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Objective: To search for predictors of placebo response in clinical trials of lisdexamfetamine dimesylate for the treatment of DSM-IV-TR-defined attention-deficit/hyperactivity disorder (ADHD) in children and adults.
Method: We used data from 2 clinical trials: (1) a 4-week, phase 3, multicenter, randomized, double-blind, forced-dose, parallel-group study of children aged 6 to 12 years with ADHD (n = 290) and (2) a 4-week, randomized, double-blind, placebo-controlled, parallel-group, forced-dose titration study in adult subjects, aged 18-55 years with ADHD (n = 420). Response and remission were defined using the ADHD Rating Scale-IV and the Clinical Global Impressions-Improvement scale.
Results: Symptom remission was inversely correlated with baseline severity in both children and adults (P < .001), with less robust effects seen for response. The time to response and remission was delayed in adult subjects prescribed placebo versus lisdexamfetamine dimesylate, while response time in children was also significantly slower with placebo versus lisdexamfetamine dimesylate (P < .01). We found little evidence that demographic factors, prior pharmacotherapy, the emergence of adverse events during the trial, or changes in ADHD symptoms from the screening to baseline assessments predicted placebo response. Certain comorbid medical symptoms reduced the response and remission rates to placebo in children (P < .001) and adults (P < .001).
Conclusions: In both children and adults, baseline symptom severity was the most consistent predictor of remission with placebo while the temporal profile of response reliably differentiated placebo from medication responders. Placebo effects are most likely to be minimized in shorter trials enrolling more severely impaired subjects. The impact of medical and psychiatric comorbidities on placebo response merits further investigation.
Trial Registration: clinicaltrials.gov identifiers NCT00556296 and NCT00334880
J Clin Psychiatry
Submitted: January 13, 2010; accepted April 1, 2010.
Online ahead of print: February 8, 2011 (doi:10.4088/JCP.10m05979pur).
Corresponding author: Stephen V. Faraone, PhD, SUNY Upstate Medical University, 750 East Adams St, Syracuse, NY 13210 ([email protected]).
Objective: We aimed to assess the effectiveness of massage as a treatment option for autism.
Data Sources: We searched the following electronic databases using the time of their inception through March 2010: MEDLINE, AMED, CINAHL, EMBASE, PsycINFO, Health Technology Assessment, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Psychology and Behavioral Sciences Collection, 6 Korean medical databases (KSI, DBpia, KISTEP, RISS, KoreaMed, and National Digital Library), China Academic Journal (through China National Knowledge Infrastructure), and 3 Japanese medical databases (Journal@rchive, Science Links Japan, and Japan Science & Technology link). The search phrase used was "(massage OR touch OR acupressure) AND (autistic OR autism OR Asperger's syndrome OR pervasive developmental disorder)." The references in all located articles were also searched. No language restrictions were imposed.
Study Selection: Prospective controlled clinical studies of any type of massage therapy for autistic patients were included. Trials in which massage was part of a complex intervention were also included. Case studies, case series, qualitative studies, uncontrolled trials, studies that failed to provide detailed results, and trials that compared one type of massage with another were excluded.
Data Extraction: All articles were read by 2 independent reviewers (M.S.L. and J-I.K.), who extracted data from the articles according to predefined criteria. Risk of bias was assessed using the Cochrane classification.
Results: Of 132 articles, only 6 studies met our inclusion criteria. One randomized clinical trial found that massage plus conventional language therapy was superior to conventional language therapy alone for symptom severity (P < .05) and communication attitude (P < .01). Two randomized clinical trials reported a significant benefit of massage for sensory profile (P < .01), adaptive behavior (P < .05), and language and social abilities (P < .01) as compared with a special education program. The fourth randomized clinical trial showed beneficial effects of massage for social communication (P < .05). Two nonrandomized controlled clinical trials suggested that massage therapy is effective. However, all of the included trials have high risk of bias. The main limitations of the included studies were small sample sizes, predefined primary outcome measures, inadequate control for nonspecific effects, and a lack of power calculations or adequate follow-up.
Conclusions: Limited evidence exists for the effectiveness of massage as a symptomatic treatment of autism. Because the risk of bias was high, firm conclusions cannot be drawn. Future, more rigorous randomized clinical trials seem to be warranted.
Submitted: November 23, 2009; accepted May 3, 2010.
Online ahead of print: December 28, 2010 (doi:10.4088/JCP.09r05848whi).
Corresponding author: Myeong Soo Lee, PhD, Korea Institute of Oriental Medicine, Daejeon, 305-811, South Korea ([email protected]).
Objective: This study evaluated the association between attention-deficit/hyperactivity disorder (ADHD) and psychometrically defined cognitive variables across the adult life span, using data from a large controlled study of adults with and without ADHD.
Method: Comparisons were made between 2 groups of adults: participants with DSM-IV-diagnosed ADHD who had never received pharmacotherapy for their ADHD (n = 116) and 146 control participants. Subjects received a battery assessing IQ, neuropsychological measures, and academic testing. We modeled cognitive measures as a function of age and group status using linear regression. The study was conducted at Massachusetts General Hospital, Boston, between 1998 and 2003.
Results: ADHD and control subjects maintained similar, statistically significant differences in all psychometrically assessed measures of cognition within each decade that was represented (all P values < .01).
Conclusion: The negative impact of ADHD on multiple, nonoverlapping, psychometrically assessed measures of cognition remained constant across the life cycle, suggesting that the association between ADHD and cognition neither improves nor deteriorates across the life cycle.
Submitted: June 8, 2009; accepted August 24, 2009.
Online ahead of print: October 5, 2010 (doi:10.4088/JCP.09m05420pur).
Corresponding author: Joseph Biederman, MD, Massachusetts General Hospital, Pediatric Psychopharmacology Unit, 55 Fruit St, YAW 6A-6900, Boston, MA 02114 ([email protected]).
Deficits in executive function have been consistently demonstrated in adults with ADHD. Rating scales that measure executive deficits in relation to daily life are useful in assessing ADHD symptoms and in measuring responses to treatment, while neuropsychological testing can measure deficits in executive function that can cause additional impairment in adults with ADHD. Treatments, including psychosocial interventions and stimulant and nonstimulant medications, can be helpful in addressing these executive deficits and the symptoms of adult ADHD.
Background: Clinical trials have demonstrated that pharmacotherapies can safely treat attention-deficit/hyperactivity disorder (ADHD) in adulthood. Eligibility criteria in these trials may significantly limit their external validity by excluding a significant portion of adults with ADHD in the general population. In particular, exclusion criteria may frequently exclude individuals with comorbid mental health conditions, which are common in the adult ADHD population.
Method: We addressed the representativeness of clinical trials by comparing 146 adult clinical trial participants with DSM-IV ADHD and a community sample composed of 124 adults with DSM-IV ADHD and 123 non-ADHD controls. Subjects were compared on socioeconomic status, Hollingshead occupational code, cognitive measures, lifetime psychopathology, and Global Assessment of Functioning (GAF) scale ratings.
Results: Adults with ADHD in the community sample had higher rates of lifetime psychiatric comorbidity, lower GAF scores, and lower occupational codes than those in the clinical trial. The clinical trial eligibility criteria would have excluded 61% of community sample adults with ADHD. This excluded portion of the community sample had higher rates of lifetime psychiatric comorbidity and lower GAF scores than clinical trial participants.
Conclusions: Adults with ADHD participating in the clinical trial had less evidence of functional impairment and endorsed less psychiatric comorbidity than the majority of community sample subjects with ADHD. This suggests that findings from clinical trials may have limited external validity for adults with ADHD in the general population, particularly for those adults with ADHD with the greatest burden of comorbid psychopathology.
Submitted: May 08, 2009; accepted July 14, 2009.
Online ahead of print: August 10, 2010 (doi:10.4088/JCP.09m05344pur).
Corresponding author: Craig B. H. Surman, MD, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Ste 2000, 185 Alewife Brook Pkwy, Cambridge, MA 02138 ([email protected]).
Adult ADHD is conceptualized as a disorder of age-inappropriate behavior that occurs because of maldevelopment of 2 related neuropsychological domains. The neuropsychological symptoms seen in adults with ADHD may be explained by deficits in executive function, which can be broadly defined as a set of neurocognitive processes that allow for the organization of behavior across time so as to attain future goals. Executive function is comprised of 2 broad domains: inhibition and metacognition. Inhibition encompasses the ability to inhibit motor, verbal, cognitive, and emotional activities. In turn, deficits in inhibition contribute to deficits in the development of 4 aspects of executive function in the domain of metacognition, which include nonverbal working memory, verbal working memory, planning and problem-solving, and emotional self-regulation. Understanding the ways in which deficits in executive function contribute to the symptoms of ADHD can help in differentiating ADHD from disorders that share similar characteristics.
Objective: To evaluate the effects of atomoxetine alone and in combination with behavior therapy on the school functioning of children with attention-deficit/hyperactivity disorder (ADHD). Most atomoxetine studies have not assessed school functioning other than by measuring the change in ADHD symptoms. Combining behavior therapy with atomoxetine may be particularly beneficial for the academic domain as medication has not been found to produce sustained benefits in this realm. However, there is little research examining the effects of combining atomoxetine and behavior therapy.
Method: In an 8-week open-label trial, 56 children aged 6-12 years with ADHD diagnosed according to DSM-IV-TR were randomly assigned to receive atomoxetine and behavior therapy or atomoxetine alone. Behavior therapy consisted of an 8-week parenting course, a child social skills course, and a teacher-implemented daily report card of classroom behavior. The primary outcome was direct observation of the subject's classroom behavior. Secondary outcomes included change in ADHD symptoms and functioning at home and school. All data were collected between March 2007 and May 2008.
Results: Classroom observations showed that atomoxetine decreased rule violations (P < .0001). Moreover, atomoxetine was associated with significant improvements in ADHD and oppositional defiant disorder symptoms at home and school and enhanced functioning in both domains (Impairment Rating Scale: all P < .001). Combined treatment led to greater improvements in parent-rated symptoms of inattention (P < .01), problem behaviors (P < .001), and academic impairment (P < .05). However, teachers did not report significant group differences.
Conclusions: Atomoxetine improved ADHD symptoms and classroom functioning as measured by parents, teachers, and direct observation. The addition of behavior therapy led to further improvements at home but not at school.
Trial Registration: clinicaltrials.gov Identifier: NCT00918567
Submitted: June 16, 2009; accepted November 2, 2009.
Online ahead of print: June 29, 2010 (doi:10.4088/JCP.09m05496pur).
Corresponding author: James G. Waxmonsky, MD, Center for Children and Families, 106 Diefendorf Hall, 3435 Main St, Bldg 20, Buffalo, NY 14214 ([email protected]).
Background: Given that adults with ADHD continue to use stimulants for extended periods of time, studies on the long-term effectiveness and adverse events are warranted. The aims of this study were to investigate factors associated with persistence in treatment in an exploratory manner and to document side effects and reasons for discontinuation.
Method: The current study describes the systematic follow-up of 133 psychiatric patients with DSM-IV-diagnosed ADHD treated with central stimulants at a specialized outpatient unit between January 1, 2001, and August 31, 2006. A standardized questionnaire, derived from the Targeted Attention-deficit Disorder Symptoms Rating Scale, was used in order to measure improvement of the following target symptoms: hyperactivity, impulsivity, irritability, distractibility, structure/organization problems, inattention, and restlessness.
Results: Eighty percent of the patients were successfully treated with stimulants at the 6- to 9-month follow-up. Fifty percent remained in treatment after 2 years or more. Forty-five percent were treated for comorbid anxiety and/or depression during the study period. Only 15% dropped out because of lack of efficacy. The amount of clinical response over the first 6 to 9 months (but not at 6 weeks) predicted adherence to treatment at 2 years. The patients' heart rate increased from a least squares mean ± SE of 70 ± 2.2 to 80 ± 2.1 bpm (P = .00003) while blood pressure remained unchanged at the ≥ 2-year follow-up. Severe side effects or drug abuse were not detected in this cohort.
Conclusions: The long-term treatment outcome shows that stimulants are effective in adult ADHD and side effects tend to be mild.
Submitted: February 24, 2009; accepted July 13, 2009.
Online ahead of print: June 1, 2010 (doi:10.4088/JCP.09m05168pur).
Corresponding author: Susanne Bejerot, MD, PhD, Northern Stockholm Psychiatry, St Göran's Hospital, SE-112 81 Stockholm, Sweden ([email protected]).
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