Table 2Evidence gaps after stakeholder input

Evidence GapaKQ
NOTE: The following group of evidence gaps relate to issues thought to be applicable across all studied disorders and include issues relating to safety, long term efficacy, and subpopulations of interest.N/A
For children, adolescents, and young adults, the extant literature is limited with regard to examining the long-term efficacy and effectiveness of 1st and 2nd generation antipsychotics in all disorders and behaviors of interest. Examples of longer term outcomes of interest may include outcomes important to parents and patients such as school performance, emotional development, or legal system interactions.KQ 1, 2
For children, adolescents, and young adults, the extant literature is limited with regard to studies examining the long-term safety of 1st and 2nd generation antipsychotics in all disorders and behaviors of interest. Examples of long term adverse outcomes of interest may include obesity, diabetes, cardiovascular events, or tardive dyskinesiaKQ 2, 3
The extant literature is limited with regard to evidence that allows for comparisons between and within classes of 1st and 2nd generation antipsychotics for any shorter term adverse event outcome. These outcomes include sedation, EPS, weight gain/body composition, insulin resistance, sexual adverse events, and dyslipidemiaKQ 3
The extant literature is limited with regard to evidence to determine if there are differences in efficacy, effectiveness, or adverse events for population sub-groups. Sub-groups include sex, age, race/ethnicity, co-morbidities, co-treatment, history of psychosis, history of treatment failure, or duration of illness.KQ 4
NOTE: The following 6 evidence gaps relate to specific disorders and focus not only on efficacy data from placebo controlled trials, but also on the state of the evidence as it relates to comparisons within and between the classes of 1st generation and 2nd generation antipsychotics. Further, these gaps discuss the state of the evidence for short and longer term outcomes.N/A
The evidence regarding the efficacy and effectiveness of 1st or 2nd generation antipsychotics is low or insufficient for the treatment of pervasive developmental disorders, including autistic disorder, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified.KQ 1
For children, adolescents, and young adults with both attention deficit hyperactivity disorder and disruptive behavior disorders, who have failed or had inadequate response to other therapies, there is moderate strength of evidence to support 2nd generation antipsychotics when compared with placebo for improving some behavior symptoms, most notably disruptive behaviors. However, the evidence regarding the efficacy and effectiveness of 1st or 2nd generation antipsychotics is low or insufficient for other clinically meaningful outcomes of interest. These other outcomes include: core ADHD symptoms, anxiety, social/occupational functioning, health related quality of life (HRQL), legal interactions, medication adherence, patient and parent-reported outcomes, and suicide related behavior.KQ 1
For older adolescents and young adults with bipolar disorder, there was moderate strength of evidence to support 2nd generation antipsychotics over placebo for clinical global impressions. However, the evidence regarding the efficacy and effectiveness of 1st or 2nd generation antipsychotics is low or insufficient for other outcomes such as: aggression, depression, manic symptoms, social/occupational functioning, health related quality of life (HRQL), legal interactions, medication adherence, patient and parent-reported outcomes, and suicide-related behavior.KQ 1
For adolescents and young adults with schizophrenia, there was moderate strength of evidence to support 2nd generation antipsychotics over placebo for several outcomes, including Children’s Global Assessment Scale (CGAS), clinical global impressions, and positive components of the Positive and Negative Symptoms Scale (PANSS). However, the evidence regarding the efficacy and effectiveness of 1st or 2nd generation antipsychotics is low or insufficient for other clinically meaningful outcomes such as: aggression, depression, social/occupational functioning, HRQL, legal interactions, medication adherence, patient and parent reported outcomes, and suicide related behavior.KQ 1
There was moderate strength of evidence favoring 2nd generation antipsychotics over placebo for tic symptom improvement from studies of all patients with Tourette syndrome. However, evidence is lacking with regard to other clinically meaningful outcomes for this group, and specifically for those who have failed previous treatments. Other clinically meaningful outcomes include: clinical global impressions, obsessive-compulsive symptoms, social/occupational functioning, HRQL, medication adherence, patient and parent reported outcomes, and suicide related behavior.KQ 1
For those with Obsessive Compulsive Disorder, Eating Disorders, and Post Traumatic Stress Disorder who have failed or had inadequate treatment with other therapies, there is a paucity of data regarding the efficacy and effectiveness of 1st or 2nd generation antipsychotics.KQ 1
NOTE: The group of gaps below relates to issues more methodological in nature and are not specific to drug class or disorder.N/A
The extant literature is limited with regard to the consistent use of standardized pediatric side-effect scales (e.g., the Safety Monitoring Uniform Report Form).KQ 2
The extant literature is limited with regard to consistent and comparable outcomes and outcome measurements across the studied disorders and behaviors of concern.KQ 3, Methods
The extant literature demonstrates a lack of consensus on minimal clinically important differences within many disorders.KQ 3, Methods
The extant literature lacks large-scale effectiveness studies that are generalizable to the broader population seen in clinical practices.Methods, All KQs
NOTE: The following gaps were not part of the list of evidence gaps that the stakeholders prioritized. The project team considered these methodological shortcomings of existing research and the issues were of implementation rather than requiring additional empiric evidence.N/A
The extant literature is limited with regard to efficacy studies with adequate blinding of study participants and outcome assessors, the adequate concealing of allocation and the appropriate handling and reporting of missing data.Methods, All KQs
The extant literature is limited with regard to independent/investigator driven research efforts which increases the potential for overestimated treatment effects associated with industry-funded research.Methods, All KQs
a

All of the evidence gaps refer to the population of children, adolescents, and young adults 24 years of age or younger.

Abbreviations: ADHD=attention deficit hyperactivity disorder; CGAS=Children’s Global Assessment Scale; EPS=extra-pyramidal symptoms; HRQL=health related quality of life; KQ=key question; PANSS=Positive and Negative Symptoms Scale.

From: Results

Cover of Future Research Needs for First- and Second-Generation Antipsychotics for Children and Young Adults
Future Research Needs for First- and Second-Generation Antipsychotics for Children and Young Adults [Internet].
Future Research Needs Papers, No. 13.
Christian R, Saavedra L, Gaynes BN, et al.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.