Autism: Comorbidities and Treatment Patterns in the Real World, a Retrospective Cohort Study Among Children, Adolescents and Adults Newly Diagnosed with Autism.

We used real world data to summarize comorbidities and interventions among patients newly diagnosed with autism spectrum disorder (ASD). Data were derived from two claims-based US healthcare databases; Medicaid and Optum to construct a retrospective cohort of 36,000 patients. Attention-Deficit-Hyperactivity-Disorder (ADHD) was the most common co-morbidity (Medicaid: 50.09%; Optum: 44.16%), followed by mood disorder (Medicaid: 16.56% and Optum: 17.47%). Most patients received at least one type of treatment. Behavioral therapy was common (74.64% in Medicaid and 71.97% in Optum). More than half the cohorts received at least 1 pharmacotherapy. However, pharmacotherapies were diverse. Combination therapy and therapy switching was common. Understanding the clinical diversity and complexity of patients with ASD is an important first step in understanding unmet therapeutic needs.

Comparison of Long-Term Efficacy and Safety of Esketamine Nasal Spray Plus Oral Antidepressant in Younger Versus Older Patients With Treatment-Resistant Depression: Post-Hoc Analysis of SUSTAIN-2, a Long-Term Open-Label Phase 3 Safety and Efficacy Study.

BACKGROUND: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD. METHODS: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance. RESULTS: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups. CONCLUSIONS: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes.

Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies.

BACKGROUND: Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. OBJECTIVE: The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). METHODS: A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. RESULTS: Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. CONCLUSION: Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies. CLINICAL TRIAL REGISTRATION: TRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Genome-wide association study and polygenic risk score analysis of esketamine treatment response.

To elucidate the genetic underpinnings of the antidepressant efficacy of S-ketamine (esketamine) nasal spray in major depressive disorder (MDD), we performed a genome-wide association study (GWAS) in cohorts of European ancestry (n = 527). This analysis was followed by a polygenic risk score approach to test for associations between genetic loading for psychiatric conditions, symptom profiles and esketamine efficacy. We identified a genome-wide significant locus in IRAK3 (p = 3.57 × 10-8, rs11465988, ß = - 51.6, SE = 9.2) and a genome-wide significant gene-level association in NME7 (p = 1.73 × 10-6) for esketamine efficacy (i.e. percentage change in symptom severity score compared to baseline). Additionally, the strongest association with esketamine efficacy identified in the polygenic score analysis was from the genetic loading for depressive symptoms (p = 0.001, standardized coefficient ß = - 3.1, SE = 0.9), which did not reach study-wide significance. Pathways relevant to neuronal and synaptic function, immune signaling, and glucocorticoid receptor/stress response showed enrichment among the suggestive GWAS signals.

Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3.

BACKGROUND: Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment. METHODS: This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset. RESULTS: For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. CONCLUSIONS: Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).

First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18.

BACKGROUND: This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents. PATIENTS AND METHODS: This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised. Adverse events were monitored throughout the trial. RESULTS: Forty-four patients who received a single dose of 1 mg/kg tapentadol OS were included in this investigation. Maximum serum concentrations of tapentadol (111 ng/mL) and tapentadol-O-glucuronide (2,400 ng/mL) observed in this trial were within the range of individual maximum concentrations observed in healthy adults administered a comparable dose (range for tapentadol 23.2-129 ng/mL, for tapentadol-O-glucuronide 1,040-4,070 ng/mL). Following tapentadol administration, pain intensity scores improved from baseline at all timepoints. Treatment-emergent adverse events, none of which were serious, were experienced by 45.5% of the patients; the most commonly reported were vomiting (29.5%) and nausea (9.1%). CONCLUSIONS: Tapentadol OS administered as a single dose of 1 mg/kg in children aged 6 to <18 years was generally well tolerated and produced similar serum concentrations as administration of 50-100 mg tapentadol immediate-release tablets in adults. A decrease in postsurgical pain was observed using exploratory subject-reported pain assessments. Tapentadol OS may provide a new treatment option in the management of moderate to severe acute pain in children and adolescents.

Risk Factors for Interstitial Cystitis in the General Population and in Individuals With Depression.

PURPOSE: To identify risk factors for interstitial cystitis (IC), a chronic bladder disorder that may have a significant detrimental impact on quality of life, in the general population and in individuals with depression. METHODS: This was a comparative study using a US claims database. Adults who had records of a visit to the health system in 2010 or later were included. The outcome was the development of IC within 2 years after the index date. The index date for the general population was the first outpatient visit, and for individuals with depression, it was the date of the diagnosis of depression. IC was defined using the concepts of ulcerative and IC. We included all medical conditions present any time prior to the index visit as potential risk factors. RESULTS: The incidence of IC was higher in individuals with depression than in the general population. Of the 3,973,000 subjects from the general population, 2,293 (0.06%) developed IC within 2 years. Of the 249,200 individuals with depression, 320 (0.13%) developed IC. The characteristics of the individuals who developed IC were similar in both populations. Those who developed IC were slightly older, more likely to be women, and had more chronic pain conditions, malaise, and inflammatory disorders than patients without IC. In the general population, subjects who developed IC were more likely to have mood disorders, anxiety, and hypothyroidism. CONCLUSION: The incidence of IC was higher in individuals with depression. Subjects who developed IC had more chronic pain conditions, depression, malaise, and inflammatory disorders.