Effects of Extended-Release Methylphenidate Treatment on Cognitive Task Performance in Children with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder.

Objective: To examine the effectiveness of four doses of psychostimulant medication, combining extended-release methylphenidate (ER-MPH) in the morning with immediate-release MPH (IR-MPH) in the afternoon, on cognitive task performance. Method: The sample comprised 24 children (19 boys and 5 girls) who met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-R and the Autism Diagnostic Observation Schedule, and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age = 8.8 years, SD = 1.7; mean intelligence quotient = 85; SD = 16.8). Effects of placebo and three dose levels of ER-MPH (containing 0.21, 0.35, and 0.48 mg/kg equivalent of IR-MPH) on cognitive task performance were compared using a within-subject, crossover, placebo-controlled design. Each of the four MPH dosing regimens (placebo, low-dose MPH, medium-dose MPH, and high-dose MPH) was administered for 1 week; the dosing order was counterbalanced across children. Results: MPH treatment was associated with significant performance gains on cognitive tasks tapping sustained attention, selective attention, and impulsivity/inhibition. Dose/response was generally linear in the dose range studied, with no evidence of deterioration in performance at higher MPH doses in the dose range studied. Conclusion: The results of this study suggest that MPH formulations are associated with significant improvements on cognitive task performance in children with ASD and ADHD.

Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms.

OBJECTIVE: The purpose of this study was to examine the behavioral effects of four doses of psychostimulant medication, combining extended-release methylphenidate (MPH) in the morning with immediate-release MPH in the afternoon. METHOD: The sample comprised 24 children (19 boys; 5 girls) who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV-TR) criteria for an autism spectrum disorder (ASD) on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), and had significant symptoms of attention-deficit/hyperactivity disorder (ADHD). This sample consisted of elementary school-age, community-based children (mean chronological age=8.8 years, SD=1.7; mean intelligence quotient [IQ]=85; SD=16.8). Effects of four dose levels of MPH on parent and teacher behavioral ratings were investigated using a within-subject, crossover, placebo-controlled design. RESULTS: MPH treatment was associated with significant declines in hyperactive and impulsive behavior at both home and school. Parents noted significant declines in inattentive and oppositional behavior, and improvements in social skills. No exacerbation of stereotypies was noted, and side effects were similar to those seen in typically developing children with ADHD. Dose response was primarily linear in the dose range studied. CONCLUSIONS: The results of this study suggest that MPH formulations are efficacious and well-tolerated for children with ASD and significant ADHD symptoms.

High concordance of parent and teacher attention-deficit/hyperactivity disorder ratings in medicated and unmedicated children with autism spectrum disorders.

OBJECTIVE: Parent and teacher ratings of core attention-deficit/hyperactivity disorder (ADHD) symptoms, as well as behavioral and emotional problems commonly comorbid with ADHD, were compared in children with autism spectrum disorders (ASD). METHOD: Participants were 86 children (66 boys; mean: age=9.3 years, intelligence quotient [IQ]=84) who met American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for an ASD on the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Parent and teacher behavioral ratings were compared on the Conners' Parent and Teacher Rating Scales (CPRS-R; CTRS-R). The degree to which age, ASD subtype, severity of autistic symptomatology, and medication status mediated this relationship was also examined. RESULTS: Significant positive correlations between parent and teacher ratings suggest that a child's core ADHD symptoms-as well as closely related externalizing symptoms-are perceived similarly by parents and teachers. With the exception of oppositional behavior, there was no significant effect of age, gender, ASD subtype, or autism severity on the relationship between parent and teacher ratings. In general, parents rated children as having more severe symptomatology than did teachers. Patterns of parent and teacher ratings were highly correlated, both for children who were receiving medication, and for children who were not. CONCLUSIONS: Parents and teachers perceived core symptoms of ADHD and closely-related externalizing problems in a similar manner, but there is less agreement on ratings of internalizing problems (e.g., anxiety). The clinical implication of these findings is that both parents and teachers provide important behavioral information about children with ASD. However, when a clinician is unable to access teacher ratings (e.g., during school vacations), parent ratings can provide a reasonable estimate of the child's functioning in these domains in school. As such, parent ratings can be reliably used to make initial diagnostic and treatment decisions (e.g., medication treatment) regarding ADHD symptoms in children with ASDs.

Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response.

OBJECTIVE: Response to atomoxetine, a nonstimulant norepinephrine-specific reuptake inhibitor, was compared with the effect of osmotic-release oral methylphenidate, a long-acting methylphenidate preparation, in patients with attention deficit hyperactivity disorder (ADHD). METHOD: In a large placebo-controlled, double-blind study, patients ages 6-16 with ADHD, any subtype, were randomly assigned to receive 0.8-1.8 mg/kg per day of atomoxetine (N=222), 18-54 mg/day of osmotically released methylphenidate (N=220), or placebo (N=74) for 6 weeks. The a priori specified primary analysis compared response (at least 40% decrease in ADHD Rating Scale total score) to osmotically released methylphenidate with response to atomoxetine and placebo. After 6 weeks, patients treated with methylphenidate were switched to atomoxetine under double-blind conditions. RESULTS: The response rates for both atomoxetine (45%) and methylphenidate (56%) were markedly superior to that for placebo (24%), but the response to osmotically released methylphenidate was superior to that for atomoxetine. Each medication was well tolerated, with completion rates and discontinuations for adverse events not significantly different from those for placebo. Of the 70 subjects who did not respond to methylphenidate, 30 (43%) subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69 patients who did not respond to atomoxetine had previously responded to osmotically released methylphenidate. CONCLUSION: Response was significantly greater with osmotically released methylphenidate than with atomoxetine. One-third of patients who received methylphenidate followed by atomoxetine responded better to one or the other, suggesting that there may be preferential responders.

Effects of atomoxetine on growth in children with attention-deficit/hyperactivity disorder following up to five years of treatment.

OBJECTIVE: To examine the effects on growth of long-term pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), we present findings from an ongoing 5-year study of the efficacy and safety of treatment with atomoxetine. METHODS: North American patients, 6-17 years old at study entry (N = 1,312) and with Diagnostic and Statistical Manual of Mental Disorders,4th edition (DSM-IV) ADHD, were studied under open-label atomoxetine treatment. Sixty-one were studied up to 5 years. RESULTS: After 1 month's treatment, patients weighed less than expected from their starting percentiles relative to population norms, with a maximum shortfall at 15 months and a return to expected weight by 36 months. Patients were slightly shorter than expected after 12 months, reaching a maximum shortfall at 18 months and returning to expected height by 24 months. Patients in the top quartile for body mass index (BMI) or weight at baseline, and those in the third quartile for height, showed 5-year decreases from expected values. Those below median height at baseline showed increases relative to expected values. CONCLUSIONS: These interim results indicate that continuous atomoxetine treatment for up to 5 years has little or no long-term effect on juvenile growth and final stature for most patients, although persistent decreases from expected may occur in some patients who are larger than average before treatment.

A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the efficacy and safety of dexmethylphenidate hydrochloride (d-MPH, Focalin) for the treatment of attention-deficit/hyperactivity disorder (ADHD) and to test an a priori hypothesis that d-MPH would have a longer duration of action than d,l-threo-methylphenidate (d,l-MPH). METHOD: This was a randomized, double-blind study conducted at 12 U.S. centers. One hundred thirty-two subjects received d-MPH (n=44), d,l-MPH (n=46), or placebo (n=42) twice daily for 4 weeks, with titration of the dose based on weekly clinic visits. The primary efficacy variable was change from baseline to last study visit on teacher-completed Swanson, Nolan, and Pelham Rating Scale (Teacher SNAP). Secondary efficacy measures included the change on parent-completed SNAP (Parent SNAP), Clinical Global Impressions Scale-Improvement (CGI-I) score, and Math Test performance. Assessments at home in late afternoon were included to test the hypothesis that d-MPH would have a longer duration of efficacy than d,l-MPH. Safety was assessed through monitoring occurrence and severity of adverse events and discontinuations related to them. RESULTS: Treatment with either d-MPH (p=.0004) or d,l-MPH (p=.0042) significantly improved Teacher SNAP ratings compared with placebo. The d-MPH group showed significant improvements compared with placebo on the afternoon Parent SNAP ratings (p=.0003) and scores on the Math Test (p=.0236) obtained late in the afternoon at 6:00 p.m. Sixty-seven percent of patients showed improvement on d-MPH and 49% on d,l-MPH based on CGI-I scores. Both d-MPH and d,l-MPH were well tolerated, no patient in the d-MPH group and only two patients each in the d,l-MPH and placebo groups discontinued the study. CONCLUSIONS: For the treatment of ADHD, an average titrated dose of 18.25 mg/day of d-MPH is as efficacious and safe as an average titrated dose of 32.14 mg/day of d,l-MPH. Both active treatments have large effect sizes. Thus, d-MPH and d,l-MPH appear to provide similar efficacy, and d-MPH may have longer duration of action after twice-daily dosing, but additional studies are needed to determine the statistical and clinical significance of this possibility.

Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial.

OBJECTIVES: Atomoxetine seems to be as effective for treating attention-deficit/hyperactivity disorder (ADHD) when the daily dose is administered once in the morning as when the dose is divided and administered in the morning and evening. In the present study, the efficacy of atomoxetine administered once daily among children with ADHD was assessed throughout the day, including the evening and early morning. Another goal was to determine how early in treatment it was possible to discern a specific effect of the drug on ADHD symptoms. METHODS: This study was a randomized, multicenter, double-blind, placebo-controlled trial conducted at 12 outpatient sites in the United States. A total of 197 children, 6 to 12 years of age, who had been diagnosed as having ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, were randomized to receive 8 weeks of treatment with atomoxetine or placebo, dosed once daily in the mornings. ADHD symptoms were assessed with parent and investigator rating scales. The primary outcome measure was the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score. Daily parent assessments of children's home behaviors in the evening and early morning were recorded with an electronic data entry system. This instrument measures 11 specific morning or evening activities, including getting up and out of bed, doing or completing homework, and sitting through dinner. RESULTS: Seventy-one percent of the children enrolled were male, 69% met criteria for the combined subtype (both inattentive and hyperactive/impulsive symptoms), and the most common psychiatric comorbidity was oppositional defiant disorder (35%). Once-daily atomoxetine (final mean daily dose of 1.3 mg/kg) was significantly more effective than placebo in treating core symptoms of ADHD. Mean reductions in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator-Administered and Scored total score were significantly greater for patients randomized to atomoxetine, beginning at the first visit after the initiation of treatment and continuing at all subsequent visits. Both inattentive and hyperactive/impulsive symptom clusters were significantly reduced with atomoxetine, compared with placebo. With continued treatment and dose titrations, core symptoms of ADHD continued to decrease throughout the 8-week study. Mean reductions in the daily parent assessment total scores for patients randomized to atomoxetine were superior during the first week, beginning with the first day of dosing, and were also superior at endpoint. Efficacy outcomes for the evening hours for atomoxetine-treated patients were superior to those for placebo-treated patients, as assessed with 2 different assessment scales. Decreases in the daily parent assessment morning subscores at endpoint showed a significant reduction in symptoms that lasted into the mornings. Rates of discontinuations attributable to adverse events were <5% for both groups. Adverse events reported significantly more frequently with atomoxetine were decreased appetite, somnolence, and fatigue. CONCLUSIONS: Among children 6 to 12 of age who had been diagnosed as having ADHD, once-daily administration of atomoxetine in the morning provided safe, rapid, continuous, symptom relief that lasted not only into the evening hours but also into the morning hours. Atomoxetine treatment was safe and well tolerated.

Treatment effects of methylphenidate on cognitive functioning in children with mental retardation and ADHD.

OBJECTIVE: Cognitive effects of stimulant medication were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Performance on tasks tapping sustained attention, visual and auditory selective attention, inhibition, and immediate memory was assessed for 24 children (mean age 10.9 years) during a placebo-controlled, double-blind, crossover treatment trial with 0.15, 0.30, and 0.60 mg/kg b.i.d. dosages of methylphenidate (MPH). RESULTS: Successively higher MPH doses were associated with consistent gains in cognitive task performance, with optimal performance noted at the highest dose. Analysis of dose-response curves revealed significant linear components of trend on measures tapping sustained attention, visual selective attention, auditory selective attention, as well as two tasks tapping inhibition/impulsivity: delay of gratification and match-to-sample. No evidence of a curvilinear dose-response relationship emerged for any measure. CONCLUSIONS: Inattention and disinhibition/impulsivity decline with MPH treatment in children with ADHD/MR, and consistent with the Multimodal Treatment Study of ADHD, higher MPH doses are most effective. These findings also suggest that cognitive testing, together with behavioral and medical assessment, can be an effective tool in assessing stimulant response in children with ADHD/MR.

Effects of methylphenidate treatment in children with mental retardation and ADHD: individual variation in medication response.

OBJECTIVE: Individual variation in cognitive and behavioral response to methylphenidate (MPH) was investigated in children with mental retardation and attention-deficit/hyperactivity disorder. METHOD: Twenty-four children (mean age 10.9 years, SD = 2.4) participated in a placebo-controlled, double-blind, crossover trial with 0.15-, 0.30-, and 0.60-mg/kg b.i.d. doses of MPH. Parent and teacher behavioral ratings, as well as cognitive task performance, were assessed at each dose. RESULTS: Relative to placebo, most children with attention-deficit/hyperactivity disorder and mental retardation showed some degree of behavioral and cognitive improvement with MPH treatment. However, fewer of these children made substantial gains (>30% improvement, relative to placebo) with MPH treatment. At the highest dose, 55% of the children showed substantial behavioral gains and 46% made substantial gains in cognitive task performance. However, there was substantial independence between changes in behavior and changes in cognitive performance. CONCLUSIONS: At the 0.60-mg/kg MPH dose, more children showed substantial cognitive and behavioral gains than those who showed substantial declines in a ratio of more than 5:1. However, it may be prudent to assess cognitive change as well as behavioral effects because improvements in the former do not necessarily forecast improvements in the latter in children with attention-deficit/hyperactivity disorder and mental retardation.

Mirtazapine vs. placebo in posttraumatic stress disorder: a pilot trial.

BACKGROUND: Based on an earlier pilot study, as well as a theoretical consideration of its mechanism of action, we undertook a placebo-controlled, double-blind trial of mirtazapine in posttraumatic stress disorder. METHODS: Twenty-nine patients were randomized to receive drug up to 45 mg/day or placebo double-blind on a 2:1 ratio for 8 weeks, with data being available for analysis in 26. Primary outcome measures comprised the Short Posttraumatic Stress Disorder Rating Interview (SPRINT) Global Improvement item and total score. Secondary measures comprised the Davidson Trauma Scale, Structured Interview for Posttraumatic Stress Disorder and Hospital Anxiety Depression Scale. Adverse events were also measured. RESULTS: On the Short Posttraumatic Stress Disorder Rating Interview Global Improvement measure, rates of response were 64.7% and 20.0% for mirtazapine and placebo. Treatment effects in favor of mirtazapine were noted on the Short Posttraumatic Stress Disorder Rating Interview global, Structured Interview for Posttraumatic Stress Disorder, and Hospital Anxiety Depression Scale anxiety subscale scores. The drug was well tolerated. CONCLUSIONS: Mirtazapine was more effective than placebo on some measures in posttraumatic stress disorder and general anxiety symptoms.

Treatment effects of methylphenidate on behavioral adjustment in children with mental retardation and ADHD.

OBJECTIVE: The effects of stimulant medication treatment were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Parent and teacher behavioral ratings and reports of side effects were obtained for children (N = 24, mean age = 10.9 years, SD = 2.4) during a placebo-controlled, double-blind, crossover treatment trial with 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg b.i.d. dosages of methylphenidate. RESULTS: The most significant improvements occurred at the 0.60 mg/kg methylphenidate dose for teacher ratings of inattention (p =.024), hyperactivity (p <.001), aggression (p <.001), and asocial behavior (p =.009). No significant improvements, relative to placebo, occurred at the 0.15 mg/kg dosage. Of interest, nearly all significant medication-related behavioral improvements were detected by teachers. However, parents were sensitive raters of side effects, noting more sleeping problems and loss of appetite at the 0.60 mg/kg dose compared with placebo. CONCLUSIONS: These results suggest that symptoms of ADHD can be treated successfully in children with ADHD/MR, and consistent with MTA study results, higher doses were most effective. Furthermore, these improvements were not accompanied by increases in symptoms such as staring, social withdrawal, or anxiety.

Efficacy of olanzapine in social anxiety disorder: a pilot study.

Based on evidence suggesting anxiolytic properties of the atypical antipsychotic olanzapine, this study was conducted to evaluate whether olanzapine may be efficacious in treating social anxiety disorder (SAD). This study was an 8-week, double-blind, placebo-controlled evaluation of olanzapine as monotherapy in which 12 patients with the DSM-IV diagnosis of SAD were randomized to either olanzapine (n = 7) or placebo (n = 5). An initial dose of 5 mg/day was titrated to a maximum of 20 mg/day. Baseline to endpoint scores from the Brief Social Phobia Scale (BSPS), Social Phobia Inventory (SPIN), Liebowitz Social Anxiety Scale and Sheehan Disability Scale, as well as Clinical Global Impression-Improvement ratings, were compared for olanzapine versus placebo. Seven subjects completed all 8 weeks of the study, four in the olanzapine group and three in the placebo group. In the intent-to-treat analysis, olanzapine yielded greater improvement than placebo on the primary measures: BSPS (p = 0.02) and SPIN (p = 0.01). Both treatments were well tolerated, although the olanzapine group had more drowsiness and dry mouth. Olanzapine and placebo were both associated with negligible weight gain. Olanzapine was superior to placebo on the primary outcome measures in this preliminary study of SAD. Additional studies of olanzapine as a treatment for SAD are warranted.