A randomized, double-blind, dose-controlled study of the use of dexmedetomidine alone for procedural sedation of children and adolescents undergoing MRI scans.

BACKGROUND: Dexmedetomidine is a selective α2-adrenergic agonist originally approved for sedation of adults in the intensive care unit and subsequently approved for procedural sedation in adults undergoing medical procedures. Dexmedetomidine is widely used off-label for procedural sedation in children. AIMS: To evaluate efficacy and safety of monotherapy dexmedetomidine for magnetic resonance imaging procedural sedation of children ≥1month-<17years across three ascending doses. METHODS: Randomized, double-blind, dose-ranging study of procedural sedation recruited patients at USA and Japanese sites from February 2020 to November 2021. Patients were stratified into Cohort A (≥1month-<2years) or Cohort B (≥2-<17years). Cohort A loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.0 mcg/kg/1.0 mcg/kg/h, and 1.5 mcg/kg/1.5 mcg/kg/h. Cohort B loading doses/maintenance infusions: 0.5 mcg/kg/0.5 mcg/kg/h, 1.2 mcg/kg/1.0 mcg/kg/h, and 2.0 mcg/kg/1.5 mcg/kg/h. Primary endpoint was percentage of overall patients completing MRI without rescue propofol at the high versus low dose. Key secondary endpoint was percentage in each age cohort who did not require propofol at the high versus low dose. RESULTS: One hundred twenty-two patients received high- (n = 38), middle- (n = 42), or low-dose (n = 42) dexmedetomidine. A greater percentage completed MRI without propofol rescue, while receiving high- versus low-dose dexmedetomidine (24/38 [63.2%] vs. 6/42 [14.3%]) (odds ratio: 10.29, 95% confidence interval: 3.47-30.50, p < .001). Similar results were seen in both age cohorts. The most common adverse events were bradypnea, bradycardia, hypertension, and hypotension, and the majority were of mild-to-moderate severity. CONCLUSIONS: Dexmedetomidine was well tolerated. The high dose was associated with meaningfully greater efficacy compared with lower doses. Based on these results, the recommended starting dose for procedural sedation in children ≥1month-<2years is loading dose 1.5 mcg/kg/maintenance infusion 1.5 mcg/kg/h; children ≥2-<17years is loading dose 2.0 mcg/kg/maintenance infusion 1.5 mcg/kg/h.

Effects of Long-Term Sertraline Use on Pediatric Growth and Development: The Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES).

Objective: To describe the results of the Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES) outcome measures of cognitive, emotional, and physical development following long-term treatment with sertraline (for up to 3 years) in children and adolescents aged 6-16 years. Methods: SPRITES was a long-term, multicenter, open-label, prospective observational study designed to compare physical and psychological development in pediatric patients exposed to sertraline (with or without psychotherapy) or psychotherapy alone in usual care settings. Data were summarized descriptively, and outcomes were evaluated using a marginal structural model. Results: Between April 2012 and September 2020, 941 patients across 44 U.S. sites participated in the study. At baseline, 695 participants were exposed to sertraline (physician prescribed) with or without psychotherapy, and 245 participants were exposed to psychotherapy alone. Of these, 432 participants (46.0%) completed the full 3-year study follow-up. No significant changes across time were found in standardized height, BRIEF (Behavior Rating Inventory of Executive Function), Trails B, and Tanner stage based on cumulative sertraline exposure or exposure since the last visit. Change in mean standardized weight across time was positively associated with both cumulative sertraline exposure (p = 0.02) and exposure since the last visit (p = 0.029). The mean changes from baseline across time in standardized weight were standard deviations of 0.02, 0.03, 0.16, and 0.17 at months 3, 6, 30, and 36, respectively. However, this finding was not observed in the mean change across time in standardized body mass index, which was not statistically significant. Conclusions: Results are consistent with normal development. Although a statistically significant finding for standardized weight was observed in comparative analyses, the magnitude of the change is small and observed at higher doses of sertraline only. No other significant differences were observed between the "sertraline" group and the "no pharmacological therapy" group on other primary outcome measures. ClinicalTrials.gov identifier: NCT01302080.

26-Week Open-Label Extension Study Evaluating the Safety and Tolerability of Flexible Doses of Oral Ziprasidone in Children and Adolescents with Bipolar I Disorder (Most Recent Episode Manic).

Objective: To describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I). Methods: A subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks. Results: The most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania. Conclusions: The overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Efficacy, Safety, and Tolerability of Flexibly Dosed Ziprasidone in Children and Adolescents with Mania in Bipolar I Disorder: A Randomized Placebo-Controlled Replication Study.

Objective: To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Methods: Participants, 10-17 years of age, meeting The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. Results: A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone (n = 86) or placebo (n = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32; p = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI z-scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Conclusions: Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: ClinicalTrials.gov. NCT02075047 and NCT03768726.

Diagnostic Trends and Prescription Patterns in Disruptive Mood Dysregulation Disorder and Bipolar Disorder.

OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) was introduced in DSM-5 to distinguish a subset of chronically irritable youth who may be incorrectly diagnosed and/or treated for pediatric bipolar disorder (BPD). This study characterized the rate of new treatment episodes and treated prevalence of BPD and DMDD from a longitudinal electronic health record database and examined the impact of DMDD on prescription trends. METHOD: A retrospective cohort study using 2008-2018 Optum electronic health record data was conducted. Youth aged 10 to < 18 years with ≥ 183 days of database enrollment before the study cohort entry were included. Annual new treatment episode rates per 1,000 patient-years and treated prevalence (%) were estimated. Prescriptions for medications, concomitant diagnoses, and acute mental health service use for 2016-2018 were evaluated. RESULTS: There were 7,677 youths with DMDD and 6,480 youths with BPD identified. Mean age (13-15 years) and ethnicity were similar for both groups. A rise in new treatment episode rates (0.87-1.75 per 1,000 patient-years, p < .0001) and treated prevalence (0.08%-0.35%, p < .0001) of DMDD diagnoses (2016-2018) following diagnosis inception was paralleled by decreasing new treatment episode rates (1.22-1.14 per 1,000 patient-years, p < .01) and treated prevalence (0.42%-0.36%, p < .0001) of BPD diagnoses (2015-2018). More youth in the DMDD group were prescribed medications compared with the BPD group (81.9% vs 69.4%), including antipsychotics (58.9% vs 51.0%). Higher proportions of youth with DMDD vs youth with BPD had disruptive behavior disorders (eg, 35.9% vs 20.5% had oppositional defiant disorder), and required inpatient hospitalization related to their mental health disorder (45.0% vs 33.0%). CONCLUSION: Diagnosis of DMDD has had rapid uptake in clinical practice but is associated with increased antipsychotic and polypharmacy prescriptions and higher rates of comorbidity and inpatient hospitalization in youth with a DMDD diagnosis compared with a BPD diagnosis.

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24 hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3 hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

Sertraline Pediatric Registry for the Evaluation of Safety: Design and Clinical Characteristics of Pediatric Patients Prescribed Sertraline.

Objectives: To describe the study design and clinical characteristics of patients in the Sertraline Pediatric RegIstry for The Evaluation of Safety (SPRITES). Methods: SPRITES is an open-label postmarketing study of development and safety outcomes in patients aged 6 to 16 years treated with sertraline (with or without psychotherapy) compared with psychotherapy alone for up to 3 years in the United States. Baseline data included demographics and psychiatric history. Primary outcomes included measures of cognitive and emotional development (Trails B, Behavior Rating Inventory of Executive Function [BRIEF]), physical development (height and weight), and pubertal status (Tanner Stage). Data were also collected on present/lifetime risk of suicide-related events using the Columbia-Suicide Severity Rating Scale. Results: SPRITES enrolled 941 patients between the ages of 6 and 16 years. Patients' baseline mean age was 11.9 years (2.9), 57.2% were female, and 84.8% were white. Most patients (78.4%) had an anxiety disorder, and 15.6% were diagnosed with obsessive-compulsive disorder. The mean age at onset of first mental illness was 7.9 years. A higher percentage of sertraline-treated patients compared with patients who received no pharmacological treatment received prior psychotherapy (59.0% vs. 34.4%, p < 0.001), psychotropic medications for a psychiatric disorder (14.1% vs. 3.3%, p < 0.001), and other non-sertraline selective serotonin reuptake inhibitors (8.6% vs. 1.2%, p < 0.001). Most patients were moderately ill on the Clinical Global Impressions-Severity scale, and a higher (p < 0.001) percentage of sertraline-treated patients had a moderate-to-severe mental illness score compared with the no pharmacological treatment group (73.0% vs. 57.8%, respectively). Although patients at high and imminent risk of a suicidal event were excluded at study entry, the sertraline-treated patients reported higher levels of lifetime suicidal behavior compared with patients treated with no pharmacological treatment (5.8% vs. 2.5%, p = 0.039). Conclusions: Baseline data from this nonrandomized observational study suggest that patients prescribed sertraline are reflective of a more mentally ill study population compared with patients receiving psychotherapy. ClinicalTrials.gov identifier: NCT01302080.

Diagnosis and Treatment Options for Preschoolers with Attention-Deficit/Hyperactivity Disorder.

Objective: The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), classifies attention-deficit/hyperactivity disorder (ADHD) as a neurodevelopmental disorder, with symptoms becoming apparent as early as the preschool years. Early recognition can lead to interventions such as parent/teacher-administered behavior therapy, the recommended first-line treatment for preschool patients. There are few data, however, to inform the use of second-line, pharmacotherapy options in this population. In this review, we identified recent literature on the diagnosis and treatment of ADHD in preschool children. Methods: A PubMed and clinicaltrials.gov search was conducted for trials assessing efficacy or safety of ADHD medications in children aged <6 years. Diagnostic methods and criteria focusing on recognition of ADHD in preschool children were also surveyed. Results: The DSM-5 describes different manifestations of ADHD in preschool versus school-aged children, but does not list separate criteria by age group. Importantly, behaviors indicative of ADHD in older children may be developmentally appropriate in preschool children. Several behavioral rating scales have been validated in children younger than 6 years of age for assessing ADHD. The Preschool ADHD Treatment Study (PATS) has provided the most extensive efficacy and safety data on methylphenidate (MPH) for ADHD in preschoolers to date, with significant improvement in ADHD symptoms observed with MPH compared with placebo, although adverse event-related discontinuation was higher in PATS compared with studies of MPH for ADHD in school-aged children. Since PATS was conducted, few studies designed to assess ADHD medication effectiveness in preschool children have been published. One article reported significant improvement in ADHD symptoms with MPH (immediate release) versus placebo, two studies showed no difference between MPH and risperidone or MPH plus risperidone in relief of ADHD symptoms, and one study demonstrated the efficacy of atomoxetine versus placebo for ADHD symptoms in preschoolers. Conclusions: Further research is needed on pharmacotherapy for preschool children with ADHD.

A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects.

The effect of steady-state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single-center, randomized, 3-way crossover, double-blind, placebo- and moxifloxacin-controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12-lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed-effect model with sequence, period, treatment, time, and treatment-by-time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure-response was assessed using linear mixed-effect modeling. Fifty-four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10-millisecond significance threshold at the 4-hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635-11.666]). In the exposure-response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady-state 400-mg/day dose.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.

Optimization of Methylphenidate Extended-Release Chewable Tablet Dose in Children with ADHD: Open-Label Dose Optimization in a Laboratory Classroom Study.

OBJECTIVE: To examine methylphenidate extended-release chewable tablets (MPH ERCT) dose patterns, attention-deficit/hyperactivity disorder (ADHD) symptom scores, and safety during the 6-week, open-label (OL) dose-optimization period of a phase 3, laboratory classroom study. METHODS: Boys and girls (6-12 years) diagnosed with ADHD were enrolled. MPH ERCT was initiated at 20 mg/day; participants were titrated in 10-20 mg/day increments weekly based on efficacy and tolerability (maximum dose, 60 mg/day). Dose-optimization period efficacy assessments included the ADHD Rating Scale (ADHD-RS-IV), analyzed by week in a post hoc analysis using a mixed-effects model for repeated measures with final optimized dose (20, 30/40, or 50/60 mg), visit, final optimized dose and visit interaction, and baseline score as terms. Adverse events (AEs) and concomitant medications were collected throughout the study. RESULTS: Mean MPH ERCT daily dose increased weekly from 29.4 mg/day after the first dose adjustment at week 1 (n = 90) to 42.8 mg/day after the final adjustment at week 5 (n = 86). Final optimized MPH ERCT dose ranged from 20 to 60 mg/day. Mean final optimized MPH ERCT dose ranged from 40.0 mg/day in 6-8 year-old participants to 44.8 mg/day for 11-12 year-old participants. There was a progressive decrease in mean (standard deviation) ADHD-RS-IV total score from 40.1 (8.72) at baseline to 12.4 (7.88) at OL week 5, with similar improvement patterns for hyperactivity/impulsivity and inattentiveness subscale scores. Participants optimized to MPH ERCT 50/60 mg/day had a significantly higher mean (standard error) ADHD-RS-IV score at baseline compared with participants optimized to MPH ERCT 20 mg/day (42.4 [1.34] vs. 35.1 [2.55]; p = 0.013). Treatment-emergent AEs were reported by 65/90 (72.2%) participants in the dose-optimization period. CONCLUSIONS: Dose-optimization period results describing relationships between change in ADHD symptom scores and final optimized MPH ERCT dose will be valuable for clinicians optimizing MPH ERCT dose.

Assessment of Suicidal Ideation and Behavior: Report of the International Society for CNS Clinical Trials and Methodology Consensus Meeting.

OBJECTIVE: To develop consensus recommendations for assessment of suicidal ideation/suicidal behavior (SI/SB) in clinical trials. PARTICIPANTS: Stakeholders from academia, industry, regulatory agencies, National Institutes of Health, National Institute of Mental Health, and patient advocacy organizations participated in a consensus meeting that was sponsored by the International Society for CNS Clinical Trials and Methodology and held November 17-18, 2015. Prior to the meeting, teams of experts identified key areas of consensus and dissent related to SI/SB. The most critical issues were presented and discussed in the consensus meeting. EVIDENCE: Literature reviews and a pre-meeting survey were conducted. Findings were discussed in pre-meeting working group sessions and at the consensus meeting. CONSENSUS PROCESS: Five pre-meeting working groups reviewed (1) nomenclature and classification schemes for SI/SB, (2) detection and assessment of SI/SB, (3) analysis of SI/SB data, (4) design of clinical trials for new treatments of SI/SB, and (5) public health approaches to SI/SB. A modification of the RAND/UCLA Appropriateness Method was used to combine review of scientific evidence with the collective views of experts and stakeholders to reach the final consensus statements. After discussion, all attendees voted using an electronic interactive audience response system. Areas of agreement and areas of continuing dissent were recorded. CONCLUSIONS: All 5 working groups agreed that a major barrier to advancement of the field of SI/SB research and the development of new treatments for SI/SB remains the lack of a universally accepted standardized nomenclature and classification system. Achieving alignment on definitions and classification of suicide-related phenomena is critical to improving the detection and assessment of SI/SB, the design of clinical trials for new treatments, and effective public health interventions.

Efficacy and Safety of a Chewable Methylphenidate Extended-Release Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: This phase 3, laboratory classroom study assessed the efficacy and safety of methylphenidate hydrochloride extended-release chewable tablets (MPH ERCT) compared with placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Following a 6-week, open-label, dose-optimization period, children 6-12 years of age (n = 90) with ADHD were randomly assigned to double-blind MPH ERCT at the final optimized dose (20-60 mg/day) or placebo. After 1 week of double-blind treatment, efficacy was assessed predose and 0.75, 2, 4, 8, 10, 12, and 13 hours postdose in a laboratory classroom setting. The primary efficacy measure was the average of postdose Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale-Combined scores, analyzed using a mixed-model, repeated-measures analysis. Secondary efficacy measures included Permanent Product Measure of Performance (PERMP) total number of problems attempted and total number of problems correct. Safety assessments included adverse event (AE) monitoring and the Columbia-Suicide Severity Rating Scale (C-SSRS). RESULTS: MPH ERCT treatment statistically significantly reduced the average of all postdose SKAMP-Combined scores versus placebo (least-squares mean difference [95% confidence interval], -7.0 [-10.9, -3.1]; p < 0.001). Statistically significant treatment differences in SKAMP-Combined scores were observed at 2 hours postdose through 8 hours postdose (p-values <0.001). Statistically significant differences between MPH ERCT and placebo in PERMP total number of problems attempted and total number of problems correct were observed at 0.75 hours postdose through 8 hours postdose (p-values ≤0.049). Common AEs in the open-label period (≥5%) were decreased appetite, upper abdominal pain, mood swings, irritability, insomnia, upper respiratory tract infection (URTI), dysgeusia, and headache; URTI was the only AE reported by >1 subject receiving MPH ERCT in the double-blind period (placebo: URTI, contusion, wound, and initial insomnia). No suicidal ideation or behavior was reported on the C-SSRS at baseline or at any postbaseline assessment. CONCLUSIONS: MPH ERCT 20-60 mg significantly improved ADHD symptoms compared with placebo at 2 hours postdose through at least 8 hours postdose. MPH ERCT was generally safe and well tolerated, with a safety profile consistent with other MPH ER formulations. ClinicalTrials.gov Identifier: NCT01654250. www.clinicaltrials.gov/ct2/show/NCT01654250 .

Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia.

INTRODUCTION: Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence. METHODS: The literature regarding SI/SB in older persons with cognitive impairment or dementia was reviewed by an Alzheimer's Association Taskforce with emphasis on epidemiology, classification, assessment, and regulatory requirements. RESULTS: Gaps in our knowledge were identified, challenges discussed and recommendations for future work provided. DISCUSSION: Currently available SI/SB data from geriatric persons with dementia do not provide adequate understanding of its epidemiology, identification, assessment, or management. The growing public health burden of this population requires greater attention from clinicians and researchers on tactics and assessment tools to meet these needs.

Suicidal ideation and behavior assessment in dementia studies: An Internet survey.

INTRODUCTION: The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials. METHODS: Investigators with experience in conducting SI/SB assessments in clinical trial subjects with MCI or dementia were invited to complete a global 19-item online survey. RESULTS: A total of 204 evaluable responses were collected with the majority from North America and Europe (83.4%) and the remainder from Asia, Latin America, and Mideast/Africa. The mean (SD) number of subjects personally assessed by the respondents in the past year with MCI, mild-moderate dementia, or severe dementia was 12.8 (26.2), 31.2 (39.6), and 10.1 (34.7), respectively. The mean number of subjects in each diagnostic group with suicidal ideation (SI), suicidal behavior (SB), or completed suicide (CS) was on average quite low (0.3 to 1.1 for SI, 0.1 to 0.2 for SB, and 0.0 to 0.2 for CS). Confidence in subject self-reports of SI/SB over different time periods declined with increasing severity of cognitive impairment and with increasing duration of the recall time period assessed. Of respondents, 56% and 75% had low confidence in self-ratings of SI/SB from subjects with severe dementia over the past 24 hours and the past week to 1 month, respectively. Ratings of the reliability of information collected on SI/SB also decreased with increasing severity of cognitive impairment. Approximately 70% of respondents rated the reliability of the information they obtained from all sources (patient, caregiver, and others) for subjects with MCI as high, but only about half (42.0% to 55.3%) and less than a quarter (17.4% to 24.3%) rated the reliability of information obtained for subjects with mild to moderate dementia or severe dementia as high, respectively. DISCUSSION: These results support the usefulness of prospective SI/SB assessments in MCI and mild dementia, raise questions about the reliability of assessments in moderate dementia, and confirm their lack of clinical utility in severe dementia. The results highlight the need for development of validated assessment instruments adapted to the stage of cognitive decline of the patients under study and may be the most effective in the earliest stages of the disease.

Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices.

OBJECTIVE: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. DESIGN: An internet-based survey. SETTING: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. PARTICIPANTS: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. MEASUREMENTS: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. RESULTS: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). CONCLUSION: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern.

Study Site Experiences and Attitudes Toward Prospective Assessments of Suicidal Ideation and Behavior in Clinical Trials: Results of an Internet-based Survey.

OBJECTIVE: The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Working Group conducted an online survey regarding clinical trial site experiences and attitudes toward suicidal ideation and behavior data collection following the 2010 release of the initial United States Food and Drug Administration draft guidance on prospective assessment of suicidal ideation and behavior in clinical trials. Sites that had participated in at least one central nervous system clinical trial in the prior two years (N=6,058) were invited, via email, to complete a 20-item online assessment survey. RESULTS: Nine hundred and seventy-nine evaluable responses were collected (42% United States). Respondents included principal investigators (36%), raters (28%), coordinators (25%), and others (10%). The majority were psychiatrists (43%) and reported using suicidal ideation and behavior assessments across many indications. Most respondents (80%) personally conducted suicidal ideation and behavior assessments. Overall, respondents indicated that suicidal ideation and behavior assessments were readily incorporated into the conduct of clinical trials and improved subject safety. The greatest challenge was obtaining an accurate baseline lifetime history (51%), while the greatest benefit was identifying subjects at risk of suicide (84%). Approximately a quarter of respondents reported implementation challenges such as training. Differences based on geographical region, respondents' roles, and responsibility for assessments were observed. Open-ended responses revealed additional challenges, e.g., use in cognitively impaired populations. CONCLUSION: Prospective suicidal ideation and behavior monitoring was generally viewed positively, though specific challenges were identified. Limitations include self-report survey methodology and recruitment of only central nervous system clinical trials sites. These findings may help guide development of better methodologies for suicidal ideation and behavior assessment in clinical trials.

Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess efficacy and safety of adjunctive ziprasidone in subjects with bipolar depression treated with lithium, lamotrigine, or valproate. METHOD: 298 adult outpatients with bipolar I disorder (DSM-IV criteria) were randomized to receive ziprasidone, 20-80 mg twice a day, or placebo twice a day for 6 weeks plus their preexisting mood stabilizer. The primary efficacy variable was change in Montgomery-Asberg Depression Rating Scale (MADRS) total scores from baseline to 6 weeks. The key secondary efficacy endpoint was change from baseline to week 6 in Clinical Global Impressions-Severity (CGI-S) scores. Computer-administered assessments for diagnostic confidence were included for quality control and to evaluate study performance. The study was conducted between October 2007 and December 2008. RESULTS: The mean ± SD daily dose of ziprasidone was 89.8 ± 29.1 mg. Least squares mean ± standard error changes from baseline to week 6 on MADRS total score for ziprasidone and placebo treatment groups were -13.2 ± 1.2 and -12.9 ± 1.1, respectively, with a 2-sided P value of .792. There was no significant difference on the key secondary variable (CGI-S). Adjunctive ziprasidone was well tolerated. Poor quality ratings at baseline were associated with a trend for better improvement on placebo than ziprasidone. Among 43 placebo-treated subjects with poor baseline quality ratings, 29 (67.4%) had baseline MADRS scores > 10 points higher on the computer-administered assessment than the MADRS administered by the site-based rater. The response favoring placebo over ziprasidone observed in this subgroup suggests that poor signal detection in some clinical trials can be a consequence of "subject inflation" as well as "rater inflation." CONCLUSIONS: Adjunctive ziprasidone treatment failed to separate from mood stabilizer alone on primary and secondary endpoints. Possible contributions to this result include enrollment of a substantial number of subjects with low diagnostic confidence, low quality ratings on the MADRS, and overzealous reporting of symptoms by subjects. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00483548.

Switching from quetiapine to ziprasidone: a sixteen-week, open-label, multicenter study evaluating the effectiveness and safety of ziprasidone in outpatient subjects with schizophrenia or schizoaffective disorder.

OBJECTIVE: The objectives of this study were to evaluate the effects of switching from quetiapine to ziprasidone on weight, safety, and effectiveness METHODS: In this study, 241 subjects with schizophrenia or schizo affective disorder who had been treated with quetiapine (≥300 mg/day) for ≥3 months with either suboptimal efficacy or poor tolerability were enrolled in a 16-week, open-label, flexible-dose trial, with a 16-week follow-up (total 32 weeks). Quetiapine was tapered and discontinued over the course of 2 weeks, while ziprasidone was titrated up and dosed at 40-80 mg b.i.d. The primary endpoint was weight change (kg) from baseline at 16 weeks. Secondary endpoints were change in waist/hip circumference, lipid profile, fasting glucose, and glycosylated hemoglobin (HbA1c). Additional secondary endpoints included changes in scores on the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions Improvement and Severity Scales (CGI-I and CGI-S), the Calgary Depression Scale for Schizophrenia (CDSS), the Schizophrenia Cognition Rating Scale (ScoRS), and the Global Assessment of Functioning (GAF). Safety measures included adverse event (AE) reporting and administration of the Abnormal Involuntary Movement Scale (AIMS). RESULTS: At week 16, there was a small but statistically significant decrease in weight, with a mean change from baseline of -0.73 kg (1-sided 95% upper confidence bound=-0.33) using the last observation carried forward [LOCF] approach. There were small mean decreases in levels of total cholesterol, low density lipoprotein (LDL), and triglycerides at week 16, but no change in fasting glucose or HbA1c. At week 16, there were also significant changes indicating improvement in the secondary clinical assessments, including the PANSS scores, CGI-S, CDSS, SCoRS and GAF. There was no change in the AIMS. AEs included insomnia (12.4%), somnolence (13.7%), and nausea (9.1%). CONCLUSION: Subjects switching from quetiapine to ziprasidone showed a small but significant decrease in weight as well as improved lipid profiles, regardless of their metabolic status and disease severity at baseline. Subjects also showed improvement in clinical symptoms and in cognitive functioning. Ziprasidone, with a comparatively neutral metabolic profile relative to other antipsychotics, may be an effective treatment alternative for patients experiencing weight gain or lack of tolerability with quetiapine.