Assessment of centanafadine in adults with attention-deficit/hyperactivity disorder: A matching-adjusted indirect comparison vs lisdexamfetamine dimesylate, atomoxetine hydrochloride, and viloxazine extended-release.

BACKGROUND: Head-to-head trials comparing centanafadine, an investigational therapy for adults with attention-deficit/hyperactivity disorder (ADHD), with other treatment options are lacking. OBJECTIVE: To compare safety and efficacy outcomes of centanafadine sustained-release vs lisdexamfetamine dimesylate (lisdexamfetamine), atomoxetine hydrochloride (atomoxetine), and viloxazine extended-release (viloxazine ER), respectively, using matching-adjusted indirect comparison (MAIC). METHODS: This MAIC included patient-level data pooled from 2 centanafadine trials (NCT03605680 and NCT03605836) and published aggregate data from comparable trials of 3 comparators-lisdexamfetamine (NCT00334880), atomoxetine (NCT00190736), and viloxazine ER (NCT04016779)-in adult patients with ADHD. Propensity score weighting was used to match characteristics of individual patients from the centanafadine trials to aggregate baseline characteristics from the respective comparator trials. Safety outcomes were rates of adverse events for which information was available in the centanafadine and respective comparator trials. Efficacy outcome was mean change from baseline in the Adult ADHD Investigator Symptom Rating Scale (AISRS) score (ADHD Rating Scale [ADHD-RS] was used as proxy in the comparison with lisdexamfetamine). Anchored indirect comparisons were conducted across matched populations of the centanafadine and respective comparator trials. RESULTS: After matching, baseline characteristics in the centanafadine trials were the same as those in the respective comparator trials. Compared with lisdexamfetamine, centanafadine was associated with a significantly lower risk of lack of appetite (risk difference [RD] in percentage points: 23.42), dry mouth (19.27), insomnia (15.35), anxiety (5.21), nausea (4.90), feeling jittery (3.70), and diarrhea (3.47) (all P < 0.05) but a smaller reduction in the AISRS/ADHD-RS score (6.58-point difference; P < 0.05). Compared with atomoxetine, centanafadine was associated with a significantly lower risk of nausea (RD in percentage points: 18.64), dry mouth (17.44), fatigue (9.21), erectile dysfunction (6.76), lack of appetite (6.71), and urinary hesitation (5.84) (all P < 0.05) and no statistically significant difference in the change in AISRS score. Compared with viloxazine ER, centanafadine was associated with a significantly lower risk of fatigue (RD in percentage points: 11.07), insomnia (10.67), nausea (7.57), and constipation (4.63) (all P < 0.05) and no statistically significant difference in the change in AISRS score. CONCLUSIONS: In an anchored MAIC, centanafadine showed a significantly better short-term safety profile than lisdexamfetamine, atomoxetine, and viloxazine ER; efficacy was lower than with lisdexamfetamine and comparable (ie, nondifferent) with atomoxetine and viloxazine ER. This MAIC provides important insights on the relative safety and efficacy of common treatment options to help inform treatment decisions in adults with ADHD. Safety assessment was limited to rates of adverse events reported in both trials of a given comparison. STUDY REGISTRATION NUMBERS: NCT03605680, NCT03605836, NCT00334880, NCT00190736, and NCT04016779.

Dispensing of attention-deficit hyperactivity disorder medications for adults in Aotearoa New Zealand.

AIM: To report dispensing trends for attention-deficit hyperactivity disorder (ADHD) in Aotearoa New Zealand, focussing on adults in order to highlight increasing demand for ADHD treatment by adults and to prompt discussion. METHOD: Demographic and dispensing data for ADHD were obtained from the Pharmaceutical Collection between the years 2006 and 2022. This was stratified according to child (<18 years) and adult (≥18 years) populations. Population dispensing rates for methylphenidate and atomoxetine were calculated. Key findings are reported to reveal demographic and dispensing trends for medication treated ADHD in Aotearoa New Zealand. RESULTS: More males are dispensed ADHD medication than females, although this is less evident for adults (54.8% male). Maori adults are dispensed ADHD medication at a lower rate (10.1%) than Maori children (22.9%). There was a 10-fold increase in dispensing of ADHD medication for adults compared to a three-fold increase for children over the study period. New dispensing for adults doubled between 2011 and 2022. CONCLUSION: Medication treatment for adult ADHD is increasing in Aotearoa New Zealand and includes treatment for persisting childhood ADHD and new diagnoses made in adulthood. Despite increases, dispensing rates for ADHD remain lower than prevalence estimates, suggesting a significant treatment gap. Addressing the treatment gap for ADHD may reduce negative effects of ADHD, but wider social influences should also be considered.

Recent updates on treatment patterns in patients with treated attention-deficit/hyperactivity disorders from a nationwide real-world database in South Korea.

The prevalence of attention-deficit/hyperactivity disorder (ADHD) is steadily increasing across Korea. We analyzed ADHD patients with ADHD medications (Rx) characteristics and treatment patterns compared to patients without Rx and identified the differences between pediatric-/adult- and active-/transient-patients with Rx. Using a nationwide claims dataset from 2020 to 2021, we conducted a prevalence-based cross-sectional study and analyzed the recent patients' characteristics and patterns among ADHD patients. Among 132 017 ADHD patients with Rx, differences from 20 312 without Rx across all characteristics except sex. We found significant differences in characteristics and treatment patterns between pediatric-/adult- and active-/transient-patients with Rx. Age-specific sex ratios notably diverged in pediatric patients (61.2%), but remained similar in adults, revealing significant psychiatric comorbidities differences. Active-patients peaked at 6-11 years (41.4%), while transient-patients at 18-30 years (36.1%). Predominantly, methylphenidate (89.7%), atomoxetine (27.8%), and clonidine (2.8%) were prescribed, with 85% experiencing treatment changes within methylphenidate formulations. In pediatric patients, extended-release methylphenidate was preferred (56.1%), adults favored oral delivery system methylphenidate (71.5%), and active-patients had higher treatment rates than transient-patients across all patterns, with low monotherapy rates. This study provides epidemiologic insights into recent characteristics and treatment patterns of ADHD patients with Rx in Korea, providing valuable evidence for identifying those actively receiving ADHD treatment in future healthcare policy decisions.

Pharmacological treatment for obstructive sleep apnea: A systematic review and meta-analysis.

OBJECTIVE: Summarize the evidence on drug therapies for obstructive sleep apnea. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. PubMed, Embase, Scopus, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched on February 17th, 2023. A search strategy retrieved randomized clinical trials comparing the Apnea-Hypopnea Index (AHI) in pharmacotherapies. Studies were selected and data was extracted by two authors independently. The risk of bias was assessed using the Cochrane Risk of Bias tool. RevMan 5.4. was used for data synthesis. RESULTS: 4930 articles were obtained, 68 met inclusion criteria, and 29 studies (involving 11 drugs) were combined in a meta-analysis. Atomoxetine plus oxybutynin vs placebo in AHI mean difference of -7.71 (-10.59, -4.83) [Fixed, 95 % CI, I2 = 50 %, overall effect: Z = 5.25, p < 0.001]. Donepezil vs placebo in AHI mean difference of -8.56 (-15.78, -1.33) [Fixed, 95 % CI, I2 = 21 %, overall effect: Z = 2.32, p = 0.02]. Sodium oxybate vs placebo in AHI mean difference of -5.50 (-9.28, -1.73) [Fixed, 95 % CI, I2 = 32 %, overall effect: Z = 2.86, p = 0.004]. Trazodone vs placebo in AHI mean difference of -12.75 (-21.30, -4.19) [Fixed, 95 % CI, I2 = 0 %, overall effect: Z = 2.92, p = 0.003]. CONCLUSION: The combination of noradrenergic and antimuscarinic drugs shows promising results. Identifying endotypes may be the key to future drug therapies for obstructive sleep apnea. Moreover, studies with longer follow-up assessing the safety and sustained effects of these treatments are needed. PROSPERO REGISTRATION NUMBER: CRD42022362639.

Comparing Pharmacotherapies for ADHD in Adults: Evidence From Outcome-Focused Analysis of Food and Drug Administration Drug Label Registration Trials.

OBJECTIVE: We appraised whether FDA registration trials for ADHD pharmacotherapy in adults provides comparable information to inform treatment expectations. METHOD: Comparison of ADHD outcome measure patterns in ADHD pharmacotherapy FDA drug label source studies. RESULTS: Among stimulants, from fixed-dose titration data, amphetamine agents had numerically higher placebo-corrected symptom improvement and symptom effect sizes than methylphenidate agents. Symptom effect sizes were lower in the flexible dosing registration studies of atomoxetine and viloxazine. Varying responder definitions were analyzable, based on ≥30% symptom improvement and/or CGI-I improvement of "much" or "very much improved." Number of exposures needed to create these responses were lower for stimulants than for viloxazine. CONCLUSION: Heterogeneity in the design and analysis of FDA drug label source trials restricts implications for clinical practice. Research conducted using replicated designs, direct comparison of available treatments, and outcome analyses that generalize to clinical care could better inform clinical decision making.

Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

RATIONALE: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. METHODS: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. RESULTS: Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline-16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. CONCLUSIONS: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. TRIAL REGISTRATION NUMBER: NCT03892772.

The Dose-Response Relationship of Atomoxetine for the Treatment of Children With ADHD: A Systematic Review and Dose-Response Meta-Analysis of Double-Blind Randomized Placebo-Controlled Trials.

OBJECTIVES: The present study aimed to meta-analytically estimate the dose-response relationship of atomoxetine for treating children with ADHD. METHODS: We systematically searched double-blind randomized placebo-controlled trials that evaluated the effectiveness of atomoxetine for treating ADHD in children. The search was carried out in PubMed, Cochrane Library, CINHAL, and ClinicalTrials.gov databases, covering articles from their inception until January 20, 2023. In addition, a dose-response meta-analysis was conducted. RESULTS: In this dose-response meta-analysis, 12 double-blind randomized placebo-controlled trials involving 2,250 patients were included. The efficacy of atomoxetine increased up to a dosage of 1.4 mg/kg, after which it reached a plateau. CONCLUSIONS: The first dose-response meta-analysis of atomoxetine dosing for children with ADHD conducted here enhances the robustness of the Food and Drug Administration and the European Medicines Agency dose recommendations.

Pharmacotherapy for ADHD in children and adolescents: A summary and overview of different European guidelines.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention, hyperactivity, and impulsivity. It is the most common neurodevelopmental disorder presenting to pediatric services, and pediatricians are often involved in the early assessment, diagnosis, and treatment of children with ADHD. The treatment of ADHD typically involves a multimodal approach that encompasses a combination of psychoeducation, parent/teacher training, psychosocial/psychotherapeutic interventions, and pharmacotherapy. Concerning pharmacotherapy, guidelines vary in drug choice and sequencing, with psychostimulants, such as methylphenidate and (lis)dexamfetamine, generally being the favored initial treatment. Alternatives include atomoxetine and guanfacine. Pharmacotherapy has been proven effective, but close follow-up focusing on physical growth, cardiovascular monitoring, and the surveillance of potential side effects including tics, mood fluctuations, and psychotic symptoms, is essential. This paper presents an overview of current pharmacological treatment options for ADHD and explores disparities in treatment guidelines across different European countries.   Conclusion: Pharmacological treatment options for ADHD in children and adolescents are effective and generally well-tolerated. Pharmacotherapy for ADHD is always part of a multimodal approach. While there is a considerable consensus among European guidelines on pharmacotherapy for ADHD, notable differences exist, particularly concerning the selection and sequencing of various medications. What is Known: • There is a significant base of evidence for pharmacological treatment for ADHD in children and adolescents. • Pediatricians are often involved in assessment, diagnosis and management of children with ADHD. What is New: • Our overview of different European guidelines reveals significant agreement in the context of pharmacotherapy for ADHD in children and adolescents. • Discrepancies exist primarily in terms of selection and sequencing of different medications.

The Modulatory Effects of Atomoxetine on Aberrant Connectivity During Attentional Processing in Cocaine Use Disorder.

BACKGROUND: Cocaine use disorder is associated with cognitive deficits that reflect dysfunctional processing across neural systems. Because there are currently no approved medications, treatment centers provide behavioral interventions that have only short-term efficacy. This suggests that behavioral interventions are not sufficient by themselves to lead to the maintenance of abstinence in patients with cocaine use disorder. Self-control, which includes the regulation of attention, is critical for dealing with many daily challenges that would benefit from medication interventions that can ameliorate cognitive neural disturbances. METHODS: To address this important clinical gap, we conducted a randomized, double-blind, placebo-controlled, crossover design study in patients with cocaine use disorder (n = 23) and healthy control participants (n = 28). We assessed the modulatory effects of acute atomoxetine (40 mg) on attention and conflict monitoring and their associated neural activation and connectivity correlates during performance on the Eriksen flanker task. The Eriksen flanker task examines basic attentional processing using congruent stimuli and the effects of conflict monitoring and response inhibition using incongruent stimuli, the latter of which necessitates the executive control of attention. RESULTS: We found that atomoxetine improved task accuracy only in the cocaine group but modulated connectivity within distinct brain networks in both groups during congruent trials. During incongruent trials, the cocaine group showed increased task-related activation in the right inferior frontal and anterior cingulate gyri, as well as greater network connectivity than the control group across treatments. CONCLUSIONS: The findings of the current study support a modulatory effect of acute atomoxetine on attention and associated connectivity in cocaine use disorder.

Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients.

OBJECTIVE: To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary- and quaternary-care university teaching hospital. PARTICIPANTS: Included patients who received at least 4 consecutive doses of droxidopa or atomoxetine and remained on concurrent midodrine. Patients were excluded if they received study medication before admission, had clinical deterioration after study medication initiation requiring additional vasoactives/escalation of IV vasoactive dosage for at least 12 hours, had a diagnosis of hepatorenal syndrome, were prisoners, or were pregnant. INTERVENTIONS: Droxidopa, atomoxetine, or both. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to discontinuation of IV vasoactive agents after initiation of study medication, analyzed using a Kaplan-Meier estimate with the Wilcoxon method, censoring death within 24 hours of the last dose of study medication. No adjustment for repetitive analyses was made, as the analysis was hypothesis-generating. Of the 72 charts reviewed, 45 patients met inclusion criteria (18 atomoxetine, 17 droxidopa, and 10 both). There were no differences in median time to discontinuation of IV vasoactive agents (21.9 days v 8.0 days v 13.9 days, respectively; p = 0.259) or ICU or hospital length of stay between groups. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% v 76.5%) than atomoxetine alone (44.4%, p = 0.028). CONCLUSIONS: Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study.

STUDY OBJECTIVES: we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA). METHODS: This randomized, placebo-controlled, double-blind, crossover trial study was conducted in adults with OSA referred to a Sleep Clinic. Participants with eligibility criteria were recruited. Patients were studied on two separate nights with one-week intervals, once treated with trazodone (50 mg) and atomoxetine (80 mg) combination and then with a placebo and the following polysomnography tests. RESULTS: A total of 18 patients with OSA completed the study protocol, 9(50%) were male, the mean age was 47.5 years (SD = 9.8) and the mean Body mass index of participants was 28.4 kg/m2 (SD = 3.4). Compared with the placebo, the A-T combination resulted in significant differences in AHI (28.3(A-T) vs. 42.7 (placebo), p = 0.025), duration of the REM stage (1.3%TST (A-T) vs. 13.1%TST (placebo), p = 0.001), and the number of REM cycles (0.8 (A-T) vs. 4.7 (placebo), p = 0.001), number of apneas (38.3 (A-T) vs. 79.3 (placebo), p = 0.011), number of obstructive apneas (37.2 (A-T) vs. 75.2 (placebo), p = 0.011), oxygen desaturation index (29.5 (A-T) vs. 42.3 (placebo), p = 0.022) and number of respiratory arousals (43.2 (A-T) vs. 68.5 (placebo), p = 0.048). This decrement effect did not change among those with a low-arousal phenotype of OSA. CONCLUSIONS: The A-T combination significantly improved respiratory events' indices compared with placebo in patients with OSA. This combination is recommended to be assessed in a large trial. It could be an alternative for those who do not adhere to the standard available treatments for OSA.

Population Pharmacokinetic Analysis of Atomoxetine and its Metabolites in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder.

Atomoxetine (ATX) is a non-stimulant used to treat attention-deficit/hyperactivity disorder (ADHD) and systemic exposure is highly variable due to polymorphic cytochrome P450 2D6 (CYP2D6) activity. The objective of this study was to characterize the time course of ATX and metabolites (4-hydroxyatomoxetine (4-OH); N-desmethylatomoxetine (NDA); and 2-carboxymethylatomoxetine (2-COOH)) exposure following oral ATX dosing in children with ADHD to support individualized dosing. A nonlinear mixed-effect modeling approach was used to analyze ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles obtained over 24-72 hours from children with ADHD (n = 23) following a single oral ATX dose. Demographics and CYP2D6 activity score (AS) were evaluated as covariates. Simulations were performed to explore the ATX dosing in subjects with various CYP2D6 AS. A simultaneous pharmacokinetic modeling approach was used in which a model for ATX, 4-OH, and NDA in plasma and urine, and 2-COOH in urine was developed. Plasma ATX, 4-OH, and NDA were modeled using two-compartment models with first-order elimination. CYP2D6 AS was a significant determinant of ATX apparent oral clearance (CL/F), fraction metabolized to 4-OH, and systemic exposure of NDA. CL/F of ATX varied almost 7-fold across the CYP2D6 AS groups: AS 2: 20.02 L/hour; AS 1: 19.00 L/hour; AS 0.5: 7.47 L/hour; and AS 0: 3.10 L/hour. The developed model closely captures observed ATX, 4-OH, and NDA plasma and urine, and 2-COOH urine profiles. Application of the model shows the potential for AS-based dosing recommendations for improved individualized dosing.

Assessment of probiotic strain Lactobacillus acidophilus LB supplementation as adjunctive management of attention-deficit hyperactivity disorder in children and adolescents: a randomized controlled clinical trial.

BACKGROUND: This study was designed to examine the possible efficacy of the probiotic strain Lactobacillus acidophilus LB (Lacteol Fort) on attention-deficit/hyperactivity disorder (ADHD) symptomatology and evaluate its influence on cognition function. METHODS: In this randomized controlled trial, 80 children and adolescents with ADHD diagnosis, aged 6-16 years, were included. The participants were randomly assigned to two groups: one group received probiotics plus atomoxetine, whereas the other group received atomoxetine only. ADHD symptomatology was assessed using the Conners Parent Rating Scale-Revised Long Version (CPRS-R-L) and Child Behavioral Checklist (CBCL/6-18). The participants were evaluated for their vigilance and executive function using Conner's Continuous Performance Test (CPT) and Wisconsin Card Sort Test (WCST). Both groups were assessed at the beginning of the study and the end of the twelve weeks. RESULTS: The probiotic group comprised 36 patients, whereas the control group comprised 40 patients in the final analysis after four patients dropped out of the trial. After 3 months of probiotic supplementation, a significant improvement in the CPRS-R-L and CBCL total T scores was observed compared with those in the control group (p = 0.032, 0.024, respectively). Additionally, the probiotic group demonstrated improved focus attention (target accuracy rate and omission errors;p = 0.02, 0.043, respectively) compared with the control group. An analysis of the Wisconsin Card Sorting Test (WCST) performance demonstrated that the probiotic group had significantly lower perseverative (p = 0.017) and non-perseverative errors (p = 0.044) but no significant differences compared to the control group. CONCLUSION: Lactobacillus acidophilus LB supplementation combined with atomoxetine for 3 months had a beneficial impact on ADHD symptomology and a favorable influence on cognitive performance. As a result, the efficacy of probiotics as an adjunctive treatment for managing ADHD may be promising. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT04167995). Registration date: 19-11-2019.

Retrospective observational study on the impact of the Covid-19 pandemic on the prescription of medications for the treatment of Attention Deficit/Hyperactivity Disorder. Comparison of a European and an American cohort.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is a neuropsychological disorder that affects the development of children and adolescents. The causes are not fully known although the origin of the disorder appears to depend on a combination of environmental, social, biochemical, and genetic factors. There is substantial evidence the Covid-19 pandemic caused an increase in mental disorders and therefore in spending related to the treatment of diseases. METHOD: We conducted a retrospective cohort study in two international centers of very different origins and cultures, one in Europe (Italy) and one in Central America (Costa Rica), to assess the impact of the Covid-19 pandemic on ADHD medication prescriptions and its costs. The analysis resulting from mining the databases in each individual nation allowed for the actual amounts of defined daily dose (DDD) prescribed and dispensed between the years 2019 and 2022 of methylphenidate and atomoxetine. RESULTS: The data show that the Italian ADHD medications DDDs and expenditure are aligned with the results in Costa Rica. It was found that from the year 2019 to the year 2022, both methylphenidate and atomoxetine prescriptions grew steadily, confirming a much higher incidence of the condition than in pre-pandemic periods. CONCLUSIONS: Our study shows that the global pandemic had an influence on the increase in the number of ADHD medication prescriptions. Individuals with ADHD are a population of individuals who may be particularly vulnerable to the distress caused by the pandemic, restrictions, and severe physical removal measures that have occurred in recent years.

Viloxazine extended-release capsules for the treatment of attention-deficit/ hyperactivity disorder in adult patients.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with symptoms that may persist in up to 90% of adults diagnosed during childhood and continue to cause significant impairment throughout the lifespan. In the United States (US), amphetamine and methylphenidate formulations have been available to treat ADHD for several decades. Only one nonstimulant, atomoxetine, was available for the treatment of ADHD in adults until recently. In April 2022, a second nonstimulant, viloxazine extended-release (VLX-ER), became available in the US for the treatment of adult ADHD. Efficacy was previously established in placebo-controlled trials in children and adolescents. AREAS COVERED: VLX-ER is a norepinephrine reuptake inhibitor with serotonin activity. The efficacy in adults, adverse event profile, pharmacokinetics, drug-drug interactions, and metabolism of VLX-ER are reviewed. EXPERT OPINION: Despite the availability of effective pharmacological treatments for ADHD, many patients discontinue treatment in less than 1 year. Stimulants are effective in more than 80% of patients; however, some may have difficulty tolerating them. Although there were no head-to-head studies, the effect size of VLX-ER in an adult efficacy trial was lower than has been shown for stimulants. Nevertheless, the approval of VLX-ER adds another effective ADHD treatment option for adults.

An updated safety review of the current drugs for managing ADHD in children.

INTRODUCTION: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent condition that causes persistent problems with attention and/or hyperactivity-impulsivity and often results in significant impairment when left untreated. Medications for this disorder continue to evolve and provide new treatment options. Ongoing review of related medication safety and tolerability remains an important task for prescribers. AREAS COVERED: This manuscript provides an updated safety review of medications used to treat ADHD in children and adolescents. PubMed and OneSearch online databases were utilized to search for literature relevant to the topic of ADHD medications and safety. Clinical trials of medications used to treat ADHD, systematic reviews and meta-analyses, and articles covering specific safety issues (adverse or unfavorable events) such as cardiovascular effects, seizures, impact on growth, depression, suicidal ideation, substance use disorders, psychosis, and tics are described. EXPERT OPINION: Available pharmacologic treatments for ADHD have favorable efficacy, safety and tolerability and allow many patients to achieve significant improvement of their symptoms. Despite the availability of multiple stimulant and non-stimulant formulations, some individuals with ADHD may not tolerate available medications or attain satisfactory improvement. To satisfy unmet clinical needs, ADHD pharmaceutical research with stimulant and nonstimulant formulations targeting dopamine, norepinephrine, and novel receptors is ongoing.

The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial.

Rationale: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs. Objectives: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the AD109 5/75 mg arm (-42.9%; both P < 0.0001 vs. placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%; P < 0.01 vs. placebo). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (P < 0.05 vs. placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (P < 0.05 vs. AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy. Conclusions: AD109 showed clinically meaningful improvement in OSA, suggesting that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

[Attention deficit hyperactivity: pharmacotherapy through life]. / Déficit de atención con hiperactividad: farmacoterapia a través de la vida.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of biological origin with a 70 to 80% genetic basis, which affects 5% of children and adolescents and 2.5% of adults, whose main symptoms are inattention, hyperactivity, and impulsivity. For many years it was thought that it only affected children; currently in the DSM 5 it is accepted that it can be diagnosed in adolescents and adults. Treatment must be individualized, the main objectives are to improve the core symptoms of people with ADHD, and their quality of life. The therapeutic approach is psychological, behavioral, and pharmacological. Medications are classified as stimulants and nonstimulants, with stimulants such as methylphenidate, lisdexamfetamine, and dexamphetamine being the first line. Non-stimulants include guanfacine and atomoxetine. Treatment is essential because it improves the quality of life of the person at the family, educational, work, and social levels.

El Trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno del neurodesarrollo de origen biológico con una base genética del 70 al 80%, que afecta al 5% de niños y adolescentes y a un 2.5% de los adultos, cuyos síntomas principales son la inatención, hiperactividad e impulsividad. Por muchos años se pensó que afectaba solo a los niños; actualmente en el DSM 5 se acepta que se puede diagnosticar en adolescentes y adultos. El tratamiento debe ser individualizado, los objetivos principales son mejorar los síntomas centrales de las personas con TDAH, y su calidad de vida. El abordaje terapéutico es psicológico, conductual y farmacológico. Los medicamentos se clasifican en estimulantes y no estimulantes, siendo los de primera línea los estimulantes tales como el metilfenidato, lisdexanfetamina y dexanfetamina. Entre los no estimulantes se cuentan a la guanfacina y atomoxetina. El tratamiento es fundamental porque mejora la calidad de vida de la persona a nivel familiar, educativo, laboral y social.