for the mother, child, family and society as a whole. Despite an increasing awareness of postpartum depression, it often remains unrecognised by clinicians and poorly understood by researchers. The current trend is undoubtedly a result of the complex nature of depressive disorders accentuated by difficulties with the current classification schemas. Systematic prospective data on the onset of depression during pregnancy and the postpartum period, as well as on the risk of relapse during these periods in women with previous histories of mood and anxiety disorders, are limited. This article reviews clinically relevant outcomes and current trends in the pharmacotherapy of postpartum depression from selected clinical trials. Critical issues of the neurobiology and phenomenology of postpartum depression are raised, and future directions of the pharmacological treatments of postpartum depression are examined.

Acute effects of alprazolam on risky decision making in humans.

RATIONALE: GABA-A receptor ligands, including benzodiapines, may induce disinhibitory effects that increase the probability of risky decision making. To date, few laboratory studies have examined the acute, dose-related effects of benzodiazepines on human risk-taking behavior. Recent data indicate that in the United States alprazolam is the benzodiazepine most frequently misused for recreational purposes. OBJECTIVES: The present study was designed to demonstrate a dose-response relationship between acute alprazolam administration and human risk taking. Furthermore, this investigation sought to examine: (1) the behavioral mechanisms that may be involved in changes in the probability of risky decision making related to alprazolam administration and (2) risk seeking-related personality variables that may predict drug effects on risk taking. METHODS: Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.5, 1.0, and 2.0 mg alprazolam in a within-subject repeated-measures design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, trial-by-trial response probabilities, and personality correlates related to drug effects at the 2.0-mg dose. RESULTS: Alprazolam administration produced dose-related changes in subjective effects, response rates, and, most importantly, dose-dependently increased selection of the risky response option. The 2.0-mg dose increased the probability of making consecutive risky responses following a gain on the risky response option. Increases at 2.0 mg were related to a combination of personality scales that included high venturesomeness and novelty seeking and low harm avoidance. CONCLUSIONS: Alprazolam administration produced increases in human risk taking under laboratory conditions. In union with previous studies, the observed shift in trial-by-trial response probabilities suggests that sensitivity to consequences (e.g., oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may be predictive of acute drug effects on risk-taking behavior.

Marijuana effects on human forgetting functions.

It has long been known that acute marijuana administration impairs working memory (e.g., the discrimination of stimuli separated by a delay). The determination of which of the individual components of memory are altered by marijuana is an unresolved problem. Previous human studies did not use test protocols that allowed for the determination of delay-independent (initial discrimination) from delay-dependent (forgetting or retrieval) components of memory. Using methods developed in the experimental analysis of behavior and signal detection theory, we tested the acute effects of smoked marijuana on forgetting functions in 5 humans. Immediately after smoking placebo, a low dose, or a high dose of marijuana (varying in delta9-THC content), subjects completed delayed match-to-sample testing that included a range of retention intervals within each test session (0.5, 4, 12, and 24 s). Performances (discriminability) at each dose were plotted as forgetting functions, as described and developed by White and colleagues (White, 1985; White & Ruske, 2002). For all 5 subjects, both delta9-THC doses impaired delay-dependent discrimination but not delay-independent discrimination. The outcome is consistent with current nonhuman studies examining the role of the cannabinoid system on delayed matching procedures, and the data help illuminate one behavioral mechanism through which marijuana alters memory performance.