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Seida JC, Schouten JR, Mousavi SS, et al. First- and Second-Generation Antipsychotics for Children and Young Adults [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Feb. (Comparative Effectiveness Reviews, No. 39.)
This publication is provided for historical reference only and the information may be out of date.
First- and Second-Generation Antipsychotics for Children and Young Adults [Internet].
Show detailsAntipsychotics are widely used to treat several psychiatric disorders in pediatric and adult populations, including schizophrenia, bipolar mania, and psychotic depression. Antipsychotics are commonly categorized into two drug classes, first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), marking two waves of historical development. FGAs were developed in the 1950s. Although FGAs provide treatment for psychotic symptoms, use of these drugs can result in extrapyramidal symptoms, which are various movement disorders characterized by repetitive, involuntary muscle movements, restlessness, or an inability to initiate movement. Other common side effects are dry mouth and sedation. Neuroleptic malignant syndrome and tardive dyskinesia are rare but serious side effects. SGAs emerged in the 1980s. They generally have lower risk of motor side effects, but are associated with significant weight gain, lipid and prolactin elevation, and the development of type 2 diabetes.
Studies have shown that prescriptions for psychotropics, including antipsychotics, have increased during the last 20 years in children and youth.1-5 Use of antipsychotics in the pediatric population is controversial mainly due to a lack of high-quality or longitudinal data on which to base conclusive clinical practice recommendations, especially with regard to safety.
In children and youth, antipsychotics vary in their use depending on the country and psychiatric condition. For the majority of antipsychotic drugs, approved indications are restricted to the treatment of childhood schizophrenia and bipolar disorders in the United States. In 2006, the U.S. Food and Drug Administration (FDA) approved risperidone and aripiprazole for the treatment of irritability associated with autism. Off-label prescriptions are given to younger children for behavioral symptoms (e.g., aggression) that are related to diagnosable conditions (e.g., attention deficit hyperactivity disorder [ADHD]). In some instances, antipsychotics may be used off-label for behaviors that are also part of a child's normal developmental trajectory or may reflect an adaptive response to an environmental stressor (e.g., parental divorce).
In general, the choice of medication for children and youth is often driven by side-effect profiles that may affect growth and development, medication adherence and persistence, and other important domains such as school performance and health-related quality of life.6 Therefore, close clinical monitoring is recommended.7
This comparative effectiveness review provides a comprehensive synthesis of the evidence on the benefits and harms associated with the use of FDA-approved FGAs and SGAs in pediatric and young adult populations (≤24 years of age). Young adults were included alongside pediatric patients in this review because age 18 is an arbitrary cutoff and falls within the peak age for the onset of schizophrenia and psychosis. Furthermore, young adults with behavioral or psychiatric conditions face unique challenges, as they often become ineligible for continued access of services once they become legal adults at age 18. The report is intended for a broad audience consisting of professional societies developing clinical practice guidelines, patients and their care providers, and researchers conducting studies in this field.
Antipsychotic Drugs
A list of FDA-approved FGAs and SGAs and their indications is presented in Table 1 and Table 2, respectively. There is no consensus on the terminology used to describe antipsychotic medications (e.g., FGA and SGA versus typical and atypical antipsychotics). For the purposes of this review, the terms “first-generation” and “second-generation” will be used. This terminology can more easily accommodate the categorization of drug classes developed in the future (i.e., third-generation antipsychotics).
Table 1
Food and Drug Administration-approved first-generation antipsychotics.
Table 2
Food and Drug Administration-approved second-generation antipsychotics.
Conditions and Prevalence
The University of Alberta Evidence-based Practice Center was commissioned to examine the use of FGAs and SGA for the following conditions: pervasive developmental disorders, ADHD, disruptive behavior disorders, bipolar disorder, schizophrenia and schizophrenia-related psychosis, Tourette syndrome, obsessive-compulsive disorder, post-traumatic stress disorder, and behavioral issues (e.g., aggression, agitation, anxiety, behavioral dyscontrol, irritability, mood lability, self-injurious behaviors, and sleep disorders).
Pervasive Developmental Disorders
Pervasive developmental disorders are characterized by impairments in reciprocal social interaction that are present before age 3 and persist to varying degrees across the lifespan. The prevalence of childhood autism is 39 per 10,000, and that of other autism spectrum disorders (e.g., Asperger's disorder, pervasive developmental disorders not otherwise specified) is 77 per 10,000.8 There has been a rising trend in prevalence rates, which may be due to broadening diagnostic criteria, better ascertainment, or increased incidence.8
The child's age, developmental level, and intellectual level strongly affect the presentation of pervasive developmental disorders. Key features are the inability to use language effectively for communication, an absence of symbolic play, stereotyped or repetitive behaviors (which may be harmful to the child), and focused, restricted patterns of interest or obsessions. Children with pervasive developmental disorders have varying degrees of problems using or interpreting language and nonverbal cues for communication.
Psychotropic medications are used as part of the management of pervasive developmental disorder-related symptoms. Antipsychotics may be used to manage aggressive outbursts in the context of emotional reactivity, reduce hyperactivity or repetitive behaviors, promote sleep onset and continuity, and treat other psychiatric comorbid symptoms. The increasing prevalence of pervasive developmental disorders raises concerns about the increased use of pharmacological interventions such as antipsychotics in young children.
ADHD and Disruptive Behavior Disorders
ADHD and disruptive behavior disorders (including oppositional defiant disorder and conduct disorder) are common childhood disorders and are so named because the core symptoms disrupt the daily functioning of children and their families. These disorders are the most common reason for presentation to child psychiatry clinics.
The prevalence of ADHD ranges between 6 and 12 percent. Similar prevalence estimates are given for oppositional defiant disorder; the prevalence of conduct disorder may be slightly lower.9 The rates of disorder vary by age and sex, but the most marked difference is the 6 to 1 ratio of boys to girls with ADHD prior to puberty. In general, sex differences are less for children with oppositional defiant disorder and conduct disorder and diminish with increasing age.
There are common causes posited for these conditions, which commonly co-occur in childhood. These causes relate to inadequate or delayed development of the prefrontal cortex, which is a key region of the brain involved in the executive control of behaviors and emotions. Because of their deficits in executive functioning, children with disruptive behaviors are particularly sensitive to their environmental context. A core ingredient of therapeutic interventions is parent and teacher education and training about how to help shape a child's behavior at home and school. When children are 6 years of age and older (latency stage), child-focused interventions that involve group- and individual-level training may be used to promote the use of the prefrontal cortex. Group-level training teaches skills in social problem solving, emotional regulation (specifically frustration tolerance), and selection of nonaggressive responses to frustration.
Many children with disruptive behaviors, particularly those with multiple disorders, require treatment with medication. Psychostimulant medications are used to treat symptoms of hyperactivity and distractibility, and may have some benefit for oppositional behaviors associated with inflexibility. Antipsychotic medications are used predominantly to manage impulsive aggression and to help regulate negative emotions (sadness, anger, and anxiety) that, left untreated, may also worsen impulsivity. Antipsychotic medications are also used in small doses to promote somnolence (an intended side effect), as many children with ADHD have sleep disturbance.
Bipolar Disorder
Bipolar disorder is a disorder characterized by unstable mood. There are several types of bipolar disorder that affect children and adolescents: bipolar type 1 (manic episodes and depressive episodes occur independently of each other), bipolar type 2 (hypomanic episodes and depressive episodes occur independently of each other), and bipolar disorder not otherwise specified (brief mood shifts between positive or agitated and negative mood states, not meeting criteria for mania or hypomanic episodes in duration). The latter disorder appears to be the most prevalent (3 percent of children in the community) and is a focus of much research and controversy because many of these children are treated with antipsychotics approved by the FDA as mood stabilizers.10 Bipolar I and bipolar II disorders are less common (approximately 1 percent and 0.5 percent prevalence, respectively) but are associated with higher morbidity.10 Children with bipolar disorders of any type often have multiple co-occurring mental health problems.
Treatment for bipolar disorder includes the use of traditional mood stabilizers (i.e., anticonvulsants, such as valproic acid or carbemazepine) and antipsychotics. Antipsychotics may be used as the first-line medication in children and adolescents even when psychosis is not present. This is due to the difficulty of clinically diagnosing an episode of mania in a child and because many children and families have concerns with monitoring mood stabilizer levels with blood testing. Both kinds of medication appear to be effective in promoting emotional stability and sleep hygiene and at reducing impulsivity, psychotic symptoms, self harm, hostility, and aggression.
Schizophrenia and Schizophrenia-Related Psychosis
Schizophrenia and schizophrenia-related psychosis are grouped together because psychotic symptoms are prominent features of both conditions. Psychotic symptoms are also associated with comorbid psychiatric disorders, most particularly substance-use disorders and depressive disorders. Schizophrenia and related psychoses are uncommon in preadolescent children; prevalence estimates in this population are not known. In adolescents, the prevalence is estimated to be 0.1 percent, and about twice as many boys are affected as girls.11 The onset of the condition is usually insidious, with symptoms gradually becoming apparent over an extended period of time. Typically, psychotic symptoms are classed as either being positive (e.g., hallucinations or delusions) or negative (e.g., anhedonia or lack of motivation). People are typically affected by both types of symptoms. Depending on the degree of impairment, patients may have little or no insight into their symptoms. However, patient insight is difficult to assess, particularly in young children or those with developmental delays. The duration of an episode of psychosis and course of illness are also highly variable across individuals.
Treatment of psychotic disorders or psychotic features includes the use of antipsychotic medications. Whether these medications are beneficial for the treatment of substance abuse and mood difficulties is not well known. A variety of psychosocial interventions are also used to target the maintenance of social engagement, cognitive development, academic achievement, and avoidance of substance use.
Tourette Syndrome
Tourette syndrome is a tic disorder. Tics are involuntary motor movements or vocalizations. Although some individuals have only motor or verbal tics, a diagnosis of Tourette syndrome requires that both types of tics occur many times a day, nearly every day, or intermittently over a period of 1 year. The prevalence is 0.04 to 0.05 percent, and three times as many boys are affected as girls.12 For a diagnosis of Tourette syndrome, the onset of symptoms must occur before age 18; the average age of onset is 7 years. Children with Tourette syndrome commonly have ADHD (up to 50 percent) or obsessive-compulsive disorder (up to 40 percent).
Abnormalities in many neurotransmitter systems are involved in the disorder; however, most evidence suggests dysfunction in the regulation of the release and reuptake of dopamine in the basal ganglia (a deep brain structure partly responsible for motor control). Medications that inhibit dopamine reuptake, such as antipsychotics, generally help to reduce tics, but may induce tics in some cases (i.e., tardive Tourette disorder). Antipsychotics may also have a beneficial impact on comorbid conditions.
Obsessive-Compulsive Disorder
Obsessive-compulsive disorder is an anxiety disorder characterized by developmentally inappropriate and persistent anxiety with associated behavioral disturbances. Behaviors include obsessions and/or compulsions that are severe enough to be time consuming (more than 1 hour per day) and significantly interfere with daily activities. Obsessions are recurrent, persistent, and unwanted thoughts, images, or impulses that are intrusive and inappropriate and that cause a great deal of anxiety, distress, fear, or worry. They often center on aggressive, sexual, or religious topics that the affected person recognizes as a product of their own mind.
Compulsions are deliberate, repetitive behaviors (e.g., hand washing, cleaning, checking, or hoarding) or mental acts (e.g., preoccupation with praying, counting, or word repetition) and may involve performing rituals according to strict rules. Compulsions are aimed at reducing the anxiety caused by the obsessions with the hope of preventing obsessive thoughts or making them go away. Performing these behaviors temporarily reduces the anxiety; not performing them increases anxiety. Core diagnostic criteria present differently depending on age. For example, young children may present with physical complaints or temper tantrums rather than anxieties and worries that may be seen in adolescents. There can also be fluctuation in symptom severity over time.13,14
Community studies of children and adolescents in many different cultures have estimated a lifetime prevalence of 1 to 2.3 percent.15 Age of onset is seen across childhood and adolescence.
Post-traumatic Stress Disorder
Post-traumatic stress disorder is an anxiety disorder that develops following a reaction of intense fear, helplessness, or horror resulting from a traumatic event. Events may involve actual or threatened death or serious injury to oneself or others. Characteristic symptoms of post-traumatic stress disorder include a persistent re-experience of the traumatic event (e.g., images, thoughts, dreams, or flashbacks), persistent avoidance of stimuli associated with the trauma, numbing of general responsiveness, and persistent symptoms of increased arousal (e.g., difficulty sleeping, irritability, or outbursts of anger). Symptoms may appear soon after the event or several years later, but are present for more than 1 month and cause clinically significant distress or impairment in social, occupational, or other areas of functioning.
The prevalence of post-traumatic stress disorder is 6 to 8 percent in children and adolescents under 18 years of age.16 Studies of at-risk individuals (i.e., groups exposed to specific traumatic incidents) indicate variation in rates across risk groups. The highest rates range from one-third to more than half among victims of rape and survivors of military combat, captivity, ethnically or politically motivated internment, and genocide.
Anorexia Nervosa
Anorexia nervosa is an eating disorder in which a fear of weight gain coupled with a distorted body image leads to refusal to maintain a minimally acceptable body weight.15 The cardinal psychological feature of the disorder is a pervasive fear of weight gain and unrealistic evaluation of physical shape despite a starved appearance. Self-employed strategies to achieve this state can include lengthy periods of starvation, excessive exercise, extreme food restriction, and purgatives (e.g., laxatives, diuretics). Because of the extreme weight loss in this disorder, physiological dysfunction occurs including amenorrhea (loss of menstruation for at least 3 consecutive months) due to abnormally low levels of estrogen, which is included as a diagnostic criterion.
This eating disorder includes two subtypes that are defined by behavioral indicators: restricting, and binge-eating and purging. The individual with the restricting subtype predominantly limits caloric intake and may engage in excessive pharmacologic (i.e., diuretics) or exercise-induced measures to lose weight. In contrast, the individual with the binge and purge subtype may engage in recurrent eating of a substantially large amount of food in a discrete period of time, followed by compensatory purging activities to expel the food (i.e., self-induced vomiting or the misuse of laxatives, enemas, or diuretics).
Though some individuals may acknowledge being thin, their illness precludes them from being able to recognize the serious medical implications of their malnourished state. The individual is often brought to professional attention by family members. Medications such as antidepressants, antipsychotics, and mood stabilizers may help treat anorexia nervosa and comorbid conditions when given as part of a complete psychological treatment program.
The prevalence of anorexia is more predominant in females, with approximately 0.13 percent of females ages 15 to 20 years having the disorder. In males, it is approximately one-tenth of that. The incidence of anorexia nervosa appears to have increased in recent decades.15
Outcome Measures
A wide variety of checklists and scales are used to assess symptomatology and side effects in patients with psychiatric and behavioral disorders. Measures vary and can be generic or disease-specific, patient-, parent-, or clinician-rated, and general or child-specific. An overview of the domains, scoring, and psychometric properties of the most common scales evaluating outcomes and extrapyramidal side effects is provided in Table 3 and Table 4, respectively. These tables provide information for the scales that were most frequently used in the studies included in this review but do not describe every outcome measure.
Table 3
Common outcome measures.
Table 4
Extrapyramidal symptom measures.
Scope and Key Questions
The Key Questions are as follows:
- What is the comparative efficacy or effectiveness of FGAs and SGAs for treating disorder-or illness-specific and nonspecific symptoms in children, youth, and young adults (≤24 years) for the following disorders or illnesses?
- Pervasive developmental disorders, including autistic disorder, Rett's disorder, childhood disintegrative disorder, Asperger's disorder, and pervasive developmental disorder not otherwise specified.
- ADHD and disruptive behavior disorders, including conduct disorder, oppositional defiant disorder, and disruptive behavior disorder not otherwise specified.
- Pediatric bipolar disorder, including manic or depressive phases, rapid cycling, and mixed states.
- Schizophrenia and schizophrenia-related psychoses, including schizoaffective disorder and drug-induced psychosis.
- Obsessive-compulsive disorder.
- Post-traumatic stress disorder.
- Anorexia nervosa.
- Tourette syndrome.
- Behavioral issues, including aggression, agitation, anxiety, behavioral dyscontrol, irritability, mood lability, self-injurious behaviors, and sleep disorders.
- Do FGAs and SGAs differ in medication-associated adverse events when used in children, youth, and young adults (≤24 years)? This includes:
- Overall adverse events.
- Specific adverse events.
- Withdrawals and time to withdrawal due to adverse events.
- Persistence and reversibility of adverse events.
- Do FGAs and SGAs differ in other short- and long-term outcomes when used in children, youth, and young adults (≤24 years)? Short-term is defined as outcomes occurring within 6 months; long-term is defined as outcomes occurring after 6 months.
- Response rates with corresponding dose, duration of response, remission, relapse, speed of response, and time to discontinuation of medication.
- Growth and maturation.
- Cognitive and emotional development.
- Suicide-related behaviors or death by suicide.
- Medication adherence and persistence.
- School performance and attendance.
- Work-related functional capacity.
- Patient insight into illness
- Patient-, parent-, or care provider–reported outcomes, including levels of physical activity or inactivity and diet (e.g., caloric intake, food preferences).
- Health-related quality of life.
- Legal or justice system interaction (e.g., arrests, detention).
- Health care system utilization (e.g., protective services, social services).
- “Outcomes that matter” to children, youth, young adults, and their families. These functional outcomes may reflect a developmental perspective.
- Do the effectiveness and risks of FGAs and SGAs vary in differing subpopulations including:
- Sex?
- Age group (<6 years [preschool], 6–12 years [preadolescent], 13–18 years [adolescent], 19–24 years [young adult])?
- Race?
- Comorbidities, including substance abuse and ADHD?
- Cotreatment versus monotherapy?
- First-episode psychosis versus treatment in context of history of prior episodes (related to schizophrenia)?
- Duration of illness?
- Treatment naïve versus history of previous antipsychotics use?
Figure 1 is an analytic framework that portrays the clinical concepts and mechanism by which treatment with antipsychotics may improve outcomes. In particular, this figure illustrates the relationship between intermediate and long-term outcomes. We have labeled each link in this pathway with the key question that addresses the various outcomes (i.e., intermediate, long-term, and adverse event outcomes).
- Introduction - First- and Second-Generation Antipsychotics for Children and Youn...Introduction - First- and Second-Generation Antipsychotics for Children and Young Adults
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