CHAPTER 134

Psychopharmacology in Children

Robin Steinberg-Epstein, MD, and Nisha Warikoo, MD

Psychopharmacologic agents are being used with increased frequency in the pediatric population. Approximately 50% of children and adolescents will, at some point before age 18 years, meet criteria for a psychiatric diagnosis. Almost 25% of children will have substantial impairment as a result of those symptoms. Unlike antibiotics or other medications used in children, psychopharmacologic agents are used daily and for extended periods. Furthermore, it is important to recognize the dearth of evidence-based information supporting the use of many medications in children, including psychotropic medications. Therefore, many of these medications are used in an off-label fashion. The medical community must rely on published data (often in adult subjects), clinical experience, and expert consensus to guide medication choice, dose, and management. This often provokes parental anxiety and sparks numerous concerns from families who do not understand that the US Food and Drug Administration (FDA) label limits the claims a manufacturer can make but does not limit a physician’s use of medications. Furthermore, families are often anxious, because physicians rely almost exclusively on history and structured behavioral observation, which is the most important “test” for most of these disorders. Unfortunately, the United States has a shortage of pediatric subspecialists trained to choose, monitor, and manage these medications for children. Pediatricians often serve as the first point of contact with families. In most cases, many months may elapse before families are able to see a child and adolescent psychiatrist for diagnostic evaluation and medication management. It is, therefore, necessary for pediatricians to be familiar with the common psychiatric conditions, different classes of psychotropic medications, and controversies facing families of affected children.

Pediatricians need to understand the principles guiding the use of these medications and become familiar with some of the more frequently used psychopharmacologic agents. The most used classes of medication in children include stimulants, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs) and atypical antipsychotics, also known as serotonin-dopamine antagonists (SDAs). This information can also be useful in helping families navigate this confusing maze.

The decision to use psychopharmacologic agents should be made only after obtaining a comprehensive history as well as a physical and mental status examination and making an accurate diagnosis. It is imperative to obtain collateral information from parents or caregivers, school, and/or therapists. Rating scales can be used as screening tools, as tools for establishing a baseline, and for monitoring progress and treatment response. For common psychiatric conditions, such as depression and anxiety, referral to therapy is indicated. If the symptoms and associated impairments are moderate or severe, however, medication management is necessary, often in addition to therapy. Medications should be an integral part of a comprehensive treatment program that addresses the academic, behavioral, medical, and developmental needs of the child. The decision to place a child on any agent should be based on significant dysfunction as well as discussion and full disclosure of potential risks and benefits with the parents or caregivers and the child. A medication trial, once undertaken, should be carefully monitored, methodically addressing adverse events and effectiveness. Generally, it is best to change 1 agent or dose at a time, followed by structured observation (eg, rating scale[s]) to determine the effect of the change. Therefore, a physician usually begins with monotherapy, optimizes the dose over the recommended period of time, and assesses risks and benefits before developing a more complex regimen. Such a trial necessitates frequent visits and discussion with the administering physician. Current scientific information and clinical experience indicate that the use of psychopharmacologic agents in young children (<5 years) should be reserved for extraordinary circumstances.

Children are not little adults. Pharmacokinetics in children is affected by increased rates of metabolism in their relatively larger livers, a faster glomerular filtration rate, and variable fatty tissues. Some children, therefore, require a dose larger than that used in adults. Conversely, perhaps because of size, fat distribution, and other explanations, a much smaller, and seemingly ineffective, dose may be sufficient. In general, it is recommended to start low and go slow to prevent adverse effects of medication. For most agents, little correlation exists between blood level and treatment response. Furthermore, some medications have a duration of effect that well exceeds the half-life (eg, atomoxetine hydrochloride); however, with other medications (eg, stimulants) the effect diminishes despite a significant level of the agent in the blood. Additionally, for most agents (eg, stimulants, SDAs), no correlation with milligrams per kilogram exists. Frequent clinical monitoring and communication with parents/caregivers and family and often with teachers and therapists as well are vital to understanding response to medication, tolerance, and treatment adherence.

Psychostimulants

Psychostimulants are the most studied psychotropic medications used in pediatrics (see Chapter 133). These medications are used to manage the hyperactivity, inattention, and impulsivity that occur with attention-deficit/hyperactivity disorder (ADHD) and disturbances of attention that occur in other disorders (eg, autism spectrum disorder [ASD], traumatic brain injury, depression). Stimulants are also used in the management of narcolepsy. During the past decade, many new delivery systems have been developed with differing durations of action, which help to cater to the specific lifestyle needs of the patient. Much work has been done to determine optimal blood level delivery resulting in the most consistent effect. Overall, the duration of action and clinical efficacy are more relevant than the blood level in this class of medication.

The mechanism of action of psychostimulants is to increase dopamine and norepinephrine in the synapse. Overall, this enhances activity in the prefrontal cortex of the brain responsible for attention, focus, and executive function (ie, organization and planning).

Substantial evidence exists in multisite, double-blind, placebo-controlled studies (eg, Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder) to support the first-line use of these medications in the treatment of school-age children and adolescents with ADHD. Evolving evidence exists (Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study) to support the use of these drugs in preschool-age children. Medications may be helpful for preschool-age children for whom an adequate trial of behavior therapy has been unsuccessful. A growing body of evidence supports their use in ASD, albeit at lower doses because of the lower threshold for side effects.

Parents and caregivers have varied concerns related to stimulants, many of which are propagated by the media; however, leaving ADHD untreated results in significant comorbidities and risks for negative outcomes. Attention-deficit/hyperactivity disorder in children and adolescents has been associated with academic underachievement, grade retention, and ultimately, school dropout in several studies as well as an increased risk for substance use disorders. Nonetheless, several areas of controversy exist and often become a primary focus for hesitant parents or caregivers. Understanding the facts can help demystify these medications for parents or caregivers. For example, a risk of substance abuse has long been linked with stimulant medication. A substantial body of evidence shows that the use of stimulant medication does not result in an increased risk of later substance abuse. In fact, it is untreated ADHD and the resultant development of maladaptive behaviors that places adolescents at increased risk for substance use disorders. The hypothesis is that management of ADHD with stimulant medication in fact reduces substance use and many other potential negative outcomes, such as early tobacco use, undesired pregnancy, and motor vehicle crashes. Because stimulants often are prescribed for extended periods of time, however, additional long-term studies are needed.

Another frequently raised concern is the association between stimulants and an increase in sudden unexpected deaths. This would raise concern for any parent or caregiver. However, FDA scrutiny of these statistics revealed a lower incidence of sudden unexpected deaths in individuals on stimulants compared with the unmedicated population. Persons who died tended to have an underlying cardiac defect. Based on the current evidence, the American Academy of Pediatrics and the American Heart Association recommend a detailed cardiovascular history, a family history, and a physical examination followed by the initiation or continuation of pharmacotherapy with ADHD medications without further assessment in patients whose history and examination are not suggestive of cardiac disease. In individuals with a positive personal or family history and/or physical examination for cardiac disease, further evaluation is necessary, consisting of electrocardiography (ECG) and/or consultation with a pediatric cardiologist. After treatment is initiated, children and adolescents must be monitored for changes in heart rate, blood pressure, and cardiovascular symptoms during treatment.

Historically, height suppression has been raised as a concern with these medications. Numerous studies have tried to answer this question. A recent longitudinal study of more than 10 years’ duration supports an initial growth suppression emphasized in the first 3 years of treatment that appears to resolve over the remaining 7 years. Parents or caregivers can be further reassured that if height suppression does occur, it seems to be minimal (eg, a median loss of <0.2 standard deviations over 2–3 years) and tends to attenuate with increasing time on treatment for both methylphenidate hydrochloride and amphetamine formulations. It is preferable for patients to graduate from high school even if their final adult height is slightly lower than that predicted by parental stature. Another 10- to 11-year longitudinal study that assessed the effect of ADHD and its treatment on growth outcomes in children followed into adulthood did not support an association between deficits in growth outcomes and ADHD or psychostimulant treatment for ADHD. However, it is important to monitor growth in routine follow-up visits.

Finally, many parents and caregivers are concerned that their children will be “zombies” on medication. Children who are over-medicated can appear glassy-eyed and overly passive; however, good communication and interaction between families and doctors will quickly alleviate this problem. Families who often want to try alternative therapies are routinely encountered in clinical practice. Families should be educated about the potential risks of alternative therapies and continually encouraged to use evidence-based pharmacotherapeutic and/or psychotherapeutic measures simultaneously. Additionally, families may have concern about worsening tics with use of stimulant medications. A recent meta-analysis concluded that most patients with ADHD and a tic disorder benefit from moderate doses of stimulant treatment without worsening of tics and that the addition of α₂ agonists was especially useful because they were therapeutic for both ADHD and the tic disorder. Additional information about these medications may be found in Chapter 133.

Selective Norepinephrine Reuptake Inhibitors

Currently, the SNRIs include 1 medication that is frequently used in children: atomoxetine hydrochloride (eg, Strattera). Atomoxetine hydrochloride is used in the management of ADHD and for the inattention and anxiety associated with ASD.

The mechanism of action for atomoxetine hydrochloride is to block the reuptake of norepinephrine in the synapse. This may have a direct effect on enhancing the signal-to-noise ratio in the brain and may also ultimately result in an increase in dopamine in the prefrontal cortex of the brain. Unlike stimulant medications, atomoxetine hydrochloride avoids the nucleus accumbens so that it has no abuse liability.

Atomoxetine hydrochloride was originally studied as an antidepressant agent, but early investigation did not yield robust antidepressant effects. Marketed as providing “continuous symptom relief,” a careful duration of action study shows little effect on core ADHD symptoms after 9 hours; however, some possible other small effects (eg, compliance) may last slightly longer. The attractiveness of atom-exitine hydrochloride stems from its identity as an FDA-approved non-stimulant. Although usually less effective than stimulants, it has a different side-effect profile and may be associated with slight mood and anxiety benefits.

Research shows that atomoxetine hydrochloride, which is FDA approved for use in patients with ADHD, is effective in managing symptoms of this disorder for a given individual but has been found in studies of groups of people to be less effective than stimulant medications. Atomoxetine hydrochloride generally has a 60% response rate (measured by 25% reduction in ADHD ratings), compared with a 70% to 80% response rate (measured by 30% reduction in ADHD ratings) with stimulant medications. Furthermore, 3 different studies in which atomoxetine hydrochloride was directly compared with stimulants have demonstrated atomoxetine hydrochloride to be less effective on average, even though, as stated previously, some individual patients do well with this medication. Atomoxetine hydrochloride should especially be considered for patients in whom use of a stimulant was unsuccessful (eg, poor tolerance or poor effect of a trial on a methylphenidate hydrochloride preparation and a trial on an amphetamine preparation), significant history of substance use and diversion, exacerbation of tic disorder with stimulants, and the presence of comorbid anxiety disorder.

The side effects of atomoxetine hydrochloride are quite similar to those of traditional stimulants, with the added concerns of drowsiness, dizziness, and cough. Furthermore, similar to SSRIs, atomoxetine hydrochloride carries a warning citing a slightly increased risk of suicidal ideation. It is important for physicians to monitor for changes in mood, irritability, agitation and suicidality, especially during first 4 to 5 months of therapy. Atomoxetine hydrochloride is not associated with tic exacerbation. Response to this medicine is more like that of an antidepressant in that it may take 4 to 6 weeks to see the full effect of a particular dose. Drug holidays are not an option with this medication. The dosage range is 0.5 mg/kg to 1.8 mg/kg. Individuals on the autism spectrum tend to respond at lower doses and with a lower threshold for adverse side effects.

A few patients have reportedly experienced a serious idiosyncratic reaction suggestive of liver failure. These patients were on FDA-approved doses of atomoxetine hydrochloride for several months. They experienced vomiting, jaundice, and elevated liver enzymes. These findings resolved when the medication was discontinued and returned with reexposure to the drug. This finding resulted in an FDA warning to consider potential liver failure in a vomiting patient on atomoxetine hydrochloride. If the patient develops jaundice or laboratory signs of hepatic injury, the medication should be discontinued.

The American Academy of Pediatrics and American Academy of Child and Adolescent Psychiatry recommend stimulants as first-line treatment for ADHD. Neither blood nor urine test monitoring is necessary for either stimulants or SNRIs. The physician should regularly monitor improvement, adverse events, and adherence using rating scales; this should be done at least every 3 months after both dose and agent have been optimized.

Parents and caregivers often want to know if these medications can be used intermittently and stopped as soon as possible. With stimulants and SNRIs, results are optimized when these medications are administered 7 days a week and without large breaks. Longitudinal studies suggest that although some symptoms may resolve over time, significant impairment from even a small number of symptoms persists into adulthood for 60% to 70% of those diagnosed with ADHD. Inattention is more likely to persist into adulthood. Therefore, many people may continue on medication for several years. To assess for continued benefit, a break from medication may be attempted annually. As children grow larger, they often need higher doses. However, as compensatory mechanisms develop and some symptoms subside, some patients may require less medication. It is beneficial to re-optimize doses and agents throughout the length of treatment. Drug holidays have no established intrinsic value on their own and should be recommended only for children with significant medication side effects, such as substantial weight loss. If a parent or caregiver is requesting a drug holiday, it is a signal that the parent or caregiver may need to review the value of the medication. A discussion should ensue as to whether the parent/caregiver and child continue to see benefit, the patient is having troubling side effects, or the medication at any dose is not helpful and is associated with concerning symptoms. The physician must take into consideration the knowledge that atomoxetine hydrochloride, once stopped and restarted, needs time to reachieve a therapeutic level.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors are frequently used in children and adolescents to manage a variety of depression- and anxiety-based symptoms (Table 134.1) (Box 134.1). Similar to SNRIs, SSRIs block presynaptic reuptake of serotonin after it is released into the synapse, thereby enhancing serotonin activity in the synapse. Empirical evidence has established the benefit of SSRIs in the management of depressive and anxiety disorders.

Medication is not a substitute for therapeutic support. In fact, most clinical guidelines recommend psychotherapy as first-line treatment for mild and moderate anxiety and depressive disorders in children. Medication management should be undertaken only if psychotherapy progress is minimal or symptom severity and impairment are moderate to severe. Most studies have proved that combination treatment of medication and therapy is more effective than either treatment modality alone. Obsessive-compulsive disorder is a unique anxiety disorder that typically requires higher doses of SSRIs than do anxiety or depressive disorders. The chronicity of the condition with the possibility of frequent exacerbations necessitates the use of a specific type of cognitive behavioral therapy, namely, exposure and response prevention.

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