Agency for Healthcare Research and Quality (AHRQ)

Agency for Healthcare Research and Quality (AHRQ)
First- and Second-Generation Antipsychotics for Children and Young Adults Prepared for: Agency for Healthcare Research and Quality (AHRQ) First- and Second-Generation Antipsychotics for Children and Young Adults This slide set is based on a comparative effectiveness review (CER 39) First- and Second-Generation Antipsychotics for Children and Young Adults that was developed by the University of Alberta Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ) under Contract No and is available online at CERs are comprehensive systematic reviews of the literature that usually compare two or more types of treatment, such as different drugs or adding a second drug to usual care for the same disease. The literature included in this review was identified in searches for trials and studies that explicitly evaluated first-generation and second-generation antipsychotics in children, adolescents, and young adults ≤24 years of age. Searches were conducted for controlled trials (randomized and nonrandomized) and cohort studies published from January 1987 up to February 2011. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at

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. Outline of Material The material begins with an introduction to pediatric use of first-generation and second-generation antipsychotics, including approved and off-label indications. The systematic review methods used to develop the comparative effectiveness review are presented. The clinical questions addressed by the comparative effectiveness review are also presented, followed by the results of studies and evidence-based conclusions about effectiveness and adverse effects of antipsychotics in pediatric use. Gaps in knowledge revealed by the review process are discussed. Some suggestions are made for what to discuss with patients and their caregivers, based on the review findings. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. These are first-generation antipsychotics (FGAs), also called conventional or typical antipsychotics, and second-generation antipsychotics, also called atypical antipsychotics. FGAs were the first successful pharmacological treatments for primary psychotic disorders such schizophrenia. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. Introduction to Antipsychotics in Pediatric Use (2 of 4) First-generation antipsychotics (FGAs) are associated with side effects that are difficult to manage and in some cases are irreversible. Neurological side effects include extrapyramidal system movement disorders. Some serious adverse effects that occur with use of FGAs are tardive dyskinesia with repetitive, involuntary muscle movements; akathisia, characterized by restlessness; and the inability to initiate movement, a Parkinson’s disease-like symptom. Development of the second-generation antipsychotics was driven by the desire to limit neuromotor adverse effects. References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Jensen PS, Buitelaar J, Pandina GJ, et al. Management of psychiatric disorders in children and adolescents with atypical antipsychotics: a systematic review of published clinical trials. Eur Child Adolesc Psychiatry 2007;16(2):104–20. PMID: Zito JM, Derivan AT, Kratochvil CJ, et al. Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring. Child Adolesc Psychiatry Ment Health 2008;2(1):24–34. PMID: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. Recommendations or advertisements that promote the use of pharmaceuticals for indications that have not been approved by the FDA (off-label) are illegal. However, off-label prescribing by physicians is permitted. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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 for pediatric treatment are reported in the clinical literature. The strength of the evidence (high, moderate, or low) found in the clinical literature does not necessarily equate with the U.S. Food and Drug Administration approval status. References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Pathak S, Arszman SP, Danielyan A, et al. Psychotropic utilization and psychiatric presentation of hospitalized very young children. J Child Adolesc Psychopharmacol 2004;14(3):433–42. PMID: Zito JM, Safer DJ, de Jong-van den Berg LT, et al. A three-country comparison of psychotropic medication prevalence in youth. Child Adolesc Psychiatry Ment Health 2008;2(1):26–33. PMID: Zito J, Safer D, dosReis S, et al. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;238(8):1025–30. PMID: Zito JM, Safer DJ, dosReis S, et al. Psychotropic practice patterns for youth: a 10-year perspective. Arch Pediatr Adolesc Med 2003;157(1):17–25. PMID: Zito JM, Safer DJ, Sai D, et al. Psychotropic medication patterns among youth in foster care. Pediatrics 2008;121(1):e157–63. PMID: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Antipsychotics Approved for Pediatric Use: First-Generation Antipsychotics
Indication Age Group Chlorpromazine Schizophrenia 1–12 years Bipolar disorder (mania) Severe behavioral problems Hyperactivity Droperidol Agitation “children” Loxapine ≥12 years Perphenazine Pimozide Tourette’s syndrome Prochlorperazine >2 years and >20 pounds Thiothixene Thioridazine Trifluoperazine ≥6 years Antipsychotics Approved for Pediatric Use: First-Generation Antipsychotics - Chlorpromazine is approved for treatment of schizophrenia, bipolar disorder (mania), severe behavioral problems, and hyperactivity for children from 1 to 12 years old. - Droperidol is approved for treatment of agitation in children, but the age group is not specified. - Loxapine is approved for treatment of schizophrenia in children aged 12 years and older. - Perphenazine is approved for treatment of schizophrenia in children aged 12 years and older. - Pimozide is approved for treatment of Tourette’s syndrome in children aged 12 years and older. - Prochlorperazine is approved for treatment of schizophrenia in children over 2 years of age and greater than 20 pounds in weight. - Thiothixene is approved for treatment of schizophrenia in children aged 12 years and older. - Thioridazine is approved for treatment of schizophrenia in children, with no age group specified. - Trifluoperazine is approved for treatment of schizophrenia in children aged 6 years and older. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Antipsychotics Approved for Pediatric Use: Second-Generation Antipsychotics
Indication Age Group Aripiprazole Schizophrenia 13–17 years Autism irritability 10–17 years Bipolar disorder (manic/mixed) 6–17 years Olanzapine Adolescents (13–17 years) Bipolar disorder: depressive episode Quetiapine Bipolar disorder (acute manic) Risperidone 5–16 years Antipsychotics Approved for Pediatric Use: Second-Generation Antipsychotics - Aripiprazole is approved for treatment of schizophrenia in children aged 13 to 17 years, autism irritability in children aged 10 to 17 years, and bipolar disorder (manic/mixed) in children aged 6 to 17 years. - Olanzapine is approved for treatment of schizophrenia, bipolar disorder (manic/mixed), bipolar disorder-related depressive episodes in adolescents aged 13–17 years. - Quetiapine is approved for treatment of schizophrenia in children aged 13 to 17 years and for bipolar disorder (acute manic) in children aged 10 to 17 years. - Risperidone is approved for treatment of schizophrenia in children aged 13 to 17 years, autism irritability in children 5–16 years, and bipolar disorder (manic/mixed) in children aged 10 to 17 years. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Disorders Treated by Antipsychotics in Pediatric 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. Disorders Treated by Antipsychotics in Pediatric Use The clinical literature includes studies 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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 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 Research Summaries and the full report, with references for included and excluded studies, are available at Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Rating the Strength of Evidence From the Comparative Effectiveness Review
The strength of evidence was classified into four broad categories: High ●●● Further research is very unlikely to change the confidence in the estimate of effect. Moderate ●●○ Further research may change the confidence in the estimate of effect and may change the estimate. Low ●○○ Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient ○○○ Evidence either is unavailable or does not permit estimation of an effect. Rating the Strength of Evidence From the Comparative Effectiveness Review The Evidence-based Practice Center GRADE approach, based on the standard GRADE approach, was used to assess the quality of the body of evidence for each outcome. The overall strength of evidence was graded as high (further research is very unlikely to change the confidence in the estimate of effect), moderate (further research may change the confidence in the estimate of effect and may change the estimate), low (further research is likely to change the confidence in the estimate of effect and is likely to change the estimate), or insufficient (evidence either is unavailable or does not permit estimation of an effect). The authors also independently evaluated the applicability to real-world practice of the total body of evidence within a given clinical indication by using the PICOTS (population, intervention, comparator, outcome, timing, and setting) framework. References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; April AHRQ Publication No. 10(12)-EHC063-EF. Chapters available at Brozek J, Oxman A, Schünemann H, for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group. GRADEpro [computer program]. Version 3.2 for Windows Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Clinical Questions Addressed by the Comparative 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 Clinical Questions Addressed by the Comparative Effectiveness Review (1 of 2) The literature reviewed for the comparative effectiveness review was limited to studies performed in children, adolescents, and young adults from 1 to 24 years of age. Key Questions addressed by the review included: 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 - Medication adherence - Patient- or caregiver-reported outcomes - Health-related quality of life - Legal or justice system interactions - Health care system utilization Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Clinical Questions Addressed by the Comparative 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? Clinical Questions Addressed by the Comparative Effectiveness Review (2 of 2) Key Questions addressed by the review included: 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? Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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: Instrument Application Aberrant Behavior Checklist (ABC) Treatment effects on profoundly mentally retarded participants Brief Psychiatric Rating Scale–Children (BPRS-C) Childhood psychiatric disorders and response to treatment Children’s Depression Rating Scale (CDRS) Severity of depression in children 6–12 years of age Children’s Global Assessment Scale (CGAS) Overall measure of disturbance; children 4–16 years of age Clinical Global Impressions (CGI) Global rating of severity (-S), improvement (-I), or overall impression Nisonger Child Behavior Rating Form (NCBRF) Childhood problems because of mental retardation Overt Aggression Scale (OAS) Physical and verbal aggressive behaviors Positive and Negative Syndrome Scale (PANSS) Positive and negative symptoms in schizophrenia Young Mania Rating Scale (YMRS) Severity (not diagnosis) of mania Clinically Significant Outcomes of Interest in the Comparative Effectiveness Review Both core illness symptoms and nonspecific symptoms were of interest in the systematic review. A wide variety of common psychiatric assessment instruments are used to evaluate symptoms in studies of pediatric use of antipsychotics. These included: - The Aberrant Behavior Checklist (ABC), which evaluates treatment effects on profoundly mentally retarded participants - The Brief Psychiatric Rating Scale–Children (BPRS-C), which evaluates childhood psychiatric disorders and response to treatment - The Children’s Depression Rating Scale (CDRS), which evaluates the severity of depression in children 6–12 years of age - The Children’s Global Assessment Scale (CGAS), which is an overall measure of disturbance used for children 4–16 years of age - The Clinical Global Impressions (CGI), which evaluates the global rating of severity (-S), improvement (-I), or overall impression - The Nisonger Child Behavior Rating Form (NCBRF), which evaluates childhood problems because of mental retardation - The Overt Aggression Scale (OAS), which evaluates physical and verbal aggressive behaviors - The Positive and Negative Syndrome Scale (PANSS), which evaluates positive and negative symptoms in schizophrenia - The Young Mania Rating Scale (YMRS), which evaluates the severity (not diagnosis) of mania Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Adverse Events of Interest in the Comparative 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 Adverse Events of Interest in the Comparative 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 For adverse events reporting, standardized instruments that evaluate extrapyramidal symptoms are also used in clinical trials. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at For adverse events reporting, standardized instruments that evaluate extrapyramidal symptoms are also used in clinical trials. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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 Summary of Study Characteristics Evaluated in the Effectiveness Review: PICOTS Development of clinical studies of effectiveness of medical interventions is guided by the PICOTS (population, interventions, comparators, outcomes, timing, and setting) framework. These items are critical elements that will help to answer important clinical questions. In the comparative effectiveness review, the clinical study literature was reviewed and summarized by using the PICOTS framework. The evidence concerning the outcomes identified here was examined in detail, and strength-of-evidence determinations were made only for the key outcomes (see below). 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 FDA-approved FGAs and SGAs 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 Abbreviations: ADHD = attention deficit hyperactivity disorder; DBD = disruptive behavior disorder; FDA = U.S. Food and Drug Administration; FGAs = first-generation antipsychotics; PDD = pervasive developmental disorder; SGAs = second-generation antipsychotics Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. Modes of Results Reporting and Statistical Analysis in the Comparative Effectiveness Review (1 of 2) 95% 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 both the MD and the 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. References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version London: The Cochrane Collaboration; March Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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|-1 for 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. 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 |-1 for a benefit or adverse event, respectively - Number of attributable events per 1000 = 1000 x | ARC-ART | References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions. Version London: The Cochrane Collaboration; March Available at handbook.org. Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at .

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 Effectiveness and Efficacy of Antipsychotics Efficacy studies are randomized, controlled trials (RCTs) designed to demonstrate a clinical benefit. Participants are enrolled 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. They 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. References: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Gartlehner G, Hansen RA, Nissman D, et al. A simple and valid tool distinguished efficacy from effectiveness studies. J Clin Epi 2006; 59(10): PMID: Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at .

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. 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 (≤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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (1 of 3)
Outcome (n studies, n participants) Meta-analytic Result (Mean Difference) and Statistically Valid Range (95% CI) Strength of Evidence Bipolar Disorder CGI (6, 978) Pooled SGA results (aripiprazole, olanzapine, quetiapine, and risperidone): CGI score is 0.67 points lower with SGAs when compared with placebo (0.51 to 0.84 points lower) ●●○ YMRS No meta-analysis of SGAs as a class due to statistical heterogeneity ●○○ YMRS (3, 328) Aripiprazole: 7.22 points lower than placebo (5.17 to 9.28 points) YMRS (1, 159) Olanzapine: 7.66 points lower than placebo (5.68 to 9.74 points) YMRS (3, 339) Quetiapine: No pooled result due to statistical heterogeneity among reports YMRS (1, 163) Risperidone: 8.31 points lower than placebo (4.88 to points) YMRS (1, 218) Ziprasidone: 5.22 points lower than placebo (2.36 to 8.08 points) CDRS (4, 532) NSD (No pooled values) Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (1 of 3) Second-generation antipsychotics (SGAs) have been compared to placebo to evaluate the clinical benefit achieved with their use. In treatment of bipolar disorder, a meta-analysis of 6 studies of 978 participants shows that the Clinical Global Impression (CGI) score is 0.67 points lower with SGAs (0.51 to 0.84 points lower). The strength of evidence for this finding is moderate. There is a significant degree of statistical heterogeneity among the studies of SGAs evaluated using the Young Mania Rating Scale (YMRS). In 3 studies of 328 participants, scores with aripiprazole treatment were 7.22 points lower than placebo (valid range from 5.17 to 9.28 points lower). In 1 study of 159 participants, scores with olanzapine treatment were 7.66 points lower than with placebo (valid range from 5.68 to 9.74 points lower). In 3 studies of 339 participants, scores with quetiapine treatment were significantly statistically heterogeneous and were not combined for meta-analysis. In 1 study of 163 participants, scores with risperidone treatment were 8.31 points lower than placebo (valid range from 4.88 to points lower). In 1 study of 218 participants, scores with ziprasidone treatment were 5.22 points lower than placebo (valid range from 2.36 to 8.08 points lower). The strength of evidence is low for these findings using the YMRS to evaluate outcomes. Four studies of SGAs measured outcomes on the Children’s Depression Rating Scale (CDRS) for 532 participants. No statistically significant difference was noted in any individual study, but a meta-analysis was not performed due to statistical heterogeneity. The strength of evidence is low. Statistical Abbreviations: 95% CI = 95-percent confidence interval; NSD = no statistically significant difference Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Outcome (n studies, n participants) Meta-analytic Result (Mean Difference) and Statistically Valid Range (95% CI) Strength of Evidence Schizophrenia CGAS (5, 880) Score is 4.56 points higher (2.55 to 6.57 points higher) with SGAs (aripiprazole, olanzapine, paliperidone, quetiapine, and risperidone) ●○○ CGI-I (3, 505) Score is 0.75 points lower (0.38 to 1.12 points lower) with SGAs (aripiprazole, olanzapine, and risperidone) PANSS (6, 987) Score is 8.69 points lower (5.61 to points lower) with SGAs (aripiprazole, olanzapine, paliperidone, quetiapine, and risperidone) Tourette’s Syndrome YGTSS (2, 54) Score is 6.98 points lower (3.62 to points lower) with SGAs (risperidone and ziprasidone) Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (2 of 3) Second-generation antipsychotics (SGAs) have been compared to placebo to evaluate the clinical benefit achieved with their use. In treatment of schizophrenia, SGAs were compared with placebo using the Children’s Global Assessment Scale (CGAS) to measure outcomes in 5 studies of 880 participants. The meta-analytic result for the CGAS score is 4.56 points higher (2.55 to 6.57 points higher) with SGAs. In a meta-analysis of 3 studies of 505 participants, the Clinical Global Impression-Improvement (CGI-I) score is 0.75 points lower (0.38 to 1.12 points lower) with SGAs. In 6 studies of 987 participants, the Positive and Negative Syndrome Scale (PANSS) score is 8.69 points lower (5.61 to points lower) with SGAs. The strength of evidence for these findings in treating schizophrenia is moderate. In a pooled analysis of 2 studies of 54 participants being treated for Tourette’s syndrome, the Yale Global Tic Severity Scale (YGTSS) score is 6.98 points lower (3.62 to points lower) with SGAs (risperidone and ziprasidone) when compared with placebo. The strength of evidence for this finding is moderate. Statistical Abbreviation: 95% CI = 95-percent confidence interval Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

. Outcome (n studies, n participants) Meta-analytic Result (Mean Difference) and Statistically Valid Range (95% CI) Strength of Evidence Pervasive Developmental Disorder ABC (3, 202) Score is points lower (9.51 to points lower) with SGAs (aripiprazole and risperidone) ●○○ CARS (2, 62) Score is 4.94 points lower (1.36 to 8.52 points lower) with SGAs (risperidone) CYBOCS ( 3, 325) Score is 1.71 points lower (0.25 to 3.17 points lower) with SGAs (aripiprazole, risperidone, and olanzapine) Attention Deficit Hyperactivity Disorder/Disruptive Behavior Disorders ABC (4, 293) Score is points lower (10.83 to points lower) with risperidone ●●○ BPI (2, 225) Score is 3.77 points lower (1.39 to 6.16 points lower) with risperidone CGI-I (3, 380) Score is 0.95 points lower (0.25 to 1.66 points lower) with risperidone NCBRF ( 4, 590) Score is 6.93 points lower (3.49 to points lower) with risperidone Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Efficacy of Second-Generation Antipsychotics: Placebo Comparisons, by Indication (3 of 3) Second-generation antipsychotics (SGAs) have been compared to placebo to evaluate the clinical benefit achieved with their use. For treatment of pervasive developmental disorder, a meta-analysis of Aberrant Behavior Checklist (ABC) scores from 3 studies of 202 participants showed that the score is points lower with SGAs; the statistically valid range is from 9.51 to points lower. A meta-analysis of CARS (Childhood Autism Rating Scale) scores from 2 studies of 62 participants showed that the score is 4.94 points lower with SGAs; the statistically valid range is from 1.36 to 8.52 points lower. A meta-analysis of Children’s Yale-Brown Obsessive Compulsive Scale (CYBOCS) scores from 3 studies of 325 participants showed that the score is 1.71 points lower with SGAs; the statistically valid range is from 0.25 to 3.17 points lower. The strength of evidence for these findings is low. For treatment of attention deficit hyperactivity disorder/disruptive behavior disorders, a meta-analysis of ABC scores from 4 studies of 293 participants showed that the score is points lower with risperidone. The statistically valid range is from to points lower. A meta-analysis of Brief Pain Inventory (BPI) scores from 2 studies of 225 participants showed that the score is 3.77 points lower with risperidone; the statistically valid range is from 1.39 to 6.16 points lower. A meta-analysis of Clinical Global Impression-Improvement (CGI-I) scale scores from 3 studies of 380 participants showed that the score is 0.95 points lower with risperidone; the statistically valid range is from 0.25 to 1.66 points lower. A meta-analysis of Nisonger Child Behavior Rating Form (NCBRF) scores from 4 studies of 590 participants showed that the score is 6.93 points lower with risperidone; the statistically valid range is from 3.49 to points lower. The strength of evidence for these findings is moderate. Statistical Abbreviation: 95% CI = 95-percent confidence interval Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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 Summary of Results: Efficacy of Antipsychotics in Placebo Comparisons (1 of 2) In the clinical literature about pediatric use of antipsychotics, the review found that second-generation antipsychotics (SGAs) result in greater improvement of disorder-specific symptoms when compared with placebo. SGAs improve both clinical global impressions (CGIs) and positive and negative symptoms of schizophrenia, an approved indication for their use. The strength of evidence for this conclusion is moderate. SGAs also improve CGIs and manic but not depressive symptoms of bipolar disorder. The strength of evidence for this conclusion is moderate for CGIs and low for manic and depressive symptoms. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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 Summary of Results: Efficacy of Antipsychotics in Placebo Comparisons (2 of 2) For the second-generation antipsychotics (SGAs) studied in pediatric use: - Risperidone and ziprasidone improve tics in Tourette’s syndrome. The strength of evidence for this conclusion is moderate. - Risperidone improves behavioral symptoms and clinical global impressions of attention deficit hyperactivity disorder/disruptive behavior disorders. The strength of evidence for this conclusion is moderate. - SGAs improve behavioral (irritability, an approved indication), obsessive-compulsive, and autistic symptoms of pervasive developmental disorders. The strength of evidence for this conclusion is low. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. Comparison Outcome (n studies, n participants) Mean Difference and Statistically Valid Range Defined by the 95% CI Strength of Evidence FGAs vs. SGAs for Pervasive Developmental Disorders Haloperidol vs. Olanzapine Autistic Symptoms (CPRS) (1, 12) Anger and hyperactivity factors reduced only in the olanzapine group (p ≤ 0.05)* ●○○ Haloperidol vs. Risperidone (ABC, CGI) (1, 30) Behavior, impulsivity, and language skills improved to a greater degree with risperidone (p ≤ 0.05)* FGAs vs. SGAs for Schizophrenia Haloperidol vs. SGAs (clozapine, olanzapine, and risperidone] BPRS (3 , 71) Score is points lower with SGAs (Statistically valid range is 3.52 to points lower) CGI-I (3, 87) Score is 0.76 points lower with SGAs (Statistically valid range is 0.26 to 1.25 points lower) PANSS (2, 27) NSD (Statistically valid range is points lower to points greater) *Single study; no meta-analysis. 95% CI = 95-percent confidence interval: the range of statistically valid results; mean difference = the difference between treatment and control group means; NSD = No statistically significant difference (p ≥ 0.05). Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Results of Comparative Effectiveness Studies: FGAs Versus SGAs For pediatric use, first-generation antipsychotics (FGAs) have been compared directly with second-generation antipsychotics (SGAs) for treatment effects in pervasive developmental disorders (PDDs) such as autism. Haloperidol and olanzapine were compared for effects on autistic symptoms, evaluated using the Comprehensive Psychopathological Rating Scale (CPRS). One study of 12 participants showed that anger and hyperactivity factors were reduced only in the olanzapine group (p ≤ 0.05); the strength of evidence for this result is low. Haloperidol and risperidone were compared for effects on autistic symptoms, evaluated with the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression (CGI) scale. One study of 30 participants showed that behavior, impulsivity, and language skills improved to a greater degree with risperidone (p ≤ 0.05); the strength of evidence for this result is low. FGAs have been compared directly to SGAs for treatment effects on schizophrenia. Haloperidol was compared with clozapine, olanzapine, and risperidone. In a meta-analysis of 3 studies of 71 participants, the score on the Brief Psychiatric Rating Scale (BPRS) is points lower with SGAs (the statistically valid range, defined by the 95-percent confidence interval [95% CI], is 3.52 to points lower). In a meta-analysis of 3 studies of 87 participants, the Clinical Global Impression-Improvement (CGI-I) scale score is 0.76 points lower with SGAs (the statistically valid range is 0.26 to 1.25 points lower). In a meta-analysis of 2 studies of 27 participants, no statistically significant difference in the Positive and Negative Syndrome Scale (PANSS) score is found (the statistically valid range is from points lower to points greater). The strength of evidence is low for each of these three results. For comparisons of FGAs and SGAs in the treatment of Tourette’s syndrome, the evidence is insufficient to permit conclusions about effect size or statistical significance. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Results of Comparative Effectiveness Studies: SGAs Versus SGAs
Comparison Outcome (n studies, n participants) Mean Difference and Statistically Valid Range Defined by the 95% CI Strength of Evidence SGAs vs. SGAs for Schizophrenia Olanzapine vs. Risperidone BPRS (3, 136) NSD ●○○ CGI-S (2, 111) PANSS (3, 143) Olanzapine vs. Clozapine BPRS (2, 27) Statistically valid range from points less to 0.64 points more CGI-S (2, 64) Statistically valid range from 1.01 points less to 0.08 points more SANS (2, 64) Statistically valid range from points less to 5.36 points more 95% CI = 95-percent confidence interval: the range of statistically valid results; mean difference = the difference between treatment and control group means; NSD = no statistically significant difference (p ≥ 0.05) Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Results of Comparative Effectives Studies: SGAs Versus SGAs For pediatric use, second-generation antipsychotics (SGAs) have been compared directly to other SGAs for treatment effects on schizophrenia. Olanzapine was compared with risperidone. In a meta-analysis of 3 studies of 136 participants, no statistically significant difference in the Brief Psychiatric Rating Scale (BPRS) score was found in 3 studies of 136 participants. An analysis of 2 studies of 111 participants demonstrated no statistically significant difference in Clinical Global Impressions Scale (CGI-S) score. A meta-analysis of 3 studies of 143 participants demonstrated no statistically significant difference in Positive and Negative Syndrome Scale (PANSS) scores. Olanzapine was compared with clozapine. In a meta-analysis of 2 studies of 27 participants, no statistically significant difference in BPRS score was found; the statistically valid range for the effect size is from points less to 0.64 points more. In a meta-analysis of 2 studies of 64 participants, no statistically significant difference in CGI-S score was found; the statistically valid range for the effect size is from 1.01 points less to 0.08 points more. In a meta-analysis of 2 studies of 64 participants, no statistically significant difference in CGI-S score was found; the statistically valid range for the effect size is from points less to 5.36 points more. For all comparisons, the strength of evidence is low. Statistical Abbreviations: 95% CI = 95-percent confidence interval; NSD = no statistically significant difference Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. Summary of Comparative Effectiveness Results (1 of 2) The evidence from within-class comparisons of first-generation antipsychotics (FGAs) with each other for pediatric use is insufficient to permit conclusions about effect sizes and statistical significance. In between-class comparisons of FGAs with second-generation antipsychotics (SGAs) for pediatric use: - Olanzapine and risperidone are more effective than haloperidol for reducing autistic symptoms in pervasive developmental disorders. The strength of evidence for this finding is low. - 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. The strength of evidence for this finding is low. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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 Summary of Comparative Effectiveness Results (2 of 2) In within-class comparisons of second-generation antipsychotics with each other for pediatric use, olanzapine is not statistically different from risperidone or clozapine for treating schizophrenia, as assessed by clinical global impressions and positive and negative symptoms. The strength of evidence in support of this finding is low. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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 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 Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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: Comparison Weight (95% CI) [n studies, n participants] Extrapyramidal Symptoms (95% CI) Sedation (95% CI) Haloperidol vs. Olanzapine 5.79 kg greater with olanzapine (from 3.0 to 8.6 kg higher) [4, 132] ●○○ 3.53-fold greater risk with haloperidol (from 1.1-fold to 10.9-fold) [3, 62] ●○○ Not reported Haloperidol vs. Risperidone NSD (statistically valid range is from 8.9 kg lower with haloperidol to kg greater with haloperidol) [3, 130] ●○○ No meta-analysis. Two different scales used; both show statistically significant, greater severity of extrapyramidal symptoms with haloperidol. [1, 34] ●○○ 6- fold greater risk of fatigue with haloperidol (from 1.5-fold to 24.2-fold) [1, 24] ˜™™ Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Adverse Effects: FGAs Compared With SGAs The evidence from comparisons of first-generation antipsychotics (FGAs) as a class versus second-generation antipsychotics (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: In comparisons of haloperidol with olanzapine, a meta-analysis of 4 studies of 132 participants showed that weight is 5.79 kg greater with olanzapine (statistically valid range from 3.0 to 8.6 kg greater); the strength of evidence for this finding is low. In 3 studies of 62 participants, extrapyramidal effects were 3.53-fold more likely with haloperidol (statistically valid range from 1.1-fold to 10.9-fold). No studies measuring sedation were reported. In comparisons of haloperidol with risperidone, a meta-analysis of 3 studies of 130 participants showed no statistically significant difference in weight (statistically valid range is from 8.9 kg lower to kg greater with haloperidol); the strength of evidence for this finding is low. In 1 study of 34 participants, extrapyramidal effects were more severe with haloperidol than with risperidone; the strength of evidence for this finding is low. In 1 study of 24 participants, the risk of sedative effects was 6-fold greater with haloperidol than with risperidone (statistically valid range from 1.5-fold to 24.2-fold); the strength of evidence for this finding is low. Statistical Abbreviations: 95% CI = 95-percent confidence interval; NSD = no statistically significant difference Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Summary of Adverse Effects of First-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. Summary of Adverse Effects of First-Generation Antipsychotics For comparisons between first-generation antipsychotics (FGAs) or with placebo, the evidence is insufficient to permit conclusions about the degree of risk or severity of adverse effects in pediatric use. In direct comparisons of the FGA haloperidol with second-generation antipsychotics (SGAs) in pediatric use: When compared with olanzapine: - Haloperidol shows lower risk for adverse effects on weight and body composition but greater risk of extrapyramidal symptoms. - No statistically significant differences are noted for prolactin-related effects or sedation. The strength of evidence in support of these conclusions is low. When compared with risperidone: - The risk of extrapyramidal symptoms and sedative effects is greater with haloperidol. - No statistically significant differences in risk are noted for adverse effects on weight and body composition or prolactin-related effects. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Relative Risk or Mean Difference (95% CI)
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: Adverse Effects Relative Risk or Mean Difference (95% CI) Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone Dyslipidemia† Elevated cholesterol Risk is elevated 2.5x (range from 1.4x to 4.4x ) NNH = 4 ●○○ Risk is elevated 10x (range from 1.4x to 73.2x) NNH = 6 ●○○ Triglyceride level Triglycerides are 29.1 mg/dL higher (range from 7.3 to 50.9 mg/dL higher) ●○○ Insufficient ○○○ No Data Weight Gain* Weight is 0.77 kg greater (range from 0.4 to 1.2 kg) ●●○ Weight is 4.60 kg greater (range from 3.07 to 6.13 kg) Weight is 1.8 kg greater (range from 1.1 to 2.5 kg) Weight is 1.8 kg greater (range from 1.5 to 2.1 kg) NSD Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ 95% CI = 95-percent confidence interval (the range of statistically valid results); NNH = number needed to harm (the number of patients to be treated to affect one patient more than in the control group); NSD = no statistically significant difference *Most studies that measured changes in weight ranged from 4 to 8 weeks duration, but some were in the range of 6 months to 1 year. † Dyslipidemia includes abnormalities in total cholesterol and triglycerides. Adverse Effects: Second-Generation Antipsychotics Versus Placebo (1 of 2) The risk and severity of key the adverse events dyslipidemia and weight gain were examined in a meta-analysis of individual second-generation antipsychotics (SGAs) when compared with placebo. For characteristics of dyslipidemia: - Aripiprazole demonstrated a 2.5-fold risk of elevated cholesterol (statistically valid range from 1.4-fold to 4.4-fold). With this increase in risk, when compared with the placebo group, one in every four patients exhibited elevated cholesterol. The strength of evidence for this finding is low. - Olanzapine demonstrated a 10-fold risk of elevated cholesterol (statistically valid range from 1.4-fold to 73.2-fold). With this increase in risk, when compared with the placebo group, one in every six patients will exhibit elevated cholesterol. The strength of evidence for this finding is low. - Quetiapine treatment elevated triglycerides to 29.1 mg/dL higher than in the placebo group (statistically valid range from 7.3 to 50.9 mg/dL higher). The strength of evidence for this finding is low. - The evidence about risperidone effects on blood lipids is insufficient to permit conclusions. - There are no available data about ziprasidone effects on blood lipids. For effects on weight: - Aripiprazole treatment resulted in greater weight of the participants, at 0.77 kg more than the placebo group (statistically valid range from 0.4 to 1.2 kg). The strength of evidence for this finding is moderate. - Olanzapine treatment resulted in greater weight of the participants, at 4.6 kg more than the placebo group (statistically valid range from 3.07 to 6.13 kg). The strength of evidence for this finding is moderate. - Quetiapine treatment resulted in greater weight of the participants, at 1.8 kg more than the placebo group (statistically valid range from1.1 to 2.5 kg). The strength of evidence for this finding is moderate. - Risperidone treatment resulted in greater weight of the participants, at 1.8 kg more than the placebo group (statistically valid range from1.1 to 2.1 kg). The strength of evidence for this finding is moderate. - Treatment with ziprasidone resulted in no statistically significant difference in weight when compared with placebo. The strength of evidence for this finding is low. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Relative Risk or Mean Difference (95% CI)
Adverse Effects: Second-Generation Antipsychotics Versus Placebo (2 of 2) Adverse Events Relative Risk or Mean Difference (95% CI) Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone EPS Risk is elevated 4.2x (from 2.4x to 7.2x) NNH = 4 ●●○ Not Reported NSD ●○○ Risk is elevated 2.7x (from 1.4x to 4.9x) NNH = 15 ●●○ Risk is elevated 10.3x (from 1.4 x to 75x) NNH = 9 ●○○ Somnolence Risk is elevated 2.7x (from 1.1x to 6.5x) NNH = 10 ●○○ 3.4x (from 2.0x to 5.8x) NNH = 4 ●○○ 2.9x (from 1.5x to 5.5x) Risk is elevated 3.0x (from 1.7x to 5.2x) NNH = 7 ●●○ Prolactin Levels 4.1 ng/mL lower (from 1.8 ng/mL to 6.3 ng/mL) ●●○ 11.5 ng/nL higher (from 8.8 ng/mL to 14.1 ng/mL) 22.6 ng/mL higher (from 10.7 to 34.5 ng/mL) Insufficient ○○○ Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ 95% CI = 95-percent confidence interval (the range of statistically valid results); EPS = extrapyramidal symptoms; NNH = number needed to harm (the number of patients to be treated to affect one patient more than in the control group); NSD = no statistically significant difference Adverse Effects: Second-Generation Antipsychotics Versus Placebo (2 of 2) The risks and severity of the key adverse effects of extrapyramidal symptoms (EPS), somnolence, and prolactin levels were examined for the second-generation antipsychotics (SGAs) in pediatric use. Extrapyramidal Symptoms - During treatment with aripiprazole, the risk of EPS is 4.2 times that of the placebo group (statistically valid range from 2.4-fold to 7.2-fold). With this elevation in risk, when compared with the placebo group, one in four patients will exhibit EPS. The strength of evidence for this finding is moderate. - The risk of EPS with olanzapine was not reported. Quetiapine demonstrated no statistically significant difference from placebo. The strength of evidence for this finding is low. - The risk of EPS is elevated 2.7-fold with risperidone (statistically valid range from 1.4-fold to 4.9-fold). With this elevation of risk, when compared with the placebo group, 1 in every 15 patients will develop EPS. The strength of evidence for this finding is moderate. - The risk of EPS is elevated 10.3-fold with ziprasidone when compared with placebo (statistically valid range from 1.4-fold to 75-fold). With this elevation of risk, when compared with the placebo group, one in every nine patients will develop EPS. The strength of evidence for this finding is low. Somnolence - The risk of somnolence is elevated 2.7-fold during treatment with aripiprazole when compared with placebo (statistically valid range from 1.1-fold to 6.5-fold). With this elevation of risk, when compared with the placebo group, 1 in every10 patients will exhibit somnolence. The strength of evidence for this finding is low. - The risk of somnolence during treatment with olanzapine is not statistically significantly different from placebo. The strength of evidence for this finding is low. - The risk of somnolence is elevated 3.4-fold during treatment with quetiapine when compared with placebo (statistically valid range from 2.0-fold to 5.8-fold). With this elevation of risk, when compared with the placebo group, one in every four patients will exhibit somnolence. The strength of evidence for this finding is low. - The risk of somnolence is elevated 2.9-fold during treatment with risperidone when compared with placebo (statistically valid range from 1.5-fold to 5.5-fold). With this elevation of risk, when compared with the placebo group, one in every four patients will exhibit somnolence. The strength of evidence for this finding is moderate. - The risk of somnolence is elevated 3.0-fold during treatment with ziprasidone, when compared with placebo (statistically valid range from 1.7-fold to 5.2-fold). With this elevation of risk, when compared with the placebo group, one in every seven patients will exhibit somnolence. The strength of evidence for this finding is moderate. Prolactin Levels - Prolactin levels are 4.1 ng/mL lower than in the placebo group during treatment with aripiprazole (statistically valid range from 1.8 ng/mL lower to 6.3 ng/mL lower). The strength of evidence for this finding is moderate. - During treatment with olanzapine, prolactin levels are 11.5 ng/mL higher than in the placebo group (statistically valid range from 8.8 ng/mL higher to 14.1 ng/mL higher). The strength of evidence for this finding is moderate. - No statistically significant difference was found between prolactin levels during treatment with quetiapine when compared with the placebo group. The strength of evidence for this finding is low. - During treatment with risperidone, prolactin levels are 22.6 ng/mL higher than in the placebo group (statistically valid range from 10.7 ng/mL higher to 34.5 ng/mL higher). The strength of evidence for this finding is low. - The evidence about ziprasidone effects on prolactin levels is insufficient to permit conclusions. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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): Comparison Dyslipidemia Weight Olanzapine vs. Quetiapine The risk with olanzapine is 3.5 times that of quetiapine (from 1.1x to 11.2x). ●○○ No summary estimate. Olanzapine vs. Risperidone Triglycerides are 17.3 mg/dL higher, on average, with olanzapine (from 3.5 to 31.1 mg/dL higher). ●●○ Weight is 2.39 kg greater, on average, with olanzapine (from 1.5 kg to 3.3 kg greater). ●●○ Olanzapine vs. Aripiprazole The risk with olanzapine is 4 times that of aripiprazole (from 1.25x to 12.5x). ●○○ Weight is 4.1 kg greater, on average, with olanzapine (from 2.7 kg to 5.5 kg greater). ●○○ Aripiprazole vs. Quetiapine Triglycerides are 39.4 mg/dL lower with aripiprazole (from 7.4 to 71.3 mg/dL lower). ●○○ Weight is 1.62 kg greater, on average, with quetiapine (from 0.3kg to 3.0 kg greater). ●○○ Strength of Evidence Symbols: High = ●●● Moderate = ●●○ Low = ●○○ Insufficient = ○○○ Adverse Effects: SGAs Versus SGAs (1 of 2) The risk and severity of key adverse events was examined in a meta-analysis of individual second-generation antipsychotics (SGAs) compared with each other 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): - In comparing olanzapine with quetiapine, the risk for dyslipidemia is 3.5-fold greater with olanzapine (from 1.1-fold to 11.2-fold). The strength of evidence for this finding is low. There is no summary estimate for differences in weight during head-to-head comparisons of olanzapine and quetiapine. - In comparing olanzapine with risperidone, triglycerides are 17.3 mg/dL higher with olanzapine (from 3.5 to 31.1 mg/dL higher). The strength of evidence for this finding is moderate. Weight is 2.39 kg greater, on average, with olanzapine (from 1.5 kg to 3.3 kg greater). The strength of evidence for this finding is moderate. - In comparing olanzapine with aripiprazole, the risk of dyslipidemia is four times greater with olanzapine (from 1.25-fold to 12.5-fold). The strength of evidence for this finding is low. Weight is 4.1 kg greater, on average, with olanzapine (from 2.7 kg to 5.5 kg greater). The strength of evidence for this finding is low. - In head-to-head comparisons of aripiprazole with quetiapine, triglycerides are 39.4 mg/dL lower with aripiprazole (from 7.4 to 71.3 mg/dL lower). The strength of evidence for this finding is low. Weight is 1.62 kg greater, on average, with quetiapine (from 0.3 to 3.0 kg greater). The strength of evidence for this finding is low. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. The strength of evidence in support of these conclusions is low. The risk of elevated prolactin is 2.6 times greater with risperidone than with olanzapine (from 1.7x to 5x). The strength of evidence for this conclusion is 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

Summary of Adverse Effects of Second-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). Summary of Adverse Effects of Second-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, 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 the 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. 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). Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. Conclusions About 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 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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) antipsychotics 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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. 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

What To Discuss With Your Patients and Their 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. What To Discuss With Your Patients and Their 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 neuromotor 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. Reference: Seida J, Schouten J, Mousavi S, et al. First- and Second-Generation Antipsychotics for Children and Young Adults. Comparative Effectiveness Review No. 39 (Prepared by the University of Alberta Evidence-based Practice Center under Contract No ). Rockville, MD: Agency for Healthcare Research and Quality; February AHRQ Publication No. 11(12)-EHC077-EF. Available at Seida J, Schouten J, Mousavi S, et al. Comparative Effectiveness Review No. 39. Available at

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Agency for Healthcare Research and Quality (AHRQ)

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Presentation on theme: "Agency for Healthcare Research and Quality (AHRQ)"— Presentation transcript:

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