Safety and tolerability of esketamine nasal spray versus quetiapine extended release in patients with treatment resistant depression.

In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) significantly increased the probability of remission at Week 8, and of being relapse-free through Week 32 after remission at Week 8, versus quetiapine extended release (XR) in patients with treatment resistant depression (TRD). Here, we explore the time course, burden and consequences of treatment emergent adverse events (TEAEs) in the phase IIIb ESCAPE­TRD trial. Patients with TRD were randomised 1:1 to esketamine NS or quetiapine XR, dosed per label alongside an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. In this secondary publication, safety analyses (comprising patients who received ≥1 dose of study treatment) included incidence, severity and durations (Kaplan­Meier method) of TEAEs, and subsequent dispositional changes. P values were not adjusted for multiple testing. 336 patients were randomised to esketamine NS and 340 to quetiapine XR; 334 and 336 received ≥1 dose of study treatment, respectively. TEAEs were significantly more common with esketamine NS than quetiapine XR (91.9 % versus 78.0 %; p < 0.001), but were typically mild/moderate and transient in nature: a greater proportion resolved on the same-day (92.0 % versus 12.1 %) and lead to treatment discontinuation in significantly fewer patients (4.2 % versus 11.0 %, respectively; p < 0.001). The proportion of days spent with TEAEs was significantly lower with esketamine NS than quetiapine XR (median: 11.9 % versus 21.3 %; p < 0.001). Although more frequent with esketamine NS, TEAEs were typically transient and mild, with discontinuation less likely versus quetiapine XR. Data were consistent with established safety profiles, with no new safety signals identified. Alongside greater efficacy, the demonstrably more favourable tolerability profile of esketamine NS versus quetiapine XR further supports its use for TRD.

Association Between Pharmacological Treatment of Attention-Deficit/Hyperactivity Disorder and Long-term Unemployment Among Working-Age Individuals in Sweden.

Importance: Adults with attention-deficit/hyperactivity disorder (ADHD) are at greater risk for unemployment. Pharmacological treatment is effective in reducing the core symptoms of ADHD, but whether it helps to reduce the unemployment rate among adult patients remains unclear. Objective: To investigate the association between use of ADHD medication and long-term unemployment in working-age adults with ADHD. Design, Setting, and Participants: Data for this population-based cohort study were extracted from Swedish national registers. Among 25 358 individuals with ADHD born from 1958 to 1978, 12 875 middle-aged adults among the workforce were included. The longitudinal cohort was followed up from January 1, 2008, to December 31, 2013. Data were analyzed from March 1, 2020, through May 31, 2021. Exposures: Use of medication for ADHD during the previous 2 years was the main exposure, as both categorical and continuous variables. Main Outcomes and Measures: Yearly accumulated unemployed days were derived from the Public Employment Service, and long-term unemployment was defined as 90 or more days of unemployment per year. Overall and sex-specific relative risks (RRs) with 95% CIs were estimated using generalized estimating equations. Results: Among 12 875 individuals with ADHD (5343 women [41.50%] and 7532 men [58.50%]; mean [SD] age, 37.9 [5.6] years), the use of ADHD medications during the previous 2 years was associated with a 10% lower risk of long-term unemployment in the following year (adjusted RR, 0.90 [95% CI, 0.87-0.95]). An association between use of ADHD medications and long-term unemployment was found among women (RR, 0.82 [95% CI, 0.76-0.89]) but not men (RR, 0.96 [95% CI, 0.91-1.01]). Longer treatment duration was associated with a lower risk of subsequent long-term unemployment among women (RR for use of 1-6 months, 0.86 [95% CI, 0.78-0.95]; RR for use of 18-24 months, 0.72 [95% CI, 0.58-0.90]; P < .001 for trend). Within-individual comparisons showed that the long-term unemployment rate was lower during periods of ADHD medication treatment compared with nontreatment periods (RR, 0.89; 95% CI, 0.85-0.94). Conclusions and Relevance: The findings of this cohort study suggest that the use of ADHD medication is associated with a lower risk of subsequent long-term unemployment for middle-aged women. These findings should be considered together with the existing knowledge of risks and benefits of ADHD medication when developing treatment plans for working-age adults.

Healthcare utilization and costs of psychiatric and somatic comorbidities associated with newly diagnosed adult ADHD.

BACKGROUND: Psychiatric and somatic problems in young adulthood have been found to be main drivers of costs in individuals with childhood ADHD. However, knowledge of the patterns of healthcare utilization and costs of comorbidities in middle-aged adults with newly diagnosed ADHD is very limited. METHOD: We studied individuals born 1966-1978 (from the Swedish Total Population Register) with newly diagnosed ADHD between the ages of 30-45 years and individuals without ADHD matched on birthdate, birth county, and sex. Healthcare utilization and expenditure for psychiatric and somatic disorders were obtained over four years (two years pre- and post-initial ADHD diagnosis). RESULTS: Middle-aged adults with newly diagnosed ADHD showed higher levels of healthcare utilization and costs (outpatient, inpatient, medications) for psychiatric and somatic comorbidities relative to adults without ADHD, both before and after the initial diagnosis. Females showed greater average group differences across the study period for medication prescriptions than males. Total incremental annual costs per capita were €2478.76 in adults with ADHD relative to those without, and costs were mainly driven by inpatient care. Psychiatric outpatient visits were statistically significantly higher the year before the ADHD diagnosis compared with two years before and after the diagnosis. CONCLUSION: This study demonstrates the substantial burden of psychiatric and somatic comorbidities in middle-aged adults newly diagnosed with ADHD. Psychiatric outpatient visits peaked in the year leading up to the ADHD diagnosis. Findings further suggested that females with ADHD may seek more treatment for comorbidities than males, which may reflect a general female tendency.

Attention-deficit/hyperactivity disorder and occupational outcomes: The role of educational attainment, comorbid developmental disorders, and intellectual disability.

BACKGROUND: Individuals with ADHD are at increased risk for poor occupational outcomes. Educational attainment and psychiatric comorbidity may be important contributing factors for these outcomes, but the role of these factors is not well characterized. This study aimed to investigate the associations between ADHD and occupational outcomes, and to examine the influence of educational attainment, comorbid developmental disorders and intellectual disability on these associations. METHODS: We linked the Swedish population graduating from compulsory school 1998-2008 (N = 1.2 millions) to population-wide register-based data on clinical psychiatric diagnoses and medications, objective annual measures of educational, and occupational outcomes. Individuals were followed for between 6 to 16 years after graduation. RESULTS: Individuals with ADHD had annually on average 17 percent lower income, ratio = 0.83 (95% CI 0.83-0.84), 12.19 (11.89-12.49) more days of unemployment, and a higher likelihood of receiving disability pension, odds-ratio = 19.0 (18.4-19.6), compared to controls. Comorbid diagnoses of intellectual disability and developmental disorder explained most of the association between ADHD and disability pension, while lifetime educational attainment partially explained associations between ADHD and all occupational outcomes. Analyses of occupational trajectories found that income was lower and unemployment elevated relative to controls with the same educational attainment. Higher educational attainment correlated with higher income similarly among individuals with ADHD and controls after accounting for individual background factors. CONCLUSIONS: The occupational burden associated with ADHD is substantial. Comorbid developmental disorders, intellectual disability and educational difficulties (e.g., failing grades) from childhood to adulthood are important factors to consider when designing interventions to improve occupational outcomes in individuals with ADHD.

Functional impairment outcomes in clinical trials of different ADHD medications: post hoc responder analyses and baseline subgroup analyses.

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement.

Efficacy of Guanfacine Extended Release in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder and Comorbid Oppositional Defiant Disorder.

OBJECTIVE: To assess the efficacy of the non-stimulant guanfacine extended release (GXR) on attention-deficit/hyperactivity disorder (ADHD) symptoms in children and adolescents, with and without comorbid oppositional defiant disorder (ODD). METHODS: Data were derived from 4 phase 3, randomized, placebo-controlled trials of dose-optimized GXR monotherapy, in which at least 10% of participants had a diagnosis of comorbid ODD. SPD503-312 and SPD503-316 were 10- to 13-week studies of GXR (1-7 mg/d). SPD503-314 and SPD503-307 were 8-week studies of GXR (1-4 mg/d). Efficacy was assessed using the ADHD Rating Scale IV (ADHD-RS-IV) total scores. RESULTS: In total, 1,084 participants were included (SPD503-312 and SPD503-316, n = 537; SPD503-314, n = 333; and SPD503-307, n = 214). GXR was associated with significant improvements in ADHD core symptoms at endpoint in participants with and without ODD (p < 0.01 in all studies). Placebo-adjusted least-squares mean (95% confidence interval) changes from baseline to endpoint in the ADHD-RS-IV total scores in participants with and without ODD were -8.6 (-14.4, -2.8) and -7.3 (-9.5, -5.0) in the pooled data from SPD503-312 and SPD503-316, -12.6 (-19.6, -5.7) and -8.7 (-11.8, -5.5) in SPD503-314, and -12.7 (-17.3, -8.1) and -11.8 (-19.3, -4.4) in SPD503-307, respectively. The corresponding effect sizes were 0.688 and 0.598 in SPD503-312 and SPD503-316, 0.876 and 0.729 in SPD503-314, and 0.962 and 0.842 in SPD503-307. CONCLUSION: The findings demonstrate the efficacy of GXR for treating ADHD in children and adolescents with comorbid ODD.

Trajectories of healthcare utilization and costs of psychiatric and somatic multimorbidity in adults with childhood ADHD: a prospective register-based study.

BACKGROUND: A better understanding of the trajectories and economic burden of psychiatric and somatic disorders (multimorbidity) in ADHD from childhood to adulthood is important for guiding more targeted areas for treatment of ADHD and prevention of multimorbidity, and for forecasting demands on the medical infrastructure. This study aimed to investigate patterns of healthcare utilization and costs of multimorbidity across young adulthood in individuals with a childhood ADHD diagnosis, and additionally in individuals who continue to have ADHD-related contact with health services (persisters) and those who do not (remitters). METHODS: We prospectively followed a cohort (N = 445,790) born 1987-1990 from the ages of 18 to 26 years. Data on healthcare utilization were obtained from the Swedish National Patient Register (inpatient and outpatient care) and the Prescribed Drug Register (medication prescriptions). RESULTS: Mean annual costs per capita from multimorbidity was €890 ($1,223) in individuals with a childhood ADHD diagnosis (persisters/remitters: €1,060[$1,456]/€609[$837]) and €304 ($418) in individuals without. Costs were largely driven by inpatient hospital admissions, mainly from drug abuse and injuries. Healthcare utilization and costs of psychiatric and somatic disorders at 18 years was significantly higher in individuals with childhood ADHD compared to those without. These group differences remained stable or increased across young adulthood for most outcomes and were generally larger in women than in men. ADHD remitters continued to show significantly greater healthcare utilization and costs compared to individuals without childhood ADHD, although their profiles were not as severe as ADHD persisters. CONCLUSIONS: Childhood ADHD has long-term associations with both psychiatric and somatic disorders. Findings demonstrate the individual and societal burden of ADHD in adulthood and highlight the importance of continued support from childhood-adolescent to adult health services and early prevention of multimorbidity. Findings also point to specific targets for intervention that may be effective, such as drug abuse and injuries.

Post hoc analyses of response rates to pharmacological treatments in children and adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION AND OBJECTIVES: Lack of consensus regarding how best to define treatment response hinders translation from trials to the clinic. These post hoc analyses examine three commonly used response criteria in six trials of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: Data from four short-term randomised controlled trials (RCTs) and two long-term open-label studies were analysed. Children and adolescents with ADHD received either dose-optimised (30-70 mg/day) or fixed-dose (70 mg/day) LDX. The RCTs included osmotic-release oral system methylphenidate (OROS-MPH) or atomoxetine (ATX) as a head-to-head comparator or as a reference treatment. Three definitions of response were used in these analyses: reductions of ⩾30% or ⩾50% in ADHD Rating Scale IV (ADHD-RS-IV) total score plus a Clinical Global Impressions - Improvement (CGI-I) score of 1 or 2, or an ADHD-RS-IV total score of ⩽18. RESULTS: At the end point, LDX response rates for the least stringent criterion of ⩾30% reduction in ADHD-RS-IV total score plus a CGI-I score of 1 or 2 ranged from 69.6% to 82.6%. The proportion achieving the more stringent criterion of a reduction in ADHD-RS-IV total score of ⩾50% plus a CGI-I score of 1 or 2 at the end point ranged from 59.8% to 74.8%. An ADHD-RS-IV total score of ⩽18 at the end point was achieved by 56.7-79.9% of participants. Response rates remained stable throughout the long-term open-label studies. CONCLUSIONS: Response rates were similar for the two more stringent response criteria. The less stringent criterion resulted in higher response rates and may include partial responders.

Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy.

OBJECTIVE: This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. METHODS: Noninstitutionalized children (aged 3-16 years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. RESULTS: Enrolled children (N = 286) had experienced 1-400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (n = 279), parents (n = 277), and patients (n = 85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. SIGNIFICANCE: Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures.

Effect of rescue medication on seizure duration in non-institutionalized children with epilepsy.

OBJECTIVES: Characterize the real-world management of and outcomes for children with epilepsy receiving rescue medication for prolonged acute convulsive seizures (PACS) in the community. METHODS: PERFECT-3 (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3) was a European, retrospective observational study. Eligible patients were non-institutionalized children with epilepsy aged 3-16 years who had experienced ≥1 PACS in the past year and had ≥1 currently prescribed PACS rescue medication. Investigators provided clinical assessments and parents/guardians completed questionnaires. Statistical tests were post hoc; p values are descriptive. RESULTS: At enrollment (N = 286), most patients had prescriptions for diazepam (69.2%) and/or midazolam (55.9%); some had two (26.6%) or three (2.4%) prescribed rescue medications. Most patients experienced PACS despite regular anti-epilepsy medication. According to parents, the average duration of their child's seizures without rescue medication was <5 min in 35.7% of patients, 5-<20 min in 42.6%, and ≥20 min in 21.7% (n = 258); with rescue medication seizure duration was <5 min in 69.4% of patients, 5-<20 min in 25.6%, and ≥20 min in 5.0%. Rescue medication use was significantly associated with average seizures lasting <5 min (χ2 = 58.8; p < 0.0001). At the time of their most recent PACS, 58.5-67.8% of children reportedly received rescue medication within 5 min of seizure onset, and 85.4-94.1% within 10 min. CONCLUSION: This study provides the first real-world data that rescue medications administered in the community reduce the duration of PACS in children with epilepsy. Study limitations including potential recall bias are acknowledged.

Kyphoplasty enhances function and structural alignment in multiple myeloma.

We prospectively evaluated 19 patients with multiple myeloma who had kyphoplasty for vertebral compression fractures. Functional status was assessed preoperatively and 3 months postoperatively using the Oswestry Disability Index. Restoration of anterior and midvertebral height was assessed using lateral radiographs. Meaningful improvement occurred in 16 of 19 patients, with a reduction of the average Oswestry Disability Index from 49 +/- 16.6 to 32.6 +/- 13.6. Partial restoration of anterior vertebral body height was achieved in 76% of levels with an average of 37.8% restoration of the defect. Partial restoration of midvertebral body height was achieved in 91% of levels with an average restoration of 53.4% of the defect. There were no significant complications. These results were compared with results of a cohort of 26 patients with osteoporotic compression fractures treated with kyphoplasty at 37 levels. There was no difference between the groups in terms of Oswestry Disability Index improvement and midvertebral height restoration after 3 months. Greater anterior vertebral height restoration was achieved in the osteoporotic group (51.2% versus 37.8%). Kyphoplasty is a safe treatment modality for myeloma-related vertebral compression fractures. Efficacy in terms of pain relief and functional outcome is comparable with the results in patients with osteoporosis.

Cytochrome C and caspase-9 expression in Huntington's disease.

There is increasing evidence implicating apoptosis-mediated cell death in the pathogenesis of neurodegenerative diseases. One important event in the apoptotic cascade is the release of cytochrome c by mitochondria into the cytoplasm, activating caspase-9, leading to the subsequent activation of downstream executioner caspases. In the present study, we examined the distribution of cytochrome c and caspase-9 in Huntington's disease (HD) patients and in a transgenic model of HD (R6/2 line). Neuronal cytochrome c immunoreactivity increased with neuropathological severity in HD patients. Concomitant with this finding, Western-blot analysis showed a shift in the distribution of cytochrome c from the mitochondrial to the cytosolic fraction with incremental cytosolic expression associated with greater striatal degeneration. Active caspase-9 immunoreactivity was present in both HD striatal neurons and in Western blots of severe-grade specimens. Similar findings were observed in the R6/2 mice. There was a temporal increase in expression and shift of cytochrome c from the mitochondrial to the cytosolic fraction from 4-13 wk of age. Activated caspase-9 and caspase 3 activities were present only at endstage disease. Although the present results provide evidence that key components of the intrinsic mitochondrial apoptotic pathway are activated in both HD patients and a transgene murine model of HD, these phenomena are prominent in only severe neuropathological grades in HD patients and HD mice, suggesting that apoptosis may play a greater role in neuronal death at endstage disease.