Evidence-Based Reports: First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update.

First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update - Executive Summary | AHRQ Effective Health Care Program

Executive Summary – Mar. 16, 2017

First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update

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Table of Contents

• Purpose of Review
• Key Messages
• Introduction
• Scope of Review and Key Questions
• Analytic Framework
• Methods
• Results and Discussion
• Conclusions
• References
• Citation
• Tables

Purpose of Review

To assess the effectiveness and harms of first- and second-generation antipsychotics (FGAs and SGAs) used for treating children, adolescents, and young adults.

Key Messages

• There was little information directly comparing different antipsychotics, on patient-important outcomes including quality of life, and on outcomes for young children.
• FGAs probably cause less weight gain than SGAs, and (for schizophrenia) there may be little or no difference between the classes for reducing symptoms and illness severity.
• SGAs probably improve to some extent symptoms for which they are usually prescribed, but also cause adverse effects including weight gain, high triglyceride levels, extrapyramidal symptoms, sedation, and somnolence.
• More research is needed comparing the effects of different antipsychotics over the long-term and developing monitoring systems.

Introduction

The use of psychotropic medications, including antipsychotics, in children, adolescents, and young adults has risen over the past 20 years,1-6 and use of antipsychotics in children with public health insurance2 and living in foster homes4 is greater than for those with private health insurance in the United States. During 2010, the percentages of young people filling prescriptions for antipsychotics in the United States was 0.11 percent (younger children), 0.8 percent (older children) 1.19 percent (adolescents), and 0.84 percent (young adults).5Antipsychotic medications are commonly categorized into two classes. First-generation antipsychotics (FGAs) were developed in the 1950s, while second-generation antipsychotics (SGAs) emerged in the 1980s. Each class is considered to have a distinct side-effect profile, although there is considerable overlap between them. FGAs are mainly associated with dry mouth, sedation, and extrapyramidal symptoms, which are movement disorders characterized by repetitive, involuntary muscle movements, restlessness, or an inability to initiate movement. Neuroleptic malignant syndrome is a rare but serious adverse effect. In the United States there has been a near disappearance of the use of FGAs over the last two decades.7 A shift towards SGAs was partly driven by the lower risk of extrapyramidal symptoms with their use, and other adverse events caused by the persistent dopamine receptor blockade by FGAs. The pharmacology of SGAs is diverse (based on action at several types of receptors) with associated heterogeneity in effects and harms; nevertheless, this class seems more prone than FGAs to adverse effects such as weight gain, elevated lipid and prolactin levels, and development of metabolic syndrome.8-10 This risk profile has led to great concern, because of the known associations between weight gain and obesity with diabetes, dyslipidemia, and hypertension, all of which are leading risk factors for future cardiovascular morbidity and mortality.11 This risk profile necessitates safety monitoring and prescription choices based on benefit-risk assessments.

For most FGAs and SGAs, the U.S. Food and Drug Administration (FDA)–approved indications for children (≤ 18 years of age) are restricted to the treatment of schizophrenia and bipolar mania. Other pediatric indications approved by the FDA include treatment of irritability associated with autism in children 5 years or older (risperidone in 2006 and aripiprazole in 2009) and of Tourette's syndrome in children aged 6-18 (aripiprazole in 2014) or over 8 years (pimozide). Off-label use of antipsychotics is common in children and adults.1,12Twenty-four to 31 percent of antipsychotic-treated children have attention deficit hyperactivity disorder (ADHD),1,13 and 34.5 percent of antipsychotic-treated young adults have depression.5 In Medicaid-enrolled children, ADHD accounted for 50 percent of total antipsychotic use in 2007;12 ADHD and mood disorders not otherwise specified were the most common uses (32% and 37.2%, respectively) for antipsychotics in a sample of Medicaid-insured children in Vermont during 2012.12 In these cases or other conditions such as conduct disorders, antipsychotics are usually given for adjunctive treatment of severe behavioral symptoms (e.g., aggression), rather than for psychoses.5-14 They may also be prescribed for mood instability or relatively minor symptomatology (e.g., insomnia) of a condition, or even outside the context of a condition;12 these uses are accompanied by considerable controversy because of concerns regarding the balance of benefits and harms. This is particularly relevant when other treatment options exist for many conditions; for instance, fewer than half of very young, privately insured children taking antipsychotics received formal mental health services in 2007.1

Because of the marked increase in FDA-approved and off-label use of antipsychotics, prescribing practices have been under ongoing scrutiny (including use of prior authorization by Medicaid in many U.S. States),15 and there is a need for ongoing investigation into the comparative effectiveness and harms of available medications. Practice parameters for antipsychotic use produced by the American Academy of Child and Adolescent Psychiatry (AACAP) are referred to when assessing practice for pediatrics in the United States,16 but these parameters may be considered outdated (all studies cited in the parameters were published prior to 2012) for providing the best evidence. The purpose of the systematic review is to provide a comprehensive synthesis of the evidence examining the benefits and harms associated with the use of FDA-approved FGAs and SGAs in children, adolescents, and young adults ≤24 years of age. This systematic review covers many psychiatric conditions, as well as behavioral issues, for which antipsychotics are being prescribed as mono- or adjunctive therapy, such that a diverse range of stakeholders can be provided with evidence on the relative benefits and harms of antipsychotics to make informed decisions.

This is an update of Comparative Effectiveness Review (CER) No. 39 published in 2012.17 The scope of this update has remained quite similar, with key changes being the addition of (1) three newly approved SGAs (i.e., brexpiprazole, asenapine, lurasidone) and the previously discontinued FGA molindone, (2) some conditions of interest (i.e., anxiety, depression, substance use), and (3) modification to some key outcomes to be more specific to symptoms targeted by clinicians when prescribing antipsychotics.

Scope of Review and Key Questions

Conditions of Interest

• Schizophrenia and schizophrenia-related psychoses, including schizoaffective disorder and prodromic (ultra high-risk) psychosis
• Autism spectrum disorders, including pervasive developmental disorder, autism, Rett's disorder, childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified.
• Bipolar disorder
• Attention deficit hyperactivity disorder, or disruptive, impulse-control, and conduct disorders
• Obsessive-compulsive disorder
• Substance use disorder
• Major and persistent depressive disorders, or disruptive mood dysregulation disorder
• Anxiety disorders
• Posttraumatic stress disorder
• Eating disorders (i.e., anorexia nervosa, bulimia nervosa, binge-eating disorder)
• Tic disorders (e.g., Tourette's syndrome)
• Behavioral issues outside the context of a mental disorder, including aggression, agitation, behavioral dyscontrol, irritability, self-injurious behaviors, and insomnia

Key Questions

Key Question 1

For each condition of interest, what are the benefits, in terms of intermediate and effectiveness outcomes, of first and second generation antipsychotics—at the level of individual antipsychotics and across each class—in comparisons with placebo, different doses of the same antipsychotic, or different antipsychotics in children and young adults (≤24 years)?

1. Do the benefits vary with respect to patient characteristics, such as age, sex, race/ethnicity, medical comorbidities, phase or features of disorder, and antipsychotic treatment history?
2. Do the benefits vary with respect to clinical characteristics such as dose of antipsychotic or cotreatments including other antipsychotics, other medications, or nonpharmacologic therapy?

Key Question 2

Across all conditions of interest, what are the harms of first and second generation antipsychotics—at the level of individual antipsychotics and across each class—in comparisons with placebo, different doses of the same antipsychotic, or different antipsychotics in children and young adults (≤24 years)?

1. Do the harms vary with respect to patient characteristics, such as age, sex, race/ethnicity, diagnosis, medical comorbidities, phase of disorder, and prior exposure to antipsychotics?
2. Do the harms vary with respect to clinical characteristics such as dose of antipsychotic or cotreatments including other antipsychotics, other medications, or nonpharmacologic therapy?