Robert Doyle

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.

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.

Reexamining Tic persistence and Tic-associated impairment in Tourette's Disorder: findings from a naturalistic follow-up study

The objective of this study was to assess tic persistence and tic-associated impairment in referred youth with Tourettes Disorder (TD). Subjects were 50 youth (ages 6–17 years) who met DSM-IV diagnostic criteria for TD, were referred to a specialized TD program, and were evaluated by clinical and structured diagnostic interview. Tic severity and impairment was measured using the Yale Global Tic Severity Scale. The total tic score at or above minimal range defined tic persistence, and a TD impairment score at or above moderate range defined tic-associated impairment. Results were assessed during administration of the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiological Version. Mean age of onset of TD was 5.1 ± 2.3 years, and mean illness duration was 5.6 ± 3.2 years. At baseline, 88% of subjects met threshold criteria for at least mild tics, but only 30% met criteria for tic-associated impairment. At 2-year follow-up, 82% of these subjects met criteria for tic persistence (NS change from baseline), but only 14% met criteria for TD-associated impairment (p < .04 change from baseline). Although tics followed a persistent course in the majority of youth with TD, they were infrequently associated with impairment. There was a significant reduction in the proportion of youth with TD impairment from baseline to follow-up. These results support the view that TD is a persistent disorder, but suggest a dissociation between tic persistence and tic-associated dysfunction.

An open trial of bupropion for the treatment of adults with attention-deficit/hyperactivity disorder and bipolar disorder.

BACKGROUND Despite the increasing recognition of comorbid attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in adults, there are no prospective trials of pharmacological agents to treat ADHD in these patients. Given the efficacy of bupropion for ADHD in adults, as well as its use in the management of bipolar depression, we studied the tolerability and efficacy of sustained-release (SR) bupropion in adults with ADHD plus BPD. METHODS This was an open, prospective, 6-week trial of bupropion SR (up to 200 mg b.i.d.) in adults with DSM-IV ADHD plus historical bipolar I disorder (BPD I) (10%) or bipolar II disorder (BPD II) (90%). Adults receiving adjunct antimanic agents (mood stabilizers and antipsychotics) at baseline were included in the study. We used standardized psychiatric instruments for diagnosis and outcome. Efficacy was based primarily on the Clinical Global Impression Scale (CGI) for ADHD and the ADHD symptom checklist. RESULTS Of 36 patients entered (75% male, mean age 34 years), 30 patients (83%) completed the protocol. At end point (last observation carried forward [LOCF]) compared to baseline, treatment with bupropion SR resulted in significant reductions in the ADHD symptom checklist (-55%, z = 5.63, p <.001) and CGI severity of ADHD (-40%, z = 6.285, p <.001). Bupropion was associated with reductions in ratings of mania and depression. CONCLUSIONS The results from this open study of adults with ADHD plus BPD suggest that sustained-release bupropion may be effective in treating ADHD in the context of a lifetime diagnosis of BPD, without significant activation of mania. Further controlled trials are warranted.

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.

Novel therapeutic targets for autism

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules.

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.

Cytokines and the brain.

The specificity of an immune response is due to lymphocytes, the only cells in the body capable of specifically recognizing different antigenic determinants (1-10). Cytokines are modulatory proteins that control the development and differentiation of lymphocytes from pluripotent stem cells; many cytokines are also potent inflammatory molecules (11-15). Cytokines are secreted under stress (16), and it has been shown that acute stress induces leukocyte trafficking and augments immune responses (16-17).

An Open Study of Adjunct OROS-Methylphenidate in Children and Adolescents Who Are Atomoxetine Partial Responders: I. Effectiveness

OBJECTIVE This study evaluated the effectiveness of adding OROS methylphenidate (MPH) to children who are partial responders to atomoxetine (ATMX) in the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS This is a two-phase, 7-week, open study in children aged 6-17 years. Phase I initiated ATMX for a minimum of 4 weeks. Phase II entered partial responders to ATMX and added up to 54 mg of OROS MPH to their regimen. Subjects were assessed on multiple outcomes, including ADHD, executive functioning, and adverse effects. All analyses were intent to treat, with last observation carried forward. RESULTS Fifty subjects who were partial responders to ATMX were treated with the combination therapy, with 41 subjects completing the entire protocol. There was a 40% reduction in their ADHD Rating Scale from the start of phase II through the end of study (from 21.14 +/- 9.9 to 12.8 +/- 9.7, t = 6.5, p < 0.0001). In addition, there was a clinically significant reduction in the Clinical Global Index of ADHD severity from moderate to mild ADHD (start of phase II, 3.7; end of phase II, 2.7, 27%, t = 6.5, p < 0.0001), as well as improvements in executive functioning. CONCLUSION These results suggest that OROS MPH added to the regimen of partial responders to ATMX improves ADHD and executive functioning, necessitating further controlled trials.

Re-examining comorbidity of Obsessive Compulsive and Attention-Deficit Hyperactivity Disorder using an empirically derived taxonomy.

Using an empirically derived instrument to reduce the assessor bias inherent in structured diagnostic interviews, we sought to re-examine and validate the putative comorbidity between Obsessive Compulsive Disorder (OCD) and Attention-Deficit/Hyperactivity Disorder (ADHD) in children and adolescents. We examined the correlation between Child Behavior Checklist (CBCL) syndrome, competence, and composite scores in children with: 1) OCD plus ADHD (OCD + ADHD), N = 47; 2) OCD without comorbid ADHD (OCD), N = 33; 3) ADHD without comorbid OCD (ADHD) N = 43; and 4) comparison controls recruited from general pediatric clinics,N = 32. CBCL findings in our ADHD children were similar to previous findings reported in ADHD youth, irrespective of the presence or absence of comorbid OCD. Comorbid youth generally had additive scores on the CBCL scales, reflecting the independent contribution of symptomatic and functional impairment from each disorder. These findings suggest that when ADHD-like symptoms are seen in OCD youth, they reflect a true comorbid state of OCD plus ADHD. The CBCL may provide a rapid assessment tool to identify comorbid ADHD in OCD youth.