Understanding and assessing potential serious adverse events: a practical approach to understanding the benefits and harm of psoriasis treatments.

BACKGROUND: Any therapeutic intervention carries with it the potential for benefit and harm. Generally, benefit is far more common than risk; however, risk aversion drives many of the treatment decisions made by patients and their physicians. OBJECTIVE: To provide guidelines to help clinicians improve their understanding of causality and the interpretation of harm. METHODS: A group of dermatologists involved in data safety monitoring boards, clinical trial investigators, and a clinical epidemiologist identified the need for practical advice on how to understand and explain causality and harm and combined to share their knowledge. RESULTS: An explanation of how data are collected and the environment that shapes the data seen by clinicians is presented. The article spans an overview of the regulatory environment that informs trial design for regulatory approval to a description of types of designs that inform safety and techniques, such as the rule of three, to provide guidance to clinicians in interpreting the data. CONCLUSION: Communicating the potential for harm to patients is critical. Placing the potential for rare and serious risks into perspective for the patient is as important as discussing the potential benefits of medication.

Canadian Alzheimer's disease caregiver survey: baby-boomer caregivers and burden of care.

OBJECTIVE: Alzheimer's disease (AD) burdens not only the person, but also the person's caregiver(s). This burden has been linked to negative health effects for caregivers. To that end, a survey of Canadian caregivers of persons with AD/other dementias was conducted to investigate the social, physical, psychological and financial impact of AD and/or dementia-related conditions on caregivers' quality of life. METHODS: A web-based survey, the Canadian Alzheimer's Disease Caregiver survey, was made available through the Canadian Alzheimer's Society website and 50plus.com, an internet portal for baby boomers (BB) (people aged 50 years or older), as well as through HarrisDecima Research's e-Vox panel. A total of 398 individuals completed the survey between 15 September and 5 November 2006. RESULTS: Of the 398 total respondents, 221 were identified as baby boomers who provided care to an individual with AD/dementia. Respondents identified several areas of burden of care. These included negative effects on emotional health (such as increased depression, more stress and greater fatigue), financial costs and a need to change a working situation (e.g. by retiring early, reducing work hours or refusing a promotion). CONCLUSION: Caregivers of persons with AD/related dementia face important social, physical, psychological and financial pressures. These negatively affect the quality of life of caregivers with a significant increased burden being placed on live-in caregivers versus caregivers who do not co-reside with their care recipients. Interventions that address these pressures will not only improve the health and well-being of caregivers, but likely also the care of persons with AD/dementia.

Persistence with cholinesterase inhibitor therapy for dementia: an observational administrative health database study.

OBJECTIVE: To determine if choice of drug and ease of administration affect persistence of therapy with cholinesterase inhibitors (ChEIs) for treatment of dementia. METHODS: An observational administrative health database study was conducted in 5622 patients aged >or=65 years who received a new prescription for donepezil (DON), rivastigmine (RIV) or galantamine (GAL) from February to May 2006. Patients were followed for 1 year from initiation of therapy to determine percentage persistence and days of therapy. Once-daily galantamine extended release (GAL-ER) was compared with twice-daily galantamine immediate release (GAL-IR) to determine if ease of administration affected persistence. Previous treatment with ChEIs was also documented. RESULTS: One-year persistence rates were significantly different among the ChEIs: GAL-ER 54% (95% CI 51, 57), DON 46% (95% CI 43, 49) and RIV 40% (95% CI 37, 43). Average days of therapy were greater for GAL-ER (293) than for RIV (272), but there were no differences between DON (287) and GAL-ER or DON and RIV. One-year persistence was significantly greater for GAL-ER 54% (95% CI 48, 59) than for GAL-IR 44% (95% CI 39, 50), although there was no significant difference in days of therapy (293 vs 286, respectively). More patients currently treated with RIV (40.5%) or GAL-ER (32.3%) had received previous treatment with a different ChEI than with DON (21.9%). CONCLUSION: Among possible factors affecting persistence of ChEI therapy for dementia, choice of drug, ease of administration and previous treatment appear to be important.

Adult ADHD and comorbid depression: A consensus-derived diagnostic algorithm for ADHD.

OBJECTIVE: Many patients present to their physician with depression as their primary symptom. However, depression may mask other comorbid disorders. This article presents diagnostic criteria and treatment recommendations (and monitoring) pertaining to the diagnosis of adult attention deficit hyperactivity disorder (ADHD), which may be missed in patients who present with depressive symptoms, or major depressive disorder (MDD). Other co-occurring conditions such as anxiety, substance use, and bipolar disorder are briefly discussed. METHODS: A panel of psychiatrist-clinicians with expertise in the area of child and adolescent ADHD and mood disorders, adult mood disorders, and adult ADHD was convened. A literature search for recommendations on the diagnosis and treatment of co-occurring conditions (MDD, anxiety symptoms, and substance use) with adult ADHD was performed. Based on this, and the panel's clinical expertise, the authors developed a diagnostic algorithm and recommendations for the treatment of adult ADHD with co-occurring MDD. RESULTS: Little information exists to assist clinicians in diagnosing ADHD co-occurring with other disorders such as MDD. A three-step process was developed by the panel to aid in the screening and diagnosis of adult ADHD. In addition, comorbid MDD, bipolar disorder, anxiety symptoms, substance use and cardiovascular concerns regarding stimulant use are discussed. CONCLUSION: This article provides clinicians with a clinically relevant overview of the literature on comorbid ADHD and depression and offers a clinically useful diagnostic algorithm and treatment suggestions.

100 years after Alzheimer: contemporary neurology practice assessment of referrals for dementia.

BACKGROUND: The prevalence of dementia is placing an increased burden on specialists. METHODS: Canadian neurologists responded to a structured questionnaire to assess reasons for referral and services provided as well as to compare the neurologists' perceptions of their practice characteristics against cases seen over a 3-month period. RESULTS: The audit confirmed the participants' perception that family practitioners are the main referral source (358/453, 79%). Sixty-two percent of patients had undergone clinical investigation for dementia prior to being seen by the neurologist; 39% (177/453) were on pharmacotherapy at the time of referral, 68% were initiated on pharmacotherapy by the neurologist. A fifth of the referrals did not meet clinical criteria for dementia, which may be directly related to the prevalence of prior workup that did not include mental status testing. CONCLUSIONS: Neurologists currently treat patients referred for dementia who may already have been adequately evaluated and treated by primary care providers.

Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen. METHOD: This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006. RESULTS: There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES at all visits and at endpoint (p = .01) and on the MAF (p < .01). No differences were observed on other secondary measures, including the CGI-I and CGI-S. There were no clinically significant findings on electrocardiogram. CONCLUSIONS: OROS methylphenidate did not demonstrate statistical significance on the MADRS at endpoint. Apathy and fatigue were significantly improved with OROS methylphenidate treatment, which was well tolerated with minimal side effects. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00246233.

Do formulation switches exacerbate existing medical illness? Results of an open-label transition to orally disintegrating risperidone tablets.

BACKGROUND: Orally disintegrating risperidone tablets (Risperdal* M-TABs*) present an alternative method of drug delivery that may benefit physicians struggling to treat non-compliant patients, since it begins to dissolve within 5 s, preventing tablet cheeking or spitting. OBJECTIVES: To evaluate safety and maintenance of effect in symptomatically stable patients transitioned from compressed risperidone tablets to orally disintegrating risperidone tablets. METHODS: This open-label, multi-centre study enrolled 82 adults from four diagnostic groups (major depressive disorder (MDD), n = 25; bipolar disorder (BP), n = 21; dementia (DE), n = 20; schizophrenia (SZ), n = 16). Patients were switched from their previous dosage of compressed tablets (0.5, 1.0, 2.0, 3.0, or 4.0 mg/day) to an equivalent dosage of orally disintegrating risperidone and followed for 4 weeks. The primary effectiveness parameter evaluated was the Clinical Global Impression-Severity (CGI-S) scale. RESULTS: Most patients (24/25 MDD; 20/21 BP; 17/18 DE; 14/15 SZ) improved by 1 point on CGI-S from baseline or experienced no change at endpoint. Adverse events (AEs) occurring in any group at a > or =10% incidence included headache (19%) and pharyngolaryngeal pain (10%), reported in the BP group only. CONCLUSIONS: Patients stabilized on compressed risperidone tablets transitioned to the equivalent dose of orally disintegrating risperidone tablets with continued maintenance of effect, no decompensation and with minimal side effects.

Management of psychiatric disorders in children and adolescents with atypical antipsychotics: a systematic review of published clinical trials.

We aimed to provide a descriptive review of treatment studies of atypical antipsychotics in paediatric psychiatric disorders. A systematic review of the literature used Medline and EMBASE databases to identify clinical trials of atypical antipsychotics in children and adolescents between 1994 and 2006. Trials were limited to double-blind studies and open-label studies of > or = 8 weeks duration that included > or = 20 patients. Nineteen double-blind and 22 open-label studies were identified. Studies included use of clozapine, olanzapine, quetiapine, risperidone, and ziprasidone in the treatment of disruptive behavioural disorders (DBDs), pervasive developmental disorders (PDDs), tic disorder, psychotic disorders, and mania. These medications generally reduced the severity of a variety of psychiatric symptoms in children and adolescents. Less frequent adverse events included extrapyramidal symptoms, hyperglycaemia and diabetes, and endocrine effects. The review of published scientific data suggests that most of the atypical antipsychotics, excluding clozapine, have a favourable risk/benefit profile and effectively reduce disabling behaviours in paediatric psychiatric patients. While there is a body of evidence published of treatment of DBDs and PDDs, there is a lack of controlled data to guide clinical practice for the use of atypical antipsychotics for paediatric psychotic disorders and bipolar disorder. While there have been studies with duration up to 2 years, no definitive data are available that suggest long-term safety; additional studies are warranted.

Does OROS-methylphenidate improve core symptoms and deficits in executive function? Results of an open-label trial in adults with attention deficit hyperactivity disorder.

OBJECTIVE: This pilot, uncontrolled, open-label study evaluated the safety/tolerability and potential effectiveness of OROS-methylphenidate (OROS-MPH) in adult attention deficit hyperactivity disorder (ADHD). METHODS: Adults with DSM-IV-defined ADHD were enrolled in this 38-day study. Retrospective childhood diagnosis was made using the Wender Utah Rating Scale. Eligible patients required a baseline Conners Adult ADHD Rating Scale (CAARS) score > or = 24, Clinical Global Impression of Severity (CGI-S) score > or = 4 (at least moderate illness), and Montgomery-Asberg Depression Rating Scale (MADRS) score < or = 16. Safety/tolerability measurements included adverse event reporting, vital signs, electrocardiograms (ECGs), weight, physical examination. Primary effectiveness evaluated changes in CAARS scores. Secondary effectiveness parameters included executive function. RESULTS: Thirty-two patients formed the safety analysis; however, 30 comprised the effectiveness analysis since two patients did not meet diagnostic inclusion criteria. No serious adverse events were reported and there were no early withdrawals due to adverse events. There were no clinically significant changes in endpoint ECGs, physical examination, or blood pressure. Mean pulse rate increased by 5.9 beats/min (p = 0.003) and mean body weight decreased by 2.2 kg at endpoint (p < 0.0001). Total CAARS scores decreased significantly at endpoint as well as the inattention (p < 0.0001) and hyperactivity/impulsivity symptom subscales (p < 0.0001) separately. Statistically significant improvements were observed in executive function and all other secondary measures, including the CAARS self report, CGI-S/CGI-I, Subject Satisfaction with treatment and the Sheehan Disability Scale (SDS). Mean dose of OROS-MPH = 52.3 +/- 14.0 mg. Modal dose = 54 mg. Study limitations include: the lack of placebo control in the study design leading to potential observer bias, the exclusion of adults with unstable psychiatric and other medical conditions which is less reflective of clinical practice, and the short study duration. CONCLUSIONS: This uncontrolled, open-label trial suggests that OROS-MPH is well tolerated, providing core symptom control with the added benefit of improving executive function. However, future larger, randomized, controlled trials are required.

Topiramate prophylaxis and response to triptan treatment for acute migraine.

OBJECTIVE: To evaluate the effect of topiramate migraine prophylaxis on subject responsiveness to triptans used for acute symptomatic migraine treatment. BACKGROUND: Clinical experience suggests that prophylactic migraine treatment may enhance the efficacy of symptomatic medications used to treat acute migraine attacks. METHODS: This open-label, single-arm multicenter study consisted of a 6-week baseline period followed by a 16-week topiramate treatment period. Subjects meeting International Headache Society (IHS) criteria for migraine with and without aura signed consent and entered the baseline period. Those with 3 to 12 migraine periods per month during baseline received topiramate prophylactic treatment. Only patients who completed at least 12 weeks of topiramate treatment were included in the data analysis. RESULTS: Of 55 patients screened, 40 subjects entered the topiramate treatment period and 21 subjects received at least 12 weeks of treatment. Mean final dose of topiramate was 124 mg per day (range 50 to 200 mg per day). During the baseline period, the mean percentage of attacks rendered pain-free at 2 hours for the 21 subjects was 46.9% (SD = 31.9), while during the topiramate treatment period it was 44.6% (SD = 32.2) (P= .8). On topiramate, after the first 8 weeks of dosage titration, patients experienced a mean of 3.68 migraine attacks/month, compared to 4.31 during the baseline period (P < .03). Thirteen subjects discontinued because of adverse events. The most commonly reported adverse events were paresthesia, fatigue, anxiety, and dizziness. CONCLUSION: Although topiramate prophylaxis did reduce migraine attack frequency, in this pilot study topiramate prophylactic migraine treatment did not increase the proportion of patients pain-free 2 hours after symptomatic triptan therapy.

A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in attention deficit-hyperactivity disorder.

BACKGROUND: The thrice daily dosing regimen of immediate release methylphenidate (IR-MPH) for Attention Deficit/Hyperactivity Disorder (ADHD) requires in-school dosing, leading to issues surrounding dispensing and storage of controlled substances by school personnel and concerns over children?s privacy and the embarrassment associated with taking medication in public at school. OROS-methylphenidate (OROS-MPH) is a once-daily controlled-release formulation of methylphenidate (MPH) developed to overcome some of the limitations associated with IR-MPH and first-generation sustained-release formulations. Randomized, controlled trials (RCTs) that focus on treatment efficacy provide the best evidence for demonstrating whether an intervention works, but under ideal conditions one cannot discount the importance of efficacy study results. However, the most useful information to clinicians comes from an effectiveness study design. OBJECTIVES: To evaluate the effectiveness and tolerability of OROS-MPH versus usual care with IR-MPH in children aged 6 to 12 years with ADHD. METHODS: This 8 week, multicentre, open-label study randomized 147 subjects to either once-daily OROS-MPH or usual care with IR-MPH. Subjects were titrated to a clinically effective dose of either study medication over 4 weeks and maintained on that dose for an additional 4 weeks. The SNAP-IV parent-rating scale was used to assess effectiveness. RESULTS: OROS-MPH showed statistically significant superiority to IR-MPH in remission rate based on the 18 ADHD symptoms (p=0.0002, X2=13.8, df=1) and severity of ADHD and ODD symptoms (p=0.004, F=8.4, df=1,127), as well as on the following secondary assessments: IOWA Conners, Conners Parent Rating Scale (short version), Parent Stress Index, (short version); Visual Analogue Scale for social play; Clinical Global Impression-Severity, Clinical Global Impression-Improvement and Parent Satisfaction with treatment. OROS-MPH and IR-MPH were both well tolerated with a similar side effect profile. CONCLUSIONS: Once-daily OROS-MPH is significantly more effective than usual care with IR-MPH based on multiple outcome measures including remission rate.

Risperidone reduces aggression in boys with a disruptive behaviour disorder and below average intelligence quotient: analysis of two placebo-controlled randomized trials.

The present study aimed to analyse the effect of risperidone on a priori defined core aggression items. Data were pooled from 163 boys (aged 5-12 years, with or without comorbid attention-deficit/hyperactivity disorder) with a DSM-IV diagnosis of either conduct disorder or oppositional defiant disorder who had participated in either of two identical, 6-week, randomized, double-blind, placebo-controlled trials. All received treatment with either placebo or oral risperidone solution (0.01-0.06 mg/kg/day). Subjects had below average intelligence [intelligence quotient (IQ) 36-84] and a score of > or =24 on the Conduct Problem subscale of the Nisonger Child Behaviour Rating Form (N-CBRF). An expert advisory panel selected six core aggression items from the N-CBRF, from which a total Aggression Score (AS, range 0-18) was constructed. Compared to those treated with placebo, risperidone-treated subjects experienced significantly greater mean decreases from baseline in the AS at each of weeks 1-6 (P<0.001). By study endpoint, aggression among risperidone-treated subjects had declined by 56.4% (mean baseline AS 10.1; mean endpoint AS 4.4), which was more than twice that of placebo-treated subjects (mean baseline AS 10.6; mean endpoint AS 8.3; 21.7% reduction). Risperidone was efficacious in reducing symptoms of aggression in boys of below average IQ with disruptive behaviour disorders.

Open-label adjunctive topiramate in the treatment of unstable bipolar disorder.

OBJECTIVE: To assess open-label adjunctive topiramate in the treatment of outpatients with unstable bipolar disorder (BD). METHOD: Outpatients with DSM-IV-defined BD (I or II) exhibiting mood instability were enrolled in this 16-week, open-label, multicentre study. Topiramate was added to existing mood stabilizers and other psychotropic treatments. The primary effectiveness measure was the Clinical Global Impression of Severity (CGI-S) scale; other scales included the Young Mania Rating Scale (YMRS) and the Montgomery-Asberg Depression Rating Scale (MADRS). Safety assessments included monitoring adverse events, measuring tremor, monitoring vital signs and weight, and laboratory indices. We also evaluated patient satisfaction with treatment. RESULTS: A total of 109 patients were enrolled. Intent-to-treat analysis showed significant improvement from baseline in the CGI-S, YMRS, and MADRS, starting at Week 2 (P < 0.001), with further accrual of benefit between Week 2 and Week 16 (P < 0.001). The mean modal dosage of topiramate during the stable dosing period was 180 mg daily. There was a mean 1.8 kg decrease in patient weight from topiramate initiation to Week 16 (P < 0.001). Topiramate was well tolerated by most patients; 11% withdrew from the study owing to adverse events. We noted a significant reduction in the mean severity score for preexisting tremor by Week 8 of treatment (P < 0.005); no notable changes in vital signs were observed. At Week 16, 50% of the patients were "completely satisfied" with topiramate treatment. CONCLUSIONS: Adjunctive topiramate treatment can reduce the severity of manic and depressive symptoms, as well as reducing tremor and weight in outpatients with BD I or II.

Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials.

OBJECTIVE: The authors explored the effect of galantamine on behavioral symptoms in Alzheimer disease (AD). METHODS: Data were pooled from 2,033 subjects with mild-to-moderate AD who had participated in one of three randomized, double-blind, placebo-controlled trials of 3-, 5-, and 6-month durations. Subjects included in this post hoc analysis had received treatment with either placebo (N=686) or galantamine (N=1347) in total daily doses of 16 mg, 24 mg, or 32 mg. Behavioral symptoms were measured on the 10-item Neuropsychiatric Inventory (NPI). Four symptom clusters were defined a priori: 1) delusions, hallucinations; 2) agitation, depression, anxiety, apathy, irritability; 3) disinhibition, elation, aberrant motor behavior; 4) hallucinations, anxiety, apathy, aberrant motor behavior. RESULTS: At endpoint, mean changes from baseline in NPI scores were significantly different between galantamine-treated subjects and placebo-treated subjects, favoring galantamine for several measures: total NPI, individual domains of agitation/aggression, anxiety, disinhibition, and aberrant motor behavior, and Clusters 1, 3, and 4. The magnitude of the effect sizes was small. CONCLUSIONS: In this pooled sample of more than 2,000 subjects with mild-to-moderate AD, those who received galantamine therapy experienced modestly better, but statistically significant, outcomes in their behavioral symptoms than placebo-treated subjects. The cluster of hallucinations, anxiety, apathy and aberrant motor behaviors may represent a specific group of cholinergic-responsive behavioral symptoms.

Pharmacotherapy of disruptive behavior and item changes on a standardized rating scale: pooled analysis of risperidone effects in children with subaverage IQ.

BACKGROUND: Disruptive behavior disorders (DBDs), excluding attention deficit/hyperactivity disorder (ADHD), are characterized by a repetitive pattern of antisocial, aggressive, and defiant behavior involving major violations of age-appropriate norms, resulting in significant functional impairment. Risperidone is licensed for the treatment of DBDs in children, adolescents, and adults in several countries. The aim of this study was to determine the effect of risperidone in a clinical setting on the symptom items of the Nisonger Child Behavior Rating Form (N-CBRF), used for the assessment of DBD patients. METHOD: Data from two 6-week, randomized, double-blind, placebo-controlled trials of risperidone oral solution (0.02-0.06 mg/kg/day) in children with DBDs and subaverage IQ (mild, moderate mental retardation and borderline IQ) were pooled for analysis. RESULTS: Risperidone produced improvement in both the Social Competence and the Problem Behavior N-CBRF subscales. Risperidone reduced symptoms in the Problem Behavior subscales (e.g., Conduct Problem, Insecure/Anxious) but also improved positive behaviors on the Social Competence subscales. Unlike most problem-behavior items, certain items reflecting "Affective insecurity" (e.g., shy, timid; clings to adults; crying, tearful episodes) failed to improve. This was also true of social disinterest and certain rituals. No items showed any worsening of symptoms with active medication. CONCLUSION: Whereas most categories of problem behavior improved with risperidone, items reflecting "affective insecurity" and some infrequently endorsed items were unaffected in these children with DBDs and subaverage IQ. These data may provide a more refined knowledge of risperidone's therapeutic effects in such children.

Acceptability and disintegration rates of orally disintegrating risperidone tablets in patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: To investigate the disintegration profile, acceptability, and tolerability of orally disintegrating risperidone tablets in patients with schizophrenia or schizoaffective disorder. METHOD: Ten patients stable for at least 10 days on monotherapy with oral risperidone 2 mg to 4 mg taken once daily were switched for 7 days to an equivalent dosage of orally disintegrating risperidone. Visual assessments for time to initial and complete disintegration were collected at each visit. Clinical Global Impression of Severity scores were collected at baseline and at the last visit. Patient acceptance of the new formulation, rated according to a visual analog scale, was obtained at the last visit. RESULTS: All patients maintained stable clinical status. Mean time to initial disintegration was 5.1 seconds, SD 0.8, and mean time to complete disintegration was 29.4 seconds, SD 18.4. The formulation was rated as very acceptable. Adverse events were reported by 5 patients; all were mild. CONCLUSION: The orally disintegrating risperidone tablets were well tolerated and rated as very acceptable by all patients.

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.

Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania.

This exploratory analysis was performed to compare the efficacy and tolerability of risperidone when added to two different mood stabilizers (lithium or valproate) for mania in bipolar disorder. Patients receiving lithium or valproate at baseline were drawn from the database of a 12-week, open-label risperidone study. The primary efficacy measure was the Young Mania Rating Scale (YMRS). Other assessments included the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI) of improvement, and safety measures. The analysis included 33 patients on lithium plus risperidone and 46 patients on valproate plus risperidone. Both subgroups had comparable baseline YMRS scores (lithium 28.2, valproate 28.7) and both had significant reductions in score by week 1 (P<0.0001). Comparable reductions in score continued for both subgroups until the end of the study (YMRS scores at week 12: lithium 4.6 and valproate 6.7). There were no significant differences in response rates (> or =50% improvement on YMRS) or remission rates (YMRS score < or = 8) between the two subgroups. At week 12, 88% of the lithium plus risperidone patients and 80% of the valproate plus risperidone patients were in remission. Similarly, HAM-D scores were significantly and comparably reduced in both subgroups, and improvement in CGI was the same. There was no difference between subgroups in the incidence of adverse events or weight gain. These data suggest that risperidone can be safely combined with either lithium or valproate, and that the efficacy is similar regardless of the mood stabilizer used.

Prolactin levels during long-term risperidone treatment in children and adolescents.

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin (SHAP). METHOD: Data from 5 clinical trials (total N = 700) were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment (0.02-0.06 mg/kg/day) for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form. RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (N = 358) and 13.0 ng/mL at weeks 52 to 55 (N = 42). There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range (

Risperidone in acute and continuation treatment of mania.

In a prospective study, we examined the efficacy of risperidone added-on to mood stabilizers in the acute and continuation treatment of mania over a 12-week period. Patients (n=108) with a DSM-IV diagnosis of bipolar disorder, manic or mixed episode requiring treatment with an antipsychotic were recruited. All subjects were on one or two mood stabilizers at the time of initiation of risperidone (range 0.5-4 mg). No other antipsychotic medication or ongoing benzodiazepine therapy was allowed. There was a significant decrease in mean Young Mania Rating Scale (YMRS) scores from baseline (27.5+/-7.5) to week 1 (-10.8, P<0.0001), week 3 (-17.7, P<0.0001) and to week 12(-22.6, P<0.0001). When response was defined as > or = 50% reduction in YMRS scores from baseline, 32%, 68% and 90% of patients met criteria at week 1, week 3 and week 12, respectively. Significant decreases in mean 21-item Hamilton Depression Rating Scale scores from baseline (12.2+/-7.7) to week 3 (-5.7, P<0.0001) and week 12 (-5.7, P<0.0001) were also observed. No significant changes in extrapyramidal symptoms were noted between baseline and endpoint. The mean daily dose of risperidone was 2 mg with a median of 1.8 mg. These findings support the results of the two previous double-blind, randomized trials and indicate that the addition of risperidone to mood stabilizers is a safe and effective treatment for acute and continuation treatment of mania. Risperidone add-on does not induce depressive symptoms and, furthermore, risperidone may have efficacy in treating comorbid depressive symptoms in bipolar patients.