AACAP Endorses the Inclusion of Methylphenidate in the WHO Model Lists of Essential Medicines.

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.

Viloxazine extended-release capsules as an emerging treatment for attention-deficit/hyperactivity disorder in children and adolescents.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention and/or hyperactivity and impulsivity. Viloxazine extended-release (ER) capsules (Qelbree®) is a US Food and Drug Administration-approved nonstimulant treatment option for children, adolescents, and adults with ADHD. AREAS COVERED: This 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 OPINION: Current 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.

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-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 long-term 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 50-mg 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.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder.

The pathophysiology of major depressive disorder (MDD) is thought to result from impaired connectivity between key brain networks. Gamma-aminobutyric acid (GABA) is the key inhibitory neurotransmitter in the brain, working primarily via GABAA receptors, with an important role in virtually all physiologic functions in the brain. Some neuroactive steroids (NASs) are positive allosteric modulators (PAMs) of GABAA receptors and potentiate phasic and tonic inhibitory responses via activation of synaptic and extrasynaptic GABAA receptors, respectively. This review first discusses preclinical and clinical data that support the association of depression with diverse defects in the GABAergic system of neurotransmission. Decreased levels of GABA and NASs have been observed in adults with depression compared with healthy controls, while treatment with antidepressants normalized the altered levels of GABA and NASs. Second, as there has been intense interest in treatment approaches for depression that target dysregulated GABAergic neurotransmission, we discuss NASs approved or currently in clinical development for the treatment of depression. Brexanolone, an intravenous NAS and a GABAA receptor PAM, is approved by the U.S. Food and Drug Administration for the treatment of postpartum depression (PPD) in patients 15 years and older. Other NASs include zuranolone, an investigational oral GABAA receptor PAM, and PH10, which acts on nasal chemosensory receptors; clinical data to date have shown improvement in depressive symptoms with these investigational NASs in adults with MDD or PPD. Finally, the review discusses how NAS GABAA receptor PAMs may potentially address the unmet need for novel and effective treatments with rapid and sustained antidepressant effects in patients with MDD.

Long-term safety and efficacy, including anhedonia, of vortioxetine for major depressive disorder: findings from two open-label studies.

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.

Assessing the educational needs of physicians in the management of patients with Tourette syndrome: results of a United States survey on practicing clinicians and caregivers.

OBJECTIVE: To better understand current practices of U.S.-based physicians in the management of Tourette syndrome (TS) and identify gaps that may be addressed by future education. METHODS: Two survey instruments were developed to gather data on management of TS and perceptions from physicians and caregivers of children with TS. The clinician survey was developed in consultation with a TS physician expert and utilized clinical vignettes to assess and quantify practice patterns. The caregiver survey was adapted from the clinician survey and other published studies and gathered details on diagnosis, treatment, and perceptions regarding management. RESULTS: Data included responses from 138 neurologists (including 57 pediatric neurologists), 162 psychiatrists (including 42 pediatric psychiatrists), and 67 caregivers. Most (65%) pediatric neurologists rely solely on clinical findings to make a diagnosis, whereas the majority of other specialists utilize additional testing (eg, neuroimaging, lab testing, and genetics). Most psychiatrists (96%) utilize standardized criteria to make a diagnosis, whereas 22% of neurologists do not. Many physicians (44% of psychiatrists and 20% of neurologists) use pharmacotherapy to treat a patient with "slightly bothersome" tics and no functional impairment, whereas caregivers favored behavioral therapy. Most (76%) caregivers preferred to make the final treatment decision, whereas 80% of physicians preferred equal or physician-directed decision-making. CONCLUSIONS: This study provides insight into practice patterns and perceptions of U.S.-based neurologists and psychiatrists in managing TS. Results highlight the potential value of physician education, including diagnostic approach, tic management and monitoring, involvement of caregivers in decision-making, and updates on TS management.

Effectiveness of Vortioxetine in Patients With Major Depressive Disorder in Real-World Clinical Practice: Results of the RELIEVE Study.

Background: Randomized controlled clinical trials have shown vortioxetine to be efficacious and well tolerated for the treatment of major depressive disorder (MDD). The Real-Life Effectiveness of Vortioxetine in Depression (RELIEVE) study was undertaken to demonstrate the effectiveness and safety of vortioxetine for the treatment of MDD in routine clinical practice. Methods: RELIEVE was a 24-week, observational, prospective cohort study in outpatients with MDD initiating treatment with vortioxetine at their physician's discretion in routine care settings in Canada, France, Italy, and the USA (NCT03555136). The primary study outcome was patient functioning assessed by the Sheehan Disability Scale (SDS). Secondary outcomes included depression severity [9-item Patient Health Questionnaire (PHQ-9)], cognitive symptoms [5-item Perceived Deficits Questionnaire-Depression (PDQ-D-5)], and cognitive performance [Digit Symbol Substitution Test (DSST)]. Mixed models of repeated measures were used to assess change from baseline at week 24, adjusted for relevant confounders. Results: A total of 737 patients were eligible for inclusion in the full analysis set. Most patients (73.7%) reported at least one comorbid medical condition, 56.0% had comorbid anxiety and 24.4% had comorbid generalized anxiety disorder. Improvement in least-squares (LS) mean SDS score from baseline to week 24 was 8.7 points. LS mean PHQ-9, PDQ-D-5 and DSST scores improved by 7.4, 4.6, and 6.2 points, respectively. Adverse events were observed in 21.2% of patients [most commonly, nausea (8.2% of patients)]. Conclusions: These results demonstrate the effectiveness and tolerability of vortioxetine for the treatment of MDD in a large and heterogeneous patient population representative of that encountered in routine clinical practice.

Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents.

Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these "pipeline" ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

Effectiveness of vortioxetine for major depressive disorder in real-world clinical practice: US cohort results from the global RELIEVE study.

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.

Adult Patient Preferences for Long-Acting ADHD Treatments: A Discrete Choice Experiment.

BACKGROUND AND OBJECTIVE: Treatment for attention deficit hyperactivity disorder (ADHD) requires a multifaceted approach including psychosocial interventions and pharmacological treatment. This study evaluates preferences for specific attributes associated with different long-acting stimulant treatment among US adults with ADHD. METHODS: Patients completed an online, cross-sectional survey, incorporating a discrete choice experiment to assess preferences for attributes. RESULTS: Analyses included 200 adults with ADHD (mean age 33.0 years; 60% self-reporting moderate severity); the mean (SD) Adult ADHD Self-Report Scale-v1.1 score was 45.9 (12.4). Overall, patients valued speed of onset most and risk of rebound least. Three population groups with distinct preferences were identified: side effect-driven (n=69, 35%), quick onset-driven (n=47, 24%) and quick onset and long duration-driven (n=84, 42%). CONCLUSION: This study shows differences in how adults with ADHD value and assess benefit-risk trade-offs when considering the desired attributes of stimulant treatments, highlighting the importance of patient-physician shared decision-making to optimize the desired benefits of individualized treatment.

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder.

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

A clinician's guide to ADHD treatment options.

Attention deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition of children and adolescents that often persists into adulthood. Primary care physicians are commonly the first to diagnosis ADHD and initiate a treatment plan with the patient. Guidelines recommend psychostimulant treatment as a first-line therapy in the management plan because it has a substantial impact on alleviating the core symptoms of ADHD. The recent development of a variety of methylphenidate and amphetamine formulations provides many options to meet individual patient lifestyle needs. Liquid, chewable, sprinkled capsule, wearable patch, and orally disintegrating tablet formulations are currently available for patients who may be noncompliant with or have difficulty swallowing traditional pills. This review provides a resource for physicians to identify the stimulant delivery formulation that best suits the patient. Formulations in development are also discussed.

Beyond the pill: new medication delivery options for ADHD.

Successful treatment of pediatric disorders has necessitated the development of alternative medication formulations, as children may prefer alternative dosage forms to tablets or capsules. This is especially true for attention-deficit/hyperactivity disorder (ADHD), which is one of the most common chronic pediatric conditions and often involves children with a variety of overlapping physical, psychological, or neurodevelopmental disorders. A special challenge for developing alternative dosage forms for ADHD treatment is the incorporation of a once-daily long-acting formulation. Traditional ADHD medication formulations have been limited, and issues surrounding prescribed dosing regimens-including poor medication adherence, difficulty swallowing, and the lack of dosing titration options-persist in ADHD treatment. In other disease areas, the development of alternative formulations has provided options for patients who have issues with consuming solid dosage forms, particularly children and individuals with developmental disorders. In the light of these new developments, several alternative formulations for ADHD medications are under development or have recently become available. This article reviews the various strategies for developing alternative dosage forms in other disease areas and discusses the application of these strategies in ADHD treatment. Alternative dosage forms may increase medication adherence, compliance, and patient preference and, therefore, improve the overall treatment for ADHD.

The impact of cognitive challenges in major depression: the role of the primary care physician.

Nearly 1 in 5 Americans will struggle with major depression in their lives; some will have recurring bouts. Recent psychiatric research has given new attention to the prevalence of cognitive deficits in major depression and the impact such deficits have on remission and overall life functioning. When depression is partially treated i.e., leaving residual symptoms, patients have higher rates of relapse and lower functional outcomes. Impaired cognitive functioning is a frequent residual symptom, persisting in about 45% of patients even when emotional symptoms have improved, and results in a disproportionate share of the functional impairment, particularly in the workplace. Patients with depression have disrupted circuitry in brain regions responsible for cognition and it is therefore important to screen depressed patients for cognitive as well as emotional symptoms. Cognitive dysfunction should be evaluated in every mood disordered patient with validated self-report scales such as the Patient Health Questionnaire-9 or the Beck Depression Inventory and objective measures of cognitive function are also very very useful. Two easily administered tests are the Trails B Test and the Digit Symbol Substitution Test. Each take less than two minutes and measure working memory, executive function, and processing speed and can track cognitive improvement in depressed patients. Treatment of cognitive dysfunction in major depression is complicated by the 'serotonin conundrum': SSRI's frequently do not treat to full remission, and can cause cognitive blunting-actually adding to cognitive problems. Based on recent data including results from a recently completed meta-analysis by McIntyre and colleagues, an evidence-based algorithm for treating cognitive symptoms in depression is presented. A hierarchy of antidepressants and augmentation strategies based on the best available evidence is discussed. In conclusion, cognitive symptoms in major depressive disorder have been recognized as a target of therapeutic improvement by the FDA and have become a focus of clinical importance.

Optimizing outcomes in ADHD treatment: from clinical targets to novel delivery systems.

Our knowledge and understanding of the underlying neurobiology and symptomatic expression of ADHD has advanced dramatically over the past decade. Associated with these advances has been a similar explosion of new treatment options to individualize treatment for our patients. This article will: ∙ review strategies to measure ADHD symptoms and functional difficulties while seeking to achieve full symptomatic remission throughout the day ∙ summarize recent findings regarding the management and prioritization of ADHD and comorbid conditions and ∙ discuss the various pharmacologic treatment options with a focus on recently developed molecules and novel delivery systems.

Response/remission with guanfacine extended-release and psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder.

OBJECTIVE: In this post hoc analysis, we assessed whether guanfacine extended-release (GXR) adjunctive to a psychostimulant resulted in greater response and remission rates than placebo + psychostimulant in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHOD: In this 9-week, double-blind, placebo-controlled dose-optimization study, participants (N = 461) aged 6 to 17 years with suboptimal response to psychostimulants were randomized to GXR on awakening (AM) + psychostimulant, GXR at bedtime (PM) + psychostimulant, or placebo + psychostimulant. RESULTS: At the final on-treatment assessment, more participants in both GXR + psychostimulant groups versus the placebo + psychostimulant group achieved response as assessed by 2 criteria: reduction from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (1) ≥40% (GXR AM + psychostimulant = 69.8%, GXR PM + psychostimulant = 70.3%, versus placebo + psychostimulant = 57.9%; p = .032 and p = .026, respectively), or (2) ≥50% (63.1%, 64.9%, versus 43.4%; p <.001 for both). Results were similar for symptomatic remission (ADHD-RS-IV total score ≤18; 61.1%, 62.2%, versus 46.1%; p = .010 and p = .005, respectively) and syndromal remission (symptomatic remission plus Clinical Global Impressions of Severity of Illness score ≤2). The most common treatment-emergent adverse events in participants receiving GXR + psychostimulant were headache (21.2%) and somnolence (13.6%). CONCLUSION: GXR + psychostimulant treatment resulted in a greater percentage of participants meeting stringent criteria for response and remission compared with placebo + psychostimulant. The adverse event profile of adjunctive therapy was consistent with known effects of either treatment alone. Clinical trial registration information-Efficacy and Safety of SPD503 in Combination With Psychostimulants; http://clinicaltrials.gov/; NCT00734578.