Using Behavioral Insights to Strengthen Strategies for Change. Practical Applications for Quality Improvement in Healthcare.

OBJECTIVES: For over 30 years, quality improvement (QI) methods have been used as a means of increasing the quality and safety of healthcare services, but with mixed success. One explanation highlighted in the literature for this outcome is the overemphasis on technical elements of change, and a failure to fully appreciate the human side of change. Behavioral insights (BI) is an approach that utilizes knowledge and tools from a broad range of scientific disciplines, such as neuroscience and behavioral psychology, to support behavior change. The aim of this paper is to explore the possibility of supplementing QI methods with tools and understanding from BI. METHODS: We outline a practical case that involved applying aspects BI methods into a QI program aimed at reducing the use of intravenous antibiotics in patients accessing services at a busy university hospital in Copenhagen, Denmark. We exemplify how to use BI tools to guide the analysis of staff behaviors during standard clinical processes and develop targeted interventions aimed at increasing actions and behaviors more aligned to best clinical practice. RESULTS: Outcomes suggest that it is possible to combine the models and methods from BI and QI in a way that is helpful in focusing attention on the human side of change when developing strategies for change. Potential psychological barriers identified from the analysis included the following: 'default inertia,' 'decision complexity,' 'risk aversion,' and biases related to confidence, confirmation, and omission. CONCLUSIONS: Future quality improvement projects could benefit from integrating models and tools from BI to guide and support behavior change.

Psychological safety during the test of new work processes in an emergency department.

BACKGROUND: Emergency medicine is a complex setting for healthcare delivery which relies on communication, negotiation, teamwork, trust, and shared dialog. The nature of the work comprises dealing with emotionally challenging situations and acting under uncertainty. For healthcare staff this poses the need to be adaptive and open to change. Psychological safety is an important component of productive teamwork and learning in such contexts. Edmondson's model of team psychological safety highlights factors which contribute to the development of psychological safety for staff groups and the mediating role this has for team performance. AIM: The aim of the study was explore the link between psychological safety and improvement work. The research question was: Do the aspects covered in the Edmondson model fully describe healthcare workers' perceptions of psychological safety and are all aspects in the model needed to describe these perceptions during testing of new work procedures in an emergency department?" METHODS: Using a mixed-method approach we investigated a change programme with interviews, a questionnaire and a workshop in an emergency department of a hospital in the Capital Region of Denmark. Thematic analysis of qualitative data and descriptive statistics of questionnaire data were undertaken. RESULTS: Data indicate the Edmondson model is useful to help understand and identify important antecedent and outcome factors during a period of testing new work-flow processes. The model could not capture all aspects in this study's data material, and was updated as a result. The main modifications were explicitly integrating the physical aspects of the work setting into the considerations of psychological safety, the inclusion of an additional antecedent factor relating to perceptions of care quality and adopting bi-directional links between the antecedent and consequence elements in the model. CONCLUSIONS: Although limited in scale, the study supports Edmondson's model of psychological safety as appropriate in describing many of the dynamics experienced by staff engaged in testing new work process. However, additional factors, not included in Edmondson's model and potential adaptations to the model are proposed.

A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI.

BACKGROUND: Ischemia-reperfusion injury remains a major clinical problem in patients with ST-elevation myocardial infarction (STEMI), leading to myocardial damage despite early reperfusion by primary percutaneous coronary intervention (PPCI). There are no effective therapies to limit ischemia-reperfusion injury, which is caused by multiple pathways activated by rapid tissue reoxygenation and the generation of reactive oxygen species (ROS). FDY-5301 contains sodium iodide, a ubiquitous inorganic halide and elemental reducing agent that can act as a catalytic anti-peroxidant. We tested the feasibility, safety and potential utility of FDY-5301 as a treatment to limit ischemia-reperfusion injury, in patients with first-time STEMI undergoing emergency PPCI. METHODS: STEMI patients (n = 120, median 62 years) presenting within 12 h of chest pain onset were randomized at 20 PPCI centers, in a double blind Phase 2 clinical trial, to receive FDY-5301 (0.5, 1.0 or 2.0 mg/kg) or placebo prior to reperfusion, to evaluate the feasibility endpoints. Participants underwent continuous ECG monitoring for 14 days after PPCI to address pre-specified cardiac arrhythmia safety end points and cardiac magnetic resonance imaging (MRI) at 72 h and at 3 months to assess exploratory efficacy end points. RESULTS: Intravenous FDY-5301 was delivered before re-opening of the infarct-related artery in 97% participants and increased plasma iodide levels ~1000-fold within 2 min. There was no significant increase in the primary safety end point of incidence of cardiac arrhythmias of concern. MRI at 3 months revealed median final infarct sizes in placebo vs. 2.0 mg/kg FDY-5301-treated patients of 14.9% vs. 8.5%, and LV ejection fractions of 53.9% vs. 63.2%, respectively, although the study was not powered to detect statistical significance. In patients receiving FDY-5301, there was a significant reduction in the levels of MPO, MMP2 and NTproBNP after PPCI, but no reduction with placebo. CONCLUSIONS: Intravenous FDY-5301, delivered immediately prior to PPCI in acute STEMI, is feasible, safe, and shows potential efficacy. A larger trial is justified to test the effects of FDY-5301 on acute ischemia-reperfusion injury and clinical outcomes. CLINICAL TRIAL REGISTRATION: CT.govNCT03470441; EudraCT 2017-000047-41.

Psychosis seminars: an open forum for service users, carers and professionals.

BACKGROUND: Psychosis seminars enable service users, their carers and mental health professionals to meet outside of a formal care setting, increase understanding of mental illness and help establish a dialogue. AIMS: To explore feasibility of psychosis seminars in the UK and the experiences of participants. METHOD: Seven meetings attended by 25 people were held over a 3-month period. An open-ended questionnaire was returned by ten participants. Responses were subjected to content analysis. RESULTS: Benefits experienced were having an open forum for talking freely about mental health issues in a neutral space, learning from others about psychosis and hearing different views. Suggested adjustments were clarifying expectations of participants at the beginning, strengthening facilitation and increasing attendance. CONCLUSIONS: Psychosis seminars may help to establish a dialogue among users, carers and professionals and seem feasible in the UK, although adjustment to delivery can help their implementation. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license.

Using social network analysis for assessing mental health and social services inter-organisational collaboration: findings in deprived areas in Brussels and London.

Fragmentation in mental health and social care delivery should be addressed at the system level. A Social Network Analysis was carried out on relations between services in order to assess Leutz's levels of care integration: linkage, coordination, and full integration. Findings for deprived areas in Brussels and London show that linkage across clusters of services is weak in both networks. However, the integration of care relies on the level of linkage in London, while in Brussels it is more dependent on central services playing brokerage roles. The method offers a useful and complementary basis for evaluating the integration of care.

Mental health-care provision for marginalized groups across Europe: findings from the PROMO study.

BACKGROUND: Providing mental health care to socially marginalized groups is a challenge. There is limited evidence on what form of mental health-care generic (i.e. not targeting a specific social group) and group-specific services provide to socially marginalized groups in Europe. AIM: To describe the characteristics of services providing mental health care for people with mental disorders from socially marginalized groups in European capitals. METHODS: In two highly deprived areas in different European capital cities, services providing some form of mental health care for six marginalized groups, i.e. homeless, street sex workers, asylum seekers/refugees, irregular migrants, travelling communities and long-term unemployed, were identified and contacted. Data were obtained on service characteristics, staff and programmes. RESULTS: In 8 capital cities, 516 out of 575 identified services were assessed (90%); 297 services were generic (18-79 per city) and 219 group-specific (13-50). All cities had group-specific services for the homeless, street sex workers and asylum seekers/refugees. Generic services provided more health-care programmes. Group-specific services provided more outreach programmes and social care. There was a substantial overlap in the programmes provided by the two types of services. CONCLUSIONS: In deprived areas of European capitals, a considerable number of services provide mental health care to socially marginalized groups. Access to these services often remains difficult. Group-specific services have been widely established, but their role overlaps with that of generic services. More research and conceptual clarity on the function of group-specific services are required.

Mixed amphetamine salts extended-release in the treatment of adult ADHD: a randomized, controlled trial.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a serious neurobehavioral disorder of childhood onset that often persists into adolescence and adulthood. Functional impairments, underachievement, and difficult interpersonal relationships illustrate the need for effective treatment of ADHD through adulthood. METHOD: This prospective, multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study was conducted to assess the efficacy, safety, and duration of action of mixed amphetamine salts extended-release (MAS XR) in adults with ADHD, combined type. Adults > or =18 years of age were given placebo or MAS XR 20, 40, or 60 mg/day for 4 weeks. The main outcome measures were the ADHD Rating Scale and Conners' Adult ADHD Rating Scale Short Version Self-Report (CAARS-S-S). RESULTS: Two hundred fifty-five subjects were randomly assigned to treatment with MAS XR or placebo. MAS XR treatment was associated with statistically and clinically significant ADHD symptom reduction at endpoint; mean ADHD Rating Scale scores were 18.5 for the 20-mg group (P=.001), 18.4 for the 40-mg group (P<.001), and 18.5 for the 60-mg group (P<.001). Adults with severe symptoms (ADHD Rating Scale score >32 at baseline) had significantly greater symptom reduction with the highest MAS XR dose (60 mg/day), however, this dose-response relationship was determined by post-hoc analysis. The mean MAS XR effect size was 0.8. Statistically significant (P<.05) improvements in CAARS-S-S ADHD index scores occurred at 4- and 12-hours postdose for all MAS XR groups, indicating a 12-hour duration of effect. Symptoms improved within the first treatment week. Most adverse events reported were mild or moderate in intensity, and the most commonly reported adverse events were consistent with the known profile of stimulant medications. Vital signs and electrocardiograms showed no clinically significant cardiovascular changes. CONCLUSION: These results suggest that MAS XR is safe and effective in adults with ADHD and controlled ADHD symptoms for up to 12 hours.

Single- and multiple-dose pharmacokinetics of an oral mixed amphetamine salts extended-release formulation in adults.

OBJECTIVES: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20, 40, and 60 mg. METHODS: Study A, an open-label single-period study, and Study B, a randomized, open-label, three-way crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20, 40, and 60 mg separated by 7-14-day washout periods. FINDINGS: Plasma dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of d-amphetamine to l-amphetamine was observed for AUC0-inf and Cmax. Tmax was 4.2 and 4.3 hours for d-amphetamine to l-amphetamine, respectively. In Study B, for d- and l-amphetamine, statistically significant differences were observed for AUC0-t, AUC0-inf, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5-5.3 hours) with all given MAS XR doses. CONCLUSION: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of d-amphetamine to l-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Long-term safety and effectiveness of mixed amphetamine salts extended release in adults with ADHD.

OBJECTIVE: Assess the long-term safety and effectiveness of mixed amphetamine salts extended release (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) combined subtype. METHODS: A 24-month, open-label extension of a 4-week, multicenter, double-blind, placebo-controlled, parallel-group, forced-dose-escalation study of MAS XR in adults (>or=18 years of age) with ADHD. The 223 enrolled subjects started treatment at 20 mg/day for 1 week, with subsequent titration up to 60 mg/day for optimal therapeutic effects. At monthly visits, efficacy was assessed based on the ADHD Rating Scale IV (ADHD-RS-IV). Safety assessments included spontaneously reported adverse events, laboratory assessments, and monitoring of vital signs. FINDINGS: ADHD symptoms significantly improved for all subjects as measured by change from baseline in mean ADHD-RS-IV total scores (-7.2+/-13.04 unit points; P<.001); this was sustained for up to 24 months. The most common treatment-related adverse events were dry mouth (43% of subjects reporting at least one occurrence), infection (33%), insomnia (32%), anorexia/decreased appetite (32%), headache (30%), and nervousness (26%). Most adverse events were mild to moderate in intensity. CONCLUSION: Treatment with MAS XR 20-60 mg/day for adult ADHD was generally well tolerated and was associated with sustained symptomatic improvement for up to 24 months.

A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR) and atomoxetine (Strattera) in school-aged children with attention deficit/hyperactivity disorder.

Mixed amphetamine salts extended release (MAS XR; Adderall XR) and atomoxetine (Strattera) were compared in children 6 to 12 years old with attention deficit/hyperactivity disorder (ADHD) combined or hyperactive/impulsive type in a randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study. Primary efficacy measure was the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) behavioral rating scale. Changes in mean SKAMP deportment scores from baseline were significantly greater for MAS XR (n = 102) than for atomoxetine (n = 101) overall (-0.56 and -0.13, respectively; p < .0001) and at each week (p < .001). Adverse events were similar for both treatment groups. The extended time course of action and greater therapeutic efficacy of MAS XR suggests that it is more effective than atomoxetine in children with ADHD.

Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children.

OBJECTIVE: To assess the short- and long-term cardiovascular effects of once-daily treatment with a mixed amphetamine salts extended-release formulation (MAS XR; Adderall XR(R)) in children age 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD). STUDY DESIGN: Short-term cardiovascular effects were assessed during a 4-week, double-blind, randomized, placebo-controlled, forced-dose-titration study of once-daily 10, 20, and 30 mg MAS XR (n = 580). Long-term cardiovascular effects were assessed in 568 subjects during a 2-year, open-label extension study of MAS XR (10 to 30 mg/day). Resting sitting blood pressure and pulse were measured at baseline and weekly during the short-term study, then monthly during long-term treatment. RESULTS: Changes in blood pressure, pulse, and QT interval corrected by Bazett's formula (QTcB) in children receiving MAS XR were not statistically significantly different than those changes seen in children receiving placebo during short-term treatment. Mean increases in blood pressure after 2 years of MAS XR treatment (systolic, 3.5 mm Hg; diastolic, 2.6 mm Hg) and pulse (3.4 bpm) were clinically insignificant, and there was no apparent dose-response relationship. CONCLUSIONS: Cardiovascular effects of short- and long-term MAS XR were minimal during short- and long-term MAS XR treatment at doses of

Long-term tolerability and effectiveness of once-daily mixed amphetamine salts (Adderall XR) in children with ADHD.

OBJECTIVE: To evaluate the long-term tolerability and effectiveness of extended-release mixed amphetamine salts (MAS XR; Adderall XR) in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: This was a 24-month, multicenter, open-label extension of TWO placebo-controlled studies of MAS XR in children with ADHD aged 6 to 12 years. Subjects (N=568) began treatment with MAS XR 10 mg once daily, with 10-mg weekly dose increases to optimal effectiveness (maximum dose, 30 mg/d). Effectiveness was assessed with analysis of quarterly Conners Global Index Scale, Parent version (CGIS-P) scores. Tolerability was assessed by monitoring adverse events (AEs), vital signs, physical examinations, and serial laboratory tests. RESULTS: Significant improvements (>30%, p < .001) in CGIS-P scores were maintained during long-term treatment. Treatment was well tolerated, and most AEs were mild. The most frequently reported drug-related AEs included anorexia, insomnia, and headache. The incidence of drug-related AEs increased with increasing MAS XR dose, suggesting a dose relationship. Changes in laboratory values and vital signs were modest and not clinically meaningful. CONCLUSIONS: In children with ADHD, once-daily 10 mg-30 mg MAS XR was well tolerated and significant behavioral improvements were consistently maintained during 24 months of treatment.

Simulation of the effect of patient nonadherence on plasma concentrations of carbamazepine from twice-daily extended-release capsules.

OBJECTIVE: Carbamazepine (CBZ) effectively treats simple, complex, and secondarily generalized partial seizures. Computer simulations were carried out to investigate the effect of missing or delaying doses of carbamazepine extended-release capsules (CBZ-ERC) on plasma CBZ levels and the optimal dosing strategy to return plasma concentrations to therapeutic levels. PATIENTS AND METHODS: A one-compartment open model with first-order absorption and elimination was generated from the results of a previous study measuring plasma concentrations following one 400-mg fasting dose of CBZ-ERC. The model was used to simulate plasma CBZ concentrations following multiple doses given every 12 h to hypothetical long-term CBZ-treated patients, with the CBZ elimination half-life set to 13.7 h to account for enzymatic autoinduction. The model was then used to simulate plasma CBZ concentrations when a dose is taken 3, 6, or 9 h late, or when two doses are taken at one time. RESULTS: Predicted plasma CBZ concentrations in this simulation fell from a trough of approximately 6.4 microg/ml only to 4 microg/ml after 24 h without medication, and only to 2.5 microg/ml after 36 h without medication. Predicted plasma CBZ concentrations in this simulation never rose above 9 microg/ml, indicating that taking missed doses of CBZ-ERC as soon as remembered, up to two missed doses 3 h before taking the next scheduled dose, will not lead to harmful spikes in plasma concentrations of CBZ. CONCLUSIONS: The simulations suggest that taking a missed dose of CBZ-ERC as soon as remembered, up to two doses at one time, may be the best strategy to return plasma CBZ concentrations to steady-state levels. Since the model used in this study is a simplified model of a highly complex situation, caution should be used when relating these results to clinical practice until trials are conducted in patients.

A pharmacokinetic/pharmacodynamic study comparing a single morning dose of adderall to twice-daily dosing in children with ADHD.

OBJECTIVE: To determine the pharmacokinetic and pharmacodynamic properties of once-daily versus twice-daily doses of Adderall. METHOD: Following a 1-week wash-out, 12 subjects with attention-deficit/hyperactivity disorder (ADHD) entered a double-blind crossover study comparing two conditions: QD (10 mg of Adderall at 7:30 a.m. and placebo at noon) or BID (10 mg of Adderall at 7:30 a.m. and at noon). At two sites, cohorts of six subjects each were assessed on two different days by a 12-hour laboratory school protocol. Plasma concentrations of d- and l-amphetamine, vital signs, teacher ratings of classroom behavior on the SKAMP, and 10-minute Math Test performance were measured repeatedly over 12 hours. An analysis of variance used center, subject-within-center, condition, and time-after-second-dose as independent variables. RESULTS: The pharmacokinetic profiles revealed similar morning concentrations of d- and l-amphetamine. However, concentrations were twice as high in the afternoon for BID as QD. The two conditions showed similar pharmacodynamic profiles in the morning, although improvement in math performance and behavior was maintained into the afternoon only in the BID condition (p <.05). CONCLUSIONS: This study suggests that twice-daily dosing of Adderall may be an effective strategy for afternoon control of attention and deportment for children with ADHD.

Analog classroom assessment of a once-daily mixed amphetamine formulation, SLI381 (Adderall XR), in children with ADHD.

OBJECTIVES: This investigation was conducted primarily to assess the safety and efficacy of SLI381 (Adderall XR), developed as a once-daily treatment for children with attention-deficit/hyperactivity disorder (ADHD). Secondary objectives included examination of the time course, pharmacokinetic, and pharmacodynamic properties of SLI381. METHOD: This was a randomized, double-blind, crossover study of three doses of SLI381 (10, 20, and 30 mg), placebo, and an active control (Adderall 10 mg) given once daily to 51 children with ADHD. Weekly assessments in an analog classroom setting included blind ratings of attention and deportment and a performance measure (math test) obtained every 1.5 hours over a 12-hour period. RESULTS: SLI381 was well tolerated. All active treatment conditions displayed significant time course effects and were superior to placebo in improving efficacy measures. Dose-dependent improvements were evident for SLI381. SLI381 20 and 30 mg and Adderall all showed rapid improvements by 1.5 hours, but only the SLI381 20- and 30-mg doses showed continued activity at 10.5 and 12 hours for classroom behavior and math test performance versus placebo. CONCLUSIONS: These data provide support for the benefit of this novel, once-daily amphetamine preparation in the treatment of ADHD. The longer duration of action of SLI381 has the potential to simplify psychostimulant dosing, thus reducing dose diversion and eliminating the need for in-school administration. SLI381 appears to be a useful treatment option for many children with ADHD.

Pharmacokinetics of SLI381 (ADDERALL XR), an extended-release formulation of Adderall.

OBJECTIVE: To assess the pharmacokinetic (PK) properties of a single daily dose of Adderall (mixed amphetamine salts) and the extended-release formulation, SLI381 (ADDERALL XR), in pediatric attention-deficit/hyperactivity disorder (ADHD). METHOD: Fifty-one children (aged 6-12 years) with ADHD participated in a 6-week, seven-visit, PK and pharmacodynamic study. PK sampling occurred during visit 1 and again at visit 7. At visit 1, subjects received an initial oral dose of SLI381, 20 mg. At visit 7 subjects completed 1 week of medication treatment following random assignment to once-daily orally dosed SLI381 10 mg, 20 mg, or 30 mg; Adderall 10 mg; or placebo. RESULTS: PK parameters evidenced substantial intersubject variability (coefficients of variation = 28-56%). Time to maximum concentration (Tmax) for SLI381 versus Adderall showed average increases of 3.0 hours for dextroamphetamine (t = -2.35, p = .04, df = 8.6) and 3.2 hours for levoamphetamine (t = -2.39, p = .04, df = 9.2). The d- and l-isomer concentrations were highly correlated and approximated a 3:1 ratio. CONCLUSIONS: SLI381 showed extended Tmax values compared with Adderall and appears suitable for once-daily dosing. Intersubject variability underscores the need for individual dose titration.

SLI381 (Adderall XR), a two-component, extended-release formulation of mixed amphetamine salts: bioavailability of three test formulations and comparison of fasted, fed, and sprinkled administration.

STUDY OBJECTIVES: To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food. DESIGN: Randomized, open-label, crossover study. SETTING: Clinical research unit. PATIENTS: Forty-one healthy adults. INTERVENTIONS: Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce. MEASUREMENTS AND MAIN RESULTS: The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition. CONCLUSION: SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.