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Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder, seen in 20–30% of young adult prisoners. Pharmacoepidemiological studies, a small randomised controlled trial and open trial data of methylphenidate suggest clinically significant reductions in ADHD symptoms, emotional dysregulation, disruptive behaviour and increased engagement with educational activities. Yet, routine treatment of ADHD in offenders is not yet established clinical practice. There is continued uncertainty about the clinical response to methylphenidate (MPH), a first-line treatment for ADHD, in offenders, who often present with an array of complex mental health problems that may be better explained by states of inattentive, overactive, restless and impulsive behaviours. To address this problem, we will conduct an efficacy trial to establish the short-term effects of osmotic-controlled release oral delivery system (OROS)-methylphenidate (Concerta XL), an extended release formulation of MPH, on ADHD symptoms, emotional dysregulation and behaviour. Methods This study is a parallel-arm, randomised, placebo-controlled trial of OROS-MPH on ADHD symptoms, behaviour and functional outcomes in young male prisoners aged 16–25, meeting Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria for ADHD. Participants are randomised to 8 weeks of treatment with OROS-MPH or placebo, titrated over 5 weeks to balance ADHD symptom improvement against side effects. Two hundred participants will be recruited with a 1:1 ratio of drug to placebo. The primary outcome is change in level of ADHD symptoms after 8 weeks of trial medication. Discussion Potential benefits include improvement in ADHD symptoms, emotional dysregulation, attitudes towards violence and critical incidents and increased engagement with educational and rehabilitation programmes. Demonstrating the efficacy and safety of MPH on ADHD symptoms and associated impairments may provide the data needed to develop effective healthcare pathways for a significant group of young offenders. Establishing efficacy of MPH in this population will provide the foundation needed to establish long-term effectiveness studies with the potential for demonstrating significant reductions in criminal behaviour and improved health-economic outcomes. Trial registration ISRCTN registry, ISRCTN16827947, 31st May 2016; EudraCT number, 2015-004271-78, 31st May 2016. Last particpant last visit 6 June 2019. Data lock 27 August 2019.

Aim To examine theeffects on the brain of 2-month treatment withamethylphenidate extended-release formulation (OROS-MPH) using [Tc- 99m ] TRODAT-1SPECT in a sample of treatment-naïve adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). In addition, to assess whether risk alleles (homozygosity for 10-repeat allele at the DAT1 gene were associated with alterations in striatal DAT availability. Methods Twenty adolescents with ADHD underwent brain single-photon emission computed tomography (SPECT) scans with [Tc- 99m ] TRODAT-1 at baseline and two months after starting OROS-MPH treatment with dosages up to 1 mg/kg/day. Severity of illness was estimated using the Clinical Global Impression Scale (CGI-S) and DuPaul ADHD Rating Scale-Clinician version (ARS) before treatment,1 month and 2 months after initiating OROS-MPH treatment. Results Decreased DAT availability was found in both the right caudate (pretreatment DAT binding: 224.76 ± 33.77, post-treatment DAT binding: 208.86 ± 28.75, p = 0.02) and right putamen (pre-treatment DAT binding: 314.41 ± 55.24, post-treatment DAT binding: 285.66 ± 39.20, p = 0.05) in adolescents with ADHD receiving OROS-MPH treatment. Adolescents with ADHD who showed a robust response to OROS-MPH (n = 7) had significantly greater reduction of DAT density in the right putamen than adolescents who showed less robust response to OROS-MPH (n = 13) (p = 0.02). However, between-group differences by treatment responses were not related with DAT density in the right caudate. Risk alleles (homozygosity for the 10-repeat allele of DAT1 gene) in the DAT1 gene were not associated with alterations in striatal DAT availability. Conclusion Two months of OROS-MPH treatment decreased DAT availability in both the right caudate and putamen. Adolescents with ADHD who showed a robust response to OROS-MPH had greater reduction of DAT density in the right putamen. However,our findings did not support an association between homozygosity for a 10-repeat allele in the DAT1 gene and DAT density, assessedusing[Tc- 99m ] TRODAT-1SPECT. [ABSTRACT FROM AUTHOR]

Long-acting methylphenidate (MPH) formulations, including OROS-MPH, were found to be effective in alleviating ADHD symptoms throughout the day. However, sustained stimulant activity may lead to prolonged suppression of appetite and insomnia. In this study, we characterized the clinical profile of children and adolescents for whom a once-daily lower dose of OROS-MPH combined with a shorter-acting agent was more tolerable than single higher OROS-MPH dose. In our cohort of 128 children treated with OROS-MPH, 47 (36.7 %) better tolerated a lower dose of OROS-MPH combined with short-acting MPH formulations (Group I). Nevertheless, for the majority (81 patients-63.3 %), a standard single moderate dose of OROS-MPH was sufficient (Group II). The mean daily doses of MPH were: 0.83 ± 0.21 mg/kg for Group I and 1.06 ± 0.29 mg/kg for Group II. There were no significant differences in the prevalence of learning disorders, tic disorders, epilepsy and conduct disorders between these two groups. However, anxiety and marginally depression were more prevalent in Group I (46.8 and 9.7 %) than in Group II (27.2 and 1.2 %). Patients in Group I were also more tending to receive psychotherapy than patients in Group II. [ABSTRACT FROM AUTHOR]

Objective Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-oneset psychiatric disease, characterized by excessive overactivity, inattention, and impulsiveness. In recent studies, it is emphasized that inflammation may have a role in ADHD. In this study, we aimed to investigate whether there are associations between ADHD and serum levels of soluble intercellular adhesion molecules (s-ICAMs) which have important role in inflammatory diseases. We also measured the levels of these molecules after treatment with oros-methylphenidate. Methods Twenty-five patients diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria and 18 healthy volunteer controls were included in this study. The levels of sICAMs were measured in the serum of the patients and healthy volunteers by ELISA kit as described. Results The levels of sICAM-1 and sICAM-2 were significantly higher in patients compared with controls. The level of sICAM-2 was decreased significantly in group treated with oros-methylphenidate. Conclusions This is the first study pointing out the relationship between sICAMs and ADHD. The changes in sICAM-2 level may have a role in the effect mechanism of oros-methylphenidate, used for the treatment of ADHD. [ABSTRACT FROM AUTHOR]

Abstract: Attention-deficit/hyperactivity disorder (ADHD) is linked to impaired executive functioning (EF). This is the first study to objectively investigate the effects of a long-acting methylphenidate on neurocognitive test performance of adults with ADHD. Twenty-two adults with ADHD participated in a 6-weeks study examining the effect of osmotic-release oral system methylphenidate (OROS-mph) on continuous performance tests (CPTs; objective measures), and on the self-reported ADHD rating scale (subjective measure) using a randomized, double-blind, placebo-controlled cross-over design. OROS-mph significantly improved reaction time variability (RTV), commission errors (CE) and d-prime (DP) as compared to baseline (Cohen's d>.50), but did not affect hit reaction time (HRT) or omission errors (OE). Compared to placebo, OROS-mph only significantly influenced RTV on one of two CPTs (p<.050). Linear regression analyses showed predictive ability of more beneficial OROS-mph effects in ADHD patients with higher EF severity (RTV: β=.670, t=2.097, p=.042; omission errors (OE): β=−.098, t=−4.759, p<.001), and with more severe ADHD symptoms (RTV: F=6.363, p=.019; HRT: F=3.914, p=.061). Side effects rates were substantially but non-significantly greater for OROS-mph compared to placebo (77% vs. 46%, p=.063). OROS-mph effects indicated RTV as the most sensitive parameter for measuring both neuropsychological and behavioral deficits in adults with ADHD. These findings suggest RTV as an endophenotypic parameter for ADHD symptomatology, and propose CPTs as an objective method for monitoring methylphenidate titration. [Copyright &y& Elsevier]

Background: Multisite trials, the gold standard for conducting studies in community-based settings, can mask variability across sites resulting in misrepresentation of effects in specific sites. In a placebo-controlled trial of osmotic-release oral system methylphenidate (OROS-MPH) as augmentation treatment for smokers with attention deficit hyperactivity/impulsivity disorder (ADHD), three types of sites were selected according to their clinical research specialty (ADHD, smoking cessation, and general mental health). Objective: Analysis was conducted to determine if clinical outcomes, that is, reduction in ADHD symptoms and smoking cessation rates, and the effect of treatment on these outcomes would differ by type of site. Method: A total of 255 adult smokers diagnosed with ADHD were enrolled in three clinic types: 72 in ADHD, 79 in tobacco dependence, and 104 in the mental health clinics. Results: The three site-types were similar in demographic characteristics, smoking history, baseline level of ADHD symptoms, and history of psychiatric illness. Site-type but not a site-type by treatment interaction predicted prolonged smoking abstinence. A significant three-way interaction of site-type, treatment, and time-predicted improvement in ADHD symptoms. Moderate to strong effects of OROS-MPH relative to placebo were observed in the mental health and the ADHD clinics; a weak effect was observed in the tobacco dependence clinics. Conclusion: OROS-MPH benefit varied by site for reducing ADHD symptoms but not for improving smoking abstinence. Scientific Significance: Assessment of site-type effects can indicate the generalizability of findings from multisite trials and should be routinely incorporated in the design of multisite trials. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study was to evaluate the association between executive function deficits (EFDs) and response to methylphenidate treatment in ADHD in adults. We conducted a 6-week, parallel design, randomized, placebo controlled study in adults with DSM-IV ADHD. Our psychometric index of executive function used standardized neuropsychological testing. We assessed behaviors reflective of EFDs using the Behavior Rating Inventory of Executive Function — Adult Version (BRIEF-A). Subjects with available measures of executive functioning (OROS-MPH N =40; Placebo N =47) were included for analysis. There was no difference in the percent of subjects completing the 6-week acute efficacy Phase I of the trial (100% (N =40) vs. 98% (N =46), p =0.4). The mean daily dose at Phase I endpoint was 84.6±31.6mg (1.04±0.29mg/kg) OROS-MPH and 100.5±21.9mg (1.20±0.11mg/kg) placebo (p =0.0007). Based on the neuropsychological testing at the baseline assessment, 40% of the ADHD subjects (N =35/87) were considered to have EFDs but 93% (N =81) of subjects had ≥2 BRIEF-A clinical scale T-scores >65. Regardless of the definition used, however, EFDs did not impact the clinical response to OROS-MPH. This randomized clinical trial showed that executive function deficits do not moderate the response to methylphenidate and measures of executive function deficits are not associated with response to OROS-MPH. [Copyright &y& Elsevier]

Abstract: Background: We conducted a post-hoc analysis of the Long-Acting MethylpheniDate in Adult attention-deficit hyperactivity disorder (LAMDA) study to investigate predictors of response in adults with ADHD randomly assigned to Osmotic Release Oral System (OROS)®-methylphenidate hydrochloride (MPH) 18, 36 or 72mg or placebo. Methods: LAMDA comprised a 5-week, double-blind (DB) period, followed by a 7-week, open-label (OL) period. A post-hoc analysis of covariance and a logistic regression analysis were undertaken to detect whether specific baseline parameters or overall treatment compliance during the double-blind phase contributed to response. The initial model included all covariates as independent variables; a backward stepwise selection method was used, with stay criteria of p <0.10. Six outcomes were considered: change from baseline CAARS:O-SV (physician-rated) and CAARS:S-S (self-report) scores at DB and OL end points, and response rate (≥30% decrease in CAARS:O-SV score from baseline) and normalization of CAARS:O-SV score at DB end point. Results: Taking into account a significant effect of OROS®-MPH treatment versus placebo in the original analysis (p ≤0.015), across the outcomes considered in this post-hoc analysis, higher baseline CAARS scores were most strongly predictive of superior outcomes. Male gender and lower academic achievement were also predictive for improved results with certain outcomes. Conclusions: Several baseline factors may help to predict better treatment outcomes in adults receiving OROS®-MPH; however, further research is required to confirm these findings and examine their neurobiological underpinnings. [Copyright &y& Elsevier]

Abstract: Objective: To explore racial/ethnic difference in OROS-methylphenidate (OMPH) efficacy when added to nicotine patch and counseling for treating nicotine dependence among smokers with attention deficit hyperactivity disorder (ADHD). Method: Participants were adult smokers with ADHD (202 whites and 51 non-whites) randomly assigned to OMPH or placebo in a multi-site, randomized controlled trial. Study outcomes were complete, prolonged, and point-prevalence abstinence at the end of treatment, and weekly ratings of ADHD symptoms, tobacco withdrawal symptoms, and desire to smoke. Results: The rate of four-week complete abstinence (no slips or lapses) was significantly higher with OMPH than placebo among non-white (OMPH=42.9%, placebo=13.3%, χ 2(1)=5.20, p =0.02) but not white participants (OMPH=23.1%, placebo=23.5%, χ 2(1)=0.00, p =0.95). Patterns of prolonged and point-prevalence abstinence among non-whites were similar but fell short of statistical significance. OMPH reduced ADHD symptoms in both race/ethnic groups, and produced greater reductions in desire to smoke and withdrawal symptoms among the non-white than white participants. Change in desire to smoke, but not in withdrawal or ADHD symptoms predicted abstinence. The ability of OMPH to reduce desire to smoke among non-whites appeared to mediate the medication''s positive effect on abstinence. Conclusion: Differential efficacy favoring non-whites of a medication for achieving smoking cessation is a potentially important finding that warrants further investigation. OROS-MPH could be an effective treatment for nicotine dependence among a subgroup of smokers. [Copyright &y& Elsevier]

Long-acting methylphenidate (MPH) formulations, including OROS-MPH, were found to be effective in alleviating ADHD symptoms throughout the day. However, sustained stimulant activity may lead to prolonged suppression of appetite and insomnia. In this study, we characterized the clinical profile of children and adolescents for whom a once-daily lower dose of OROS-MPH combined with a shorter-acting agent was more tolerable than single higher OROS-MPH dose. In our cohort of 128 children treated with OROS-MPH, 47 (36.7 %) better tolerated a lower dose of OROS-MPH combined with short-acting MPH formulations (Group I). Nevertheless, for the majority (81 patients-63.3 %), a standard single moderate dose of OROS-MPH was sufficient (Group II). The mean daily doses of MPH were: 0.83 ± 0.21 mg/kg for Group I and 1.06 ± 0.29 mg/kg for Group II. There were no significant differences in the prevalence of learning disorders, tic disorders, epilepsy and conduct disorders between these two groups. However, anxiety and marginally depression were more prevalent in Group I (46.8 and 9.7 %) than in Group II (27.2 and 1.2 %). Patients in Group I were also more tending to receive psychotherapy than patients in Group II.