Dextroamphetamine transdermal system (d-ATS) is the first and only amphetamine-based transdermal system FDA-approved for attention-deficit/hyperactivity disorder (ADHD) in adults and children aged ≥ 6 years, providing an alternative to oral stimulants. Although transdermal systems can cause local skin reactions, in the d-ATS pivotal study, no discontinuations due to patch application site reactions occurred, and discomfort/pain typically resolved within 2–4 h post-application. d-ATS is approved for five bilateral application sites (10 unique locations). This paper evaluates the pharmacokinetic (PK) bioequivalence between different application sites and summarizes dermal safety and irritation findings from four d-ATS clinical studies (studies 1–4). The application site PK bioequivalence study was a single-dose, open-label, 5-way crossover study assessing amphetamine bioavailability, discomfort, and irritation in healthy adults after a 9 h application of 20 mg/19.05 cm2 d-ATS to five distinct sites. Other studies, studies 1–4, conducted in healthy adults or patients with ADHD, evaluated dermal irritation from d-ATS alone or vs placebo under intended-use or exaggerated-use conditions. The application site PK study population included 50 patients. All 90

OBJECTIVE:Esketamine nasal spray (ESK) is approved in combination with an oral antidepressant (OAD) for the treatment of adults with treatment-resistant depression (TRD); however, direct comparisons with atypical antipsychotics for TRD are limited. This secondary analysis of the ESCAPE-TRD study compared rates of remission and response, and improvements in depressive symptoms over time, between ESK and quetiapine extended-release (XR) in patients with TRD treated in accordance with US prescribing information (USPI). METHODS:ESCAPE-TRD (NCT04338321) was a randomized, open-label, rater-blinded phase 3b trial investigating ESK versus quetiapine XR for acute and maintenance treatment of patients with TRD. This secondary analysis included patients aged 18-64 years who were treated/dosed according to USPI. The primary endpoint was remission, defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 10. Treatment-emergent adverse events (TEAEs) leading to discontinuation were summarized descriptively. RESULTS:Among 636 patients in this secondary analysis (ESK, n = 316; quetiapine XR, n = 320), significantly more ESK-treated patients achieved remission starting at week 8 (28.3% versus 18.6%; P = 0.005) through week 32 (55.7% versus 36.3%; P < 0.001), compared with quetiapine XR-treated patients. There were clinically and statistically significant improvements in MADRS scores with ESK versus quetiapine XR at each visit from day 8 onwards. Fewer patients discontinued treatment because of TEAEs with ESK (4.5%) versus quetiapine XR (10.1%). CONCLUSIONS:Consistent with the primary analysis, this secondary analysis demonstrated that ESK improves short- and long-term outcomes compared with quetiapine XR in patients with TRD treated according to USPI.

BACKGROUND:Centanafadine (CTN) is a potential first-in-class norepinephrine, dopamine, and serotonin reuptake inhibitor (NDSRI) currently in development for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. Safety, tolerability, and exploratory efficacy of CTN sustained release (SR) in adults were assessed over 52 weeks. METHODS:Adults were enrolled after completing a phase 3 pivotal trial or de novo. The monitoring schedule employed a screening (up to 28 d for de novo group only), 52-week open-label, and 10-day safety follow-up periods. Participants received CTN SR 400 mg total daily dose, twice daily. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratories, vital signs, electrocardiogram measures, the Study Medication Withdrawal Questionnaire, and the Columbia-Suicide Severity Rating Scale. Exploratory efficacy was assessed using the Adult Investigator Symptom Rating Scale (AISRS) and the Clinical Global Impression of Severity (CGI-S). Safety was analyzed with a mixed-effect model; efficacy was reported using summary statistics. RESULTS:Of 662 adults enrolled [mean (SD) age, 36.7 (10.1) y; 51.1% female; 82.9% white], 653 received CTN SR, and 345 completed the trial. Altogether, 61.4% reported ≥1 TEAE, mostly mild or moderate in severity; insomnia (8.0%), nausea (7.7%), diarrhea and headache (7.0% each) were most common. Eighty (12.3%) discontinued because of TEAEs. Serious adverse events occurred in 12 (1.8%) participants; none were CTN SR-related per investigators. AISRS total scores improved up to 57% and CGI-S by 1.5 points from baseline. CONCLUSIONS:Results from this trial demonstrate that CTN SR 400 mg is safe and effective for long-term treatment of adults with ADHD.

IMPORTANCE Esketamine nasal spray, administered in conjunction with an oral antidepressant, is approved for treatment-resistant depression (TRD). However, the efficacy of esketamine nasal spray administered as monotherapy for patients with TRD has not yet been evaluated. OBJECTIVE To assess the efficacy and safety of esketamine monotherapy compared to placebo in reducing depressive symptoms in patients with TRD. DESIGN, SETTING, AND PARTICIPANTS This phase 4, double-blind, placebo-controlled randomized clinical trial was conducted from November 2020 to January 2024 at 51 outpatient centers in the US. Adults with major depressive disorder (DSM-5 criteria) without psychotic features who experienced inadequate response (<= 25% improvement) to 2 or more oral antidepressants during the current depressive episode were eligible for inclusion. Data analyses were conducted from March 1, 2024, to July 8, 2024. INTERVENTIONS After a 2-week or longer antidepressant-free period, participants were randomized at a 1:1:2 ratio to fixed-dose intranasal esketamine (56 mg or 84 mg) or matching intranasal placebo, administered twice weekly for4 weeks. MAIN OUTCOMES AND MEASURES Change in Montgomery-& Aring;sberg Depression Rating Scale (MADRS) score from baseline to day 28 (primary efficacy end point) and to 24 hours post-first dose (day 2; key secondary efficacy end point) were analyzed by a mixed-effects model using repeated measures. RESULTS In this multicenter randomized clinical trial, 378 participants who met prerandomization MADRS severity criteria received 1 or more study drug doses (esketamine, 56 mg [n = 86]; esketamine, 84 mg [n = 95]; or placebo [n = 197]). Mean (SD) participant age was 45.4 (14.1) years, 231 participants (61.1%) were female, and baseline mean (range) MADRS total score was 37.3 (28-50). At day 28, the least-square (LS) mean difference (SE) between esketamine and placebo was-5.1 (1.42) (95% CI, -7.91 to-2.33) for the 56-mg dose and-6.8 (1.38) (95% CI, -9.48 to-4.07) for the 84-mg dose (for each, 2-sided P < .001). Observed effect sizes were 0.48 and 0.63 for the 56-mg and 84-mg dose groups, respectively. At day 2 (approximately 24 hours post-first dose), the between-group difference was significant for both esketamine doses: -3.8 (1.29) (95% CI, -6.29 to-1.22; 2-sided P = .004) for 56 mg and-3.4 (1.24) (95% CI, -5.89 to-1.00; 2-sided P = .006) for 84 mg. The most common treatment-emergent adverse events reported for esketamine (combined doses) were nausea (56 participants [24.8%]), dissociation (55 [24.3%]), dizziness (49 [21.7%]), and headache (43 [19.0%]). CONCLUSIONS AND RELEVANCE According to results of this multicenter, double-blind randomized clinical trial, esketamine monotherapy may expand treatment options for adult patients with TRD by addressing an unmet need of patients experiencing treatment-limiting tolerability concerns and nonresponse with oral antidepressants.

This review article describes why and how aripiprazole was formulated as aripiprazole lauroxil (AL), an extended-release antipsychotic agent that is delivered via a long-acting injectable formulation, and the clinical trials investigating its use. AL was formulated as an inactive prodrug of aripiprazole using LinkeRx® technology to provide a prolonged-release antipsychotic with predictable dissolution over time. The resulting AL pharmacokinetic profile is characterized by a long half-life and little peak-to-trough aripiprazole concentration variability across dosing intervals of every 1 month, every 6 weeks, and every 2 months. The prodrug technology was further refined to develop an AL initiation formulation with a somewhat faster release of aripiprazole, eliminating the need for a 21-day oral aripiprazole supplementation period. With this initiation formulation, AL treatment can be started in 1 day. Key AL characteristics, including pharmacokinetic profile and efficacy, safety, and tolerability data, are presented. In addition to the efficacy and safety established in clinical trials of oral aripiprazole, a placebo-controlled 12-week pivotal study investigated AL 441 mg and 882 mg monthly regimens in patients with acutely exacerbated schizophrenia and provided efficacy and safety information that led to US Food and Drug Administration approval in 2015. Thereafter, studies established the long-term safety profile and durability of the AL treatment effect. The 25-week, active-controlled ALPINE study evaluated the feasibility and effectiveness of AL 1064 mg every 2 months, initiated using the 1-day AL initiation regimen, without further oral supplementation beyond day 1, in patients hospitalized for acutely exacerbated schizophrenia with subsequent transition to outpatient care. In short-term and long-term studies, AL was generally well tolerated at initiation and during acute and maintenance treatment. Pharmacokinetic, efficacy, and safety characteristics support the use of AL across inpatient and outpatient treatment settings.

Despite decades of clinical use and a large body of evidence, the WHO continues to exclude methylphenidate for attention-deficit/hyperactivity disorder (ADHD) from its EML.1 The exclusion of methylphenidate has dire implications for millions of individuals with ADHD worldwide, especially those living in low and low-middle income countries (LMIC), where governmental decisions to make medicines available are contingent on EML listing.

Changing practice patterns caused by the pandemic have created an urgent need for guidance in prescribing stimulants using telepsychiatry for attention-deficit hyperactivity disorder (ADHD). A notable spike in the prescribing of stimulants accompanied the suspension of the Ryan Haight Act, allowing the prescribing of stimulants without a face-to-face meeting. Competing forces both for and against prescribing ADHD stimulants by telepsychiatry have emerged, requiring guidelines to balance these factors. On the one hand, factors weighing in favor of increasing the availability of treatment for ADHD via telepsychiatry include enhanced access to care, reduction in the large number of untreated cases, and prevention of the known adverse outcomes of untreated ADHD. On the other hand, factors in favor of limiting telepsychiatry for ADHD include mitigating the possibility of exploiting telepsychiatry for profit or for misuse, abuse, and diversion of stimulants. This Expert Consensus Group has developed numerous specific guidelines and advocates for some flexibility in allowing telepsychiatry evaluations and treatment without an in-person evaluation to continue. These guidelines also recognize the need to give greater scrutiny to certain subpopulations, such as young adults without a prior diagnosis or treatment of ADHD who request immediate-release stimulants, which should increase the suspicion of possible medication diversion, misuse, or abuse. In such cases, nonstimulants, controlled-release stimulants, or psychosocial interventions should be prioritized. We encourage the use of outside informants to support the history, the use of rating scales, and having access to a hybrid model of both in-person and remote treatment.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once -daily, 14 -day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open -label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the longterm safety and efficacy of zuranolone in adults with MDD are reported. Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17 -item Hamilton Rating Scale for Depression (HAMD-17) total score >= 20 received an initial 30 -mg or 50 -mg 14 -day zuranolone course. HAMD-17 responders (>= 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for <= 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s). Results: As of September 2021, among patients in the 30 -mg (n = 725) and 50 -mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment -emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30 -mg Cohort, 90.9% [448/493]; 50 -mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30 -mg and 50 -mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30 -mg Cohort and 54.8% (80/146) in the 50mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received <= 2 total treatment courses (30 -mg Cohort, 68.5% [335/489]; 50 -mg Cohort, 79.5% [116/146]). Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.

IntroductionCentanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI) that has demonstrated efficacy, safety, and tolerability vs placebo (PBO) in adults with ADHD in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).MethodsPooled data from 2 double-blind, multicenter, PBO-controlled trials enrolling adults (18–55 years) meeting DSM-5 ADHD criteria were analyzed. Patients were randomized 1:1:1 to CTN sustained release (SR) 200 mg or 400 mg total daily dose (TDD) or matching PBO if Adult ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic ADHD treatment) or ≥22 at screening and ≥28 at baseline (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of different classes, use of prohibited medications, and positive alcohol/drug screens were exclusionary. Studies had 4 periods: (1) screening and washout (≤28 days), (2) single-blind PBO run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% Adult ADHD Self-report Scale (ASRS) improvement from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of PBO run-in were terminated early. A mixed model for repeated measures analysis evaluated CTN SR vs PBO based on ADHD treatment history; least squares mean (LSM) change from baseline (BL) in AISRS at day 42 was the outcome of interest.ResultsIn total, 859 patients were analyzed (CTN SR 200 mg TDD, n=287; 400 mg TDD, n=287; PBO, n=285). LSM change from BL in AISRS score was significant at day 42 for each CTN SR TDD group (both, P<0.001) in the overall population vs PBO. Among patients with prior stimulant/nonstimulant treatment (n=542), LSM change from BL was significant at day 42 vs PBO in the CTN SR 200 mg (P=0.016) and 400 mg (P=0.008) TDD groups. Although cohort size was limited (n=47), LSM change from baseline with CTN SR 400 mg TDD was significant (P<0.05) from days 14 to 42 in those who took 2 prior stimulant/nonstimulant treatments, with P=0.030 at day 42. In those with no prior stimulant/nonstimulant treatment (n=317), LSM change from BL was significant at day 42 for the CTN SR 200 mg (P=0.007) and 400 mg (P=0.008) TDD groups vs PBO. When analyzed by history of any past stimulant use, LSM change from BL was significant at day 42 for CTN 200 mg (n=179; P=0.013) and 400 mg (n=166; P=0.006), with significance (P<0.05) noted at day 7 (200 mg TDD) and at day 21 (400 mg TDD), remaining significant to day 42.ConclusionsThis pooled analysis suggests that CTN SR treatment is efficacious in adults with ADHD, regardless of prior treatments, an encouraging finding given reported adult ADHD treatment patterns.Study Registration: NCT03605680, NCT03605836FundingOtsuka

IntroductionIn ESCAPE-TRD (NCT04338321), a randomized, open-label, rater-blinded, long-term, phase 3b trial, augmentation with esketamine nasal spray (ESK) demonstrated increased probability of achieving meaningful clinical benefit versus quetiapine extended release (QUE XR) in patients (pts) with treatment-resistant depression (TRD). This subgroup analysis of ESCAPE-TRD evaluated the incidence, duration, and impact of treatment-emergent adverse events (TEAEs) on treatment discontinuation in adults with TRD treated with ESK or QUE XR according to US prescribing information.MethodsPts aged 18-64 years were randomly assigned to receive flexibly dosed ESK (56 or 84 mg) or QUE XR (150-300 mg), both consistent with US label dosing and in combination with an ongoing oral antidepressant. The incidence and duration of the most commonly occurring TEAEs, as well as the most common TEAEs leading to treatment discontinuation, were summarized descriptively. All randomly assigned participants receiving ≥1 dose of study drug were included in the safety analyses.ResultsAmong the 636 pts included in the subgroup analysis, 316 and 320 were randomly assigned to ESK and QUE XR, respectively; 314 and 316 were included in the safety population. In the combined acute and maintenance phases, TEAEs occurred in 92.0% of pts in the ESK group and 78.5% of pts in the QUE XR group. The most commonly reported TEAEs with ESK or QUE XR in the combined acute and maintenance phases were dizziness (47.1% and 7.9%, respectively), headache (25.5% and 13.0%, respectively), somnolence (15.0% and 23.4%, respectively), and nausea (29.9% and 3.2%, respectively). Across all TEAE events reported in >5% of pts in either arm, 91.8% (5831 of 6351) resolved within 1 day in the ESK arm compared to 11.6% (90 of 776) with QUE XR. For specific TEAE events of clinical interest for ESK, same-day resolution rates for increased blood pressure, sedation, and dissociation in the ESK group were 93.5% (116 of 124), 96.2% (127 of 132), and 99.6% (740 of 743), respectively. The majority of TEAEs of clinical interest in the ESK group that occurred on the same day of dosing resolved within the first 2 hours after dosing. For the most frequently reported TEAEs with QUE XR, same-day resolution rates for somnolence, headache, and fatigue were 7.8% (8 of 103), 49.2% (29 of 59), and 9.5% (4 of 42), respectively. Fewer pts treated with ESK discontinued treatment due to TEAEs compared to QUE XR (4.4% versus 10.6%).ConclusionsSafety data from this subgroup analysis were consistent with the overall study population as well as the known tolerability profile of each treatment. TEAEs were reported at higher incidence with ESK than with QUE XR; however, the majority of TEAEs occurring with ESK were transient in nature and did not result in a higher rate of treatment discontinuation compared to QUE XR.FundingJanssen Scientific Affairs, LLC

Introduction Zuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD. Objectives To assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL. Methods CORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course. Results Among the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed. Conclusions Safety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study. Disclosure of Interest G. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared

IntroductionAlthough many patients respond equally well to both stimulant and nonstimulant medications for ADHD, some patients respond preferentially to one class over another. Currently, most patients receive a stimulant as first-line therapy; however, nonstimulants present fewer obstacles for prescribers and patients and have low abuse/misuse potential. Still, when patients have suboptimal response to stimulants, physicians may be reticent to switch to a nonstimulant medication due to concerns that the nonstimulant response will be less robust or less preferable for patients. Viloxazine ER (viloxazine extended-release capsules; Qelbree®) is a nonstimulant, FDA-approved treatment for ADHD in children (≥6 years) and adults. This post-hoc analysis of adult Phase 3 trial data (NCT04016779) evaluates response to viloxazine ER (200-600 mg/day) based on whether or not patients reported a history of previous stimulant use.MethodsFor patients randomized to viloxazine in this Phase 3, double-blind, placebo-controlled trial, the change from baseline (CFB) in Adult ADHD Investigator Symptom Rating Scale (AISRS) score (primary trial outcome) was analyzed for prior stimulant users vs. nonusers using MMRM. Prior stimulant use was based on patient-reported medication history recorded upon enrollment. Subjects using stimulants at the time of study screening were required to undergo a ≥1-week washout period prior to randomization.ResultsOf 372 patients treated, 189 received viloxazine ER. Of the patients who received viloxazine ER, 40 reported prior stimulant use and 149 did not. Mean (SD) baseline AISRS scores for prior stimulant users and nonusers were 38.5 (7.40) and 38.3 (6.44), respectively. Response appeared similar in both patient groups. At Week 6/End of Study (EOS) the least squares (LS) mean (SE) CFB AISRS scores for prior stimulant users and nonusers were -15.8 (2.51) and -15.6 (1.08)]; treatment difference -0.2 (2.41); P=0.93. Though not significant, prior stimulant users showed a larger magnitude of improvement on the AISRS at early timepoints compared to those without prior stimulant use [Week 1, LS mean (SE) CFB AISRS Total scores: -9.2 (1.40) vs. -6.8 (0.70), respectively; treatment difference: -2.4 (1.56); P=0.12.]ConclusionsA history of prior stimulant use did not appear to influence the magnitude of ADHD symptom response to viloxazine ER in this preliminary analysis of Phase 3 trial data in adults. Rather, subjects with prior stimulant use showed numerically larger reductions in AISRS scores at early timepoints that were not significantly different from those without prior stimulant use. Additional analysis should be undertaken to evaluate patterns of response in the pediatric population.FundingSupernus Pharmaceuticals, Inc.

With more than 30 available stimulant medications, choosing among therapeutic options for attention-deficit/hyperactivity disorder (ADHD) has become increasingly complex and patient specific. All ADHD stimulants owe their action to variants of either amphetamine or methylphenidate, yet formulation and delivery system differences create unique pharmacokinetic and clinical profiles for each medication. A benefit of the diversity within ADHD pharmacotherapy is that it facilitates tailoring treatment to meet patient needs. Historically, there has been a constant among long-acting stimulant options, regardless of formulation, which was morning dosing. The introduction of delayed-release and extended-release methylphenidate (DR/ER-MPH) is the first long-acting stimulant that patients take in the evening, with the clinical effect delayed until awakening in the morning. This paradigm shift has generated questions among clinicians and continued interest in real-world experience and data. This review used available clinical data, real-world evidence, emerging analyses, and clinical experience to evaluate the characteristics of DR/ER-MPH and its clinical utility within the greater context of ADHD medications and to provide clinicians with practical guidance on the use of DR/ER-MPH in children, adolescents, and adults with ADHD.

IntroductionAttention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and/or hyperactivity and impulsivity. Viloxazine extended-release (ER) capsules (Qelbree (R)) is a US Food and Drug Administration-approved nonstimulant treatment option for children, adolescents, and adults with ADHD.Areas coveredThis review manuscript summarizes the neurobiology of ADHD and currently available treatment options before discussing viloxazine pharmacology, efficacy, safety, and tolerability data from phase II and III trials in children and adolescents (6-17 years old). Viloxazine clinical efficacy has also been further demonstrated by post hoc analyses of pediatric clinical trial results.Expert opinionCurrent stimulant and nonstimulant treatments for ADHD may be suboptimal given low response rates and that tolerability issues are frequently experienced. Preclinical and clinical evidence has implicated both the role of catecholamine and serotonin signaling in the pathophysiology of ADHD and the pharmacologic effect of viloxazine on these critical neurotransmitter systems. With a relatively rapid onset of action, sustained symptom improvement, and clinical benefit in ADHD-associated impairments (functional and social), viloxazine ER represents a novel and emerging ADHD treatment option.

IntroductionCentanafadine (CTN) is a potential first-in-class norepinephrine/dopamine/serotonin triple reuptake inhibitor (NDSRI). The efficacy, safety, and tolerability of CTN sustained release (SR) for adults with ADHD was demonstrated in 2 pivotal phase 3 trials (Adler LA, et al. J Clin Psychopharmacol. 2022;42:429-39).MethodsAdults (18–55 years) meeting DSM-5 criteria for ADHD enrolled in these double-blind, multicenter, placebo-controlled trials and randomized to treatment if ADHD Investigator Symptom Rating Scale (AISRS) score was ≥28 at screening (if not receiving pharmacologic treatment for ADHD) or ≥22 at screening and ≥28 at baseline (BL) (if receiving treatment). Having had no prior benefit from ≥2 ADHD therapies of 2 different classes, taking prohibited medications, and positive alcohol/drug screen were exclusionary. Trials had 4 periods: (1) screening and washout (≤28 days), (2) single-blind placebo run-in (1 week), (3) double-blind treatment (6 weeks), and (4) follow-up (10 days after last dose). Patients with ≥30% improvement in the Adult ADHD Self-report Scale (ASRS) from start to end of screening were screen failures; those with ≥30% ASRS improvement from start to end of placebo run-in were terminated early. Patients were randomized 1:1:1 to twice-daily CTN SR (200 or 400 mg total daily dose [TDD]) or matching placebo. The 200 mg/d group received CTN SR 200 mg TDD from days 1–42; the 400 mg/d group received 200 mg TDD on days 1–7, and increased to 400 mg TDD on day 8. This analysis assessed CTN SR effects based on median BL AISRS severity score (<38 or ≥38) using a mixed model for repeated measures analysis. Least squares mean (LSM) differences (95% CI) from BL at day 42 were compared between individual CTN SR dose groups and placebo, tested at a 2-sided significance level of 0.05.ResultsIn total, 859 patients were randomized (200 mg TDD, n=287; 400 mg TDD, n=287; placebo, n=285). Significant LSM differences on the AISRS were observed vs placebo in the overall population (200 mg TDD and 400 mg TDD, P<0.0001 for each), in the low BL severity (200 mg TDD [P=0.016]; 400 mg TDD [P=0.019]), and in the high BL severity (200 mg TDD [P=0.005]; 400 mg TDD [P=0.003]) populations at day 42. Significant LSM differences vs placebo (P<0.01) began at day 7 (200 mg) and day 14 (400 mg) overall, remaining significant to day 42. Significant LSM differences were observed vs placebo (P<0.05) from day 14 (400 mg TDD) and day 21 (200 mg) in the low severity populations, and from day 21 (400 mg TDD) and day 7 (200 mg TDD) in the high severity population, remaining significant (P<0.05) to day 42.ConclusionsCTN SR, a potential first-in-class NDSRI, is efficacious for patients with adult ADHD of low or high BL symptom severity, with significant improvements observed vs placebo within the first 3 weeks.Study Registration: NCT03605680, NCT03605836FundingOtsuka

Introduction Effective treatment of major depressive disorder (MDD) involves addressing both depressive and functional symptoms, increasing patients’ overall sense of well-being and quality of life (QoL). Methods RELIEVE was an international observational, prospective study in patients ≥18 years with a current diagnosis of a major depressive episode (MDE) initiating vortioxetine in routine clinical practice; outcomes for the cohort of participants from the United States are presented here. Functioning was assessed at weeks 12 and 24 versus baseline using the Sheehan Disability Scale (SDS). Secondary effectiveness analyses assessed changes from baseline to weeks 12 and 24 in functioning, depression severity, cognitive symptoms, sexual function, and QoL. Results 244 participants had an average of 8.2 previous MDEs; mean duration of their current MDE at baseline was 93.5 weeks. Vortioxetine was used as second- or later-line treatment for 80.5% of participants. Least-squares mean (SE) SDS total score significantly decreased from baseline by 7.19 (0.52) points at week 12 and 8.19 (0.56) points at week 24 (p < 0.0001 for both). Significant improvements were also reflected across SDS subscores, depression severity, cognitive function, sexual function, and QoL. Healthcare resource utilization and productivity parameters also improved. Adverse events were observed in 21.8% of patients, with nausea being the most common (7.3%). Conclusion This real-world study demonstrated improvements in functioning, depressive symptoms, and cognitive function in patients with MDD treated with vortioxetine in routine clinical practice in the cohort of patients enrolled in the United States. Outcomes were consistent with the efficacy and safety profile of vortioxetine in randomized controlled trials.

Abstract Objective Evaluate the long-term safety and efficacy of vortioxetine in the management of major depressive disorder (MDD) in two open-label one-year studies, including a post-hoc analysis of its effects on symptoms related to anhedonia. Methods Both studies were 52-week, open-label, flexible-dose extension studies to evaluate the safety and efficacy of vortioxetine in adult patients with MDD following prior double-blind studies. Patients in the first study (NCT00761306) were flexibly treated with vortioxetine 5 or 10 mg/day (N = 74), and patients in the second study (NCT01323478) received vortioxetine 15 or 20 mg/day (N = 71). Results The safety and tolerability profile of vortioxetine was similar between the two studies; treatment-emergent adverse events with the highest incidence were nausea, dizziness, headache, and nasopharyngitis. Across both studies, improvements achieved during the preceding double-blind studies period were maintained, and additional improvements were observed with open-label treatment. Patients showed a mean ± SD reduction (improvement) in Montgomery and Åsberg Depression Rating Scale (MADRS) total score from open-label baseline to Week 52 of 4.3 ± 9.2 points in the 5–10 mg study, and 10.9 ± 10.0 in the 15–20 mg study. Post-hoc MMRM analyses of MADRS anhedonia factor scores also showed continued improvements over long-term treatment; patients showed a mean ± SE reduction from an open-label baseline to Week 52 of 3.10 ± 0.57 points in the 5–10 mg study, and 5.62 ± 0.60 in the 15–20 mg study. Conclusions Data from both studies confirm the safety and efficacy of flexibly dosed vortioxetine over 52 weeks of treatment and demonstrate that MADRS anhedonia factor scores continue to improve with long-term maintenance treatment.