Craig B. H. Surman

A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder

BACKGROUND The few controlled studies of methylphenidate (MPH) in adults with attention deficit/hyperactivity disorder (ADHD) have reported equivocal results. A previous, pilot study by our group suggested that these results were due to inadequate dosing. METHOD We conducted a randomized, 6-week, placebo-controlled, parallel study of MPH in 146 adult patients with DSM-IV ADHD using standardized instruments for diagnosis, separate assessments of ADHD, depressive and anxiety symptoms, and a robust average oral daily dose of 1.1 mg/kg/day. RESULTS We found a marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response (76% vs. 19%). Treatment was safe and well tolerated. Response to MPH was independent of socioeconomic status, gender, and lifetime history of psychiatric comorbidity. CONCLUSIONS These results confirm that robust doses of MPH are effective in the treatment of adult ADHD.

Cognitive behavioral therapy vs relaxation with educational support for medication-treated adults with ADHD and persistent symptoms: A randomized controlled trial

CONTEXT Attention-deficit/hyperactivity disorder (ADHD) in adulthood is a prevalent, distressing, and impairing condition that is not fully treated by pharmacotherapy alone and lacks evidence-based psychosocial treatments. OBJECTIVE To test cognitive behavioral therapy for ADHD in adults treated with medication but who still have clinically significant symptoms. DESIGN, SETTING, AND PATIENTS Randomized controlled trial assessing the efficacy of cognitive behavioral therapy for 86 symptomatic adults with ADHD who were already being treated with medication. The study was conducted at a US hospital between November 2004 and June 2008 (follow-up was conducted through July 2009). Of the 86 patients randomized, 79 completed treatment and 70 completed the follow-up assessments. INTERVENTIONS Patients were randomized to 12 individual sessions of either cognitive behavioral therapy or relaxation with educational support (which is an attention-matched comparison). MAIN OUTCOME MEASURES The primary measures were ADHD symptoms rated by an assessor (ADHD rating scale and Clinical Global Impression scale) at baseline, posttreatment, and at 6- and 12-month follow-up. The assessor was blinded to treatment condition assignment. The secondary outcome measure was self-report of ADHD symptoms. RESULTS Cognitive behavioral therapy achieved lower posttreatment scores on both the Clinical Global Impression scale (magnitude -0.0531; 95% confidence interval [CI], -1.01 to -0.05; P = .03) and the ADHD rating scale (magnitude -4.631; 95% CI, -8.30 to -0.963; P = .02) compared with relaxation with educational support. Throughout treatment, self-reported symptoms were also significantly more improved for cognitive behavioral therapy (beta = -0.41; 95% CI, -0.64 to -0.17; P <001), and there were more treatment responders in cognitive behavioral therapy for both the Clinical Global Impression scale (53% vs 23%; odds ratio [OR], 3.80; 95% CI, 1.50 to 9.59; P = .01) and the ADHD rating scale (67% vs 33%; OR, 4.29; 95% CI, 1.74 to 10.58; P = .002). Responders and partial responders in the cognitive behavioral therapy condition maintained their gains over 6 and 12 months. CONCLUSION Among adults with persistent ADHD symptoms treated with medication, the use of cognitive behavioral therapy compared with relaxation with educational support resulted in improved ADHD symptoms, which were maintained at 12 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00118911.

A Randomized, Placebo-Controlled Trial of OROS Methylphenidate in Adults with Attention-Deficit/Hyperactivity Disorder

BACKGROUND The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD). METHODS We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day. RESULTS Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm). CONCLUSIONS These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.

Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task.

CONTEXT Previous studies have reported hypofunction, structural abnormalities, and biochemical abnormalities of the dorsal anterior midcingulate cortex (daMCC) in attention-deficit/hyperactivity disorder (ADHD). Stimulant medications are effective treatments for ADHD, but their neural effects have not been fully characterized. OBJECTIVE To determine whether the methylphenidate hydrochloride osmotic-release oral system (OROS) would increase functional magnetic resonance imaging (fMRI) activation, compared with placebo, in the daMCC and other frontoparietal regions subserving attention during the Multi-Source Interference Task (MSIT). DESIGN Randomized, placebo-controlled, 6-week, before-after fMRI study. SETTING Academic medical center ambulatory clinic. PATIENTS Twenty-one adults with ADHD randomized to 6 weeks of treatment with methylphenidate OROS (n = 11) or placebo (n = 10). INTERVENTIONS Patients underwent fMRI twice while performing the MSIT (scan 1 at baseline and scan 2 at 6 weeks). MAIN OUTCOME MEASURES Group-averaged, random-effects, repeated-measures, general linear model analyses were used to compare daMCC (and whole-brain) fMRI activation during the MSIT. Individual-based daMCC volume-of-interest confirmatory analyses and behavioral data are also presented. RESULTS Performance and baseline fMRI measures in the daMCC and other a priori brain regions did not differ between groups. Group comparisons showed a group x scan interaction and t test confirmation of higher activation in the daMCC at 6 weeks in the methylphenidate OROS group than in the placebo group (P < 1 x 10(-4), cluster corrected for multiple comparisons). Individual daMCC volume-of-interest analyses confirmed group-averaged findings and suggested that daMCC activity might be related to clinical response. Methylphenidate OROS also produced higher activation in the dorsolateral prefrontal cortex and the parietal cortex at 6 weeks. CONCLUSION Methylphenidate OROS increased daMCC activation during the MSIT and may act, in part, by normalizing daMCC hypofunction in ADHD.

Are girls with ADHD at risk for eating disorders? Results from a controlled, five-year prospective study.

Objective: To evaluate the association between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in a large adolescent population of girls with and without ADHD. Method: We estimated the incidence of lifetime eating disorders (either anorexia or bulimia nervosa) using Cox proportional hazard survival models. Comparisons between ADHD girls with and without eating disorders were then made on measures of comorbidity, course of ADHD, and growth and puberty. Results: ADHD girls were 3.6 times more likely to meet criteria for an eating disorder throughout the follow-up period compared to control females. Girls with eating disorders had significantly higher rates of major depression, anxiety disorders, and disruptive behavior disorder compared to ADHD girls without eating disorders. Girls with ADHD and eating disorders had a significantly earlier mean age at menarche than other ADHD girls. No other differences in correlates of ADHD were detected between ADHD girls with and without eating disorders. Conclusions: ADHD significantly increases the risk of eating disorders. The presence of an eating disorder in girls with ADHD heightens the risk of additional morbidity and dysfunction.

Deficient Emotional Self-Regulation and Adult Attention Deficit Hyperactivity Disorder: A Family Risk Analysis

OBJECTIVE A growing body of research suggests that deficient emotional self-regulation (DESR) is prevalent and morbid among patients with attention deficit hyperactivity disorder (ADHD). Family studies provide a method of clarifying the co-occurrence of clinical features, but no family studies have yet addressed ADHD and DESR. METHOD Participants were 83 probands with and without ADHD and 128 siblings. All were assessed for axis I DSM-IV conditions with structured diagnostic interviews. The authors defined DESR in adult probands and siblings using items from the Barkley Current Behavior Scale. Analyses tested hypotheses about the familial relationship between ADHD and DESR. RESULTS Siblings of ADHD probands were at elevated risk of having ADHD, irrespective of the presence or absence of DESR in the proband. The risk for DESR was elevated in siblings of ADHD plus DESR probands but not in siblings of ADHD probands. ADHD and DESR cosegregated in siblings. The risk for other psychiatric disorders was similar in siblings of the ADHD proband groups. CONCLUSIONS The pattern of inheritance of ADHD with DESR preliminarily suggests that DESR may be a familial subtype of ADHD. Our data suggest that DESR is not an expression of other axis I DSM-IV disorders or of nonfamilial environmental factors. The authors cannot exclude contribution of non-axis-I DSM-IV disorders to risk for DESR and cannot determine whether the cosegregation of ADHD in DESR within families is a result of genes or familial environmental risk factors. Further investigation of DESR and its correlates and treatment both in and outside the context of ADHD is warranted.

Toward Defining Deficient Emotional Self-Regulation in Children with Attention-Deficit/Hyperactivity Disorder Using the Child Behavior Checklist: A Controlled Study

Abstract Objective: Deficient emotional self-regulation (DESR) is characterized by deficits in self-regulating the physiological arousal caused by strong emotions. We examined whether a unique profile of the Child Behavior Checklist (CBCL) would help identify DESR in children with attention-deficit/hyperactivity disorder (ADHD). Methods: Subjects included 197 children with ADHD and 224 children without ADHD. We defined DESR if a child had an aggregate cut-off score of > 180 but < 210 on the Anxiety/Depression, Aggression, and Attention scales of the CBCL (CBCL-DESR). This profile was selected because of: 1) its conceptual congruence with the clinical concept of DESR; and 2) because its extreme (> 210) form has been previously associated with severe forms of mood and behavioral dysregulation in children with ADHD. All subjects were comprehensively assessed with structured diagnostic interviews and a wide range of functional measures. Results: Forty-four percent of children with ADHD had a positive CBCL-DESR profile versus 2% of controls (P < 0.001). The CBCL-DESR profile was associated with elevated rates of anxiety and disruptive behavior disorders, as well as significantly more impairments in emotional and interpersonal functioning. Conclusions: The CBCL-DESR profile helped identify a subgroup of children with ADHD who had a psychopathological and functional profile consistent with the clinical concept of DESR.

A Randomized, 3-phase, 34-week, Double-blind, Long-term Efficacy Study of Osmotic-release Oral System-methylphenidate in Adults With Attention-deficit/hyperactivity Disorder

We conducted a 3-phase, double-blind, placebo-controlled, parallel study design of osmotic-release oral system (OROS)-methylphenidate (MPH) in adults (19-60 years of age) with attention deficit/hyperactivity disorder as classified by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Phase 1 of the study was a 6-week, acute efficacy trial (n = 223), phase 2 was a 24-week, double-blind continuation study of responders (n = 96), and phase 3 was a double-blind, placebo-controlled, 4-week discontinuation study (n = 23). The mean daily dosage at phase 1 endpoint was 78.4 ± 31.7 mg (0.97 ± 0.32 mg/kg) OROS-MPH and 96.6 ± 26.5 mg (1.16 ± 0.19 mg/kg) placebo (P < 0.0001). Clinical response at phase 1 endpoint was significantly greater in the OROS-MPH group (62%, n = 67 vs 37%, n = 41; P < 0.001) and was maintained throughout 24 weeks of double-blind treatment. With double-blind, placebo-controlled discontinuation, however, there was no statistically significant difference in the rate of relapse between OROS-MPH responders randomized to placebo and those randomized to continue active treatment (18%, n = 2 vs 0%, n = 0; P = 0.1). As expected, decreased appetite, insomnia, being tense/jittery, mucosal dryness, and neurological symptoms were statistically significantly associated with OROS-MPH treatment. More work is needed to be conducted with larger samples being followed to study completion to better understand the long-lasting impact of pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Severity of the aggression/anxiety-depression/attention child behavior checklist profile discriminates between different levels of deficits in emotional regulation in youth with attention-deficit hyperactivity disorder.

Objective: We examined whether severity scores (1 SD vs 2 SDs) of a unique profile of the Child Behavior Checklist (CBCL) consisting of the Anxiety/Depression, Aggression, and Attention (AAA) scales would help differentiate levels of deficits in children with attention-deficit hyperactivity disorder (ADHD). Study Design: Subjects were 197 children with ADHD and 224 without ADHD. We defined deficient emotional self-regulation (DESR) as an aggregate cutoff score of >180 but <210 (1 SD) on the AAA scales of the CBCL (CBCL-DESR) and Severe Dysregulation as an aggregate cutoff score of ≥210 on the same scales (CBCL-Severe Dysregulation). All subjects were assessed with structured diagnostic interviews and a range of functional measures. Results: Thirty-six percent of children with ADHD had a positive CBCL-DESR profile versus 2% of controls (p < .001) and 19% had a positive CBCL-Severe Dysregulation profile versus 0% of controls (p < .001). The subjects positive for the CBCL-Severe Dysregulation profile differed selectively from those with the CBCL-DESR profile in having higher rates of unipolar and bipolar mood disorders, oppositional defiant and conduct disorders, psychiatric hospitalization at both baseline and follow-up assessments, and a higher rate of the CBCL-Severe Dysregulation in siblings. In contrast, the CBCL-DESR was associated with higher rates of comorbid disruptive behavior, anxiety disorders, and impaired interpersonal functioning compared with other ADHD children. Conclusion: Severity scores of the AAA CBCL profiles can help distinguish 2 groups of emotional regulation problems in children with ADHD.

Association between attention-deficit/hyperactivity disorder and sleep impairment in adulthood: evidence from a large controlled study.

OBJECTIVE To examine whether sleep impairment is associated with attention-deficit/hyperactivity disorder (ADHD) in adults. METHOD In a study conducted from 1998 to 2003, we identified sleep characteristics in a community sample of 182 cases of DSM-IV ADHD or ADHD not otherwise specified and 117 non-ADHD controls aged 18 to 55 years. Attention-deficit/hyperactivity disorder status, current and lifetime psychiatric comorbidity, and pharmacologic treatment of ADHD were identified with the Structured Clinical Interview for DSM-IV and with modules from the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version. Sleep problems were characterized by self-report. We separately accounted for the contribution of age at ADHD onset, ADHD pharmacotherapy, lifetime bipolar disorder, and the following lifetime and current comorbidities: depression, generalized anxiety, substance abuse, and multiple anxiety disorders. RESULTS Adults with ADHD went to bed later than control subjects and had a wider range of bedtimes (mean +/- SD = 18 +/- 92 min vs 54 +/- 69 min before midnight; P < .001), were more likely to take over an hour to fall asleep (OR = 5.22, P = .001), and were more likely (P < .003) to experience difficulty going to bed, going to sleep, sleeping restfully, or waking in the morning. Adults with ADHD experienced daytime sleepiness more often (OR = 2.23, P = .003) and reported more sleep problems (mean +/- SD = 6.7 +/- 2.5 vs 4.3 +/- 2.2; P < .001) than controls. All sleep impairments were significantly associated with ADHD independent of contributions to sleep disruption from ADHD pharmacotherapy, comorbidities likely to contribute to sleep disturbance, and age at ADHD onset. CONCLUSION Sleep disturbances that are not attributable to comorbid mental health conditions or ADHD pharmacotherapy are associated with ADHD in adulthood. Clinicians and researchers should consider the potential contribution of sleep disruption to the clinical presentation of adults with ADHD.