Safety Profile of Methylphenidate Under Long-Term Treatment in Adult ADHD Patients - Results of the COMPAS Study.

INTRODUCTION: The Comparison of Methylphenidate and Psychotherapy in adult ADHD Study (COMPAS) was a prospective, randomized multicenter clinical trial, comparing methylphenidate (MPH) with placebo (PLAC) in combination with cognitive behavioral group psychotherapy (GPT) or individual clinical management (CM) over the period of 1 year. Here, we report results on treatment safety. METHODS: MPH and PLAC were flexibly dosed. Among 433 randomized patients, adverse events (AEs) were documented and analyzed on an "as received" basis during week 0-52. Electrocardiogram data were recorded at baseline and week 24. RESULTS: Comparing 205 patients who received ≥1 dose of MPH with 209 patients who received PLAC, AEs occurring significantly more frequently in the MPH group were decreased appetite (22 vs. 3.8%), dry mouth (15 vs. 4.8%), palpitations (13 vs. 3.3%), gastrointestinal infection (11 vs. 4.8%), agitation (11 vs. 3.3%), restlessness (10 vs. 2.9%), hyperhidrosis, tachycardia, weight decrease (all 6.3 vs. 1.9%), depressive symptom, influenza (both 4.9 vs. 1.0%), and acute tonsillitis (4.4 vs. 0.5%). Syncope occurred significantly more often in the PLAC group (2.4 vs. 0%). Clinically relevant ECG changes occurred very rarely in both groups. Serious AEs were rare and without a significant group difference. The comparison of 206 patients treated with GPT versus 209 patients who received CM revealed no major differences. Serious AE classified as psychiatric occurred in 5 cases in the CM group and in 1 case in the GPT group. CONCLUSION: In this so far longest-running clinical trial, methylphenidate treatment was safe and well-tolerated.

Hyperactivity/restlessness is associated with increased functional connectivity in adults with ADHD: a dimensional analysis of resting state fMRI.

BACKGROUND: Adult attention-deficit/hyperactivity disorder (ADHD) is a serious and frequent psychiatric disorder of multifactorial pathogenesis. Several lines of evidence support the idea that ADHD is, in its core, a disorder of dysfunctional brain connectivity within and between several neurofunctional networks. The primary aim of this study was to investigate associations between the functional connectivity within resting state brain networks and the individual severity of core ADHD symptoms (inattention, hyperactivity, and impulsivity). METHODS: Resting state functional magnetic resonance imaging (rs-fMRI) data of 38 methylphenidate-naïve adults with childhood-onset ADHD (20 women, mean age 40.5 years) were analyzed using independent component analysis (FSL's MELODIC) and FSL's dual regression technique. For motion correction, standard volume-realignment followed by independent component analysis-based automatic removal of motion artifacts (FSL's ICA-AROMA) were employed. To identify well-established brain networks, the independent components found in the ADHD group were correlated with brain networks previously found in healthy participants (Smith et al. PNAS 2009;106:13040-5). To investigate associations between functional connectivity and individual symptom severity, sex, and age, linear regressions were performed. RESULTS: Decomposition of resting state brain activity of adults with ADHD resulted in similar resting state networks as previously described for healthy adults. No significant differences in functional connectivity were seen between women and men. Advanced age was associated with decreased functional connectivity in parts of the bilateral cingulate and paracingulate cortex within the executive control network. More severe hyperactivity was associated with increased functional connectivity in the left putamen, right caudate nucleus, right central operculum and a portion of the right postcentral gyrus within the auditory/sensorimotor network. CONCLUSIONS: The present study supports and extends our knowledge on the involvement of the striatum in the pathophysiology of ADHD, in particular, in the pathogenesis of hyperactivity. Our results emphasize the usefulness of dimensional analyses in the study of ADHD, a highly heterogeneous disorder. TRIAL REGISTRATION: ISRCTN12722296 ( https://doi.org/10.1186/ISRCTN12722296 ).

Does intensive multimodal treatment for maternal ADHD improve the efficacy of parent training for children with ADHD? A randomized controlled multicenter trial.

BACKGROUND: This is the first randomized controlled multicenter trial to evaluate the effect of two treatments of maternal attention-deficit hyperactivity disorder (ADHD) on response to parent-child training targeting children's external psychopathology. METHODS: Mother-child dyads (n = 144; ADHD according to DSM-IV; children: 73.5% males, mean age 9.4 years) from five specialized university outpatient units in Germany were centrally randomized to multimodal maternal ADHD treatment [group psychotherapy plus open methylphenidate medication; treatment group (TG): n = 77] or to clinical management [supportive counseling without psychotherapy or psychopharmacotherapy; control group (CG): n = 67]. After 12 weeks, the maternal ADHD treatment was supplemented by individual parent-child training for all dyads. The primary outcome was a change in the children's externalizing symptom scores (investigator blinded to the treatment assignment) from baseline to the end of the parent-child training 6 months later. Maintenance therapy continued for another 6 months. An intention-to-treat analysis was performed within a linear regression model, controlling for baseline and center after multiple imputations of missing values. RESULTS: Exactly, 206 dyads were assessed for eligibility, 144 were randomized, and 143 were analyzed (TG: n = 77; CG: n = 66). After 6 months, no significant between-group differences were found in change scores for children's externalizing symptoms (adjusted mean TG-mean CG=1.1, 95% confidence interval -0.5-2.7; p = .1854), although maternal psychopathology improved more in the TG. Children's externalizing symptom scores improved from a mean of 14.8 at baseline to 11.4 (TG) and 10.3 (CG) after 6 months and to 10.8 (TG) and 10.1 (CG) after 1 year. No severe harms related to study treatments were found, but adverse events were more frequent in TG mothers than in CG mothers. CONCLUSIONS: The response in children's externalizing psychopathology did not differ between maternal treatment groups. However, multimodal treatment was associated with more improvement in maternal ADHD. Child and maternal treatment gains were stable (CCT-ISRCTN73911400).

Effectiveness of Psychotherapy in Adult ADHD: What Do Patients Think? Results of the COMPAS Study.

OBJECTIVE: In the multicenter study Comparison of Methylphenidate and Psychotherapy in Adult ADHD (COMPAS), the efficacy of treatments has been primarily evaluated by observer-rated symptom change. Here, we additionally analyzed the patients' subjective evaluation of therapy effects. METHOD: COMPAS compared ADHD-specific group therapy with unspecific clinical management with/without concomitant pharmacotherapy in a four-armed design. Evaluation through the patients' retrospective perspective was performed after 1 year (post-treatment) and after another 1.5 years (follow-up). RESULTS: In respect to patients' subjective ratings, ADHD-specific group psychotherapy outperformed unspecific management post-treatment ( z = 4.88, p < .0001) and at follow-up ( z = 2.90, p = .004). Rank correlations with rater-based symptom change were small to moderate (post-treatment: rs = 0.28, follow-up: rs = 0.16). CONCLUSION: Therapy evaluation based on the patients' perspective supports the concept of ADHD-specific group psychotherapy as a potentially useful therapy option in ADHD.

Effects of Group Psychotherapy, Individual Counseling, Methylphenidate, and Placebo in the Treatment of Adult Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high prevalence in adulthood. There is a recognized need to assess the efficacy of psychotherapy in adult ADHD. OBJECTIVE: To evaluate the efficacy of cognitive behavioral group psychotherapy (GPT) compared with individual clinical management (CM) and that of methylphenidate hydrochloride compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, randomized clinical trial of 18- to 58-year-old outpatients with ADHD from 7 German study centers. Patients were recruited between January 2007 and August 2010, treatment was finalized in August 2011, and final follow-up assessments occurred in March 2013. INTERVENTIONS: Sessions of GPT and CM were held weekly for the first 12 weeks and monthly thereafter (9 months). Patients received either methylphenidate or placebo for 1 year. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the ADHD Index of the Conners Adult ADHD Rating Scale from baseline to the end of the 3-month intensive treatment (blinded observer ratings). Secondary outcomes included ADHD ratings after 1 year, blinded observer ratings using the Clinical Global Impression Scale, and self-ratings of depression. RESULTS: Among 1480 prescreened patients, 518 were assessed for eligibility, 433 were centrally randomized, and 419 were analyzed as randomized. After 3 months, the ADHD Index all-group baseline mean of 20.6 improved to adjusted means of 17.6 for GPT and 16.5 for CM, with no significant difference between groups. Methylphenidate (adjusted mean, 16.2) was superior to placebo (adjusted mean, 17.9) (difference, -1.7; 97.5% CI, -3.0 to -0.4; P = .003). After 1 year, treatment effects remained essentially stable. Descriptive analyses showed that methylphenidate was superior to placebo in patients assigned to GPT (difference, -1.7; 95% CI, -3.2 to -0.1; P = .04) or CM (difference, -1.7; 95% CI, -3.3 to -0.2; P = .03). Regarding depression, no significant differences were found. In contrast, GPT was superior to CM for all visits in the Clinical Global Impression global assessment of effectiveness. CONCLUSION AND RELEVANCE: Highly structured group intervention did not outperform individual CM with regard to the primary outcome. Psychological interventions resulted in better outcomes during a 1-year period when combined with methylphenidate as compared with placebo. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54096201.

A randomized controlled multicenter trial on the multimodal treatment of adult attention-deficit hyperactivity disorder: enrollment and characteristics of the study sample.

Adult ADHD is a frequent psychiatric disorder affecting relevant aspects of an individual's life. The aim of our study group was to carry out the first randomized controlled multicenter study to evaluate the effects of psychotherapy compared to clinical management in combination with psychopharmacological treatment with methylphenidate (MPH) or placebo (Plac) in a factorial four-arm design. Here, we present the enrollment procedure and description of adult ADHD patients recruited for the trial. Four hundred and thirty-three adult patients with ADHD were randomized at seven study sites in Germany to four treatment conditions: manualized dialectical-behavioral-therapy-based group psychotherapy (GPT) plus MPH or Plac, or clinical management (CM) including supportive counseling plus MPH or Plac with weekly sessions in the first 12 weeks and monthly sessions thereafter. Assessment for eligibility included standardized scales and instruments. After prescreening of 1,480 patients, 518 were evaluated for trial participation and 433 were randomized. The main reasons for prescreening failure were lack of interest in participating (n = 205), difficulties in meeting the time and effort requirements for participation (n = 186), and contraindications for psychopharmacological treatment with MPH (n = 194). The full analysis set (FAS) comprised 419 adult ADHD patients (mean age 35.2 years, males/females 1:1). Fifty-seven percent of the patients suffered from the combined ADHD subtype. Prevalence of at least one current or lifetime axis-I comorbidity was 66 %. Axis-II comorbidity rates was 18 % (patients with comorbid borderline and antisocial personality disorders were excluded). Our network was able to recruit an adult ADHD sample essentially comparable to community samples. A selection bias was created by excluding patients unable or unwilling to participate, or who had somatic and psychiatric contraindications for stimulant treatment (Current Controlled Trials ISRCTN54096201, FUNDING: Federal Ministry of Education and Research 01GV0606).