Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions.

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research.

Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder.

Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence-based literature to make critical therapeutic decisions for pediatric patients. Effective and scientifically justified dosing recommendations are needed to improve treatment outcomes in pediatric patients with schizophrenia and bipolar I disorder. Extrapolation-based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the US Food and Drug Administration (FDA) released a general advice letter to sponsors highlighting the acceptance of extrapolating efficacy of atypical antipsychotics to pediatric patients. This review provides insight into the FDA's justification for extrapolating efficacy from adult to pediatric patients and provides a rationale for dose selection in pediatric patients with schizophrenia and bipolar I disorder.

Shortened Positive and Negative Symptom Scale as an Alternate Clinical Endpoint for Acute Schizophrenia Trials: Analysis from the US Food & Drug Administration.

Objective: To evaluate the performance of the individual Positive and Negative Symptom Scale (PANSS) items, and to assess the feasibility of using a shortened version of the PANSS as an alternative regulatory endpoint for evaluating the efficacy of drugs to treat schizophrenia. Design: Data from 32 randomized, placebo-controlled, multiregional trials from eight atypical antipsychotic programs (N=14,219) submitted to the US Food and Drug Administration were used in the analyses. Item response theory analysis on baseline PANSS item scores was used to identify the best performing items of the PANSS to derive the shortened, or modified, PANSS (mPANSS). Concordance rates of mPANSS total with the PANSS total trial results at week 6 were examined, and implications of using mPANSS on trial sample size evaluated. Results: Five of the positive items, six of the negative items, and eight of the general items were assessed as sensitive to describe the underlying symptom severity and comprise mPANSS. The overall concordance rate between mPANSS and total PANSS results at week 6 was 97.6%. Using mPANSS resulted in a 32% reduction in samples size relative to using total PANSS. Conclusions: Based on this research, mPANSS may be considered a potential alternative clinical endpoint for acute schizophrenia trials. However, it will need psychometric validation before it can be fully implemented in clinical trials in place of total PANSS. If such implementation occurs, the development of new drugs for schizophrenia, a public health imperative, may be considerably improved.

Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications.

Importance: Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. Objectives: To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment. Data Sources: A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs). Study Selection: All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. Data Extraction and Synthesis: Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016. Main Outcomes and Measures: The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment-emergent AEs. Results: The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial. Conclusions and Relevance: Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.

The Trend of Increasing Placebo Response and Decreasing Treatment Effect in Schizophrenia Trials Continues: An Update From the US Food and Drug Administration.

OBJECTIVE: Concerns of increasing placebo response and declining treatment effect in acute schizophrenia trials have been reported for new drug applications (NDAs) submitted to the US Food and Drug Administration (FDA) during an 18-year period from 1991 through January 2009 (ie, the pre-2009 period). Current exploratory analyses provide an update in the trends observed in placebo response, treatment effect, and dropout rates for NDAs submitted from February 2009 to 2015 (ie, the post-2009 period). DATA SOURCES: Clinical trial data from all acute schizophrenia trials that were submitted as part of NDAs to the US FDA during a 24-year period from 1991 to 2015. STUDY SELECTION: Aggregate trial-level efficacy data from multicenter, multiregional, randomized, placebo-controlled, 4- to 8-week, fixed- and flexible-dose trials in adult schizophrenia patients were compiled. There were 12 NDAs pre-2009 (32 trials, N = 11,567) and 3 NDAs post-2009 (14 trials, N = 6,434). DATA EXTRACTION: Baseline demographic and disease variables and scores on the Positive and Negative Syndrome Scale (PANSS) were summarized and compared for the two time periods (pre-2009 and post-2009). The primary efficacy measure was mean change from baseline to endpoint in total PANSS score obtained by last-observation-carried-forward analysis. Regional differences in placebo response and treatment effect were explored for the two time periods based on baseline patient characteristics, sample size, and dropout rates. RESULTS: Trials were predominantly multiregional (10/14; 71%) during the post-2009 period compared to the pre-2009 period (11/32; 34%). The overall trial success rates were 57% (8/14) and 78% (25/32) during the post-2009 and pre-2009 periods, respectively. Comparing the pre-2009 and post-2009 periods, the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5 and the mean treatment effect (drug response - placebo response) declined from -8.6 to -5.8 , with substantial differences observed especially in North American trials. In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009). The difference in placebo response (pre- and post-2009: -10.0 and -11.3 ) and treatment effect (pre and post-2009: -8.1 and -6.4 ) in multiregional trials for the two time periods remained minimal. Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100. Trials with higher mean baseline PANSS scores tended to show higher treatment effect irrespective of the time period and region. Post-2009, dropout rates were higher (55%) in North American trials compared with 33% in multiregional trials, similar to the pre-2009 trend. CONCLUSIONS: The continuing trend of increasing placebo responses and decreasing treatment effects in schizophrenia trials over the 24-year period does remain of great concern, especially with respect to North American trials. However, given the current global nature of drug development, close attention to trial conduct and reexamination of design elements for future trials may be warranted.

Assessment of Similarity in Antipsychotic Exposure-Response Relationships in Clinical Trials Between Adults and Adolescents With Acute Exacerbation of Schizophrenia.

Despite agreement that early-onset schizophrenia is continuous with the adult-onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second-generation antipsychotic development programs (N = 5951 adults and N = 1035 adolescents ranging from 12 to 17 years old) were collected from available new drug applications submitted to the US Food and Drug Administration from 1993 to 2017. The developed disease-drug trial models adequately predicted the longitudinal trend in total positive and negative syndrome scale scores in both adults and adolescents using a Weibull placebo response, time-delayed drug effect, and a Weibull structural dropout model. Maximum drug effect was similar between the two populations and was estimated to be between a range of 5% to 11% in adults and 5% to 7% in adolescents. Half maximal effective concentration parameter estimates also indicated similar exposure-response relationships in adults and adolescents across all 4 antipsychotics. Simulated adolescent data using final model parameter estimates from the adult model were in agreement with adolescent observations. This analysis confirms similarity in exposure-response for efficacy and could expedite the development of second-generation antipsychotics for adolescents.

A Quantitative Justification of Similarity in Placebo Response Between Adults and Adolescents With Acute Exacerbation of Schizophrenia in Clinical Trials.

Early-onset schizophrenia, or "adolescent schizophrenia," has a global incidence ranging up to 4% of all schizophrenia cases. Clinical data from antipsychotic programs were collected from new drug applications submitted to the US Food and Drug administration from 1993 to 2015. A placebo response-dropout model was developed to describe the time course of total positive and negative syndrome scale (PANSS) scores in adults and adolescents. The final model in both populations suggested that patients with higher baseline scores exhibited a greater absolute reduction from baseline. Higher baseline total PANSS, enrollment in US trials, and increases or small improvements in total PANSS were found to be predictors of dropout in both populations. Simulated adolescent data using the final adult placebo response model resembled the observed adolescent data. By confirming similar changes in disease symptomology during an acute exacerbation, efficient regulatory pathways for adolescents can be facilitated by using the extrapolation paradigm.

Psychiatric Medications and Reproductive Safety: Scientific and Clinical Perspectives Pertaining to the US FDA Pregnancy and Lactation Labeling Rule.

Pregnancy labeling of prescription medications in the US is in the midst of a major transformation. The FDA's previous system, which used letter ratings to convey drug safety, was simple but led to misunderstandings-both faulty assurances and undue concerns. The new system, established under the Pregnancy and Lactation Labeling Rule, aims for more descriptive and up-to-date explanations of risk as well as context needed for informed decision-making based on available data. In April 2017, a conference titled "Pharmacovigilance, Reproductive Safety, and the Pregnancy and Lactation Labeling Rule" brought together clinicians and researchers, FDA officials, and representatives of the public and industry to discuss a host of questions relating to the new system. This Academic Highlights article summarizes their discussions, which included topics such as how the new system came about and how the new labeling can be used effectively to inform physician-patient conversations about use of medications during pregnancy and ultimately the clinical decisions that follow.​​.

The US Food and Drug Administration's Perspective on the New Antipsychotic Pimavanserin.

OBJECTIVE: To summarize the US Food and Drug Administration's (FDA's) review of the safety and effectiveness for pimavanserin, an atypical antipsychotic, for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. We describe the regulatory and clinical issues important to the FDA's approval of this New Drug Application, with special focus on the risk-benefit balance. We also describe a new labeling feature that presents additional efficacy data to clinicians. DATA SOURCES: Data sets for all relevant clinical trials of pimavanserin and the Applicant's and FDA's analyses of these data were considered in this review. Data were available from 616 patients with Parkinson's disease with hallucinations and delusions who received at least 1 dose of pimavanserin, with a total exposure of 825 patient-years in the Parkinson's disease psychosis population. RESULTS: Pimavanserin 34 mg/d was effective in treating hallucinations and delusions associated with Parkinson's disease. In the Applicant's single pivotal trial, 80.5% of pimavanserin patients experienced at least some improvement in symptoms compared to 58.1% of patients taking placebo. Pimavanserin did not worsen motor function, an adverse effect commonly observed with other antipsychotics, probably because of a lack of consequential dopamine binding. CONCLUSIONS: Pimavanserin is the only FDA-approved treatment for the hallucinations and delusions seen in patients with psychosis of Parkinson's disease. Although pimavanserin appears to have a pharmacologic mechanism that is different from other atypical antipsychotics, concern remained that the increased risk of death seen with antipsychotic use in elderly demented patients, and described in all approved antipsychotic labels, would also occur with pimavanserin. Pimavanserin bears the same boxed warning about the risk of death associated with antipsychotic use in elderly patients with dementia.

Exposure-response analyses of blood pressure and heart rate changes for methylphenidate in healthy adults.

The aim of the study was to evaluate the exposure-response (E-R) relationships of blood pressure (BP) and heart rate (HR) changes in healthy adults taking methylphenidate (MPH). Intensive time profiles of BP and HR from healthy adults in placebo and MPH treatment arms of seven clinical trials from the FDA internal database were utilized for this analysis. The analysis model contains a circadian component for placebo effect and an E-R component to describe drug effect. Internal validation was performed using goodness-of-fit plots and visual predictive check. A meta-database based on a systemic literature search was constructed and used for external validation of the developed models. We found that circadian models could quantify the time profiles of BP/HR in placebo arms. Linear models could describe the correlations between MPH concentrations, and BP/HR changes. The BP and HR changes were highly dependent on the shapes of MPH pharmacokinetic (PK) profiles without an apparent time delay. MPH has the greatest effect on HR, followed by systolic BP, and diastolic BP. Internal validation revealed that the developed models could adequately describe the circadian rhythms of HR and BP in placebo arms and the E-R relationships of MPH. External validation showed the models had good predictive capability of the literature data. In conclusion, the developed models adequately characterized the circadian rhythm and the MPH induced effects on BP and HR. The changes in BP and HR were highly correlated with MPH blood levels with no apparent delay. The time courses of BP and HR are similar to the MPH PK profiles. As a result, the immediate-release formulation may yield larger maximum BP and HR effect than the extended-release formulation under similar dose.

Is bipolar disorder specifically associated with aggression?

OBJECTIVE: Several studies have suggested that bipolar disorder (BP) in adults is associated with aggressive behaviors. However, most studies have included only inpatients and have not taken into consideration possible confounding factors. The goal of the present study was to compare the prevalence of aggression in subjects with BP compared to subjects with other, non-BP psychopathology and healthy controls. METHODS: Subjects with bipolar I disorder (BP-I) and bipolar II disorder (BP-II) (n = 255), non-BP psychopathology (n = 85), and healthy controls (n = 84) were recruited. Aggression was measured using the Aggression Questionnaire (AQ). Group comparisons were adjusted for demographic and clinical differences (e.g., comorbid disorders) and multiple comparisons. The effects of the subtype of BP, current versus past episode, polarity of current episode, psychosis, the presence of irritable mania/hypomania only, and pharmacological treatment were examined. RESULTS: Subjects with BP showed significantly higher total and subscale AQ scores (raw and T-scores) when compared to subjects with non-BP psychopathology and healthy controls. Exclusion of subjects with current mood episodes and those with common comorbid disorders yielded similar results. There were no effects of BP subtype, polarity of the current episode, irritable manic/hypomanic episodes only, or current use of pharmacological treatments. Independent of the severity of BP and polarity of the episode, those in a current mood episode showed significantly higher AQ scores than those not in a current mood episode. Subjects with current psychosis showed significantly higher total AQ score, hostility, and anger than those without current psychosis. CONCLUSIONS: Subjects with BP display greater rates of anger and aggressive behaviors, especially during acute and psychotic episodes. Early identification and management of these behaviors is warranted.

Differential patterns of abnormal activity and connectivity in the amygdala-prefrontal circuitry in bipolar-I and bipolar-NOS youth.

OBJECTIVE: The functioning of neural systems supporting emotion processing and regulation in youth with bipolar disorder not otherwise specified (BP-NOS) remains poorly understood. We sought to examine patterns of activity and connectivity in youth with BP-NOS relative to youth with bipolar disorder type I (BP-I) and healthy controls (HC). METHOD: Participants (18 BP-I youth, 16 BP-NOS youth, and 18 HC) underwent functional magnetic resonance imaging while performing two emotional-face gender labeling tasks (happy/neutral, fearful/neutral). Analyses focused on a priori neural regions supporting emotion processing (amygdala) and emotion regulation (ventromedial prefrontal cortex (VMPFC), dorsolateral prefrontal cortex (DLPFC). Connectivity analyses used VMPFC as a seed region. RESULTS: During the happy-face task, BP-I youth had greater amygdala, VMPFC, and DLPFC activity to happy faces whereas BP-NOS youth had reduced VMPFC and DLPFC activity to neutral faces relative to HC, and reduced amygdala, VMPFC, and DLPFC activity to neutral faces versus BP-I. During the fearful-face task, BP-I youth had reduced DLPFC activity to fearful faces whereas BP-NOS youth had reduced DLPFC activity to neutral faces relative to HC. BP-NOS youth showed greater VMPFC-DLPFC connectivity to happy faces relative to HC and BP-I youth. BP-I youth showed reduced VMPFC-amygdala connectivity to fearful faces relative to HC and BP-NOS youth. CONCLUSIONS: This is the first study to document differential patterns of abnormal neural activity in, and connectivity between, neural regions supporting emotion processing and regulation in BP-NOS versus BP-I youth. Findings suggest that despite similarities in symptom presentation, there are differential patterns of abnormal neural functioning in BP-NOS and BP-I relative to HC, which might reflect an "intermediate state" in the course of BP-I illness. Future longitudinal studies are needed to relate these findings with future conversion to BP-I/II.

Practice parameter for child and adolescent forensic evaluations.

This Parameter addresses the key concepts that differentiate the forensic evaluation of children and adolescents from a clinical assessment. There are ethical issues unique to the forensic evaluation, because the forensic evaluator's duty is to the person, court, or agency requesting the evaluation, rather than to the patient. The forensic evaluator clarifies the legal questions to be answered and structures the evaluation to address those issues. The forensic examination may include a review of collateral information, interviews and other assessments of the child or adolescent, and interviews with other relevant informants. The principles in this Parameter suggest the general approach to the forensic evaluation of children and adolescents and are relevant to delinquency, child custody, child maltreatment, personal injury, and other court-ordered and noncourt-ordered evaluations.

Practice parameter for the assessment and treatment of children and adolescents with posttraumatic stress disorder.

This Practice Parameter reviews the evidence from research and clinical experience and highlights significant advances in the assessment and treatment of posttraumatic stress disorder since the previous Parameter was published in 1998. It highlights the importance of early identification of posttraumatic stress disorder, the importance of gathering information from parents and children, and the assessment and treatment of comorbid disorders. It presents evidence to support trauma-focused psychotherapy, medications, and a combination of interventions in a multimodal approach.