Further understanding of the comorbidity between Attention-Deficit/Hyperactivity Disorder and bipolar disorder in adults: an MRI study of cortical thickness.

Although Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) frequently co-occur and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this comorbidity is scarce. Our aim was to evaluate cortical thickness in ADHD and BPD, testing the hypothesis that comorbid subjects (ADHD+BPD) would have neuroanatomical correlates of both disorders. Magnetic Resonance Imaging (MRI) findings were compared between 31 adults with ADHD+BPD, 18 with BPD, 26 with ADHD, and 23 healthy controls. Cortical thickness analysis of regions of interest was estimated as a function of ADHD and BPD status, using linear regression models. BPD was associated with significantly thicker cortices in 13 regions, independently of ADHD status and ADHD was associated with significantly thinner neocortical gray matter in 28 regions, independent of BPD. In the comorbid state of ADHD plus BPD, the profile of cortical abnormalities consisted of structures that are altered in both disorders individually. Results support the hypothesis that ADHD and BPD independently contribute to cortical thickness alterations of selective and distinct brain structures, and that the comorbid state represents a combinatory effect of the two. Attention to comorbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Height and risk of heart failure in the Physicians' Health Study.

Although previous studies have reported an association between height and cardiovascular disease, it is unclear whether height is associated with the risk of heart failure (HF). We hypothesized that height would be inversely associated with HF risk. We used prospective data from 22,042 male physicians (mean age 53.8 years) from the Physicians' Health Study. Height was self-reported at baseline. Incident HF was ascertained using follow-up questionnaires and validated through review of the medical records in a subsample. The Cox proportional hazard model was used to compute the hazard ratio (HR) and corresponding 95% confidence interval (CI). The mean height ± SD was 1.78 ± 0.07 m. A total of 1,444 HF cases occurred during a mean follow-up of 22.3 years. Compared to subjects in the lowest height category (1.40 to 1.73 m), the HR for HF was 0.86 (95% CI 0.74 to 0.99), 0.82 (95% CI 0.70 to 0.95), and 0.76 (95% CI 0.63 to 0.91) for the height categories of 1.74 to 1.78 m, 1.79 to 1.83 m, and 1.84 to 2.08 m, respectively, after adjustment for age, weight, hypertension, and diabetes mellitus (p for trend = 0.0023). The HR per SD increment in height was 0.92 (95% CI 0.86 to 0.98) in a fully adjusted model. The exclusion of those with prevalent atrial fibrillation, left ventricular hypertrophy, valvular heart disease, and a history of coronary artery bypass grafting yielded similar results (HR per SD 0.88, 95% CI 0.83 to 0.94). In conclusion, our data demonstrated an inverse association between height and incident HF in United States male physicians. Additional studies to elucidate the underlying biologic mechanisms are warranted.

Working memory network alterations and associated symptoms in adults with ADHD and Bipolar Disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, however underlying neural circuitry contributing to the comorbidity remain understudied. Our aim was to investigate functional brain circuitry during working memory in a group of participants who meet criteria for both disorders (ADHD + BPD), and to explore the relationship of symptoms of each disorder to brain function. We used fMRI to image brain activity in 18 male adults with both ADHD and BPD, and 18 healthy control participants matched one-to-one on age, sex, and handedness, while they performed a sequential letter N-back task. We investigated differences in activation between these groups, and also correlations of brain activity during the task to symptoms of ADHD and BPD independently. We found significant hypoactivity in the subjects with ADHD + BPD vs. controls across frontal and parietal regions, and further, found that BPD and ADHD symptoms related to activity in anatomically distinct regions that were respectively characterized by activation and suppression during task. We conclude that comorbid ADHD + BPD is associated with alterations across anterior and posterior nodes of the working memory network, and symptoms of each disorder are related to anatomically and functionally distinct brain regions.

A randomized, single-blind, substitution study of OROS methylphenidate (Concerta) in ADHD adults receiving immediate release methylphenidate.

OBJECTIVE: The main aim of this study was to examine the efficacy, tolerability, and compliance of an extended-release formulation of methylphenidate (OROS-MPH) in adults with ADHD receiving immediate-release methylphenidate (IR-MPH). METHOD: Participants were outpatient adults with ADHD who were stable on IR-MPH-administered TID. Participants were randomized (4:1) to equipotent doses of OROS-MPH or to continue IR-MPH and were assessed weekly for 6 weeks with the Adult ADHD Investigator System Symptom Report Scale (AISRS). RESULTS: Randomization of 53 IR-MPH responders to IR- or OROS-MPH had no effect on AISRS score at endpoint (11.2 ± 6.9 vs. 10.7 ± 5.1, p = .8). Participants stabilized on IR-MPH and switched to OROS-MPH remained satisfied over 71% of the time. However, the IR-MPH group missed more doses (7.3 ± 6.8 vs. 3.3 ± 4.2, p = .02) than the OROS-MPH group. CONCLUSION: Findings showed that adults with ADHD can be successfully switched from an effective regimen of IR-MPH TID to once-daily OROS-MPH. Results also demonstrated better compliance with OROS-MPH than with IR-MPH treatment.

A prospective open-label trial of extended-release carbamazepine monotherapy in children with bipolar disorder.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of extended release carbamazepine (CBZ-ER) monotherapy in the treatment of pediatric bipolar disorder (BD). METHOD: This was an 8-week, open-label, prospective trial of CBZ-ER monotherapy (788 +/- 252 mg/day) to assess the effectiveness and tolerability of this compound in treating pediatric bipolar spectrum disorders. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions-Improvement scale, Children's Depression Rating Scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self-reports, vital signs weight monitoring, and laboratory analysis. RESULTS: Of the 27 participating children with BD, 16 (59.%) completed the study. CBZ-ER treatment was associated with statistically significant, but modest, levels of improvement in mean YMRS scores (-10.1 +/- 10.2, p < 0.001) with end-point mean YMRS score (21.8 +/- 12.2) suggesting a lack of complete resolution of mania. CBZ-ER treatment also resulted in significant improvement in the severity of depressive, attention-deficit/hyperactivity disorder, and psychotic symptoms. With the exception of 2 participants who discontinued due to skin rash, CBZ-ER was well tolerated with marginal increase in body weight (0.8 +/- 2.5 kg, p = 0.04) and was not associated with any abnormal changes in laboratory parameters. CONCLUSIONS: Open-label CBZ-ER treatment was beneficial for the treatment of BD in children. Future controlled trials are warranted.

Risperidone treatment for ADHD in children and adolescents with bipolar disorder.

OBJECTIVE: Children and adolescents with bipolar disorder are also at high risk of having comorbid attention-deficit hyperactivity disorder (ADHD). The objective of this study was to estimate improvement in ADHD symptoms in children with bipolar disorder. METHODS: This was an open-label, study of risperidone monotherapy for the treatment of pediatric bipolar disorder. Thirty-one children and adolescents 4-15 years of age (7.2 +/- 2.8 years) of both sexes (71%, N = 22 male) with pediatric bipolar disorder (YMRS score = 32.9 +/- 8.8) and ADHD (ADHD-RS score = 37.9 +/- 8.9) were included in these analyses. RESULTS: Improvement in ADHD symptoms was contingent on improvement in manic symptoms. Although both hyperactive/impulsive (-7.5 +/- 5.5.6, p < 0.05) and inattentive (-6.8 +/- 5.0, p < 0.05) ADHD symptoms were significantly improved with risperidone, improvement was modest, and only 29% of subjects (N = 6) showed a 30% reduction in ADHD rating scale scores and had a CGI-I

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.

Utility of an abbreviated questionnaire to identify individuals with ADHD at risk for functional impairments.

OBJECTIVE: To discern whether a subset of items from the 99-item Current Behavior Scale (CBS) of behaviorally defined Executive Function Deficits (EFDs) in adults with Attention-Deficit/Hyperactivity Disorder (ADHD) can identify a group at risk for poor outcome. METHODS: Subjects were 200 adults with ADHD participating in a family study of ADHD in adults. Factor analysis was used to reduce the number of items in the 99-item CBS. RESULTS: The one factor solution provided eight items with factor loadings above 0.70. This abbreviated set of items was highly correlated with the 99-item CBS (0.91) and was similarly related to functional outcomes compared to the 99-item CBS (average correlation of 0.30 versus 0.32). CONCLUSION: For adults with ADHD, a set of eight empirically-derived from the CBS similarly correlated with negative outcomes compared to the 99-item CBS, raising the possibility of utilization as a mechanism for identification of EFDs in adults with ADHD.

A prospective open-label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder.

OBJECTIVE: To assess the effectiveness and tolerability of ziprasidone for treating pediatric mania. METHODS: This was an eight-week, open-label, prospective study of ziprasidone monotherapy (57.3 +/- 33.9 mg/day) in 21 bipolar youth [manic, mixed, or bipolar not otherwise specified (NOS); 6-17 years old]. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions-Improvement scale (CGI-I), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis. RESULTS: Fourteen of the 21 youth (67%) completed the study. Ziprasidone treatment was associated with clinically and statistically significant improvement in mean YMRS scores (-10.8 +/- 8.4, p < 0.0001) and 57% had a CGI-I

An open-label trial of aripiprazole monotherapy in children and adolescents with bipolar disorder.

INTRODUCTION: Aripiprazole is a novel second-generation antipsychotic approved for the treatment of bipolar disorder in adults but there is no systematic data available in pediatric bipolar disorder. METHODS: This was an 8-week, open-label, prospective study of aripiprazole 9.4+/-4.2 mg/day monotherapy to assess the efficacy and tolerability of this compound in treating pediatric bipolar disorder. Assessments included the Young Mania Rating Scale, Clinical Global Impressions-Improvement scale, and Brief Psychiatric Rating Scale. Adverse events were assessed through spontaneous self-reports, vital signs weight monitoring, and laboratory analysis. RESULTS: Fifteen of the 19 bipolar youth (79%) completed the study. Aripiprazole treatment was associated with clinically and statistically significant improvement in mean Young Mania Rating Scale scores (-18.0+/-6.9, P<.0001). With the important exception of two cases of extrapyramidal symptoms that precipitated dropout, aripiprazole was well tolerated with no statistically significant increase in body weight (1.8+/-1.7 kg, P=.2). CONCLUSION: Open-label aripiprazole treatment was beneficial in the treatment of mania in youth with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.

A laboratory driving simulation for assessment of driving behavior in adults with ADHD: a controlled study.

BACKGROUND: It is now estimated that attention deficit-hyperactivity disorder (ADHD) afflicts at least 4% of adults in the United States and is associated with high levels of morbidity and functional impairment. One key area of dysfunction associated with ADHD is impaired motor vehicle operation. Our goal was to examine the association between ADHD and specific driving outcomes in a sample of adults using a driving simulator. METHODS: Subjects were 20 adults with full DSM-IV ADHD and 21 controls without ADHD of equal gender distribution. However, the mean age of subjects with ADHD was somewhat older. All analyses were adjusted for age and gender. All subjects participated in a driving simulation that lasted for one hour and consisted of a short training period, a high stimulus segment and a low stimulus segment with two distinct monotonous periods. RESULTS: In the second monotonous period within the low stimulus environment, ADHD subjects were significantly more likely than controls to collide with an obstacle suddenly appearing from the periphery, adjusting for age and gender. CONCLUSION: Adults with ADHD were more likely than controls to collide with an obstacle during a driving simulation suggesting that deficits in directed attention may underlie driving impairments in this population.

Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: a proton magnetic resonance spectroscopy study of the anterior cingulate cortex.

BACKGROUND: The purpose of this study was to investigate the anterior cingulate cortex (ACC) glutamate/glutamine (Glx) to creatine ratio (Glx/Cr) in two groups of children with Bipolar Disorder (BPD): those exhibiting manic symptoms requiring treatment and those being stably treated with the atypical antipsychotic risperidone. Atypical antipsychotics have been shown to increase serum glutamate levels and ACC Glx/Cr in subjects with schizophrenia. In this study, we hypothesized that the children with BPD in need of treatment would have lower Glx/Cr compared with the children with BPD being stably treated with risperidone. METHODS: Proton MR spectra were acquired, at 1.5 T, from the ACC of eighteen subjects with a DSM-IV diagnosis of BPD: ten (11.10+/-3.48 years; five female) were manic and not medicated with any antipsychotic and eight (10.88+/-2.99 years; one female) were medicated with the atypical antipsychotic risperidone. RESULTS: Children with BPD exhibiting manic symptoms requiring treatment had lower Glx/Cr than children with BPD being stably treated with the atypical antipsychotic risperidone. The children treated with risperidone also had significantly lower YMRS and CGI-Mania scores than the children not treated with risperidone. Both YMRS and CGI-Mania scores correlated negatively with ACC Glx/Cr levels. LIMITATIONS: The cross-sectional design, small sample size, the use of Glx rather than glutamate or glutamine and the use of Cr ratios rather than absolute concentrations are limitations of this study. CONCLUSIONS: Children with mania have lower Glx/Cr levels than children with BPD being stably treated with the atypical antipsychotic risperidone. Mania may be associated with reduced glutamate/glutamine levels in the ACC: other imaging studies have shown mania associated with hypometabolism in the ACC. These reductions in glutamate/glutamine may be increased following successful treatment with glutamatergic agents.

Functional impairments in adults with self-reports of diagnosed ADHD: A controlled study of 1001 adults in the community.

OBJECTIVE: The objective of this study was to evaluate functional impairments in a nonreferred sample of adults identifying themselves as having been diagnosed with attention-deficit/hyperactivity disorder (ADHD) by a clinician in their community. METHOD: We completed a survey in April and May 2003 of a community sample of 500 adults who reported having received a diagnosis of ADHD in the community and 501 gender- and age-matched comparisons from a national sample representative of the U.S. population. RESULTS: Adults with self-reports of diagnosed ADHD in the community were significantly less likely to have graduated high school (83% vs. 93% of controls; p < or = .001) or obtain a college degree (19% vs. 26%; p < .01), were less likely to be currently employed (52% vs. 72%; p < or = .001), and had significantly more mean job changes over 10 years (5.4 vs. 3.4 jobs; p < or = .001). They also were significantly more likely to have been arrested (37% vs. 18% of controls; p < or = .001) or divorced (28% vs. 15%; p < or = .001) and were significantly less satisfied (p < or = .001) with their family, social, and professional lives. CONCLUSION: Adults who reported having received a diagnosis of ADHD in the community had significant impairment in multiple domains of functioning compared with age- and gender-matched controls without this diagnosis, highly consistent with findings derived from carefully diagnosed referred samples.

Characterizing impaired driving in adults with attention-deficit/hyperactivity disorder: A controlled study.

OBJECTIVE: We sought to confirm previously documented findings that individuals with attention-deficit/hyperactivity disorder (ADHD) demonstrate impaired driving behavior when compared with controls. METHOD: Subjects were adults with (N = 26) and without (N = 23) DSM-IV ADHD ascertained through clinical referrals to an adult ADHD program and through advertisements in the local media. Driving behavior was assessed using the Manchester Driving Behavior Questionnaire (DBQ) and 10 questions from a driving history questionnaire. Neuropsychological testing and structured interviews were also administered to all subjects. RESULTS: Substantially more ADHD subjects had been in an accident on the highway (35% vs. 9%, p = .03) or had been rear-ended (50% vs. 17%, p = .02) compared with controls. Analysis of the DBQ findings showed that ADHD subjects had significantly higher mean +/- SD scores than control subjects on the total DBQ (34.1 +/- 15.2 vs. 18.0 +/- 8.6, p < .001) and in all 3 subscales of the DBQ: errors (9.3 +/- 5.4 vs. 4.6 +/- 3.5, p < .001), lapses (12.4 +/- 6.2 vs. 6.1 +/- 3.5, p < .001), and violations (12.4 +/- 5.2 vs. 7.4 +/- 4.1, p < .001). Using the score that separated ADHD from control drivers on the DBQ as a cutoff, ADHD drivers at high risk for poor driving outcomes had more severe rates of comorbidity and exhibited more impaired scores on neuropsychological testing. CONCLUSIONS: Our results confirm and extend previous work documenting impaired driving behavior in subjects with ADHD. Results also suggest that ADHD individuals at high risk for poor driving behavior might be distinguishable from other ADHD individuals on DBQ scores, neuropsychological deficits, and patterns of comorbidities.

An open-label trial of OROS methylphenidate in adults with late-onset ADHD.

INTRODUCTION: Many adults with current impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) do not report an age at onset before 7 years of age and cannot, therefore, be assigned the full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnosis of ADHD. We hypothesized that treatment with oral release osmotic system (OROS) methylphenidate (MPH) will be safe and efficacious for the treatment of adults with late-onset ADHD. METHOD: This was a 6-week, open-label, prospective treatment study of OROS MPH monotherapy in 36 adult patients with late-onset ADHD (onset later than the required 7 years of age) using standardized instruments for diagnosis and a robust oral daily dose of up to 1.3 mg/kg/day. Symptom severity was assessed with the Adult ADHD Investigator Symptom Report Scale (AISRS) and the Clinical Global Impression (CGI) scale. RESULTS: Subjects reported robust current symptoms of ADHD at pre-treatment baseline (11.1+/-2.8 DSM-IV symptoms), but had an atypical mean age at onset of 14.2+/-8.6 years. Treatment with OROS MPH at an average daily dose of 78.2+/-29.4 mg was associated with a statistically and clinically significant reduction in ADHD symptoms relative to baseline as assessed through the AISRS (-16.4+/-10.5; P<.001). Using a categorical definition of response (CGI-I much or very much improved), a majority (n = 26; 72%) of subjects were rated as improved at endpoint. CONCLUSION: These results extend previous findings in adults with full ADHD to adults meeting criteria for late-onset ADHD and support the need for further controlled clinical trials in this population.

A double-blind comparison of galantamine hydrogen bromide and placebo in adults with attention-deficit/hyperactivity disorder: a pilot study.

BACKGROUND: Galantamine hydrogen bromide (HBr) is a competitive and reversible inhibitor of acetylcholinesterase. Because of its cholinergic nicotinic mechanism of action, galantamine HBr was hypothesized to have therapeutic activity in the treatment of attention-deficit/hyperactivity disorder (ADHD). METHOD: We conducted a 12-week, double-blind, placebo-controlled, randomized clinical trial using daily doses of up to 24 mg/d of galantamine HBr in the treatment of adults who met full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD with childhood-onset and persistent adult symptoms. All analyses were intention to treat with the last observation carried forward for subjects who did not complete the full study schedule. RESULTS: The mean daily doses at week 12 were 19.8 +/- 6.4 mg for galantamine HBr and 21.8 +/- 4.6 mg for placebo (P = 0.3). There was no statistically or clinically significant greater reduction in ADHD symptoms in subjects treated with galantamine HBr relative to those receiving placebo (P = 0.5). Using last observation carried forward, 4 (22%) of 18 of patients receiving galantamine HBr were considered responders (much or very much improved on the Clinical Global Impression Improvement Scale and at least a 30% reduction on the ADHD Investigator Symptom Report Scale compared with 11% [2/18] on placebo; P = 0.4). CONCLUSION: These results do not support the clinical utility of galantamine HBr in the treatment of ADHD at the doses used in this pilot study.

Differences in brain chemistry in children and adolescents with attention deficit hyperactivity disorder with and without comorbid bipolar disorder: a proton magnetic resonance spectroscopy study.

OBJECTIVE: The authors' goal was to investigate phosphatidylinositol and glutamatergic metabolism in the anterior cingulate cortex of children and adolescents with attention deficit hyperactivity disorder (ADHD) alone, children with ADHD plus bipolar disorder, and children with no axis I diagnosis. METHOD: Proton spectra were acquired from a 4.8-ml voxel placed in the anterior cingulate cortex of 30 subjects who were 6 to 13 years old. Fifteen subjects had ADHD and no comorbid disorder, eight had ADHD plus bipolar disorder, and seven were healthy comparison subjects. RESULTS: Children with ADHD had a significantly higher ratio of glutamate plus glutamine to myo-inositol-containing compounds than children with ADHD plus bipolar disorder and healthy children. CONCLUSIONS: myo-Inositol-containing compounds may provide information on the action of antimanic treatments such as lithium, valproate, and carbamazepine. Glutamate and glutamine are measures of glutamatergic neurotransmission and thus may also reflect changes in serotonin and dopamine pathways.

Adults with ADHD and sleep complaints: a pilot study identifying sleep-disordered breathing using polysomnography and sleep quality assessment.

OBJECTIVE: ADHD and sleep-disordered breathing are both prevalent in adulthood. Because both conditions may be responsible for similar symptoms of cognitive impairment, the authors investigate whether their presentation may overlap in adults diagnosed with ADHD. METHOD: Data are collected from six adults with sleep complaints who were diagnosed with ADHD using rigorous clinical criteria. All participants undergo overnight polysomnography and complete questionnaires about sleep quality, circadian sleep pattern, and daytime fatigue. RESULTS: On standardized measures, all participants report poor sleep quality, two report daytime fatigue, and none report distinct deviation from normal sleep and wake cycle pattern. Polysomnography reveals evidence of sleep-disordered breathing and sleep fragmentation in all participants. CONCLUSION: Objective evidence of breathing-related sleep disorders can be found in some adults with carefully diagnosed ADHD who report sleep complaints. This report highlights the importance of identifying treatable sleep disorder comorbidity in adults with ADHD.

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.

Comparing the efficacy of medications for ADHD using meta-analysis.

OBJECTIVE: Medications used to treat attention-deficit/hyperactivity disorder (ADHD) have been well researched, but comparisons among drugs are hindered by the absence of direct comparative trials. METHODS: We analyzed recent published literature on the pharmacotherapy of ADHD to describe the variability of drug-placebo effect sizes. A literature search was conducted to identify double-blind, placebo-controlled studies of ADHD youth published after 1979. Meta-analysis regression assessed the influence of medication type and study design features on medication effects. RESULTS: Twenty-nine trials met criteria and were included in this meta-analysis. These trials studied 15 drugs using 17 different outcome measures of hyperactive, inattentive, impulsive, or oppositional behavior. The most commonly identified treatments included both methylphenidate and amphetamine compounds. After stratifying trials on the class of drug studied (short-acting stimulant vs long-acting stimulant vs nonstimulant), we found significant drug differences for both study design variables and effect sizes. The differences among the 3 classes of drug remained significant after correcting for study design variables. CONCLUSION: Uniformity appears to be lacking in how medication effectiveness is assessed and in many study design parameters. Comparing medication effect sizes from different studies will be biased without accounting for variability in study design parameters. Although these differences obscure comparisons among specific medications, they do allow for conclusions about the differential effects of broad classes of medications used to treat ADHD.