Faculty Bibliography

OBJECTIVE: To examine the efficacy and safety of atomoxetine combined with buspirone versus atomoxetine monotherapy and placebo in adult attention-deficit/hyperactivity disorder (ADHD). METHOD: In this randomized, 8-week, 3-arm, double-blind, placebo-controlled trial conducted from November 2004 through December 2005, 241 adults with ADHD were randomly assigned in a 2:2:1 ratio to receive up to twice-daily atomoxetine and thrice-daily buspirone (n = 97), twice-daily atomoxetine (n = 97), or placebo (n = 47). Participants met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for ADHD. The primary efficacy measure was the adult ADHD Investigator Symptom Rating Scale (AISRS). RESULTS: Decrease in the AISRS total score was significantly greater for atomoxetine-buspirone than placebo at all time points from weeks 1 to 7, with an estimated mean difference of -4.80 (P = .001). Reduction in the mean AISRS total score was numerically greater for atomoxetine-buspirone than for atomoxetine at all time points, but statistically significant at week 4 only (estimated difference = -2.04, P < .10). The effect size for atomoxetine plus buspirone was 0.51, and for atomoxetine alone, it was 0.40. Insomnia, nausea, dry mouth, headache, and asthenia were frequently reported adverse events for both active treatment groups, and dizziness was also frequently reported for the atomoxetine-buspirone group. Discontinuations due to treatment-related adverse effects were 15.5% for atomoxetine-buspirone, 11.3% for atomoxetine, and 14.9% for placebo. CONCLUSIONS: There was little indication of improvement for atomoxetine plus buspirone versus atomoxetine monotherapy, as most efficacy measures showed only slightly greater quantitative improvement for the combination, generally without statistical significance. It is of note, however, that the quantitative differences between these 2 groups were virtually all in the direction of greater efficacy for the atomoxetine plus buspirone group. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174226.

BACKGROUND: Many children with attention-deficit/hyperactivity disorder (ADHD) continue to experience this disorder as adults, which may, in part, be due to the discontinuity of health care that often occurs during the transition period between late adolescence and young adulthood. Although atomoxetine is reported to be efficacious in both adolescents and young adults, no longitudinal studies have been designed to assess directly the effects of atomoxetine treatment during this transition period. As a first step, we present the results of a post hoc, pooled analysis that compared the efficacy and safety profile of atomoxetine in these 2 patient populations. OBJECTIVE: The aim of the present study was to assess the efficacy and safety profile of atomoxetine treatment in adolescents and young adults with ADHD. METHODS: A post hoc, pooled analysis was conducted by combining data from 6 double-blind trials (6-9 weeks in duration) that studied adolescents (12-17 years of age; atomoxetine, n = 154; placebo, n = 88; mean final dose = 1.38 mg/kg) and 3 trials (10 weeks in duration) that studied young adults (18-30 years of age; atomoxetine, n = 117; placebo, n = 125; mean final dose = 1.21 mg/kg). Efficacy measures used in these analyses were ADHD Rating Scale (ADHDRS) for adolescents, Conners' Adult ADHD Rating Scale (CAARS) for young adults, and Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) for both age groups. Treatment response was defined as >/=30% reduction from baseline in total ADHD symptom score. RESULTS: In adolescents (mean age, 13.4 years), atomoxetine improved ADHD significantly compared with placebo (ADHDRS total score change, -12.9 vs -7.5; P < 0.001). In young adults (mean age, 24.7 years), atomoxetine improved ADHD significantly (CAARS total score change, -13.6 vs -7.7; P < 0.001; CGI-ADHD-S change, -1.1 vs -0.6; P < 0.001). No significant treatment-by-age subgroup interaction was observed. Tolerability was similar for both age subgroups, except for treatment-emergent nausea, which occurred significantly more frequently with atomoxetine than with placebo in young adults (13.7% vs 4.8%, respectively; P = 0.024); in adolescents no statistically significant differences were observed in frequency of nausea between atomoxetine and placebo treatment (4.5% vs 10.2%, respectively; P = 0.108). CONCLUSIONS: Results from this post hoc, pooled analysis suggest that acute treatment with atomoxetine was efficacious in both adolescent and young adult patients with ADHD. The safety profile findings from this study were consistent with the previously reported atomoxetine safety and tolerability profiles, suggesting that it may be continued during the transition from adolescence to young adulthood.

RATIONALE: alpha(4)beta(2) Neuronal nicotinic receptors (NNRs) are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). OBJECTIVES: This study examined the efficacy and safety of the alpha(4)beta(2) NNR partial agonist ABT-089 versus placebo in adults with ADHD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled crossover study, subjects received placebo followed by ABT-089 (2 mg once daily [QD], 5 mg QD, 15 mg QD, 40 mg QD, or 40 mg twice daily [BID]), or vice versa, in a 2 x 2 crossover design. Each treatment period was 4 weeks, separated by a 2-week washout period. The primary efficacy endpoint was the Conners' Adult ADHD Rating Scale-Investigator Rated (CAARS:Inv) total score at the end of each treatment period. Secondary outcomes based on clinician- and self-rated efficacy scales were evaluated. RESULTS: Of the 221 subjects enrolled, 171 met criteria for inclusion in the completers dataset for efficacy analyses. ABT-089 was superior to placebo on the CAARS:Inv total score at 40 mg QD and 40 mg BID (model-based least square mean difference from placebo: -4.33, P = 0.02; -3.02, P = 0.03, respectively). ABT-089 also demonstrated significant improvements on several secondary measures of efficacy. ABT-089 was generally safe and well tolerated. The most commonly reported adverse events (>/=5%) for total ABT-089-treated subjects at rates higher than placebo were headache, upper respiratory tract infection, irritability, insomnia, and nasopharyngitis. CONCLUSIONS: In this phase 2 crossover study, the NNR partial agonist ABT-089, at doses of 40 mg QD and 40 mg BID, was efficacious and generally well tolerated in treatment of adults with ADHD

Introduction: Attention deficit/hyperactivity disorder (ADHD) often presents as an impairing lifelong condition in adults, yet it is currently under-diagnosed and under-treated in many European countries. Objectives: To establish the characteristics of the European (EU) adult ADHD patient relative to adult patients outside the EU (OEU). Aims: To compare the baseline characteristics of patients with ADHD in regions where adult ADHD is relatively well established (e.g., USA), with EU adult ADHD patients. Methods: Baseline data was used from the open-label acute treatment period of a multicenter, randomized, withdrawal trial of atomoxetine in adult patients with ADHD (N=2017; EU, n=1217; OEU, n=800). All enrolled patients were included in the baseline analyses. Results: The demographics for patients in the EU region and regions OEU were comparable. Patients in the EU region had a somewhat lower percentage of prior exposure to psychostimulants compared to the region OEU (32.7% versus 38.9%, p=.005). Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version with adult ADHD prompts (18 item total, inattentive and hyperactive/impulsive subscales, and index) were comparable. The adult ADHD Quality of Life life outlook and life productivity domain scores were different between groups (p? .0004). The EuroQol-5 Dimension UK and US population-based Index score, and health state score were comparable between groups. Conclusions: There were some subtle differences between study groups; however, overall, the adult ADHD patients were not substantially different between the EU region and regions OEU, suggesting that baseline features of ADHD in adult EU patients manifest comparable to those in patients OEU

Abstract Background: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorder are often comorbid in adults. The effects of ADHD treatment on comorbid alcohol use disorder have not been extensively studied. Objective: To assess correlates of ADHD and alcohol use outcomes in ADHD with comorbid alcohol use disorders, via a post-hoc exploratory subgroup analysis of a previously conducted, randomized, double-blind, placebo-controlled study of recently abstinent adults. Methods: Adults who had ADHD and alcohol use disorders and were abstinent for 4-30 days were randomized to daily atomoxetine 25-100 mg (mean final dose = 89.9 mg) or placebo for 12 weeks. Changes in ADHD symptoms from baseline to endpoint were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) total score, alcohol use by the timeline followback method, and alcohol cravings by the Obsessive Compulsive Drinking Scale. Results: Of 147 subjects receiving atomoxetine (n = 72) or placebo (n = 75) in the primary study, 80 (54%) completed 12 weeks (n = 32 atomoxetine; n = 48 placebo). Improvements in ADHD symptoms on the AISRS correlated significantly with decreases in alcohol cravings (Pearson's r = 0.28; 95% confidence interval [CI] = 0.11-0.43; p = 0.002), and the correlation was most notable with atomoxetine (r = 0.29; CI [0.04 - 0.51]; p = 0.023) rather than with placebo (r = 0.24; CI [0.00-0.46]; p = 0.055). On-treatment drinking levels correlated with AISRS scores (r = 0.12; CI [0.05 -0.19]; p = 0.001). Relapse to alcohol abuse significantly correlated with worse ADHD symptoms on 15 of 18 items of the AISRS in the placebo group (p < 0.05 for each). Conclusions: No baseline predictor (other than degree of sobriety) of alcohol use or ADHD outcomes emerged. ADHD symptom improvements correlated significantly with reductions in alcohol cravings, and relapse to alcohol abuse correlated significantly with worsening of most ADHD symptoms in the placebo group, but not in the atomoxetine group. This post-hoc subgroup analysis is of a hypothesis-generating nature, and the generalizability of the findings may be limited by exclusion of adults with common ADHD comorbidities from the base study. Further, prospective clinical trials in larger and more heterogeneous patient populations are warranted to confirm or reject these preliminary associations. Trial Registration (base study): ClinicalTrials.gov Identifier: NCT00190957

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Time-Sensitive ADHD Symptom Scale (TASS) to evaluate change of attention-deficit/hyperactivity disorder (ADHD) symptoms over the course of a day in adults. METHODS: Eighty adults with ADHD participated in 1 or 2 visits, 1 to 9 weeks apart. At each visit, participants completed the TASS followed by raters administering the ADHD Rating Scale (ADHD-RS). Additional TASS and ADHD-RS ratings were completed 2 to 6 hours after each visit via telephone. Internal consistency of TASS items was assessed by Cronbach's alpha. Convergent validity of TASS and ADHD-RS total mean item scores was assessed using Pearson's correlation coefficients. kappa correlations were calculated to assess item-by-item reliability between TASS and ADHD-RS items. RESULTS: Internal consistency of TASS items was high, with an overall Cronbach's alpha coefficient of .93. The Pearson's correlation coefficient between the TASS and ADHD-RS was significant for all visits (r = 0.70, P < .0001). There was moderate agreement between individual items on the TASS and ADHD-RS, with significant kappa coefficients for almost all items (P < .05). DISCUSSION: The TASS showed high internal consistency and concurrent validity with the clinician-administered ADHD-RS and is a valid and reliable scale for measuring change in ADHD symptoms over the course of a day in adults

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition subclassified in DSM-IV according to its core symptoms domains as (a) predominantly inattentive (ADHD-IN), (b) predominantly hyperactive/impulsive (ADHD-H), and (c) combined inattentive and hyperactive/impulsive (ADHD-C). Whether these subtypes represent distinct clinical entities or points on a severity continuum is controversial. Divergence in treatment response is a potential indicator of qualitative heterogeneity. This study examined smoking cessation response by ADHD subtype to osmotic-release oral system methylphenidate (OROS-MPH). METHODS: Male and female adult smokers (ADHD-C = 167 and ADHD-IN = 87) were randomized to receive OROS-MPH or placebo as augmentation treatment to nicotine patch and counseling. Logistic regression was conducted to test the effect of OROS-MPH versus placebo on prolonged smoking abstinence by ADHD subtype. RESULTS: The subtypes were similar in baseline demographic, smoking, and psychiatric history but differed in smoking cessation response to OROS-MPH or placebo as a function of nicotine dependence level. The 3-way interaction was significant; chi(2)(1) = 8.22, p < .01. Among highly dependent smokers, the prolonged abstinence rates were greater with OROS-MPH than with placebo in the ADHD-C group (60% vs. 31.3%, respectively, p < .05) but higher with placebo than with OROS-MPH in the ADHD-IN group (60% vs. 11.8%, respectively, p < .01). Abstinence rates did not differ by subtype or treatment among smokers who were less nicotine dependent. Conclusion: Contrasting treatment response and divergence in the impact of nicotine dependence level support the hypothesis of ADHD subtypes as distinct clinical entities and may indicate the need and directions for personalized targeted treatments of smokers with ADHD

OBJECTIVE: Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non-substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD. METHOD: Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13-18) with at least one non-nicotine SUD and one with 255 adult smokers (18-55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). RESULTS: Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults. CONCLUSIONS: With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence

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

Objectives: To validate the Time-Sensitive ADHD Symptom Scale (TASS) in the assessment of symptom change during the day in adolescents with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 40 participants with ADHD aged 13 to 17 years completed 1 or 2 visits, 1 to 9 weeks apart. The TASS and the ADHD Rating Scale-IV (ADHD-RS-IV) were completed twice at each visit: at the time of the clinic visit (in-clinic assessment) and 2 to 6 hours afterwards (evening assessment). Results: Internal consistency of the TASS was high, with Cronbach's alpha coefficients of 0.91 (in-clinic) and 0.90 (evening) for visit 1, and 0.88 (in-clinic) and 0.86 (evening) for visit 2. Pearson's correlation coefficients between the TASS and ADHD-RS-IV were significant at both visits (P < 0.0001). Stability analyses of the TASS found no significant effect between ratings performed at different visits (P = 0.936), but there was a significant effect of the assessment time within visits (P < 0.0001). There was not a significant visit by assessment time interaction (P = 0.924). Conclusions: The TASS showed high internal consistency and high concurrent validity with the ADHD-RS-IV. Results of this preliminary study indicate that the TASS is a valid and reliable self-report scale for adolescents with ADHD