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First- and Second-Generation Antipsychotics for Children and Young Adults

First- and Second-Generation Antipsychotics for Children and Young Adults. Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov. Outline of Material.

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First- and Second-Generation Antipsychotics for Children and Young Adults

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  1. First- and Second-Generation Antipsychotics for Children andYoung Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

  2. Outline of Material • Introduction to pediatric use of first-generation and second-generation antipsychotics, including approved and off-label indications. • Systematic review methods. • The clinical questions addressed by the comparative effectiveness review. • Results of studies and evidence-based conclusions about effectiveness and adverse effects of antipsychotics in pediatric use. • Gaps in knowledge. • What to discuss with patients and their caregivers. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  3. Introduction to Antipsychotics in Pediatric Use (1 of 4) • Antipsychotics can be classified into two categories based on the timeline of their development, their mechanisms of action, and their anticipated adverse effect profiles. • First-generation antipsychotics (FGAs), also called conventional or typical antipsychotics • Second-generation antipsychotics (SGAs), also called atypical antipsychotics • FGAs were the first successful pharmacological treatments for primary psychotic disorders such as schizophrenia. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  4. Introduction to Antipsychotics in Pediatric Use(2 of 4) • First-generation antipsychotics are associated with side effects that are difficult to manage and in some cases are irreversible. • Neurological side effects include extrapyramidal system movement disorders: • Tardive dyskinesia: repetitive, involuntary muscle movements • Akathisia: restlessness • Inability to initiate movement; Parkinson’s disease-like symptoms • Development of the second-generation antipsychotics was driven by the need to limit neurological adverse effects. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  5. Introduction to Antipsychotics in Pediatric Use (3 of 4) • Many first-generation and second-generation antipsychotics are approved by the U.S. Food and Drug Administration (FDA) for use in children and/or adolescents. • The FDA prohibits manufacturers from advertising or promoting the use of pharmaceuticals for indications that it has not approved. To do so is illegal. • Off-label prescribing by physicians is permitted. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  6. Introduction to Antipsychotics in Pediatric Use (4 of 4) • Prescribing of antipsychotics for children with mental and behavioral disorders continues to increase and includes off-label use. • However, the effects of both first-generation (FGAs) and second-generation (SGAs) antipsychotics on patient-centered outcomes such as growth, development, and quality of life are not well understood. • Studies of efficacy, benefits, and adverse effects of FGAs and SGAs used in pediatric treatment are reported in the clinical literature. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  7. Antipsychotics Approved for Pediatric Use:First-Generation Antipsychotics Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  8. Antipsychotics Approved for Pediatric Use:Second-Generation Antipsychotics Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  9. Disorders Treated by Antipsychotics inPediatric Use • The clinical literature includes studies of pediatric use of first-generation and second-generation antipsychotics for treatment of these disorders: • Pervasive developmental disorders • Attention deficit hyperactivity disorder and disruptive behavior disorders • Bipolar disorder • Schizophrenia and related psychosis • Tourette’s syndrome • Behavioral issues • No clinical studies were found for obsessive-compulsive disorder, post-traumatic stress disorder, or anorexia nervosa. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  10. Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development • Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. • A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. • The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  11. Rating the Strength of Evidence From the Comparative Effectiveness Review • The strength of evidence was classified into four broad categories: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  12. Clinical Questions Addressed by theComparative Effectiveness Review (1 of 2) • The reviewed literature was limited to studies performed in children, adolescents, and young adults from 1 to 24 years of age. • What is the comparative efficacy or effectiveness of first-generation (FGAs) and second-generation (SGAs) antipsychotics for treating disorder-specific and nonspecific symptoms? • Do FGAs and SGAs differ in short-term (within 6 months) and long-term (after 6 months) outcomes, including: • Response rate and relationship to dosage; speed of response; duration of response; remission; relapse; time to discontinuation; and adherence • Growth and maturation; cognitive and emotional development • Suicidal behaviors and ideation • Work-related functional capacity; school performance • Patient insight into illness • Patient- or caregiver–reported outcomes • Health-related quality of life • Legal or justice system interactions • Health care system utilization Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  13. Clinical Questions Addressed by theComparative Effectiveness Review (2 of 2) • Do first-generation (FGAs) and second-generation (SGAs) antipsychotics differ in the following medication-associated adverse events: • Overall adverse events? • Specific adverse events? • Withdrawals and time to withdrawal due to adverse events? • Persistence and reversibility of adverse events? • Do the efficacy and risks of FGAs and SGAs vary in differing subpopulations including: • Sex, age group, and race? • Comorbidities? • Cotreatment versus monotherapy • First episode versus prior episodes (for schizophrenia)? • Duration of illness? • Treatment naïve versus history of antipsychotic use? Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  14. Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review • Both core illness symptoms and nonspecific symptoms were of interest. • A wide variety of psychiatric assessment instruments are used to evaluate symptoms in studies of pediatric use of antipsychotics. Lower scores indicate less severity. The assessments included: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  15. Adverse Events of Interest in theComparative Effectiveness Review • Adverse events data extracted from published studies included: • Mortality • Cardiac and cerebrovascular events • Weight and body composition • Dyslipidemia • Insulin resistance and diabetes • Prolactin-related and sexual effects • Neuromotor (extrapyramidal) • Sedation • Liver toxicity • Neutropenia and agranulocytosis • Thyroid dysfunction • Seizures • Neuroleptic malignant syndrome • Constipation • Exercise intolerance • Precocious puberty • Behavioral effects • Dermatological effects • Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm. • For adverse events reporting, standardized instruments that evaluate extrapyramidal symptoms are also used in clinical trials.

  16. Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS • Population: Children to age 12 years, adolescents ages 12–17 years, and young adults ages 18–24 years with these diagnosed mental disorders: PDD, ADHD, DBD, bipolar disorder, schizophrenia or related psychosis, Tourette’s syndrome, or other behavioral symptoms • Interventions: Any FGAs and SGAs approved by the FDA • Comparators: Other FGAs or SGAs, placebo • Outcomes: Core and nonspecific symptoms; response; remission; growth and maturation; cognitive and emotional development; suicide-related behaviors; adherence; school and work capacity and performance; patient insight; patient-, parent-, or caregiver-reported outcome; health-related quality of life; legal system interaction; health care system utilization; adverse events (e.g., weight; dyslipidemia; insulin and blood glucose effects and diabetes; extrapyramidal symptoms; prolactin effects) • Timing: No minimum or maximum duration specified • Setting: Community and hospitalized care Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  17. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (1 of 2) • 95-Percent Confidence Interval: The range of statistically valid results that will include the true population mean in 95 of 100 repeated experiments. • Mean Difference (MD): The difference between treatment and comparison group means. • To determine a standardized mean difference (SMD), results from different scales are normalized to a common, “standardized” scale before calculating the mean difference. • For MD and SMD, the result is statistically significant (p < 0.05) when the 95-percent confidence interval does not include 0.0, which is the point of no difference between groups. • Relative Risk (RR): The ratio of the rate (absolute risk, probability) of an event in the treatment group, to the rate of the event in the comparison group. • For RR, the result is statistically significant at p < 0.05 when the 95-percent confidence interval does not include 1.0, which is the point of equal risk for both groups. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  18. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (2 of 2) • Absolute Risk Difference: The absolute value of the mathematical difference between the rates (risk) of an event in the treatment and comparison groups. • ARD = |ARC-ART| • Number Needed to Treat or Harm (NNT, NNH): The number of patients to be treated to observe benefit or harm in one patient more than seen in the comparison group. The number of patients to be treated in order to find a benefit or harm attributable to the intervention. • NNT or NNH = |ARC-ART|-1for a benefit or adverse event, respectively • Number of attributable events per 1000 = 1000 x |ARC-ART| • The smaller the NNT or NNH, the greater the attributable effect. . Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  19. Effectiveness and Efficacy of Antipsychotics • Efficacy studies • Are randomized, controlled trials (RCTs) designed to demonstrate a clinical benefit • Enroll participants based on restrictive inclusion and exclusion criteria • The comparator is usually placebo • Effectiveness studies • May be RCTs but can include retrospective cohort studies and other study formats • Are designed to examine clinical effects of treatments in typical medical practice • Inclusion and exclusion criteria are not as restrictive as in efficacy trials • The comparator is usually an active control or “usual care,” rather than placebo • The treatment setting may vary widely among the participants Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm. .

  20. Summary of Efficacy and Effectiveness Studies of Antipsychotics in Pediatric Use • The included studies were limited to those that enrolled children (≤12 years of age), youth (12–18 years of age), and young adults (19–24 years of age). • Comparisons of second-generation antipsychotics (SGAs) with placebo were the most commonly reported studies. • Too few placebo comparison studies of first-generation antipsychotics (FGAs) for treatment of psychiatric disorders of children were reported to permit conclusions about effect sizes and statistical significance. • Head-to-head comparisons of FGAs with other FGAs included in this review (two studies) were studies about treatment of schizophrenia. • Head-to-head comparisons of FGAs versus SGAs that met the criteria for inclusion in this review (17 studies) were investigations for treatment of schizophrenia, pervasive developmental disorder (autism), and Tourette’s syndrome. • Head-to-head comparisons of SGAs with other SGAs (46 studies) were investigated for treatment of bipolar disorder, schizophrenia, and behavioral issues. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  21. Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (1 of 3) Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  22. Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (2 of 3) Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  23. Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (3 of 3) . Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  24. Summary of Results: Efficacy of Antipsychotics in Placebo Comparisons (1 of 2) • When compared with placebo, second-generation antipsychotics (SGAs) result in greater improvement of disorder-specific symptoms. • SGAs (aripiprazole, olanzapine, paliperidone, quetiapine, and risperidone) improve both clinical global impressions and positive and negative symptoms of schizophrenia (an approved indication). • Strength of Evidence = Moderate • SGAs (aripiprazole, olanzapine, quetiapine, and risperidone) improve clinical global impressions (CGIs) of bipolar disorder and manic but not depressive symptoms of bipolar disorder. • Strength of Evidence = Moderate for CGIs • Strength of Evidence = Low for manic and depressive symptoms Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  25. Summary of Results: Efficacy of Antipsychotics in Placebo Comparisons (2 of 2) • Risperidone and ziprasidone improve tics in Tourette’s syndrome. • Strength of Evidence = Moderate • Risperidone improves behavioral symptoms and clinical global impressions of attention deficit hyperactivity disorders/ disruptive behavior disorders. • Strength of Evidence = Moderate • Second-generation antipsychotics (aripiprazole and risperidone) improve behavioral (irritability, an approved indication), obsessive-compulsive, and autistic symptoms of pervasive developmental disorders. • Strength of Evidence = Low Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  26. Results of Comparative Effectiveness Studies:FGAs Versus SGAs • The evidence from comparisons of first-generation (FGAs) and second-generation (SGAs) antipsychotics in Tourette’s syndrome is insufficient to permit conclusions about effect size or statistical significance. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  27. Results of Comparative Effectiveness Studies: SGAs Versus SGAs Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pediantipsych.cfm.

  28. Summary of Comparative Effectiveness Results (1 of 2) • The evidence from within-class comparisons of FGAs with FGAs is insufficient to permit conclusions about effect sizes and statistical significance. • In between-class comparisons of FGAs with SGAs: • Olanzapine and risperidone are more effective than haloperidol for reducing autistic symptoms (anger, hyperactivity, and Aberrant Behavior Checklist scores) in pervasive developmental disorders. • Strength of Evidence = Low • In pooled analyses, SGAs (clozapine, olanzapine, and risperidone) are more effective than haloperidol in treating schizophrenia, as assessed by clinical global impressions, but not by effects on positive and negative symptoms. • Strength of Evidence = Low Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  29. Summary of Comparative Effectiveness Results (2 of 2) • In within-class comparisons of second-generation antipsychotics with each other: • Olanzapine is not statistically different from risperidone or clozapine in treating schizophrenia, as assessed by clinical global impressions and positive and negative symptoms. • Strength of Evidence = Low Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  30. Adverse Effects of Antipsychotics In Children • Adverse events were examined across all indications in total: adverse events are not expected to be dependent on diagnosis. • Several adverse events of interest had no data reported. • The analysis focused on key adverse event categories reported in at least one study: • Weight and body composition • Blood lipids • Blood glucose, insulin, and diabetes • Neuromotor effects (e.g., extrapyramidal symptoms, akathisia, tardive dyskinesia) • Prolactin and related sexual adverse effects • Sedative effects Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  31. Adverse Effects: First-Generation Antipsychotics • Placebo Comparisons: • There are few comparisons of first-generation antipsychotics (FGAs) with placebo that report differences in adverse events in children. • The evidence is insufficient for all key adverse events. • FGAs versus FGAs: • The evidence is insufficient for all head-to-head comparisons of FGAs. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  32. Adverse Effects: FGAs Compared With SGAs FGAs versus SGAs: The evidence from comparisons of FGAs as a class versus SGAs as a class, and for FGAs compared with the SGA clozapine, is insufficient to permit conclusions. Comparisons of haloperidol with two SGAs, olanzapine and risperidone, yielded the following results in a meta-analysis: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  33. Summary of Adverse Effects ofFirst-Generation Antipsychotics • For comparisons between FGAs or with placebo, the evidence is insufficient to permit conclusions about the degree of risk or severity of adverse effects. • In direct comparisons of the FGA haloperidol with SGAs: • When compared with olanzapine: • Haloperidol is associated with a lower risk for adverse effects on weight and body composition but with a greater risk of extrapyramidal symptoms. • No statistically significant differences are noted for prolactin-related measures or sedation. • Strength of Evidence = Low • When compared with risperidone: • Haloperidol is associated with greater severity of extrapyramidal symptoms. • No statistically significant differences in risk are noted for adverse effects on weight and body composition or prolactin-related effects. • Strength of Evidence = Low Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  34. Adverse Effects: Second-Generation Antipsychotics Versus Placebo (1 of 2) The risk and severity of key adverse events was examined in a meta-analysis of individual SGAs compared with placebo, in pediatric use. SGAs showed these effects: Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  35. Adverse Effects: Second-Generation Antipsychotics Versus Placebo (2 of 2) Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  36. Adverse Effects: SGAs Versus SGAs (1 of 2) The risk and severity of key adverse events were examined in a meta-analysis of individual SGAs compared with other SGAs in head-to-head evaluations in pediatric use. The analysis found the following summary effects and statistically valid range of values for the effects, as defined by the 95-percent confidence interval (95% CI): Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  37. Adverse Effects: SGAs Versus SGAs (2 of 2) • For other adverse events in direct comparisons, there is limited evidence of no statistically significant difference between second-generation antipsychotics (SGAs) for effects on insulin levels and glucose control, extrapyramidal symptoms, and sedative effects. • Strength of Evidence = Low • The risk of elevated prolactin is 2.6 times greater with risperidone than with olanzapine (from 1.7x to 5x). • Strength of Evidence = Moderate • The evidence from other head-to-head comparisons is insufficient to permit conclusions about differences in prolactin levels. • Study durations were typically too short to evaluate adverse effects on some important outcomes such as insulin and glycemic control. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  38. Summary of Adverse Effects ofSecond-Generation Antipsychotics • Current evidence indicates that there are differences between individual second-generation antipsychotics (SGAs) in the risk and severity of key adverse effects. • However, in the absence of direct comparisons, only subjective interpretations of relative risk and severity can be made using data from placebo comparisons. • In the current evidence base of direct comparisons of SGAs, statistically significant differences are noted in rate or severity of dyslipidemia and in adverse changes in weight and body composition. • Among the SGAs, olanzapine exhibits the most severe adverse effects on weight and blood lipids, and risperidone has the strongest effect for elevating prolactin levels, both in placebo comparisons and when compared with olanzapine. • There is limited evidence of no statistically significant difference between SGAs in other direct comparisons of adverse effects (insulin and glucose control, extrapyramidal symptoms, and sedative effects). Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  39. Conclusions About the Benefits and Adverse Effects of Antipsychotics (1 of 2) • Evidence about the use of antipsychotics in children and adolescents is inadequate to support strong conclusions about their comparative effectiveness. • Moderate-strength evidence indicates that second-generation antipsychotics (SGAs) as a class improve clinical global impressions in bipolar disorder, and low-strength evidence supports benefits for treating mania. • Moderate-strength evidence shows that SGAs as a class improve both clinical global impressions and positive and negative symptoms of schizophrenia. • Moderate-strength evidence shows that risperidone is effective for attention deficit hyperactivity disorder and disruptive behavior disorders, and that risperidone and ziprasidone can reduce tics in Tourette’s syndrome. • Limited evidence suggests that SGAs are more effective than first-generation antipsychotics for improving some autistic symptoms of pervasive developmental disorders. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  40. Conclusions About the Benefits and Adverse Effects of Antipsychotics (2 of 2) • Adverse effects of second-generation antipsychotics (SGAs) include extrapyramidal symptoms (EPS), somnolence, weight gain, dyslipidemia, and elevated prolactin levels. • In head-to-head comparisons of SGAs, the risk and severity of abnormalities of weight and blood lipids are greatest with olanzapine. • Risperidone raises prolactin levels more than olanzapine. • There is low-strength evidence of no differences between SGAs in effects on insulin and glucose control, EPS, and sedation. • The long-term safety of both first-generation antipsychotics (FGAs) and SGAs and their effectiveness for improving quality-of-life outcomes are not established. • Although SGAs have been perceived as having fewer side effects than FGAs, data are very limited to compare the relative risks of adverse effects. The spectrum of adverse effects should be taken into account, along with possible alternatives, when considering use of these drugs. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  41. Gaps in Knowledge (1 of 2) • The effectiveness review revealed areas where the evidence about the effectiveness of first-generation (FGAs) and second-generation (SGAs) in treating pediatric psychiatric disorders is limited or absent, including: • Few head-to-head comparisons of FGAs and SGAs exist, either within or between classes, to demonstrate their effectiveness, benefits, and adverse effects for use in pediatric and young adult populations. • No studies were found that reported pediatric use of antipsychotics to treat obsessive-compulsive disorder, post-traumatic stress disorder, or anorexia nervosa. • Studies of young adults (ages 19–24) were rare. • Few studies reported outcomes that are important to patients (e.g., health-related quality of life, school performance, and legal interactions), and there is no consensus on the minimal clinically important effects to be produced by treatments. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  42. Gaps in Knowledge (2 of 2) • Evidence about efficacy and safety over several years is unavailable. • Standardized scales and methods for systematically investigating adverse events are needed. • How the characteristics of key patient subpopulations affect patient-centered outcomes is not understood. • Large-scale effectiveness studies that apply few patient restrictions and closely match typical clinical practice are needed to inform clinical decisionmaking. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

  43. What To Discuss With Your Patients andTheir Caregivers • The role that antipsychotics may play as one component in the broader array of treatments for child and adolescent psychiatric disorders. • The ability of both first-generation and second-generation antipsychotics to improve symptoms of psychiatric disorders in children, and the differences in strength of evidence for benefits in particular indications. • The risks of extrapyramidal effects, weight gain, and blood lipid abnormalities, and the evidence about differences in risk among drugs in both classes. • The limited evidence about long-term benefits and adverse effects on health and quality of life. Seida J, Schouten J, Mousavi S, et al. ComparativeEffectiveness Review No. 39. Available at www.effectivehealthcare.ahrq.gov/pedantipsych.cfm.

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