Risk of Major Malformations in Infants After First-Trimester Exposure to Stimulants: Results From the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

PURPOSE/BACKGROUND: The prevalence of attention-deficit/hyperactivity disorder in adult females is 3% to 4%. Attention-deficit/hyperactivity disorder is highly comorbid with other psychiatric disorders such as mood, anxiety, and substance use disorders. For reproductive-aged women, the treatment of attention-deficit/hyperactivity disorder with stimulant medications may be considered during pregnancy or breastfeeding, although historically, data are lacking to inform these decisions. The aim of this investigation was to determine the risk of major malformations in infants after first-trimester prescription stimulant exposure in a small but rigorously characterized sample. METHODS/PROCEDURES: The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications systematically ascertains information from pregnant females including demographic information, medical and psychiatric history, use of prescription medications, and other information relevant to fetal outcomes. Participants provide verbal informed consent and are interviewed twice during gestation and again at approximately 3 months postpartum. The primary outcome of interest is the presence of a major malformation identified within 6 months after birth. Redacted cases of major malformations are reviewed by a dysmorphologist blinded to medication exposure. FINDINGS/RESULTS: A total of N = 1988 women were eligible for this analysis, including the following exposures: n = 173 to mixed amphetamine salts; n = 40 to lisdexamfetamine; n = 45 to methylphenidate; n = 3 to dexmethylphenidate; and n = 1755 controls. The odds ratio of a major malformation among infants after first-trimester exposure to any stimulant was 0.39 (95% confidence interval, 0.09-1.61) compared with controls. There were no major malformations observed in infants exposed to lisdexamfetamine, methylphenidate, or dexmethylphenidate. IMPLICATIONS/CONCLUSIONS: Although preliminary, this analysis from an ongoing pregnancy registry provides reassurance that these stimulants do not appear to have major teratogenic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01246765 .

Analysis of Growth Velocity in Children with Attention-Deficit/Hyperactivity Disorder Treated for up to 12 Months with Serdexmethylphenidate/Dexmethylphenidate.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this post hoc analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months. Methods: This was a post hoc analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height Z-score analyses were conducted. Z-score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point. Results: Subjects (N = 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height Z-scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation [SD]) Z-score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment. Conclusion: The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.

Evaluating serdexmethylphenidate and dexmethylphenidate capsules as a once-daily treatment option for ADHD.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) is a common behavioral disorder which is best treated through a combination of medication and behavioral therapy, with stimulant medications serving as a first-line treatment approach. Serdexmethylphenidate (SDX), a prodrug of dexmethylphenidate (d-MPH), a commonly utilized stimulant medication, has recently received approval and is marketed in the U.S.A. AREAS COVERED: This review summarizes peer-reviewed literature on SDX published between 2021-2023 and a review of data available from ClinicalTrials.gov. EXPERT OPINION: SDX represents a new option for treatment for ADHD. It is unique in its prodrug design and achieves a relatively extended duration of action in comparison to other stimulant formulations. Although the research is relatively limited thus far, early data suggests it to be a safe medication to consider with side effects being similar to other stimulant medications. Its prodrug design is useful in potentially serving as a deterrent to intentional parenteral abuse and its ability to be opened and sprinkled makes it an option for those individuals with ADHD who might be unable to swallow pills.

Safety and Tolerability of Serdexmethylphenidate/Dexmethylphenidate Capsules in Children with Attention-Deficit/Hyperactivity Disorder: A 12-Month, Open-Label Safety Study.

Objective: Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A pivotal double-blind (DB) study of children aged 6-12 years with ADHD demonstrated efficacy for ADHD with good tolerability. In this study, we assessed the safety and tolerability of daily oral SDX/d-MPH for up to 1 year in children with ADHD. Methods: This was a dose-optimized, open-label safety study with SDX/d-MPH in children aged 6-12 years with ADHD that included subjects who successfully completed the DB study (rollover) and new subjects. The study consisted of a 30-day screening phase, a dose optimization phase for new subjects only, a 360-day treatment phase, and follow-up. Adverse events (AEs) were assessed from the first day of SDX/d-MPH administration to the end of the study. During the treatment phase, ADHD Rating Scale-5 (ADHD-RS-5) and Clinical Global Impressions-Severity (CGI-S) scale assessments were used to evaluate ADHD severity. Results: Of the 282 subjects enrolled (70 rollover; 212 new), 28 discontinued treatment in the dose optimization phase and 254 entered the treatment phase. By study completion, 127 had discontinued and 155 had completed the study. The treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. Of 238 subjects assessed in the treatment-phase safety population, 143 (60.1%) had ≥1 treatment-emergent adverse events (TEAEs), and 36 (15.1%), 95 (39.9%), and 12 (5.0%) had mild, moderate, or severe TEAEs, respectively. The most common TEAEs were decreased appetite (18.5%), upper respiratory tract infection (9.7%), nasopharyngitis (8.0%), decreased weight (7.6%), and irritability (6.7%). There were no clinically meaningful trends in electrocardiograms, cardiac events, or blood pressure events, and none led to discontinuation. Two subjects had eight serious AEs that were unrelated to treatment. There were overall reductions in ADHD symptoms and severity as assessed by ADHD-RS-5 and CGI-S during the treatment phase. Conclusions: In this 1-year study, SDX/d-MPH was found to be safe and well tolerated and comparable with other methylphenidate products, with no unexpected safety findings. SDX/d-MPH also showed sustained efficacy during the 1-year treatment period. ClinicalTrials.gov identifier: NCT03460652.

Short-Term Vision-Related Ocular Side Effects of Treatment with Dexmethylphenidate for Attention-Deficit/Hyperactivity Disorder.

Objective: To evaluate the short-term effect of dexmethylphenidate (D-MPH) on visual acuity (VA), pupil size, anterior chamber depth, and accommodation-convergence reflex in children treated with D-MPH for attention-deficit/hyperactivity disorder (ADHD). Method: Prospective cohort study including 15 patients aged 8-16 (11.58 ± 2.39) treated with D-MPH for ADHD. Patients were questioned for subjective complaints such as blurred vision and photosensitivity. An ophthalmic evaluation was performed twice; before and 1.5 hours after D-MPH administration. The examination included evaluation of best corrected visual acuity at distance and near, accommodation range, convergence range, 3D vision test (stereopsis), and anterior segment optical coherence tomography. Results: A significant association between change in pupil diameter and D-MPH treatment dose was demonstrated (p = 0.01). In addition, a positive correlation between complaints about blurred vision and pupil's size change was found (p < 0.05). There were no significant changes in VA, convergence range, stereopsis, accommodation range, or anterior chamber measures. Conclusions: Our findings provide support for the effect of stimulants on pupil diameter in a dose-dependent manner. No clinically significant differences in visual functions were found 1.5 hours after consumption of D-MPH. Institutional review board clinical trial refference no. 0122-17-TLV.

Dose Proportionality and Steady-State Pharmacokinetics of Serdexmethylphenidate/Dexmethylphenidate, a Novel Prodrug Combination to Treat Attention-Deficit/Hyperactivity Disorder.

Objective: The study was designed to determine (1) the pharmacokinetic (PK) profile of dexmethylphenidate (d-MPH) after oral administration of three dosage strengths of a new treatment containing d-MPH and a novel prodrug, serdexmethylphenidate (SDX); (2) the dose proportionality of the different SDX/d-MPH dosages; and (3) the steady-state PK profile of d-MPH and SDX after multiple dosing of SDX/d-MPH. Methods: Twenty-three healthy volunteers (aged 18-55 years) under fasted conditions received in a crossover design SDX/d-MPH 26.1/5.2 mg (Treatment A), 39.2/7.8 mg (Treatment B), and 52.3/10.4 mg (Treatment C) for a total d-MPH hydrochloride equivalent dose of 20, 30, and 40 mg, respectively. After a 96-hour washout period, all participants received four consecutive daily doses of SDX/d-MPH 52.3/10.4 mg. Blood samples were collected for measurement of plasma d-MPH and SDX and for PK analysis. Results: Administration of all three doses of SDX/d-MPH resulted in a rapid rise and slow decline in the plasma concentration of d-MPH. For Treatments A, B, and C, mean (± standard deviation) maximum concentrations (Cmax) were 7.1 ± 2.1, 9.8 ± 2.8, and 13.8 ± 3.8 ng/mL, and overall exposures (AUC0-last) were 97.2 ± 28.8, 142.5 ± 41.2, and 199.8 ± 57.2 h*ng/mL, respectively. Dose-normalized Cmax, AUC0-last, and AUC0-inf for d-MPH were similar when comparing the high and low doses versus the middle dose. Power model regression analysis revealed that Cmax and AUC0-inf proportionally increased with an increase in SDX/d-MPH dose. In the multiple-dose study, d-MPH reached steady state before the third dose, and SDX after the first dose. Conclusion: The PK profile of SDX/d-MPH is characterized by a rapid rise and a gradual decline in d-MPH concentration, with proportional Cmax and AUC0-inf across doses. The PK attributes of SDX/d-MPH may optimize symptom control from early morning to early evening, while the demonstrated dose proportionality may facilitate initial dose titration and ongoing dose adjustment.

Medication Use in the Management of Comorbidities Among Individuals With Autism Spectrum Disorder From a Large Nationwide Insurance Database.

Importance: Although there is no pharmacological treatment for autism spectrum disorder (ASD) itself, behavioral and pharmacological therapies have been used to address its symptoms and common comorbidities. A better understanding of the medications used to manage comorbid conditions in this growing population is critical; however, most previous efforts have been limited in size, duration, and lack of broad representation. Objective: To use a nationally representative database to uncover trends in the prevalence of co-occurring conditions and medication use in the management of symptoms and comorbidities over time among US individuals with ASD. Design, Setting, and Participants: This retrospective, population-based cohort study mined a nationwide, managed health plan claims database containing more than 86 million unique members. Data from January 1, 2014, to December 31, 2019, were used to analyze prescription frequency and diagnoses of comorbidities. A total of 26 722 individuals with ASD who had been prescribed at least 1 of 24 medications most commonly prescribed to treat ASD symptoms or comorbidities during the 6-year study period were included in the analysis. Exposures: Diagnosis codes for ASD based on International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: Quantitative estimates of prescription frequency for the 24 most commonly prescribed medications among the study cohort and the most common comorbidities associated with each medication in this population. Results: Among the 26 722 individuals with ASD included in the analysis (77.7% male; mean [SD] age, 14.45 [9.40] years), polypharmacy was common, ranging from 28.6% to 31.5%. Individuals' prescription regimens changed frequently within medication classes, rather than between classes. The prescription frequency of a specific medication varied considerably, depending on the coexisting diagnosis of a given comorbidity. Of the 24 medications assessed, 15 were associated with at least a 15% prevalence of a mood disorder, and 11 were associated with at least a 15% prevalence of attention-deficit/hyperactivity disorder. For patients taking antipsychotics, the 2 most common comorbidities were combined type attention-deficit/hyperactivity disorder (11.6%-17.8%) and anxiety disorder (13.1%-30.1%). Conclusions and Relevance: This study demonstrated considerable variability and transiency in the use of prescription medications by US clinicians to manage symptoms and comorbidities associated with ASD. These findings support the importance of early and ongoing surveillance of patients with ASD and co-occurring conditions and offer clinicians insight on the targeted therapies most commonly used to manage co-occurring conditions. Future research and policy efforts are critical to assess the extent to which pharmacological management of comorbidities affects quality of life and functioning in patients with ASD while continuing to optimize clinical guidelines, to ensure effective care for this growing population.

Update on methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder.

PURPOSE: Current literature on the safety and efficacy of intermediate- and long-acting formulations of methylphenidate and dexmethylphenidate for attention-deficit/hyperactivity disorder (ADHD) is evaluated. SUMMARY: Methylphenidate has been an established treatment for ADHD, but due to its relatively short half-life, numerous intermediate- and long-acting products have been developed. While these extended-release products provide efficacy similar to that of immediate-acting products, the pharmacokinetics and adverse effects can vary. Intermediate-acting methylphenidate products have effects that can last as long as 8 hours, but clinically patients have still required twice-daily dosing. Long-acting products have helped to address these challenges, with recently developed products including controlled-release and bimodal-delivery systems and a patch formulation. Many of these products can be opened and sprinkled on applesauce for ease of administration. CONCLUSION: Knowledge of the various formulations of methylphenidate and dexmethylphenidate is crucial for appropriate medication selection for control of ADHD symptoms. Knowledge of differences between release mechanisms and the pharmacokinetic properties are essential for appropriate use of these products.

Effects of Dexmethylphenidate on Targeted and Non-Targeted Behaviours during Functional Analyses: A Brief Report.

Objective: This study evaluated the effects of dexmethylphenidate on problem behavior during functional analyses conducted across dexmethylphenidate and placebo conditions for a child with multiple disabilities. Methods: We conducted functional analyses in a multielement format embedded in a withdrawal design and collected data on the frequency of disruptive behavior and duration of crying. Results: Results suggest disruptive behaviour was maintained by attention when DMPH was absent, but not when it was present. Results also suggest DMPH may have had collateral effects on the probability of non-targeted behaviour (crying). Consistent with previous research, functional analyses exhibited a change in disruptive behaviour's function between medication and placebo conditions. Conclusion: These findings provide further support that stimulant medication may change the function of disruptive behavior and highlight the need to investigate the effects of stimulants on non-targeted behaviors.

Drug Regimen Individualization for Attention-Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations.

In 2000, the first biphasic modified-release (MR) formulation of methylphenidate (MPH) was approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). An immediate-release (IR) MPH pulse (22% of the dose) facilitates rapid onset of stimulant action, while the remaining MR portion of the dose provides for day-long duration of efficacy. A wide array of oral MR-MPH products has subsequently been approved that also allows for once-daily dosing, though each product is characterized by distinctive exposure time courses. This review compares each member of the current MPH armamentarium to assist in the rational selection of a specific MPH regimen for the individualized treatment of patients with ADHD. The IR portion of biphasic MPH formulations now ranges from 15%, 20%, 22%, 25%, 30%, and 37% IR-MPH, as well as a 50% IR-MPH product whose distinctly pulsatile time course closely resembles that of the pre-century "gold standard" twice-daily IR-MPH regimen. Further, transdermal, suspension, and orally disintegrating tablet products are now available to overcome any solid dosage form swallowing difficulties. Most of these formulations are racemic, though in 2001, a chiral switch drug IR-dexmethylphenidate (dexMPH) was approved, followed by biphasic MR-dexMPH (50% IR) in 2005. New U.S. Food and Drug Administration (FDA) partial area under the curve (pAUC) bioavailability metrics have improved discrimination between specific generic MR-MPH products. This has resulted in two Orange Book MR-MPH products being recoded from "AB" (i.e., meets necessary bioequivalence requirements) to "BX" (i.e., insufficient data to confirm bioequivalence). The metabolic drug interaction between MPH and alcohol, which increases MPH bioavailability, potentiates euphoric effects, and heightens abuse liability, is discussed. This review concludes with brief considerations of pharmacogenomic predictors of ADHD first-line drug selection, carboxylesterase allelic variants influencing interindividual MPH metabolism, and novel MPH formulations in the regulatory pipeline.

Mitigating risks of students use of study drugs through understanding motivations for use and applying harm reduction theory: a literature review.

As postsecondary students' use of "study drugs" becomes more popular with increasingly reported negative effects on health and academic performance, failing prohibitionist policies to reduce consumption, and ambiguity in literature towards best practices to address this population, we present a literature review that seeks effective solutions educational institutions can apply to improve outcomes for students who use drugs. Motivations for use, effects of the substances, an analysis of efforts to control use from educational institutions, and suggestions on promoting most effective outcomes based on harm reduction, are described. Theory, quantitative, and qualitative works from systematic reviews, cohort studies, and epidemiological assessments are examined on the "study drugs" methylphenidate, dextroamphetamine, and amphetamine, also known as Adderall, Ritalin, Focalin, and Concerta. There is a focus on postsecondary students ages 18-25 in North America. Results show important risk factors for drug use including low perceived self-efficacy or enjoyment in courses, poor accommodation of special needs, reliance on external validation, having a low GPA, and experiencing a mental health issue. There is much misconception on the health and academic effects of these drugs in literature, among students, and on online knowledge sources. We suggest these drugs do not improve GPA and learning, while they might temporarily increase memory, but with detrimental negative health effects. Campaigns that address underlying factors of use can be most successful in mitigating harms.

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers.

BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl-methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. METHODS: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed-release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. FINDINGS/RESULTS: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. IMPLICATIONS/CONCLUSIONS: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder.

Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue: A Meta-analysis.

IMPORTANCE: Cancer-related fatigue (CRF) remains one of the most prevalent and troublesome adverse events experienced by patients with cancer during and after therapy. OBJECTIVE: To perform a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the 4 most commonly recommended treatments for CRF-exercise, psychological, combined exercise and psychological, and pharmaceutical-and to identify independent variables associated with treatment effectiveness. DATA SOURCES: PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane Library were searched from the inception of each database to May 31, 2016. STUDY SELECTION: Randomized clinical trials in adults with cancer were selected. Inclusion criteria consisted of CRF severity as an outcome and testing of exercise, psychological, exercise plus psychological, or pharmaceutical interventions. DATA EXTRACTION AND SYNTHESIS: Studies were independently reviewed by 12 raters in 3 groups using a systematic and blinded process for reconciling disagreement. Effect sizes (Cohen d) were calculated and inversely weighted by SE. MAIN OUTCOMES AND MEASURES: Severity of CRF was the primary outcome. Study quality was assessed using a modified 12-item version of the Physiotherapy Evidence-Based Database scale (range, 0-12, with 12 indicating best quality). RESULTS: From 17 033 references, 113 unique studies articles (11 525 unique participants; 78% female; mean age, 54 [range, 35-72] years) published from January 1, 1999, through May 31, 2016, had sufficient data. Studies were of good quality (mean Physiotherapy Evidence-Based Database scale score, 8.2; range, 5-12) with no evidence of publication bias. Exercise (WES, 0.30; 95% CI, 0.25-0.36; P < .001), psychological (WES, 0.27; 95% CI, 0.21-0.33; P < .001), and exercise plus psychological interventions (WES, 0.26; 95% CI, 0.13-0.38; P < .001) improved CRF during and after primary treatment, whereas pharmaceutical interventions did not (WES, 0.09; 95% CI, 0.00-0.19; P = .05). Results also suggest that CRF treatment effectiveness was associated with cancer stage, baseline treatment status, experimental treatment format, experimental treatment delivery mode, psychological mode, type of control condition, use of intention-to-treat analysis, and fatigue measures (WES range, -0.91 to 0.99). Results suggest that the effectiveness of behavioral interventions, specifically exercise and psychological interventions, is not attributable to time, attention, and education, and specific intervention modes may be more effective for treating CRF at different points in the cancer treatment trajectory (WES range, 0.09-0.22). CONCLUSIONS AND RELEVANCE: Exercise and psychological interventions are effective for reducing CRF during and after cancer treatment, and they are significantly better than the available pharmaceutical options. Clinicians should prescribe exercise or psychological interventions as first-line treatments for CRF.

Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB) during acute and long-term treatment of youth with attention-deficit/hyperactivity disorder. METHODS: Two hundred seven participants aged 7-14 years enrolled in an 8-week double-blind randomized trial of GUAN-IR (1-3 milligrams (mg)/day), DMPH (5-20 mg/day), or COMB with fixed-flexible dosing and titrated to optimal behavioral response. Heart rate, systolic blood pressure (BP), diastolic BP, and electrocardiograms were assessed at baseline, end of blinded optimization, and over a 1-year open-label maintenance phase. RESULTS: During acute titration, GUAN-IR decreased heart rate, systolic BP, and diastolic BP; DMPH increased heart rate, systolic BP, diastolic BP, and corrected QT (QTc) interval; COMB increased diastolic BP, but had no effects on heart rate, systolic BP, or QTc. During maintenance, GUAN-IR-associated decreases in heart rate and DMPH-associated increases in systolic BP returned to baseline values. Other variables across the three groups remained unchanged from the end of blinded titration. There were no discontinuations due to CV adverse events. CONCLUSION: GUAN-IR, DMPH, and COMB were well tolerated and safe. Expected changes in CV parameters during acute titration were seen in GUAN-IR and DMPH groups, with COMB values falling intermediately between the two other treatment groups. No serious CV events occurred in any participant. GUAN-IR- and DMPH-associated CV changes generally returned to baseline with sustained therapy. These data suggest that COMB treatment might attenuate long-term CV effects of GUAN-IR and stimulant monotherapy, possibly reducing risk of the small but statistically significant changes associated with either single treatment. Clinicaltrials.gov Identifier: NCT00429273.

Development of a refill pattern method to measure polypharmacy in administrative claims databases.

PURPOSE: The purposes of the study were to develop a refill pattern method to identify polypharmacy in pharmacy billing records and to compare the method with traditional days' supply overlap algorithms. METHODS: This method is characterized by the assessment of prescription refill pattern. Concomitant therapy is assumed when two drugs are dispensed repeatedly during the active days' supply of each other. We tested the refill pattern method in a simplified scenario in which two drugs (methylphenidate/dexmethylphenidate and atomoxetine) for attention deficit/hyperactivity disorder (ADHD) were considered. Children who had at least one prescription of methylphenidate/dexmethylphenidate or atomoxetine in 2008 were included for the calculation of 2-year prevalence of ADHD treatment polypharmacy. Results were compared with traditional method that requires a minimum overlap of 30, 60 or 90 days of filled prescriptions. We compared polypharmacy prevalence estimated by the two methods and explored reasons for disagreement. RESULTS: Among 131 385 children who had at least one prescription of methylphenidate/dexmethylphenidate or atomoxetine, the refill pattern method identified 4021 patients who had ADHD treatment polypharmacy (2-year prevalence = 3.1%). This prevalence estimate fell between those from a 30- to 60-day overlap method. The Cohen's kappa regarding determination of polypharmacy was 0.83, 0.92 and 0.80 considering 90-, 60- and 30-day overlap method, respectively. CONCLUSIONS: The refill pattern method can be used as another way to measure polypharmacy in administrative claims databases and can be adapted to a wide variety of research questions, diseases and study populations. Copyright © 2016 John Wiley & Sons, Ltd.

Absorption Differences between Immediate-Release Dexmethylphenidate and dl-Methylphenidate.

The postulate that twice the milligram/kilogram dose of dl-methylphenidate (dl-MPH) would result in equal exposure to d-MPH compared with half that milligram/kilogram dose of the chiral switch product dexmethylphenidate (d-MPH) was tested. Using a randomized, crossover study design, 12 men and 12 women received either immediate-release (IR) dl-MPH (0.3 mg/kg) or IR d-MPH (0.15 mg/kg). Relative bioavailability comparisons included partial area under the plasma concentration-time curves (pAUC0-3 h) for d-MPH. The pAUC0-3 h is a new regulatory metric presently only required for bioequivalence testing of a specific dl-MPH modified-release product. The geometric mean ratios for both the Cmax and area under the plasma concentration-time curve (AUC0-∞) were within the 90% confidence interval (CI) regulatory range of 0.8-1.25, indicating that these two drugs were bioequivalent in terms of d-MPH. However, the pAUC0-3 h geometric mean ratio for d-MPH after IR dl-MPH versus IR d-MPH was 0.76 (P < 0.001; 90% CI, 0.67-0.87), showing significantly less early exposure to the d-isomer than IR d-MPH. The 1-hour d-MPH concentration after dl-MPH was 56% of that after the enantiopure drug. The maximum d-MPH plasma concentration (Cmax) for dl-MPH was also significantly lower for dl-MPH (P < 0.05; CI, 1.02-1.19), whereas the AUC0-∞ ratio of 0.89 was not significantly different (P = 0.21; CI, 0.98-1.13). The AUC0-3 h difference reported here points to the potential limitations of using bioequivalence for sound predictions of dose-response relationships. Knowledge of the greater early exposure to d-MPH after the pure d-isomer drug compared with the racemate may contribute to drug individualization/optimization in the treatment of attention deficit hyperactivity disorder.

Comparative Ethanol-Induced Potentiation of Stimulatory Responses to Dexmethylphenidate Versus Methylphenidate.

The potentiation of positive subjective responses to immediate-release dexmethylphenidate (d-MPH) or dl-methylphenidate (dl-MPH) by ethanol was investigated over the time course of maximal drug exposure after a single dose. In a 4-way, randomized, crossover study design, 12 men and 12 women normal volunteers received d-MPH (0.15 mg/kg) or dl-MPH (0.3 mg/kg) with or without ethanol (0.6 g/kg). Serial visual analog scales were used as surrogates for drug abuse liability ("high," "good," "like," "stimulated," and "any drug effect"). Combining pure d-MPH with ethanol significantly (P < 0.005) increased the area under the effect curves (AUC(0-5.25h)) of all 5 subscales. The dl-MPH-ethanol combination significantly (P < 0.05) increased these AUCs with the exception of like (P = 0.08). Effects of the pure d-MPH-ethanol combination exhibited delayed potentiation relative to dl-MPH-ethanol. A pharmacokinetic interaction between the l-isomer of dl-MPH and ethanol has previously been shown to increase early exposure to d-MPH. Administration of the pure isomer d-MPH precludes this absorption phase pharmacokinetic interaction with ethanol. This notwithstanding, the pure d-MPH-ethanol combination resulted in comparable, if not greater, cumulative stimulant potentiation than the dl-MPH-ethanol combination. These findings provide evidence of a pharmacodynamic component to d-MPH-ethanol synergistic interactions and carry implications for the rational drug individualization in the treatment of attention-deficit/hyperactivity disorder.

Effect of extended-release dexmethylphenidate and mixed amphetamine salts on sleep: a double-blind, randomized, crossover study in youth with attention-deficit hyperactivity disorder.

OBJECTIVE: We sought to determine the dose-response effects of extended-release (ER) dexmethylphenidate (d-MPH) and ER mixed amphetamine salts (MAS) on objective measures of sleep. METHODS: This was an 8-week, double-blind, placebo-controlled, randomized, two period, crossover study of youth with attention-deficit hyperactivity disorder (ADHD) as confirmed by the Kiddie Schedule for Affective Disorders for School-Age Children-Present and Lifetime version (K-SADS-PL). Children aged 10-17 years were recruited from clinical practice, colleague referrals, and flyers. Participants were randomized to initially receive either d-MPH or MAS. During each 4-week drug period, children received three dose levels (10, 20, and 25/30 mg) in ascending order, with placebo substituted for active medication in a randomized fashion during 1 week of the study. After 4 weeks, participants were switched to the alternative medication for another 4 weeks of treatment. The main outcome measure was sleep duration as measured by actigraphy. Children, parents, and researchers were blinded to drug, dose, and placebo status. RESULTS: Sixty-five participants met the inclusion criteria and were enrolled in the study. Of these, 37 participants with sufficient sleep data for analysis were included. Sleep schedule measures showed a significant effect for dose on sleep start time (F(1,36) = 6.284; p < 0.05), with a significantly later sleep start time when children were receiving 20- or 30-mg doses, compared with placebo (p < 0.05). A significant dose effect was found on actual sleep duration (F(1,36) = 8.112; p < 0.05), with significantly shorter actual sleep duration for subjects receiving 30 mg compared with those receiving placebo (p < 0.05). There were no significant differences on sleep duration or sleep schedule between the two stimulant medications. The trial is complete and closed to follow-up. CONCLUSIONS: Higher stimulant doses were associated with reduced sleep duration and later sleep start times, regardless of medication class. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00393042.