CHAPTER 23

According to recent estimates from the National Health Interview Survey, up to 7.5% of children from 6 to 17 years of age are prescribed medication to treat a behavioral or emotional difficulty.1 Due to the limited availability of specialty providers, such as developmental-behavioral pediatricians and child and adolescent psychiatrists, the burden of first-line diagnosis and treatment often falls upon the patient’s primary pediatric health care professional, within the context of a medical home. Further, the American Academy of Pediatrics (AAP) states, “Pediatric primary care providers have unique opportunities and a growing sense of responsibility to prevent and address mental health and substance abuse problems in the medical home.”²

Despite this AAP statement, nearly 50% of children with mental/behavioral health needs are unable to access appropriate treatment.³ Many primary pediatric health care professionals feel responsible for the identification, but not necessarily the ongoing medical management, of many mental/behavioral health disorders.⁴ Although mandatory rotations in developmental-behavioral pediatrics during pediatric residency training have increased pediatricians’ familiarity with the treatment of common childhood mental/behavioral health conditions, relatively few pediatric residency graduates rate their mental/behavioral health treatment skills as “very good” or “excellent.”⁵ Further, many family physicians, pediatric nurse practitioners, and physician assistants who provide primary care to children and adolescents receive no formal training in developmental-behavioral pediatrics.

This chapter will review general principles for using psychotropic medications in children and adolescents with developmental-behavioral disorders, and it will provide additional information regarding the evidence base and clinical use of these agents to treat hyperactive and disruptive behaviors, aggression and self-injury, anxiety and mood disorders, rigid and compulsive behaviors, and sleep problems. Where available, the authors will reference clinical practice guidelines and evidence-based practices, although off-label uses will also be discussed. Information regarding epidemiology, diagnosis, and non-pharmaceutical treatment options for the disorders discussed is provided elsewhere in this volume (see Chapter 8, Development and Disorders of Feeding, Sleep, and Elimination; Chapter 18, Attention-Deficit/Hyperactivity Disorder; Chapter 19, Autism Spectrum Disorder; Chapter 21, Disruptive Behavior Disorders; and Chapter 22, Anxiety and Mood Disorders).

General Principles for Using Psychotropic Medications in Children and Adolescents

Identify the primary underlying developmental-behavioral disorder rather than treat the symptoms. A thorough diagnostic evaluation to accurately identify the underlying developmental-behavioral disorder is necessary before developing a treatment plan. Behavioral and mood problems can be complex in their presentation and etiology. Is the child appearing inattentive primarily because of a short attention span or pervasive anxiety, or secondary to demands and expectations at school that exceed his or her underlying developmental abilities? Does the child act aggressively because of mood dysregulation, impulsivity, or a lack of appropriate social regard? Inappropriate medication use can mask, exacerbate, and delay identification of the underlying problem(s). A variety of screening instruments and assessment tools, as discussed elsewhere in this manual, along with careful interview of the child and his or her caregivers, can help the primary pediatric health care professional arrive at a likely diagnosis (see Chapter 9, Developmental and Behavioral Surveillance and Screening Within the Medical Home; Chapter 10, Developmental Evaluation; Chapter 11, Making Developmental-Behavioral Diagnoses; Chapter 15, Cognitive Development and Disorders; Chapter 17, Learning Disabilities; Chapter 18, Attention-Deficit/Hyperactivity Disorder; Chapter 19, Autism Spectrum Disorder; Chapter 21, Disruptive Behavior Disorders; and Chapter 22, Anxiety and Mood Disorders).

Consider medication as a component of a multimodal approach to treatment. For most developmental-behavioral disorders, a multimodal approach of medication and evidence-based psychosocial treatments yields the best outcomes. These may be employed sequentially (eg, parent behavioral training, then stimulant medication, if needed, to treat attention-deficit/hyperactivity disorder [ADHD] in preschool-aged children) or concurrently (eg, cognitive-behavioral therapy [CBT] and antidepressant medication for depression in adolescents). Psychotropic medications generally do not “fix” the problem, but they can enable the child to participate in and benefit from the psychosocial treatments.

Carefully review any previous trials of medication treatment. Clinicians should review previous medication trials. Important details, such as the child’s age at the time the medication was tried, the target behaviors or symptoms, dosing and titration schedule, experience of side effects, and the reasons for treatment failure or discontinuation, provide guidance as to the next steps of treatment. Medications that have failed in the past may be relatively contraindicated; however, if the clinician determines that the medication had been used inappropriately or inadequately (eg, wrong dose, wrong target, or not titrated sufficiently), another trial may be warranted.

Ensure that the patient’s caregivers understand the targets of treatment, the timing of effects, and the potential for side effects. Educating patients and caregivers regarding the medication’s expected effects on symptoms and potential adverse effects is a critical component of medication management. Caregivers should have a clear understanding of the reasons for prescribing medication, the potential risks and benefits of the medication, and realistic expectations for how well and how quickly a medication will address the target symptoms. Discussing potential adverse effects and how they might be addressed (eg, change dose, change timing, or change medication) can increase the likelihood of adherence to medication treatment. The importance of routine monitoring should also be emphasized.

Consider discontinuing treatment at least on an annual basis. Although many children prescribed psychotropic medication will likely require long-term treatment, the prescribing clinician should periodically evaluate whether medication continues to be necessary. For patients who have achieved target goals, or whose symptoms and behaviors appear to have resolved, a trial off the medication can identify those who no longer require it.

The AAP has published clinical recommendations for the treatment of ADHD (see Chapter 18, Attention-Deficit/Hyperactivity Disorder), as summarized below.^6,7

■ Preschool-aged children (4 to 5 years): Parent- or teacher-based behavior therapy is recommended as first-line treatment; methylphenidate is recommended only if behavioral therapy does “not demonstrate significant improvement and there is moderate-to-severe continuing disturbance in the child’s function.”

■ Elementary school–aged (6 to 11 years of age): Stimulant therapy is recommended as the first line of therapy along with behavioral therapy, parent training, and/or school intervention; nonstimulant therapy is the second line.

■ Adolescents (12 to 18 years of age): Medication treatment is recommended with consideration for the addition of behavior therapy.

Stimulants

Psychostimulant medications have been used in practice since the 1960s for the treatment of hyperactivity and inattention, and these medications have a substantial evidence base demonstrating their efficacy in children (including preschoolers), adolescents, and adults. All stimulant medications have FDA approval for the treatment of ADHD in children ≥6 years of age. Only immediate-release dextroamphetamine and its derivatives are approved for use in children from 3 to 5 years of age. (See Table 23.1.)

Stimulants appear to exert their effect by increasing the available amount of dopamine and norepinephrine for neurotransmission in the synapses of the prefrontal cortex and especially in the striatum. Methylphenidate inhibits reuptake of dopamine, while amphetamine both stimulates release of dopamine and norepinephrine, as well as inhibits their uptake. Stimulants are easily absorbed and readily cross the blood-brain barrier; they bind poorly to plasma proteins and are rapidly excreted in the urine (on average, in 4 hours). The maximum drug effects occur while the medication is increasing in serum levels, not when a steady state has been achieved.⁸ Due to this pharmacokinetic profile, when stimulants were first used for ADHD, immediate-release stimulants would have to be administered multiple times per day, usually with at least one dose administered at school. This treatment regimen was associated with difficulties coordinating with school personnel, interruptions in the child’s academic schedule, risk of stigma for the student, variability in the time of medication administration (resulting in gaps of medication coverage), and a higher potential for abuse or diversion.

Advances in drug development have resulted in a greater variety of extended-release stimulant formulations that allow for less frequent dosing as well as new extended-release formulations for children who are unable to swallow pills. Examples include the following:

In general, randomized controlled trials (RCTs) have not consistently demonstrated the superiority of one stimulant formulation over another; clinicians are encouraged to initiate a trial with stimulant medications that have a well-established evidence base. The ADHD Medication Guide (http://www.adhdmedicationguide.com/), made available online by Cohen Children’s Center, is updated frequently with new developments and includes pictures of pills for easy identification.

Common clinical practice is to initiate a methylphenidate or amphetamine preparation at the lowest dose and then titrate on a per-visit rate (eg, monthly to every few months) based on parent, teacher, and/or self report of the patient’s response and experience of side effects. Parents who are somewhat ambivalent about medication, however, may be too quickly satisfied with suboptimal improvements on a low dose, even if there is ongoing impairment due to ADHD symptoms. In contrast to community-based “care as usual,” stimulant titration protocols using parent and teacher rating scales at regular, scheduled (weekly to monthly) intervals often result in more rapid attainment of optimal dosing and efficacy in the research setting.9

Clinicians may choose to utilize a more aggressive (eg, “forced-dose”) titration schedule when starting a stimulant. One approach is to dispense 30 capsules of a medication and have the patient try 3 different doses, each for 5 days at a time, with follow-up in 2 weeks. For example, 30 capsules of dexmethylphenidate extended release 5 mg can be distributed with instructions to take 1 capsule (5 mg) for 5 days, 2 capsules (10 mg) for 5 days, and 3 capsules (15 mg) for 5 days. Titration can be halted if there are significant side effects lasting more than a few days. At the 2-week follow-up visit, the clinician and caregiver can decide which dose is the most appropriate. If the initial stimulant choice does not demonstrate a favorable risk-benefit balance, a trial of another stimulant is recommended. Studies have demonstrated that approximately 75% to 80% of individuals with ADHD will respond to either methylphenidate or amphetamine.

– Side Effects

All stimulant medications share a similar adverse effect profile, although the experience of individual patients can vary depending on the medication, formulation, and dose. The presence of significant adverse effects with a particular preparation in one stimulant class (eg, methylphenidate) does not necessarily preclude a trial with a different preparation in the same class.

Common side effects include headaches, stomachaches, mild increases in heart rate or blood pressure, appetite suppression, and difficulty with sleep onset. Headaches and stomachaches may spontaneously resolve as the individual adjusts to the medication and may also improve when the stimulant is administered with food. Sleep onset difficulty generally does not resolve over time and is typically related to the length of drug duration or to “rebound” effects after the medication has worn off. Both irritability and mood dysregulation can occur, most often in the mid to late afternoon or early evening as the medication effect wears off. These adverse drug events may limit tolerance of the medication, if they outweigh the benefit to the child. Alternatively, clinicians may adjust the medication regimen to minimize side effects.

Uncommon side effects of stimulant medication treatment include stimulant-induced psychosis (visual, auditory, or tactile hallucinations or psychotic thoughts), aggression, or behavioral disinhibition and/or mania. These may occur with high doses or in individuals predisposed toward schizophrenia or bipolar disorder.10 The oft-cited “zombie” effect is also usually associated with too high a dose.

The relationship between chronic administration of stimulants and growth is complex. While the primary concern has been poor weight gain and likelihood of attaining adult height due to decreased caloric intake from appetite suppression, other mechanisms, such as stimulant effects on central nervous system growth regulation, changes induced in hepatic metabolism, and alterations in cartilage, have also been proposed. Emerging evidence suggests that any deleterious effects on growth may be primarily on growth rate (ie, children will eventually reach their true adult height) or may be quite modest, dose-dependent, and reversible with discontinuation of the drug.^11,12 Common clinical practices to diminish negative effects on weight and height include increasing caloric intake, administering appetite stimulants (eg, cyproheptadine), and taking “drug holidays” on weekends or vacations; however, these have not been supported by research. When deciding to decrease, interrupt, or discontinue medication treatment due to effects on weight, the clinician should take into account the potential benefits to the individual in academic, social, and behavioral functioning. There is no indication to cease stimulant therapy over the summer, for example, simply to “give the brain a break.”

The relationship between tics and stimulant use is controversial. Although there has historically been concern that stimulants may worsen tic behaviors, tics wax and wane over time; increased frequency of tics may be due to the natural history of the disorder rather than to stimulant use. The presence of a tic disorder concurrent with ADHD is no longer considered a contraindication for stimulant use;¹³ however, if transient tics develop or tics clearly worsen while on medication, an alternative therapy may be indicated. Clinicians may opt to try an “ABAB” withdrawal trial in which the medication is withdrawn and reintroduced in a scheduled fashion to monitor for effects on tic frequency.

Finally, much concern has been raised regarding the possible cardiac side effects of stimulant use. Stimulants have been associated with minor increases in systolic blood pressure (SBP, ≤7 mmHg) and heart rate (≤10 bpm); 5% to 15% of treated individuals may have more significant changes in these parameters (defined as SBP ≥ 120 mmHg, increases in SBP ≥20 mmHg, or increase in heart rate ≥20 bpm), but these are typically transient.¹⁴ However, in the early 2000s, cases of sudden death among individuals taking stimulant medication were reported, raising concern about the possible arrhythmogenic effects of stimulants. In 2005, the FDA added a warning to mixed amphetamine salts that “sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalities.” In May 2008, the American Heart Association (AHA) released recommendations that all individuals with ADHD who are being considered for stimulant therapy should be carefully evaluated for potential cardiac abnormalities. Evaluations should include a thorough family history, investigation of potential subtle cardiac signs and symptoms in the individual (eg, palpitations, syncope, or chest pain with exercise), a detailed cardiac exam, and a consideration for a screening electrocardiogram (ECG), preferably read by a pediatric cardiologist. In August 2008, the AAP and AHA released a joint statement clarifying that screening ECGs were reasonable to consider, but not mandatory to obtain, and that “treatment of a patient with ADHD should not be withheld because an ECG is not done.”15 In current clinical practice, it is generally held that cardiology clearance for stimulant treatment is indicated only if concerning elements arise in the individual’s history, family history, or physical exam. Clinicians are urged to document pertinent negative findings in the medical record prior to beginning treatment with a stimulant.

Alpha-2 Agonists

Alpha-2 agonists, available as clonidine and guanfacine, have also demonstrated efficacy in the treatment of hyperactivity and inattention. Clonidine was initially developed in the 1960s as a treatment for hypertension and acts on the alpha-2 receptors 2A, 2B, and 2C in the prefrontal cortex. Guanfacine was developed in the late 20th century and more specifically binds to alpha-2A receptors (therefore exerting less effect on blood pressure). Alpha-2 receptors in the prefrontal cortex have been implicated in the maintenance of attention and focus. The exact mechanism of action for these medications is not well understood. It is theorized that these medications enhance the transmission of dopamine and norepinephrine in this region, albeit through different mechanisms than with stimulants. Alpha-2 agonists were used off-label in the treatment of ADHD until the FDA approved their use in the early 21st century (2009 and 2010) for children 6 years and older. Only the extended-release forms of clonidine and guanfacine have FDA approval as monotherapy for ADHD as well as adjuncts to stimulants. In clinical practice, however, off-label use of immediate-release clonidine and guanfacine is common. Although alpha-2 agonists are not approved for other psychiatric disorders, they are sometimes used for the treatment of oppositional behavior, aggression, and delayed sleep onset.

Extended-release alpha-2 agonists have demonstrated efficacy in decreasing ADHD symptoms.¹⁶ The effect size of these medications (0.7) is moderate but smaller than the large stimulant effect size of 1.0. Effects are not immediate and may take 2 to 4 weeks to become apparent. Therefore, practice parameters by the AAP and the American Academy of Child and Adolescent Psychiatry (AACAP) classify alpha-2 agonists as second-line therapies. They may be used as monotherapy in individuals who have not been able to tolerate any stimulant. Clinicians may also choose to utilize an alpha-2 agonist as first-line therapy in children with comorbid diagnoses of ADHD and autism spectrum disorder (ASD), given the possibility of higher rates of stimulant side effects experienced in this population. Finally, alpha-2 agonists may function well to target defiant behavior in children with ADHD (although a stimulant remains the first-line treatment).¹⁷ Alpha-2 agonists also have a role in combination therapy. They can be particularly useful as adjunctive therapies if a patient is not able to tolerate a higher dose of stimulant but continues to show impairment due to ADHD symptoms. Unlike stimulants, alpha-2 agonists demonstrate coverage throughout the day and can be helpful particularly for individuals who struggle with attention problems in the afternoon or evening (after a stimulant has worn off). Individuals with ADHD and co-occurring tics may benefit from the use of an alpha-2 agonist, although, as stated previously, stimulants are still recommended as a first-line therapy even if tics are present. Those individuals with ADHD and sleep difficulties may also benefit from the addition of an alpha-2 agonist.

As with stimulants, dosing of alpha-2 agonists is generally limited by the side effects rather than directed by weight-based targets (although average and maximum doses can be seen in Table 23.2). The most common adverse effects of alpha-2 agonists include fatigue, sedation, and somnolence, with higher rates being reported with clonidine than with guanfacine. These effects are dose dependent and may decrease over time as an individual becomes accustomed to the medication; however, if these side effects do not improve within the first week, they are unlikely to resolve. For those taking a short-acting formulation, sedation may decrease if patients are changed to a long-acting medication (especially if it can be given in the evening). Anticholinergic effects, such as dry eyes, dry mouth, and constipation, can also be seen. Some concerns have been raised about possible QT prolongation, particularly for guanfacine, but a meta-analysis of available data did not demonstrate clinically significant events; screening ECGs are not indicated.¹⁸

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