Osmotic-release Oral System Methylphenidate Treatment Research Articles

Protocol of a monocentric, double-blind, randomized, superiority, controlled trial evaluating the effect of in-prison OROS-methylphenidate vs. placebo treatment in detained people with attention-deficit hyperactivity disorder (BATIR)

BackgroundAttention-deficit hyperactivity disorder (ADHD) is characterized by difficulty paying attention, poor impulse control, and hyperactive behavior. It is associated with several adverse health and social outcomes and leads to an increased risk of criminality and recidivism. Worldwide, ADHD is thus highly prevalent in prisons. However, ADHD treatment has been neglected in such environments. Stimulant medications such as osmotic-release oral system methylphenidate (OROS-MPH) are first-line treatments in the general population, but they are under-prescribed in prisons due to concerns about abuse, even though such claims are not empirically supported. This project aims to compare the efficacy of a 3-month in-prison OROS-MPH vs. placebo treatment on the severity of core ADHD symptoms and relevant in- and post-prison outcomes.MethodsThis study is a phase III, double-blinded, randomized, superiority, controlled trial of OROS-MPH vs. placebo. After randomization, the participants will receive 3 months of treatment with OROS-MPH or placebo (1:1 ratio) while incarcerated. Upon release, all participants will be offered the treatment (OROS-MPH) for 1 year but will remain blinded to their initial study group. The study will be conducted at the Division of Prison Health, Geneva, Switzerland, among incarcerated men (n = 150). Measures will include (1) investigator-rated ADHD symptoms, (2) acute events collected by the medical and prison teams, (3) assessment of the risk of recidivism, (4) medication side effects, (5) medication adherence, (6) study retention, (7) health care/prison costs, and (8) 1-year recidivism. Analyses will include bivariable and multivariable modeling (e.g., regression models, mixed-effects models, survival analyses) and an economic evaluation (cost-benefit analysis).DiscussionWe expect that early identification and treatment of ADHD in prison will be an important public health opportunity and a cost-effective approach that is likely to reduce the vulnerability of incarcerated individuals and promote pathways out of criminal involvement. The study will also promote standards of care for people with ADHD in prison and provide recommendations for continuity of care after release.Trial registrationClinicalTrials.govNCT05842330. Registered on June 5, 2023.Kofam.ch SNCTP000005388. Registered on July 17, 2023.

Mullerian inhibiting substance, sex hormone binding globulin and sex hormone levels in stimulant-naïve, first-diagnosed prepubertal boys with attention-deficit/hyperactivity disorder: comparison with matched healthy controls as well as before and after oros-methylpenidate treatment

Objectives: Attention-Deficit/Hyperactivity Disorder (ADHD) is a complex neurodevelopmental disorder with strong male predominance. Since Müllerian Inhibiting Substance (MIS) produces sex-linked bias in animal studies, we aimed to investigate the role of MIS, Sex Hormone Binding Globulin (SHBG) and sex hormone levels in boys with ADHD.Methods: We compared prepubertal, psychostimulant-naïve boys with ADHD with age-matched healthy control boys (HCs). Patients were re-evaluated after 30 days of methylphenidate treatment assessing ADHD severity, and serum MIS, testosterone, estradiol, and albumin concentrations.Results: Compared to 30 HCs, with ADHD (n = 49, age = 6.9 ± 0.2 years) had lower SHBG (p = .014), and higher free testosterone (p = 0.006) and bioavailable testosterone (p = .002) percentages. Methylphenidate improved ADHD measures (all p < .0001) and abnormal baseline hormonal levels, increasing SHBG levels (p = .024), and lowering free (p = .001) and bioavailable testosterone (p = .016) percentages so that only free testosterone percentages remained higher versus HCs post-treatment (p = .02).Conclusions: Compared to age- and sex-matched HCs, prepubertal, stimulant-naïve boys with ADHD had significantly lower SHBG and higher free and bioavailable testosterone percentages, suggesting a possible contribution of sex hormones to ADHD. Osmotic-release oral system methylphenidate treatment for 30 days significantly improved ADHD symptoms and abnormal sex hormone levels, normalizing SHBG and bioavailable testosterone percentages that were similar to HCs while free testosterone remained elevated versus HCs.Key pointsCompare to healthy matched controls prepubertal stimulant-naïve boys with ADHD had significantly lower SHBG and higher free and bioavailable testosterone percentages, suggesting a possible effect on sex hormones to ADHD.After 30-day methylphenidate treatment, ADHD symptoms significantly improved, and SHBG and bioavailable testosterone percentages normalized which were similar to HCs, while free testosterone remained elevated versus HCs.We found a negative relationship between MIS levels and hyperactivity scores in ADHD boys. This finding suggests that MIS may contribute to hyperactivity symptoms, either directly by affecting behavior or indirectly by affecting sex hormone levels.

The possible effect of methylphenidate on kleptomania in a school-age girl with attention-deficit/hyperactivity disorder

Kleptomania is an impulse-control disorder (ICD) defined as the recurrent failure to resist impulses to steal objects that are not needed for personal use or for their monetary value. Kleptomania is a relatively rare condition; therefore, few studies have been conducted, and the treatment of the disorder tends to be based on small studies or case reports [1, 4, 6, 8]. Because the frequency of attention deficit/ hyperactivity disorder (ADHD) was found to be higher in patients with ICD [2], some research has focused on the effects of ADHD drugs on the treatment of kleptomania. Two different case reports examined the effect of methylphenidate (MPH) in these patients. In the first report, the authors showed that a combination of sertraline and MPH was successful in treating a child with kleptomania and ADHD [4]. In the second report, the positive effect of MPH on kleptomania was examined on an adolescent with kleptomania and ADHD [8]. The current report presents the case of a 7-year-old girl with kleptomania and ADHD who displayed a complete remission from kleptomania during MPH therapy. The subject patient was referred to the child and adolescent psychiatry outpatient clinic with complaints of stealing behavior, oppositional behavior, and inattention. Her stealing behavior had been observed since she had attended kindergarten. She had stolen her friends’ school materials, including pencil sharpeners, pen cap, eraser dust, a puzzle piece, or Legos. The frequency of her stealing behaviors increased over time, and for last 6 months, she had been stealing these materials nearly every day. Her parents reported that although she collected the things that she had stolen, she almost never used them. They also reported that the girl did not steal the items in anger, and her stealing behavior did not show a temporal relationship with her oppositional attitudes. Although her parents were unsure whether she experienced tension prior to stealing, she typically seemed to be comfortable after the acts. Although the parents had used various punishments to reprimand her for her actions, no reduction in her stealing behaviors was observed. During her psychiatric assessment, inattentiveness, mild hyperactivity, and impulsiveness were clinically observed. There were no signs of anxiety, elevated or depressed mood, psychosis, or compulsive behaviors. Her physical examination was within normal limits, and she had no history of any physical disease. According to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR), she met criteria for ADHD (inattentive type) and kleptomania. The severity of her ADHD and kleptomania were detected with using Conner’s Parent Rating Scale and Clinical Global Impression Scale (Table 1) [5, 7]. The patient’s parents were reluctant to try behavioral intervention, so it was not undertaken at this stage. An 18 mg osmotic-release oral system MPH treatment was initiated daily. It resulted in moderate improvement in the girl’s ADHD symptoms and the complete resolution of the kleptomania within the first 10 days. The parents reported improvement in her ADHD, and her coexisting disruptive behavioral disorders’ symptoms continued over time. Complete resolution of the kleptomania continued as well. At the 4-month follow-up, the girl had not exhibited any stealing behavior. According to DSM-IV-TR, when diagnosing kleptomania, a patient’s stealing behavior is not better accounted for S. Yilmaz (&) A. Bilgic Meram School of Medicine, Necmettin Erbakan University, Konya, Turkey e-mail: drsavash@gmail.com

Health-Related Quality of Life and Functional Outcomes from a Randomized, Controlled Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention Deficit Hyperactivity Disorder

BackgroundOptimal management of attention deficit hyperactivity disorder (ADHD) aims not only to ameliorate patients’ symptoms, but also to improve health-related quality of life (HRQL) and functioning. A pivotal, 7-week, randomized, double-blind, placebo-controlled, phase III study in children and adolescents in ten European countries demonstrated that the stimulant prodrug lisdexamfetamine dimesylate (LDX) is an effective and generally well-tolerated treatment for symptoms of ADHD.ObjectiveThe aim of this study was to assess HRQL and functional impairment outcomes in this clinical trial, using the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P), respectively.MethodsPatients (aged 6–17 years) with diagnosed ADHD and a baseline ADHD Rating Scale IV total score ≥28 were randomized (1:1:1) to 7 weeks of double-blind treatment with once-daily LDX, placebo or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH). Participants’ parents (or legally authorized representatives) completed the CHIP-CE:PRF and WFIRS-P questionnaires at baseline, at weeks 4 and 7, and/or at early termination. Endpoint was defined as the last on-treatment visit with valid data (≤30 % missing items). The CHIP-CE:PRF Achievement domain was pre-specified as the primary HRQL outcome.ResultsThe full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107), the majority of whom completed the study (LDX, n = 77; placebo, n = 42; OROS-MPH, n = 72). Baseline CHIP-CE:PRF T-scores in four of the five domains were ≥1 standard deviation below norms (US community samples). Compared with placebo, LDX was associated with statistically significantly improved T-scores from baseline to endpoint in these four domains, with effect sizes of 1.280 (p < 0.001) in Achievement, 1.079 (p < 0.001) in Risk Avoidance, 0.421 (p < 0.01) in Resilience and 0.365 (p < 0.05) in Satisfaction. In LDX-treated patients, placebo-adjusted improvements from baseline to endpoint in WFIRS-P scores were statistically significant (p < 0.001) for total score and four of the six domains, with effect sizes of 0.924 (total score), 1.249 (Learning and School), 0.730 (Family), 0.643 (Social Activities) and 0.640 (Risky Activities). OROS-MPH treatment showed similar patterns of improvement from baseline to endpoint in both CHIP-CE:PRF and WFIRS-P scores.ConclusionsBaseline HRQL and functional impairment scores reflect the burden of untreated ADHD. The benefits of short-term stimulant treatment in children and adolescents with ADHD extend beyond symptomatic relief and impact positively on HRQL and daily functioning.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-013-0095-5) contains supplementary material, which is available to authorized users.

Remission in Children and Adolescents Diagnosed with Attention-Deficit/Hyperactivity Disorder via an Effective and Tolerable Titration Scheme for Osmotic Release Oral System Methylphenidate

The purpose of this study was to identify the optimal dose of osmotic release oral system methylphenidate (OROS-MPH) using a dosage forced-titration scheme to achieve symptomatic remission in children with attention- deficit/hyperactivity disorder (ADHD). We also evaluated the efficacy and safety of, and patient and parent satisfaction with, the change in therapy from immediate-release methylphenidate (IR-MPH) to OROS-MPH over 10 weeks. We recruited 521 children and adolescents aged 6-18 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnosis of ADHD, who had received IR-MPH treatments (<70 mg/day) for at least 1 month. The treatment, switched from IR-MPH to OROS-MPH according to a conversion scheme, started with a 6-week forced-titration phase of OROS-MPH to achieve symptomatic remission (defined as a score of 0 or 1 for each of the first 18 ADHD items in the Chinese version of the Swanson, Nolan, and Pelham, Version IV [SNAP-IV]), followed by a 4-week maintenance phase. The global ADHD severity and drug side effects of the participants were evaluated. Parents completed the ratings scales for the ADHD-related symptoms. Patient and parent satisfaction for the OROS-MPH treatment was also assessed. Among the 439 participants with ADHD who completed the trial, 290 participants (66.1%) achieved symptomatic remission. The mean dose of OROS-MPH among participants in remission was 36.7 mg (1.08 mg/kg) per day. Increased efficacy, superior satisfaction, and safety equivalent to that of IR-MPH were demonstrated in intra-individual comparisons from the baseline to the end of study. Determinants for remission included less severe ADHD symptoms (SNAP-IV score < 40), no family history of ADHD, and an appropriate dosage of medication according to the patient's weight. The findings suggest remission as a treatment goal for ADHD therapy by providing an optimal dosage of medication for children and adolescents with ADHD through using an effective and tolerable forced-titration scheme.

Naturalistic exploration of the effect of osmotic release oral system‐methylphenidate on remission rate and functional improvement in Taiwanese children with attention‐deficit–hyperactivity disorder

To determine the differences in the remission rate, recovery rate, functional improvement, and treatment adherence related to treatment with short-acting immediate-release methylphenidate (IR-MPH) and long-acting osmotic-release oral system-methylphenidate (OROS-MPH) in a naturalistic setting among Taiwanese children with attention-deficit-hyperactivity disorder (ADHD). A total of 757 children with ADHD, aged 6-18 years, was evaluated using the following in order determine functional improvement and treatment adherence: the Chinese version of the Swanson, Nolan, and Pelham, version IV scale (SNAP-IV-C), Clinical Global Impression-ADHD-Severity (CGI-S) to measure remission and recovery rates, the Chinese version of the Social Adjustment Inventory for Children and Adolescents (CSAICA), and caregiver's satisfaction rate, treatment adherence, and frequency of adverse effects. According to the SNAP-IV-C scores, the remission rate was 30.72%, and the recovery rate was 16.38%. Compared to short-acting IR-MPH, OROS-MPH was associated with greater functional improvement and treatment adherence among children with ADHD. OROS-MPH treatment at the adequate dosage can achieve higher remission and recovery rates, produce greater functional improvement, and result in better treatment adherence than IR-MPH treatment.

Comparative study of OROS-MPH and atomoxetine on executive function improvement in ADHD: a randomized controlled trial

This study aimed to compare the effects of osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine (ATX) on executive function in children and adolescents with attention deficit hyperactivity disorder (ADHD) by a randomized controlled trial. Subjects who met DSM-IV ADHD criteria were randomized to receive either OROS-MPH or ATX treatment. The doses were titrated to achieve optimal response and then maintained for 4-6 wk. A battery of executive function tests and the Behavior Rating Inventory of Executive Function (BRIEF) were administered to subjects who completed the dose titration (OROS-MPH, n=85; ATX, n=57) at the pre- and post-treatment periods. Forty-six children without ADHD were recruited as controls. Both OROS-MPH and ATX significantly improved scores in the Rey Complex Figure Test (RCFT), digit span, and Stroop color-word task. The scores in RCFT and the reverse digit span were not significantly different from the control group at post-treatment assessment (OROS-MPH=ATX=control, p>0.05), whereas the word interference time of the Stroop test was still more than that of the control group (OROS-MPH=ATX>control, p>0.05). OROS-MPH also significantly improved the total correct response in the verbal fluency test to normal level, and the shifting time in the trail-making test to subnormal level. The current findings suggest both OROS-MPH and ATX improved executive function generally in children and adolescents with ADHD, and could return working memory back to normative performance level.

Long-term efficacy and safety outcomes with OROS-MPH in adults with ADHD

Methylphenidate (MPH) is widely prescribed for adults with attention deficit hyperactivity disorder (ADHD), but data on long-term treatment and maintenance of effect are lacking. Osmotic release oral system-methylphenidate (OROS–MPH) was evaluated in a 52-wk open-label study in subjects who had previously completed a short-term placebo-controlled trial and short-term open-label extension. Efficacy was assessed using the investigator- and subject-rated Conners’ Adult ADHD Rating Scales (CAARS:O-SV and CAARS:S-S), and the Clinical Global Impression – Severity (CGI-S), Sheehan Disability Scale (SDS) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Subjects completing ≥52 wk of treatment were eligible for a 4-wk randomized, placebo-controlled withdrawal phase in which loss of treatment effect was assessed using CAARS:O-SV and CGI-S. In the open-label phase (n=156), mean CAARS:O-SV score decreased from baseline by 1.9±7.8 (p<0.01), and small, statistically significant improvements from baseline were observed for CAARS:S-S, CGI-S and SDS. In the double-blind phase (OROS-MPH, n=23; placebo, n=22), CAARS:O-SV increased from double-blind baseline in the OROS-MPH and placebo arms (4.0±7.6 vs. 6.5±7.8, not statistically significant). Long-term OROS-MPH treatment was well tolerated, and there was no evidence of withdrawal or rebound after discontinuation. In conclusion, the short-term benefits of OROS-MPH continue during long-term open-label treatment. Maintenance of efficacy in a placebo-controlled withdrawal design remains to be confirmed in larger patient populations.

PW01-57 - Lisdexamfetamine dimesylate as treatment for ADHD in children previously treated with osmotic-release oral system methylphenidate: parental impressions

ObjectivesWe assessed parents’ perceptions of and satisfaction with daily lisdexamfetamine dimesylate (LDX; Vyvanse®, US tradename, Shire US Inc.) treatment for their children with attention-deficit/hyperactivity disorder (ADHD) previously treated with osmotic-release oral system methylphenidate (OROS-MPH).MethodsParents of children with ADHD were surveyed via telephone or Internet about their child's experience before and approximately 6 weeks after initiating LDX treatment. Participants received a $25 coupon toward their child's next LDX prescription after survey completion. Post hoc analyses using the Wilcoxon signed rank test were performed.ResultsSchool time was the most frequently reported most bothersome time of day at baseline (41%), followed by homework time (23%). At follow-up, most parents reported improvement during their child's most bothersome time of day. Significantly less interference from ADHD symptoms with school activities, family interactions, homework, and social interactions was reported (all P&lt; .01). LDX tolerability and convenience were rated, on average, 7.1 and 8.0, respectively (1=not at all well tolerated/convenient, 9=very well tolerated/convenient). Satisfaction with LDX was significantly higher than satisfaction with OROS-MPH treatment (6.9 and 5.0, respectively, P&lt; .01 [1=not at all satisfied, 9=very satisfied]). Eighty-four percent of parents reported that they intend for their child to continue taking LDX.ConclusionsParents of children with ADHD who were previously treated with OROS-MPH and currently taking LDX reported less interference of ADHD symptoms with daily activities after LDX treatment and high satisfaction with LDX. LDX was also well tolerated and convenient to use.Supported by funding from Shire Development Inc.

Neurocognitive effects of switching from methylphenidate‐IR to OROS‐methylphenidate in children with ADHD

This study evaluated neurocognitive changes after switching from immediate release forms of methylphenidate (MPH-IR) to osmotic release oral system methylphenidate (OROS-MPH). 102 children with attention-deficit/hyperactivity disorder (ADHD) participated in an open label, 28 day trial, performing neurocognitive test at baseline and at 28 days after the switch from MPH-IR to OROS-MPH. There were significant improvements in the commission error and the reaction time of both visual and auditory continuous performance tests (CPTs) at 28 days after switching from MPH-IR to OROS-MPH. A positive correlation was observed between the improvement in parent/caregiver-rated IOWA Conners total score (Delta IOWA) and the reduction in commission error (r = 0.3, p = 0.001) and reduction in reaction time variability (r = 0.3, p = 0.006) of visual CPT. In a linear regression model, the change in parent/caregiver-rated IOWA Conners scale total scores were significant predictors of change in commission error (beta = 0.3, p = 0.005, CI = 0.4-2.3, adjusted R(2) = 0.12) and RT variability (beta = 0.3, p = 0.004, CI = 0.5-2.4, adjusted R(2) = 0.09) of visual CPT. These data suggest that MPH-IR may be successfully switched to OROS-MPH treatment with associated improvements in neurocognitive performance. Large-scale controlled trials are needed to replicate these findings.

Osmotic-Release Oral System Methylphenidate Augmentation of Antidepressant Monotherapy in Major Depressive Disorder

To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen. This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006. There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES at all visits and at endpoint (p = .01) and on the MAF (p < .01). No differences were observed on other secondary measures, including the CGI-I and CGI-S. There were no clinically significant findings on electrocardiogram. OROS methylphenidate did not demonstrate statistical significance on the MADRS at endpoint. Apathy and fatigue were significantly improved with OROS methylphenidate treatment, which was well tolerated with minimal side effects. ClinicalTrials.gov identifier NCT00246233.