Lifespan persistence of ADHD: the life transition model and its application.

BACKGROUND: The understanding that attention-deficit/hyperactivity disorder (ADHD) often persists throughout life has heightened interest of patients, families, advocates, and professionals in a longitudinal approach to management. Such an approach must recognize and address known patient- and systems-based challenges of long-term mental health treatment, shifting of clinical presentations of ADHD, and commonality of psychiatric comorbidity with ADHD. OBJECTIVE: The ADHD Life Transition Model is a step toward developing criteria to optimize recognition and clinical management of ADHD (eg, response, remission) across an individual's lifespan and across diverse medical subspecialties. To support therapeutic efficiency and adaptability, our proposed model highlights periods when external resources for managing ADHD are reduced, cognitive and behavioral stressors are increased, and individuals may be reevaluating how they perceive, accept, and adhere to ADHD treatment. Such a model aims to support the clinical community by placing in context new findings, which suggest that the prevention of adult psychopathology in individuals with pediatric ADHD may be possible. CONCLUSIONS: The ADHD Life Transition Model seeks to improve care for individuals with ADHD by (1) underscoring that ADHD persists beyond childhood in at least two-thirds of patients, (2) raising awareness of the need to approach ADHD from a chronic illness standpoint, and (3) increasing mental health professionals' diligence in symptom recognition and management of ADHD across developmental phases from childhood through adulthood.

Clinically relevant changes in emotional expression in children with ADHD treated with lisdexamfetamine dimesylate.

OBJECTIVE: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. METHOD: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to determine proportion of participants with different categories of clinical response based on (a) clinically significant (movement >2 SD from baseline mean)/reliable change (not due to measurement error) and (b) standard error of measurement (SEM) as a measure of clinically meaningful change. RESULTS: With LDX, no participants showed clinically significant/reliable improvement; 0.7% showed clinically significant/reliable deterioration of EE by reliable change index and movement from baseline mean. One third of participants had improved EE by SEM criteria; 9.2% had categorical worsening. CONCLUSION: Using clinically meaningful change and clinically significant/reliable change categories derived from the EESC, most participants had no worsening of EE with LDX.

Time courses of improvement and symptom remission in children treated with atomoxetine for attention-deficit/hyperactivity disorder: analysis of Canadian open-label studies.

BACKGROUND: The relatively short durations of the initial pivotal randomized placebo-controlled trials involving atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder (ADHD) provided limited insight into the time courses of ADHD core symptom responses to this nonstimulant, selective norepinephrine reuptake inhibitor. The aim of this analysis was to evaluate time courses of treatment responses or remission, as assessed by attainment of prespecified scores on the ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS-IV-PI) and the Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scales, during up to 1 year of atomoxetine treatment in children with ADHD. METHODS: Using pooled data from three Canadian open-label studies involving 338 children ages 6-11 years with ADHD who were treated with atomoxetine for 3, 6 and 12 months, and survival analysis methods for interval-censored data, we estimated the time to: 1) improvement and robust improvement defined by ≥25% and ≥40% reductions from baseline ADHDRS-IV-PI total scores, respectively; and 2) remission using two definitions: a final score of ADHDRS-IV-PI ≤18 or a final score of CGI-ADHD-S ≤2. RESULTS: The median time to improvement was 3.7 weeks (~1 month), but remission of symptoms did not occur until a median of 14.3 weeks (~3.5 months) using the most stringent CGI-ADHD-S threshold. Probabilities of robust improvement were 47% at or before 4 weeks of treatment; 76% at 12 weeks; 85% at 26 weeks; and 96% at 52 weeks. Probabilities of remission at these corresponding time points were 30%, 59%, 77%, and 85% (using the ADHDRS-IV scale) and 8%, 47%, 67%, and 75% (using the CGI-ADHD-S scale). The change from atomoxetine treatment month 5 to month 12 of -1.01 (1.03) was not statistically significant (p = .33). CONCLUSIONS: Reductions in core ADHD symptoms during atomoxetine treatment are gradual. Although approximately one-half of study participants showed improvement at 1 month of atomoxetine treatment, remission criteria were not met until about 3 months. Understanding the time course of children's responses to atomoxetine treatment may inform clinical decision making and also influence the durations of trials comparing the effects of this medication with other ADHD treatments. TRIAL REGISTRATIONS: clinicaltrials.gov: NCT00191633, NCT00216918, NCT00191880.

Executive function deficits in children with attention-deficit/hyperactivity disorder and improvement with lisdexamfetamine dimesylate in an open-label study.

OBJECTIVE: To assess the effects of lisdexamfetamine dimesylate (LDX) on executive function (EF) behaviors in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This observational, open-label, 7-week, dose-optimization study of LDX (20-70 mg/day) in children with ADHD evaluated efficacy with the ADHD Rating Scale IV; safety measures included adverse events (AEs). EF was assessed with the Behavior Rating Inventory of Executive Function (BRIEF). Post hoc analyses examined BRIEF scores by sex, ADHD subtype, comorbid psychiatric symptoms, and common treatment-emergent AEs (TEAEs). ADHD Rating Scale IV scores were assessed in subjects categorized by baseline BRIEF global executive composite T scores with clinically significant (≥65) or not clinically significant (<65) impairment in EF. RESULTS: Mean (standard deviation) change from baseline to endpoint for BRIEF of -17.9 (12.5) for Global Executive Composite, -15.4 (12.6) for Behavioral Regulation Index, and -17.6 (12.3) for Metacognition Index demonstrated improvement with LDX (pooled doses; p < 0.0001 for all). Improvements in BRIEF scores were seen regardless of sex, ADHD subtype, comorbid psychiatric symptoms, common TEAEs, or baseline EF impairment category. TEAEs included decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. CONCLUSIONS: Improvements were demonstrated in EF behaviors and ADHD symptoms with LDX. LDX safety profile was consistent with long-acting stimulant use.

Psychopharmacological treatment of oppositional defiant disorder.

Oppositional defiant disorder (ODD) consists of an enduring pattern of uncooperative, defiant and hostile behaviour toward authority figures that does not involve major antisocial violations and is not accounted for by the developmental stage of the child. The rate of ODD in children and adolescents in the general population has been reported to be between 2% and 16%. The International Classification of Diseases 10th Revision (ICD-10) classifies ODD as a mild form of conduct disorder (CD), and it has been estimated that up to 60% of patients with ODD will develop CD. Therefore, ODD should be identified and treated as early and effectively as possible.In more than one-half of patients with attention-deficit hyperactivity disorder (ADHD), ODD is also part of the clinical picture. There is strong evidence in the literature to suggest that ODD and ADHD overlap; many medications that are used to treat ADHD may also be efficacious in the treatment of ODD. A few studies have reported the positive effects of psychostimulants or atomoxetine in the treatment of ODD associated with ADHD. Patients with ODD and CD with severe aggression may respond well to risperidone, with or without psychostimulants. Mood regulators, alpha(2)-agonists and antidepressants may also have a role as second-line agents in the treatment of ODD and its co-morbidities.

Investigation of attention deficit and hyperactivity disorder in adult patients with atopic dermatitis.

Background. Atopic dermatitis (AD) is a common chronic inflammatory disease that is associated with significant psychosocial morbidity and a decrease in health-related quality of life. Attention deficit hyperactivity disorder may be present in atopic dermatitis patients. Objective. The present study aims to investigate the co-presence of ADHD in adult patients with AD. Material and method. The study registered 60 adult patients with AD (48 females and 12 males) and 50 non-atopic control subjects (38 females and 12 males). The AD patient group and the control group were assessed using the Turgay adult Attention-Deficit/Hyperactivity Disorder (ADD/ADHD) DSM-IV-Based Diagnostic Screening and Rating Scale (Turkish Version), which was studied by a team of psychologists and psychiatrists in Turkey for validity, reliability and norms. The scale covers three dimensions of the disease, namely inattention, hyperactivity and impulsivity, and associated features of ADHD. The groups were compared and contrasted in terms of their similarities and differences in ADD/ADHD symptoms. Results. Three sub-dimensions of ADD/ADHD scale (Attention Deficit, Hyperactivity/ Impulsivity and Problem subdivisions) in AD patients were found statistically significantly elevated relative to controls (P<0.001, P<0.001, P<0.001, respectively). Conclusions. In conclusion we established the co-presence of ADHD in AD patients in the adult age group.

Once-daily multilayer-release methylphenidate in a double-blind, crossover comparison to immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: The purpose of this study was to evaluate the comparative efficacy and safety of a novel long-duration multilayer-release (MLR) methylphenidate (MPH) formulation and immediate-release (IR) MPH in attention-deficit/hyperactivity disorder (ADHD) children. PATIENTS AND METHODS: This study was a randomized, double-blind, crossover comparison of once-daily MLR and twice-daily IR-MPH in home and school settings in children with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of ADHD. Patients completed a 1-week baseline followed by two active medication titration phases. Each phase of treatment was 1-4 weeks of titration with an additional stable dose week. The final dose was based on efficacy and adverse events for each patient. Efficacy measures included Clinical Global Impressions (CGI) and Conners' Parent and Teacher Rating Scales (CPRS and CTRS). The Clinical Assessment of Side Effects (CASE) scale assessed frequency of adverse events. RESULTS: Of the 90 enrolled patients, aged 6.4-17.5 years, 79 (88%) completed the study. Stable daily doses were 32.0 and 32.5 mg for MLR and IR-MPH, respectively. All efficacy parameters were significantly improved from baseline. A total of 73.2% and 81.0% of patients on MLR and IR-MPH were rated as "much" or "very much improved" on the CGI. A total of 77.4% and 81.1% of patients were normalized on the CPRS-R and 78.9 and 90.4% of patients were normalized on the CTRS-R for MLR and IR-MPH, respectively. The mean CASE score was not different from baseline for either treatment.

High-dose atomoxetine treatment of ADHD in youths with limited response to standard doses.

OBJECTIVE: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). METHOD: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than standard efficacious doses (study 1: up to 3.0 mg . kg . day; study 2: up to 2.4 mg . kg . day). RESULTS: The primary outcome measure for both studies was mean ADHD Rating Scale (ADHD RS) total score. For study 1 (N = 122), decreases in ADHD RS total scores were not significantly different between treatment groups (mean change [SD]: continued same dose, -8.9 [11.2]; high dose, -9.8 [13.1]; p = .595). Likewise, for study 2 (N = 125), treatment groups did not differ (mean change [SD]: continued same dose, -6.2 [12.2]; high dose, -8.9 [10.0], p =.110). Tolerability was not significantly different between the continued same-dose and high-dose groups. CONCLUSIONS: These studies provide evidence that current dose recommendations are appropriate for most patients, suggesting no systematic advantage to increasing atomoxetine doses beyond current guidelines. In both studies, continued treatment, whether at a higher dose or the previous dose, was associated with improved outcomes in patients who demonstrated incomplete/inadequate response to acute ADHD treatment, although without a placebo arm, we cannot rule out the possibility that expectancy played a role in symptom improvement.

A multidimensional approach to medication selection in the treatment of children and adolescents with ADHD.

The objective of this paper is to outline clinical patient characteristics to individualize medication selection for children and adolescents with ADHD. The treatment guidelines and clinical parameters outlined in this paper are based on clinical research and evidence- and/or consensus-based guidelines for medication treatment of children and adolescents with ADHD and associated symptoms or comorbid disorders. Recommendations are made for medication selection in different clinical situations. The increased availability of ADHD medications over the past few years has provided a number of treatment options with longer symptom control and improved the remission or "multidimensional normalization" for ADHD patients. Selection of the most appropriate medication(s) for complicated cases may present a serious challenge in some situations. This paper outlines selected complicated cases and treatment options.

Major Depression with ADHD: In Children and Adolescents.

The objective of this paper is to review recent studies on comorbidity and treatment of major depression (MD) and attention deficit/hyperactivity disorder (ADHD) in children and adolescents. Both ADHD and MD are commonly associated with other DSM-IV Axis I psychiatric disorders. ADHD is more commonly associated with oppositional defiant disorder and conduct disorder in children and adolescents. The literature on comorbidities of MD and ADHD suggests that when these two disorders occur together, they bring their own unique profiles, often including a number of other psychiatric disorders and severe symptoms. The guidelines for the use of first-line ADHD medications (psychostimulants and atomoxetine) and the use of antidepressants in patients with MD comorbid with ADHD (with and without psychostimulants) will also be reviewed. Recommendations for the sequencing of these medications in patients with comorbid MD and ADHD and other disorders (anxiety disorders, oppositional defiant disorder, conduct disorder) will also be made. The concept of "goodness of fit" as it applies to medication choices will also be outlined. Some antidepressants, such as imipramine, desipramine, and bupropion have been effective in treating major depression, anxiety disorders, and ADHD in adults. Tricyclic antidepressants have not been as effective in treating MD in children and adolescents; however, they can be used to treat adults with ADHD and MD. Some of the SSRIs are proven to be effective and safe in children and adolescents and can be considered in patients with comorbid MD and ADHD.

Treatment of comorbidity in conduct disorder with attention-deficit hyperactivity disorder (ADHD).

Conduct disorder (CD) is one of the most common psychiatric disorders in childhood and adolescence. It is characterized by a variety of chronic antisocial behaviors, a repetitive and persistent pattern of behavior that violates the basic rights of others, major age-appropriate societal norms, or both. Aggressive behavior, lying, stealing, fire-setting, and running away from home and school are the most frequent manifestations of CD and are often accompanied by hyperactivity, impulsive behavior, explosiveness, cognitive and learning problems, and poor social skills. The rate of comorbidity is high, with attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) being the most common; comorbid anxiety and depressive disorders are also seen, especially in adolescents. The diagnostic process should include the use of structured interviews, and scores from reliable and valid rating scales that cover all psychiatric disorders must be considered in the differential diagnosis, because CD alone is an extreme rarity and multiple disorders are almost always the rule rather than exception. Treatment should include parenting skills training combined with training of the child to improve his or her relationships with peers, academic performance, and compliance with legitimate demands of authority figures. The appropriate use of medications and integration of patient/parent education and support, as well as individual, group, family, residential, and inpatient treatment may be beneficial for patients with CD and ADHD. The article describes a number of psychopharmacological agents that are used in patients with CD with ADHD and other comorbid disorders. Drugs that may be useful include psychostimulants; atomoxetine (Strattera); antidepressants (imipramine [Tofranil], desipramine [Norpramin]); Selective Serotonin Reuptake Inhibitors (SSRIs); atypical antipsychotics such as risperidone (Risperdal); or mood regulators including lithium (Eskalith).

Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders.

OBJECTIVE: To investigate the efficacy and safety of risperidone for the treatment of disruptive behavioral symptoms in children with autism and other pervasive developmental disorders (PDD). METHODS: In this 8-week, randomized, double-blind, placebo-controlled trial, risperidone/placebo solution (0.01-0.06 mg/kg/day) was administered to 79 children who were aged 5 to 12 years and had PDD. Behavioral symptoms were assessed using the Aberrant Behavior Checklist (ABC), Nisonger Child Behavior Rating Form, and Clinical Global Impression-Change. Safety assessments included vital signs, electrocardiogram, extrapyramidal symptoms, adverse events, and laboratory tests. RESULTS: Subjects who were taking risperidone (mean dosage: 0.04 mg/kg/day; 1.17 mg/day) experienced a significantly greater mean decrease on the irritability subscale of the ABC (primary endpoint) compared with those who were taking placebo. By study endpoint, risperidone-treated subjects exhibited a 64% improvement over baseline in the irritability score almost double that of placebo-treated subjects (31%). Risperidone-treated subjects also exhibited significantly greater decreases on the other 4 subscales of the ABC; on the conduct problem, insecure/anxious, hyperactive, and overly sensitive subscales of the Nisonger Child Behavior Rating Form (parent version); and on the Visual Analog Scale of the most troublesome symptom. More risperidone-treated subjects (87%) showed global improvement in their condition compared with the placebo group (40%). Somnolence, the most frequently reported adverse event, was noted in 72.5% versus 7.7% of subjects (risperidone vs placebo) and seemed manageable with dose/dose-schedule modification. Risperidone-treated subjects experienced statistically significantly greater increases in weight (2.7 vs 1.0 kg), pulse rate, and systolic blood pressure. Extrapyramidal symptoms scores were comparable between groups. CONCLUSIONS: Risperidone was well tolerated and efficacious in treating behavioral symptoms associated with PDD in children.

Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ.

OBJECTIVE: The aim of this study was to examine the safety and efficacy of risperidone, with or without concomitant psychostimulant use, in the treatment of children with conduct disorder (CD) or other disruptive behavior disorders [oppositional defiant disorder (ODD), disruptive behavior disorder-not otherwise specified (DBD-NOS)], and comorbid attention-deficit hyperactivity disorder (ADHD). METHODS: Data from two 6-week placebo-controlled trials assessing risperidone therapy in children with subaverage IQs and CD, ODD, DBD-NOS were combined, and patients with comorbid ADHD were selected for this post hoc analysis. Patients were grouped according to randomized drug therapy (risperidone or placebo), and then subgrouped according to their use of a concomitant psychostimulant. Safety outcomes included adverse events and weight change, while efficacy outcomes included changes in scores on disruptive behavior and hyperactivity-based subscales of two behavior-rating instruments (Nisonger Child Behavior Rating Form and the Aberrant Behavior Checklist). RESULTS: The analysis included 155 of 208 originally tested children divided into four sub-groups (35-43 patients each). There was no significant difference in the frequency of adverse events in patients who received risperidone alone and those who received risperidone plus a stimulant. The most common adverse events in risperidone-treated patients were somnolence, headache, dyspepsia, rhinitis, and vomiting. Within each randomized treatment group, actual weight gain was comparable, regardless of concomitant stimulant use. Risperidone-treated patients had clinically and statistically significant reductions in both disruptive behavior and hyperactivity subscale scores, compared to placebo, regardless of concomitant stimulant use. The addition of risperidone to a psychostimulant resulted in significantly better control of hyperactivity (p < 0.001) than was achieved with stimulant treatment alone, without causing an increase in adverse events. CONCLUSION: Risperidone was a safe and effective treatment, with or without a combined psychostimulant, for both disruptive behavior disorders and comorbid ADHD in children.

Aggression and disruptive behavior disorders in children and adolescents.

Aggression is a common symptom of many psychiatric disorders including attention deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, Tourette's disorder, mood disorders (including bipolar disorder), substance-related disorders, alcohol-related disorders, mental retardation, pervasive developmental disorders, intermittent explosive disorder and personality disorders (particularly antisocial personality disorder). Many forms of organic brain disorders may present with aggressive behavior. Aggression is common in some epileptic patients and some endocrinological diseases (e.g., diabetes and hyperthyroidism) may be associated with aggressive behavior. Physicians need to rule out many medical and psychiatric disorders before diagnosing aggressive behavior. A thorough diagnostic work up is the most important step in determining the nature of comorbid disorders associated with the behavioral problem. Structured interviews and rating scales completed by patients, parents, teachers and clinicians may aid the diagnosis and provide quantification for the change process related to treatment. The integration of medication, individual and family counseling, educational and psychosocial interventions including the school and community, may increase the effectiveness of interventions. Due to the common association of aggression and disruptive behaviors with attention deficit hyperactivity disorder, psychostimulants including new generation long-acting medications and other nonstimulant medications are considered the drug of choice for managing aggressive behavior and disruptive behavior disorders. Severe aggressive behavior not responding to these medications may require the single or combined use of mood regulators including lithium and/or antispychotic medications. Drugs such as risperidone (Risperdal, Janssen-Cilag) have documented effectiveness and safety in children and adolescents, and can be used in treatment.

Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs.

OBJECTIVE: To determine whether risperidone is effective in reducing symptoms of disruptive behaviors (such as aggression, impulsivity, defiance of authority figures, and property destruction) associated with conduct disorder, oppositional defiant disorder, and disruptive behavior disorder-not otherwise specified in children with subaverage IQs. METHOD: The trial consisted of a 1-week, single-blind, placebo run-in period and was followed by a 6-week, double-blind, placebo-controlled period. One hundred ten children (aged 5-12 years inclusive) with an IQ of 36-84 with a disruptive behavior disorder and a score of at least 24 on the Conduct Problem subscale of the Nisonger Child Behavior Rating Form (NCBRF) were enrolled. Eighty percent of subjects had comorbid attention-deficit/hyperactivity disorder (ADHD). Risperidone doses ranged from 0.02 to 0.06 mg/kg per day. Subjects were rated on the NCBRF, Aberrant Behavior Checklist, Behavior Problems Inventory, Clinical Global Impressions (CGI), modified California Verbal Learning Test (CVLT), and a continuous performance task (CPT). RESULTS: The intention-to-treat analysis of risperidone-treated subjects showed a significant (p < .001) reduction in mean scores (from 33.4 at baseline to 17.6 at end point; 47.3% reduction) versus placebo-treated subjects (mean baseline of 32.6 to 25.8 at end point; 20.9% reduction) on the Conduct Problem subscale of the NCBRF. Between-group differences in favor of risperidone were seen as early as week 1 and were significant at all post-baseline visits. Other subscales showed significant improvement with risperidone compared with placebo. CGI scale ratings of improvement showed highly significant gains for risperidone over placebo. A subanalysis demonstrated that the effect of risperidone was unaffected by diagnosis, presence/absence of ADHD, psychostimulant use, IQ status, and somnolence. Risperidone produced no changes on the cognitive variables (CPT/modified CVLT). The most common side effects included somnolence, headache, appetite increase, and dyspepsia. Side effects related to extrapyramidal symptoms were reported in 7 (13.2%) and 3 (5.3%) of the subjects in the risperidone and placebo groups, respectively (p = .245). CONCLUSIONS: Risperidone appears to be an adequately tolerated and effective treatment in children with subaverage IQs and severe disruptive behaviors such as aggression and destructive behavior.

Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs.

OBJECTIVE: The objective of this study was to investigate the long-term safety and efficacy of risperidone in disruptive behavior disorders in children with subaverage IQs. Disruptive behavior disorders were defined as oppositional defiant disorder, disruptive behavior disorder, and conduct disorder as per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. METHODS: This was a 48-week open-label (OL) extension study of risperidone in 77 children diagnosed with a disruptive behavior disorder, and either borderline intellectual function or mild or moderate mental retardation who had participated in a previous 6-week, double-blind (DB) study and completed at least 2 weeks of DB therapy. Children, aged 5 to 12 years inclusive, who had: 1) a DSM-IV Axis I diagnosis of conduct disorder, oppositional defiant disorder, or disruptive behavior disorder- not otherwise specified; 2) a parent-assessed rating of > or =24 in the Conduct Problem Subscale of the Nisonger-Child Behavior Rating Form(28); 3) a DSM-IV Axis II diagnosis of mild or moderate mental retardation or borderline intellectual functioning with an IQ > or =36 and < or =84; and 4) a score of < or =84 on the Vineland Adaptive Behavior Scale. Participants received oral solution risperidone given at a once daily dose of between 0.02 and 0.06 mg/kg for a maximum of 48 weeks. Participants in the DB study who had been randomized would have had a maximum of 54 weeks of risperidone therapy. Study visits were scheduled at entry, weekly for the first month, and monthly for the remaining 11 months. RESULTS: Baseline scores on the conduct problem subscale at the start of the previous DB study were similar for both treatment groups: mean values of 33.5 and 33.3 were recorded for placebo- and risperidone-treated participants, respectively. At the time of the OL baseline visit, mean Conduct Problem Subscale scores were lower in those who had been treated with risperidone than in those who remained risperidone-naïve (17.5 and 26.1, respectively). Within 1 week of receiving daily risperidone therapy (mean daily dose: 1.38 mg), those participants who had been risperidone-naïve at OL entry showed a rapid improvement in the Conduct Problem Subscale score. At the week 1 assessment, the mean change from baseline for those who had been risperidone-naïve at OL entry was similar in magnitude to the change from DB baseline recorded for participants who had received risperidone in the DB study. This mean improvement was sustained in both groups throughout the remainder of the OL study. At study endpoint, those participants who had been risperidone-naïve at OL entry experienced a highly significant mean decrease from OL baseline in the mean Conduct Problem Subscale score of 10.6 +/- 2.18. The response to risperidone in the OL trial remained stable in those participants who had been treated with risperidone in the previous DB trial; in this group, the mean change at study endpoint from OL baseline was a nonsignificant decrease of 1.26 +/- 1.45. At DB baseline, 68% of participants had a Clinical Global Impression assessment rated as marked, severe, or extremely severe. By DB study endpoint, only 17% of participants (15% of whom had received placebo and 19% of whom had been treated with risperidone in the previous study) had this severe an assessment; 63% of participants had symptoms rated as either none, very mild, or mild. Similarly, highly significant decreases from baseline in the Vineland Adaptive Behavior Scale rating of the most troublesome symptom (often identified as either aggression (hitting, fighting, or temper tantrums) were observed by study endpoint after 48 weeks of risperidone therapy. For those participants who had received placebo in the previous study, a mean decrease of 47.1 +/- 4.87 mm from a DB baseline of 79.4 +/- 2.69 mm was observed. In those who had received risperidone, a mean decrease of 43.5 +/- 4.57 mm from a DB baseline of 79.3 +/- 3.66 mm was observed. Five subgroup analyses of the primary efficacy outcome were performed. These included analysis by diagnosis (conduct disorder, oppositional defiant disorder, and disruptive behavior disorder-not otherwise specified), degree of mental retardation (borderline, mild, moderate), and presence or absence of somnolence, attention-deficit/hyperactivity disorder, and psychostimulants. The results showed that the efficacy of risperidone was not affected by type of disorder, level of retardation, presence/absence of somnolence or attention-deficit/hyperactivity disorder, or use of psychostimulants. Adverse events were reported for 76 participants; none were serious and most were mild/moderate in severity. Somnolence (52%), headache (38%), and weight gain (36%) were the most common adverse events. The degree of sedation was mild and not associated with cognitive deterioration. In fact, for most parameters assessed on the modified California Verbal Learning Test (a test for verbal learning and memory), there were statistically significant improvements relative to both OL and DB baselines in the mean scores. In addition, statistically significant improvements over baseline were also seen for some Continuous Performance Task (which is a test for attention and impulsivity) parameters. Overall, no deterioration of cognitive function was observed while participants were treated with risperidone. Almost half of the 8.5 kg gained was attributable to normal growth. Asymptomatic peak prolactin levels were observed within 4 weeks of beginning risperidone treatment and declined over time to within normal range. At study endpoint, mean prolactin levels were statistically significantly greater than baseline only in male participants but still <20 ng/mL, which is within the normal range. Twenty participants experienced mild or moderate extrapyramidal symptoms, although none withdrew for this reason. CONCLUSIONS: Risperidone, administered as an oral solution at a mean dose of 1.38 mg/d (range: 0.02-0.06 mg/kg/d) for 1 year, was well tolerated, safe, and showed maintenance of effect in the treatment of disruptive behavior disorders in children aged 5 to 12 years with subaverage IQs.