Ensuring Stakeholder Feedback in the Design and Conduct of Clinical Trials for Rare Diseases: ISCTM Position Paper of the Orphan Disease Working Group.

The 1983 Orphan Drug Act in the United States (US) changed the landscape for development of therapeutics for rare or orphan diseases, which collectively affect approximately 300 million people worldwide, half of whom are children. The act has undoubtedly accelerated drug development for orphan diseases, with over 6,400 orphan drug applications submitted to the US Food and Drug Administration (FDA) from 1983 to 2023, including 350 drugs approved for over 420 indications. Drug development in this population is a global and collaborative endeavor. This position paper of the International Society for Central Nervous System Clinical Trials and Methodology (ISCTM) describes some potential best practices for the involvement of key stakeholder feedback in the drug development process. Stakeholders include advocacy groups, patients and caregivers with lived experience, public and private research institutions (including academia and pharmaceutical companies), treating clinicians, and funders (including the government and independent foundations). The authors articulate the challenges of drug development in orphan diseases and propose methods to address them. Challenges range from the poor understanding of disease history to development of endpoints, targets, and clinical trials designs, to finding solutions to competing research priorities by involved parties.

Calibration and cross-validation of MCCB and CogState in schizophrenia.

RATIONALE: Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison. OBJECTIVES: The objective of this study was to assess the reliability and validity of these two assessment batteries. METHODS: One hundred forty-three participants with DSM-IV schizophrenia and schizoaffective disorder were recruited into three similar studies. Each study administered MCCB and SB tests on consecutive days (baseline 1 and 2) and follow-up 3-4 weeks later. RESULTS: Batteries' test-retest reliability was similar: SB composites correlated r = 0.66-0.78 between baselines, MCCB domains r = 0.69-0.90. Baseline 2 and follow-up SB composites correlated r = 0.65-0.80 and MCCB domains r = 0.62-0.87. MCCB tasks' practice effects (Glass' ∆ = 0.02-0.46) exceeded SB's (Glass' ∆ = 0.02-0.34). While the batteries' total scores correlated strongly (r = 0.79-0.82), apparently equivalent cognitive domains on each battery (e.g. psychomotor-attention) correlated r = 0.22-0.60, indicating substantial differences between some supposed counterparts. CONCLUSIONS: Clinical trials using either battery would benefit from initial practice sessions to ameliorate practice effects but the SB may be more suitable to measure change in the absence of repeated baselines. The MCCB domains' better correlations with social skills performance suggest that it may have an advantage for measuring cognition in relation to functional outcome.

Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder.

BACKGROUND: Psychostimulants, including methylphenidate and amphetamine preparations, are commonly prescribed for the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adults. Histamine H3 receptors reside on non-histamine neurons and regulate other neurotransmitters (e.g. acetylcholine, noradrenaline [norepinephrine]) suggesting that H3 antagonists have the potential to improve attention and impulsivity. Research indicates that H3 receptor antagonists due to their novel mechanism of action may have a unique treatment effect offering an important alternative for the treatment of ADHD. Bavisant (JNJ-31001074) is a highly selective, orally active antagonist of the human H3 receptor with a novel mechanism of action, involving wakefulness and cognition, with potential as a treatment for ADHD. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and tolerability of three dosages of bavisant compared with placebo in adults with ADHD. STUDY DESIGN: This randomized, double-blind, placebo- and active-controlled, parallel-group, multicentre study evaluated three dosages of bavisant (1 mg/day, 3 mg/day or 10 mg/day) and two active controls in adults with ADHD. The study consisted of a screening phase of up to 14 days, a 42-day double-blind treatment phase and a 7-day post-treatment follow-up phase. Efficacy and safety assessments were performed. SETTING: The study was conducted at 37 study centres in the US from April 2009 through January 2010. PARTICIPANTS: Men and women aged 18-55 years with an established diagnosis of ADHD as confirmed by clinician and self-report diagnostic measures were enrolled. INTERVENTION: Participants were randomly assigned equally to one of six treatment groups: placebo, bavisant 1 mg/day, 3 mg/day or 10 mg/day, atomoxetine hydrochloride 80 mg/day or osmotic-release oral system (OROS) methylphenidate hydrochloride 54 mg/day. MAIN OUTCOME MEASURE: The primary efficacy endpoint was the change in the Attention Deficit Hyperactivity Disorder Rating Scale, Version IV (ADHD-RS-IV) total score from baseline (day 1) to the end of the treatment phase (day 42), and included all randomized participants who received one or more doses of study drug and had baseline and one or more post-baseline assessments (intent-to-treat [ITT] population). Safety assessments included treatment-emergent adverse events (TEAEs), laboratory tests and ECG readings. RESULTS: 430 participants were randomized, 424 received one or more doses of study medication and 335 (78%) of those randomized completed the study. Study participants had a mean age of 33.9 years and were predominantly White men. Mean treatment duration ranged from 31.4 to 38.8 days across groups. Mean change from baseline in the total ADHD-RS-IV score at day 42 (primary efficacy endpoint) was -8.8 in the placebo group versus -9.3, -11.2 and -12.2 in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively; the change in the 10 mg/day group was not statistically superior to placebo (p=0.161), and hence statistical comparisons of the 1 mg/day and 3 mg/day groups with placebo based on a step-down closed testing procedure were not performed. Mean change from baseline in the total ADHD-RS-IV score at day 42 was superior to placebo in the atomoxetine (-15.3) and OROS methylphenidate (-15.7) groups (p<0.005). Secondary efficacy assessments demonstrated a similar pattern with a non-significant trend towards improvement in the bavisant groups. The two lower dosages showed a good tolerability profile, but the higher dosage of bavisant was less well tolerated, as evidenced by the incidence of total TEAEs (61.8%, 82.4%, 89.0%), and discontinuations due to TEAEs (4.4%, 7.4%, 19.2%) in the bavisant 1 mg/day, 3 mg/day and 10 mg/day groups, respectively, compared with 58.9% and 2.7%, respectively on placebo. In the atomoxetine and OROS methylphenidate groups, the incidence of total TEAEs was 83.8% and 82.4% and discontinuations due to TEAEs was 10.8% and 8.8%, respectively. CONCLUSION: Bavisant, a highly selective, wakefulness-promoting H3 antagonist, did not display significant clinical effectiveness in the treatment of adults with ADHD. CLINICAL TRIAL REGISTRATION NUMBER: NCT00880217.

A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia.

This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.

Cognitive effects of topiramate in migraine patients aged 12 through 17 years.

Neuropsychologic data are presented from a randomized, double-blind, placebo-controlled, multicenter study with placebo, topiramate 50 mg/day, and topiramate 100 mg/day. The Cambridge Neuropsychological Test Automated Battery (CANTAB) and cognitive adverse events were used to evaluate neurocognitive effects of topiramate. Topiramate 100 mg/day vs placebo was associated with slight statistically significant score increases, indicating slowing, from baseline vs placebo in three CANTAB measures: five-choice reaction time (P = 0.028), pattern recognition memory mean correct latency (P = 0.027), and rapid visual information processing mean latency (P = 0.040). No other patterns related to topiramate treatment were observed in measurements of learning, memory, and visual information processing, except for potential improvement with topiramate 100 mg/day vs placebo in spatial span total errors (accuracy test) (P = 0.040). The most common cognitive and neuropsychiatric adverse events with a higher incidence in the topiramate 50 and 100 mg/day groups vs placebo were anorexia (9% and 11% vs 3%), insomnia (9% and 3% vs 3%), fatigue (6% and 9% vs 6%), and dizziness (6% and 9% vs 0%). Thus, topiramate 100 mg/day was associated with modest increases in psychomotor reaction times. Learning, memory, and executive function were unchanged. The tolerability profile, including cognitive adverse events, appeared to be acceptable.

Psychometric evaluation of a Patient-Rated Most Troubling Symptom Scale for Depression: findings from a secondary analysis of a clinical trial.

The objective of this study was to assess the reliability and validity of the presence and severity of eight symptoms rated on the Patient-Rated Troubling Symptoms for Depression (PaRTS-D) instrument used in a risperidone augmentation trial. PaRTS-D total score (sum of four most severe symptoms) and global total score (sum of all eight symptoms) were determined weekly. Clinician-rated and patient-rated instruments were completed at selected time points. Statistical tests of reliability and validity were performed. The frequency of symptoms rated as one of the four most troubling were sadness, 73.5%; trouble concentrating, 70.9%; reduced involvement, 61.9%; tense/uptight, 56.0%; reduced sleep, 52.2%; negative thoughts, 42.9%; inability to feel emotion, 26.5%; and reduced appetite, 13.1%. Evidence of two factors (somatic-related and depression-related) was observed in the exploratory factor analysis. Baseline PaRTS-D total score correlated with the Quality of Life Enjoyment and Satisfaction Questionnaire and the Sheehan Disability Scale. PaRTS-D global total score showed high internal consistency reliability. PaRTS-D total score and global total score distinguished between patients with high and low-Hamilton Rating Scale for Depression Scores and were responsive to Patient Global Improvement Scale changes. The PaRTS-D total score minimal important difference was 4-5 points. In conclusion, PaRTS-D may be useful in symptom presence and severity assessments from the patient's perspective and as an adjunctive to other instruments in major depressive disorder diagnosis and response to treatment.

Cognitive function with long-term risperidone in children and adolescents with disruptive behavior disorder.

OBJECTIVE: The aim of this study was to evaluate cognitive effects from long-term risperidone treatment for disruptive behavior disorders (DBDs) in children and adolescents. METHODS: Patients 5-17 years old with DBDs and an intelligence quotient (IQ) > or =54 were randomized to flexibly dosed risperidone or placebo in a 6-month recurrence prevention trial. Cognitive function was assessed with a modified California Verbal Learning Test for Children (MVLT-C) and Continuous Performance Test (CPT), which assessed vigilance through computer testing with both an easy and a hard test. Somnolence was also evaluated throughout treatment. Clinically meaningful treatment effects were assessed as changes of > or =0.5 or > or =1.0 standard deviation (SD) from baseline. RESULTS: A total of 284 subjects participating in 6-month maintenance treatment had both baseline and end point cognition assessments and were included in this analysis. Significant improvements from baseline occurred in risperidone-treated subjects for CPT hard hit rates and discrimination ability (Pr) (p < 0.05 for both), and in placebo subjects for CPT easy false alarms rates (p < 0.001) and hard Pr (p < 0.05). Both the easy and hard CPTs correct mean response time worsened with placebo. The MVLT-C short-delay free recall improved significantly for both risperidone and placebo. After adjusting for country, somnolence, age, IQ, and baseline scores, no significant differences were noted in cognition between treatment groups. Clinically meaningful changes were generally similar for risperidone and placebo patients. Mild to moderate somnolence occurred in only 2% of patients treated with either risperidone or placebo. The change in cognitive testing was not different in subjects experiencing somnolence as an adverse event (AE) compared with subjects not experiencing somnolence. CONCLUSIONS: Risperidone treatment resulted in no decline in cognitive function among children and adolescents. These results extend on previous results from risperidone studies in DBD in patients with lower IQ.

Patient-rated troubling symptoms of depression instrument results correlate with traditional clinician- and patient-rated measures: a secondary analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The Patient-Rated Troubling Symptoms of Depression (PaRTS-D) instrument assesses the presence and troublesomeness of 8 commonly reported depression-related symptoms from the patient's perspective. A post hoc analysis of a double-blind, randomized risperidone augmentation to antidepressant therapy trial in patients with major depressive disorder explored the relationship between the PaRTS-D instrument and other clinician- and patient-rating scales. METHODS: Patients completed the PaRTS-D; the Patient Global Improvement Scale (PGIS), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS), while clinicians completed the Hamilton Rating Scale for Depression (HRSD-17), and the Clinical Global Impressions of Severity (CGI-S) at baseline and at pre-determined study weeks. RESULTS: In the PaRTS-D instrument, the four most frequently reported and troublesome symptoms were sadness (73.5%, severity 6.8), trouble concentrating (70.9%, 7.3), reduced involvement in pleasurable activities (61.9%, 7.3), and being tense or uptight (56.0%, 6.7). The improvement in PaRTS-D total score was significantly greater in risperidone-augmented compared with placebo-augmented patients at week 4 (p=0.034) and week 6 (p=0.007). Pearson correlations between the PaRTS-D scores and the measures of HRSD-17, CGI-S, PGIS, Q-LES-Q, and SDS were significant at both baseline and at week 6 LOCF (p<0.001 for each comparison). LIMITATIONS: Results are from a post hoc analysis. CONCLUSIONS: Significant correlations were observed between the PaRTS-D and other clinician- and patient-rated measures, with PaRTS-D being sensitive to the effects of treatment. These findings suggest that the PaRTS-D instrument is a reliable scale to assess antidepressant activity as experienced by the patients.

Psychometric evaluation of a patient-rated troubling symptom scale for generalized anxiety disorder clinical trials.

BACKGROUND: The majority of clinical outcome assessments developed for generalized anxiety disorder (GAD) may not efficiently and sensitively reflect heterogeneous symptom clusters from a patient perspective. The Patient-Rated Troubling Symptoms Scale for Anxiety (PaRTS-A) instrument was developed to provide an individualized assessment of patient relevant GAD symptoms. OBJECTIVE: The objective of this analysis was to evaluate the psychometric characteristics of the PaRTS-A. METHODS: Data were taken from a 6-week clinical trial evaluating the efficacy of adjunctive risperidone therapy in GAD patients undergoing standard treatment. Patients completed the PaRTS-A, the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS) as well as impressions of improvement. Physicians completed the Hamilton Anxiety Rating Scale (HAM-A). A instrument characteristics were assessed through statistical tests of reliability, reproducibility, construct and discriminant validity, and responsiveness. RESULTS: In the item response theory (IRT) analysis, the PaRTS-A items fit into a single construct of anxiety. Internal consistency reliability exceeded 0.70. The PaRTS-A total score was moderately correlated with the Q-LES-Q and the SDS. The PaRTS-A distinguished between patients with high and low HAM-A scores (p<0.001). The PaRTS-A was responsive to changes in clinical status and the minimal important difference was identified. CONCLUSION: The PaRTS-A provides a unique patient-rated assessment of anxiety symptoms. The instrument may provide clinicians with useful information regarding patient's self-rated anxiety disorder symptoms and the hierarchy of symptoms that they considered most troubling. Our analysis suggests that the PaRTS-A is an internally consistent, valid, and responsive instrument that may be a beneficial adjunct to other instruments in clinical trials.

Treating disruptive behavior disorders with risperidone: a 1-year, open-label safety study in children and adolescents.

OBJECTIVE: The aim of this study was to determine the long-term safety of risperidone as maintenance therapy in children and adolescents with disruptive behavior disorders (DBDs) and normal intelligence. METHOD: An open-label, 1-year extension study was conducted from January, 2002, to July, 2004, in 232 subjects with DBDs (5-17 years) previously randomized to risperidone (RIS) (n = 115, RIS/RIS) or placebo (PLA) (n = 117, PLA/RIS) in a double-blind, 6-month withdrawal study. Adverse events (AEs) and clinical laboratory test results were recorded. Efficacy was assessed using Nisonger Child Behavior Rating Form. Safety and efficacy were evaluated in the intent-to-treat population. RESULTS: A total of 169/232 (73%) subjects completed the study. Subjects were predominantly male, with a diagnosis of oppositional defiant disorder. Risperidone was generally well tolerated. Weight gain and extrapyramidal symptoms were each reported as AEs by 10 subjects (4.3%). Mean weight z-scores decreased for RIS/RIS subjects (-0.04 +/- 0.28) and increased for PLA/RIS subjects (0.11 +/- 0.43). No subject developed tardive dyskinesia. Prolactin tended to increase with risperidone, although this effect diminished with prolonged use and was infrequently associated with AEs. There were no clinically relevant changes in glucose or lipid metabolism. Clinical improvement in DBD symptoms was observed with flexible risperidone doses, regardless of previous treatment and whether subjects had experienced symptom recurrence. CONCLUSIONS: Risperidone reinitiated for DBD in children with normal intelligence quotients (IQ) was safe and well tolerated over an additional year of treatment. Patients demonstrated clinical benefits, including those who previously experienced symptom recurrence.

Assessment of strategies for switching patients from olanzapine to risperidone: a randomized, open-label, rater-blinded study.

BACKGROUND: In clinical practice, physicians often need to change the antipsychotic medications they give to patients because of an inadequate response or the presence of unacceptable or unsafe side effects. However, there is a lack of consensus in the field as to the optimal switching strategy for antipsychotics, especially with regards to the speed at which the dose of the previous antipsychotic should be reduced. This paper assesses the short-term results of strategies for the discontinuation of olanzapine when initiating risperidone. METHODS: In a 6-week, randomized, open-label, rater-blinded study, patients with schizophrenia or schizoaffective disorder, on a stable drug dose for more than 30 days at entry, who were intolerant of or exhibiting a suboptimal symptom response to more than 30 days of olanzapine treatment, were randomly assigned to the following switch strategies (common risperidone initiation scheme; varying olanzapine discontinuation): (i) abrupt strategy, where olanzapine was discontinued at risperidone initiation; (ii) gradual 1 strategy, where olanzapine was given at 50% entry dose for 1 week after risperidone initiation and then discontinued; or (iii) gradual 2 strategy, where olanzapine was given at 100% entry dose for 1 week, then at 50% in the second week, and then discontinued. RESULTS: The study enrolled 123 patients on stable doses of olanzapine. Their mean age was 40.3 years and mean (+/- standard deviation (SD)) baseline Positive and Negative Syndrome Scale (PANSS) total score of 75.6 +/- 11.5. All-cause treatment discontinuation was lowest (12%) in the group with the slowest olanzapine dose reduction (gradual 2) and occurred at half the discontinuation rate in the other two groups (25% in abrupt and 28% in gradual 1). The relative risk of early discontinuation was 0.77 (confidence interval 0.61-0.99) for the slowest dose reduction compared with the other two strategies. After the medication was changed, improvements at endpoint were seen in PANSS total score (-7.3; p < 0.0001) and in PANSS positive (-3.0; p < 0.0001), negative (-0.9; p = 0.171) and anxiety/depression (-1.4; p = 0.0005) subscale scores. Severity of movement disorders and weight changes were minimal. CONCLUSION: When switching patients from olanzapine to risperidone, a gradual reduction in the dose of olanzapine over 2 weeks was associated with higher rates of retention compared with abrupt or less gradual discontinuation. Switching via any strategy was associated with significant improvements in positive and anxiety symptoms and was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378183.

Risperidone for treatment-refractory major depressive disorder: a randomized trial.

BACKGROUND: Major depressive disorder has high prevalence, morbidity, and mortality. Inadequate results with antidepressants have prompts addition of a nonstandard treatment (augmentation therapy). OBJECTIVE: To assess whether augmentation therapy with risperidone reduces symptoms and increases response to antidepressant therapy and remission of depression in adults. DESIGN: Multicenter, double-blind, placebo-controlled, randomized trial conducted from 19 October 2004 to 17 November 2005. SETTING: 75 primary care and psychiatric centers. PATIENTS: 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy. INTERVENTION: After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly assigned to receive risperidone, 1 mg/d, or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/d in some cases. MEASUREMENTS: Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various clinician- and patient-rated assessments. RESULTS: Of the intention-to-treat population (268 patients), 81% (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treatment. Mean (+/-SE) HRSD-17 scores improved more in the risperidone augmentation group than in the placebo group (13.4 +/- 0.54 vs. 16.2 +/- 0.53; difference, -2.8 +/- 0.72 [95% CI, -4.2 to -1.4]; P <0.001). More risperidone recipients than placebo recipients experienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs. 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs. 14.5% of placebo recipients), somnolence (5.1% vs. 1.5%), and dry mouth (5.1% vs. 0.8%) were the most frequently reported adverse events. LIMITATIONS: Patients were receiving many different antidepressants, and the duration of augmentation therapy was limited. CONCLUSION: Risperidone augmentation produced a statistically significant mean reduction in depression symptoms, substantially increased remission and response, and improved other patient- and clinician-rated measures. ClinicalTrials.gov registration number: NCT00095134.

Adjunctive risperidone in the treatment of generalized anxiety disorder: a double-blind, prospective, placebo-controlled, randomized trial.

BACKGROUND: Residual symptoms despite treatment are common in generalized anxiety disorders (GAD). The Patient-Rated Troubling Symptoms for Anxiety (PaRTS-A) is a newly created and validated instrument that measures the symptoms most troublesome to each individual patient and was used to test the hypothesis that adjunctive risperidone improves residual GAD symptoms. METHODS: Primary care and psychiatry clinicians enrolled adults (n = 417) with GAD and a Clinical Global Impressions of Severity rating ≥ 4 despite ≥ 8 weeks of anxiolytic treatment. Subjects were randomized to adjunctive risperidone or placebo. The primary endpoint was change from baseline to week 4 endpoint in PaRTS-A. RESULTS: Improvement from baseline to week 4 endpoint in PaRTS-A total score (mean +/-SE) was similar between treatment groups (-8.54 [0.63] and -7.61 [0.64] for adjunctive risperidone and placebo, respectively; P = .265). Patients in each treatment group exhibited significant improvements from baseline in nearly all patient- and clinician-rated measures. A post-hoc analysis of PaRTS-A symptoms of moderate to severe severity at baseline suggested greater improvement with risperidone than placebo (P = .04). Headache, weight increase, and increased appetite were the most frequently reported adverse events in both groups. CONCLUSIONS: Residual GAD symptoms assessed by the PaRTS-A improved with either adjunctive risperidone or placebo. Alternative analyses or scoring approaches may improve the ability of the PaRTS-A to provide clinically meaningful information on patient-rated symptoms. Further exploration of the benefits of risperidone in patients with more severe GAD may be indicated.

Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD.

BACKGROUND: Movement disorders (MD) in children are relatively common and may be associated with medication use. Objective methods (ie rating scales) and specific research criteria may be helpful in identifying MD-related adverse events that would otherwise not be apparent from spontaneous reports. We assessed whether more stringent and rigorous criteria would provide MD rates similar to those derived subjectively from spontaneous reports. METHODS: MDs were assessed in children with disruptive behavior disorders (DBDs) and subaverage intelligence receiving risperidone. Data were from three 1-year, open-label studies in subjects 4-14 years old. Dyskinesia severity was rated by the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale. Tardive dyskinesia (TD) was defined: mild dyskinesia (scores 2, 3) in two anatomical areas; or moderate dyskinesia (score >or= 4) in one area for >or= 4 weeks in subjects without dyskinesia at baseline (scores 0, 1). RESULTS: The mean (+/- SD) age of subjects was 9.4 +/- 2.4 years, the mean (+/- SD) risperidone dose was 1.6 +/- 0.7 mg/day, and the mean (+/- SD) exposure was 317.8 +/- 104.5 days. ESRS data were available for 668 subjects. Mean ESRS scores were low throughout the study. At baseline, 655 subjects had no dyskinetic symptoms. One subject met predefined TD criteria after a risperidone dose reduction. Symptoms persisted for 4 weeks, resolving with continued treatment and no dosage change. Two different subjects had TD by spontaneous adverse-event reports, with dyskinetic symptoms at 1-2 visits, and symptoms that resolved after treatment discontinuation. Thirteen subjects had dyskinesia at baseline; their mean ESRS dyskinesia scores decreased at endpoint. CONCLUSION: Using objective rating scales and research criteria, low-dose risperidone was associated with low risk of TD and other MDs in children with DBDs in three large 1-year studies. Careful, objective evaluation of emergent MDs during all stages of treatment is essential for identifying treatment-emergent TD.

Observed clinical and health services outcomes in pediatric inpatients treated with atypical antipsychotics: 1999-2003.

OBJECTIVE: The aim of this study was to compare clinical and health services outcomes in pediatric inpatients prescribed an atypical antipsychotic (AA) to those not prescribed an AA at discharge. METHODS: Descriptive statistics, analysis of variance (ANOVA), and, where necessary, analysis of covariance (ANCOVA) were used to compare differences between and within an inpatient group prescribed risperidone, olanzapine, or quetiapine (n=1,131) with an inpatient group not prescribed an antipsychotic at discharge (n=1,741). RESULTS: The AA treatment group showed greater psychiatric symptom difficulty at admission as measured by the Brief Psychiatric Rating Scale for Children (Mean BPRS-C) than the group not prescribed AAs (40.3 [n=433] vs. 35.2 [n=452], respectively, p<0.001). AA-treated inpatients also had a higher number of mental health outpatient visits during the 6 months prior to admission. Patients receiving AAs (n=1,050) had significantly longer adjusted length of stay (LOS) than those not receiving antipsychotics (n=1,664): 26.4 days versus 22.4 days, respectively (p<0.04). CONCLUSIONS: The findings suggested pediatric inpatients presenting with greater psychiatric symptom difficulty at hospital admission were more likely to be prescribed an AA. Choice of AA may influence certain clinical and health services outcomes. Additional prospective controlled studies evaluating AA efficacy and safety, including head-to-head comparisons, in pediatric inpatients are warranted.

Risperidone and cognitive function in children with disruptive behavior disorders.

BACKGROUND: Effects of risperidone on cognitive function in children with disruptive behavior disorders (DBDs) and subaverage intelligence quotient (IQ) were assessed. METHODS: Data from two 6-week, double-blind, placebo-controlled studies (n = 228) were combined, as were three 1-year, open-label studies (n = 688). Patients with DBDs and subaverage IQ, 5 to14 years, received placebo or risperidone .02 to .06 mg/kg/day. Cognitive measures included the Continuous Performance Task (CPT) and Verbal Learning Test for Children (VLT-C). Efficacy was assessed using the Nisonger Child Behavior Rating Form (NCBRF). Adverse events were collected via spontaneous report; sedation was assessed using visual analog scale. RESULTS: Improvements on the NCBRF Conduct Problem subscale were significantly greater for risperidone- versus placebo-treated patients (-15.8 vs. -6.4, p < .0001) in short-term studies; significant reductions were observed in long-term studies (-16.3, p < .0001). No overall decline and some significant improvement in attention (CPT) and memory (VLT-C) were noted regardless of treatment in short-term studies. VLT-C improved significantly (p < .0001) for both groups, with no difference between treatment groups. Improvements in memory (VLT-C) and attention (CPT) were noted in long-term studies. Somnolence/sedation did not affect cognitive function. CONCLUSIONS: Cognitive function was not altered by risperidone in short-term studies and was maintained or improved with one year of treatment in children with DBDs and subaverage IQ, potentially representing age-appropriate gains.

Risperidone improves behavioral symptoms in children with autism in a randomized, double-blind, placebo-controlled trial.

Subgroup analysis of children (5-12 years) with autism enrolled in an 8-week, double-blind, placebo-controlled trial of risperidone for pervasive developmental disorders. The primary efficacy measure was the Aberrant Behavior Checklist-Irritability (ABC-I) subscale. Data were available for 55 children given risperidone (n=27) or placebo (n=28); mean baseline ABC-I ( +/- SD) was 20.6 (8.1) and 21.6 (10.2). Risperidone [mean dose ( +/- SD): 1.37 mg/day (0.7)] resulted in significantly greater reduction from baseline to endpoint in ABC-I versus placebo [mean change ( +/- SD): -13.4 (1.5) vs. -7.2 (1.4), P<0.05; ES=-0.7]. The most common adverse effect with risperidone was somnolence (74% vs. 7% with placebo). Risperidone treatment was well tolerated and significantly improved behavioral problems associated with autism.