Chapter 49 Neuropsychopharmacology
Introduction
Historically, very few safe and effective medications were available to treat pediatric neuropsychiatric disorders. Children received either no treatment, or treatment that emphasized psychological or behavioral interventions. With a growing evidence base of tolerable and effective psychotropic medications, psychopharmacology has become standard practice for many neuropsychiatric disorders, resulting in increased use of medications in children [Zito, 2007; Zito et al., 2003] and broadening of the practitioner base for prescribing [Olfson et al., 2002].
The database for the safety and efficacy of psychotropic medications in children has increased dramatically in the past decade, although much remains to be done. There is support for the short-term efficacy of many commonly prescribed psychotropics, but there is limited data on their long-term efficacy and safety, the comparative efficacy of psychological and pharmacologic treatments, and the best practices for combining psychological and pharmacologic interventions. For example, there are excellent efficacy and safety data for the short-term treatment of attention-deficit hyperactivity disorder (ADHD) with stimulants [Greenhill et al., 2006; Jensen et al., 2001], of anxiety disorders with selective serotonin reuptake inhibitors [Birmaher et al., 2003; RUPP, 2001; Rynn et al., 2001; Walkup et al., 2008], of obsessive-compulsive disorder (OCD) with clomipramine and selective serotonin reuptake inhibitors [DeVeaugh-Geiss et al., 1992; Geller et al., 2001, 2004; March et al., 1998; POTS, 2004; Riddle et al., 2001], of depression with selective serotonin reuptake inhibitors [Emslie et al., 1997, 2002, 2009; TADS, 2004], and of schizophrenia [Findling et al., 2008b; Haas et al., 2009b; Kryzhanovskaya et al., 2009; Kumra et al., 1996, 2008], bipolar disorder [Delbello et al., 2002, 2006, 2008; Findling et al., 2005, 2009a; Haas et al., 2009a; Tohen et al., 2007], and irritability and behavioral dysregulation in different pediatric disorders with atypical antipsychotics [Aman et al., 2002; Hollander et al., 2006; McCracken et al., 2002; Owen et al., 2009]. In contrast, there remain very little data from placebo-controlled efficacy studies on the short-term benefit of mood stabilizers (e.g., lithium, anticonvulsants) for neuropsychiatric disorders [Wagner et al., 2006, 2009]. There is little information on the long-term usefulness of any psychotropic medication and also increasing concern about the long-term effects of psychotropic drugs on growth and development [MTA, 2004; Nilsson et al., 2004; Swanson et al., 2006; Weintrob et al., 2002]. Although medication combinations are commonly used in children [Martin et al., 2003], studies of medication combinations are uncommon [Abikoff et al., 2005; Delbello et al., 2002].
The expansion of the evidence base in pediatric neuropharmacology has been due, in large part, to the National Institute of Mental Health (NIMH)’s support of partnership between government, academic institutions, and drug companies [Satcher, 2001], and to legislation supporting medications studies in children. In 1997, the passage of the Food and Drug Administration (FDA) Modernization Act mandated the study of medication in children and offered 6-month patent extensions to pharmaceutical companies who studied their products in pediatric populations. As a result, a number of efficacy and safety studies of newer medications targeting a variety of disorders in children and adolescents emerged and contributed to a growing evidence base of medications that have FDA pediatric labeling. The list of psychotropic medications that have FDA approval for use in the treatment of psychiatric conditions in children has grown (Table 49-1). However, a number of studies supporting the safety and efficacy of psychotropic medication (e.g., stimulants for ADHD in children with tics [TSSG, 2002]; selective serotonin reuptake inhibitors for childhood anxiety [Ipser et al., 2009]) are not reflected in current labeling, leaving clinicians in an awkward position as to whether to prescribe medications with evidence for efficacy but without an FDA indication or appropriate labeling. Additionally, older medications that have gone off patent have no labeling, have FDA labeling but have not been subject to the rigorous study, or have out-of-date labeling. As a result, many psychotropic medications prescribed for children are prescribed off-label. Off-label use of medications increased in the past two decades for a variety of indications, including stimulants for children younger than 5 years, selective serotonin reuptake inhibitors for OCD and anxiety, and atypical antipsychotics for aggression. Increased off-label use resulted from downward extension of a current indication to a younger age group (e.g., stimulants in children younger than 5 years, antidepressants in teens and children) and the availability of newer medications with a reduced potential for serious side effects. Sometimes, off-label use has been extremely helpful (e.g., selective serotonin reuptake inhibitors for anxiety disorders), but some off-label prescribing may not be helpful. For example, based on its low side-effect profile, a few positive case reports and open trials, and an aggressive marketing campaign, gabapentin was prescribed for the treatment of bipolar affective disorder; however, subsequent controlled trials have not supported its efficacy [Frye et al., 2000; Pande et al., 2000].
Table 49-1 Labeled and Off-label Use of Neuropsychopharmacologic Agents in Children and Adolescents
| Drug | Labeled Use in Children and Adolescents | Off-label Use/Clinical Practice in Children and Adolescents |
|---|---|---|
| Stimulants Amphetamine, mixed salts Dextroamphetamine |
ADHD (≥3 yrs – IR, ≥6 yr – ER, Narcolepsy (≥6 yrs, IR only) ADHD (≥6 yrs), Narcolepsy (≥6 yrs) ADHD (≥6 yrs), Narcolepsy (≥6 yrs) |
|
| Pemoline | None (withdrawn 2005) | ADHD |
| Atomoxetine | ADHD (≥6 yrs) | |
| Clonidine | ADHD (6–17 yrs – ER) | Aggression, Tic disorders |
| Guanfacine | ADHD (6–17 yrs – ER) | Aggression, Tic disorders |
| Benzodiazepines Clonazepam Lorazepam |
None Anxiety (≥12 yrs), Insomnia (≥12 yrs) |
As a group – agitation, catatonia |
| Tricyclic Antidepressants Amitriptyline Clomipramine Desipramine Imipramine Nortriptyline |
Depression (≥12 yrs) OCD (>10 yrs) None Enuresis Depression |
As a group – depression, anxiety disorders, ADHD and pain syndromes |
| Buproprion | None | Depression, ADHD |
| Serotonin Norepinephrine Re-uptake Inhibitors Desvenlavaxine Duloxetine Venlafaxine |
None |
Depression, anxiety disorders |
| Mirtazapine | None | Depression, Anxiety disorders |
| Serotonin Re-uptake Inhibitors Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline |
None Depression (≥12 yrs) OCD (≥7 yrs), Depression (≥8 yrs) OCD (≥8 yrs) None OCD (≥6 yrs) |
As a group – depression, anxiety disorders |
| Lithium | Bipolar Disorder (≥12 yrs) | Aggression |
| Anticonvulsants Carbamazepine Gabapentin Lamotrigine Topiramate Valproate |
Seizure disorders Seizure disorders Seizure disorders Seizure disorders Seizure disorders |
As a group – bipolar disorder, aggression, mood instability |
| Typical Neuroleptics Chlorpromazine Haloperidol Piimozide |
Severe behavioral disturbances Psychosis, tics, severe behavioral disturbance Tics |
As a group – psychotic disorders |
| Atypical Neuroleptics Aripiprazole Clozapine Quetiapine Risperidone Ziprasidone |
Irritability in Autistic Disorder (6-17 yrs) Bipolar I Disorder (≥10 yrs), Schizophrenia (≥13 yrs) None Bipolar I Disorder (≥13 yrs), Schizophrenia (≥13 yrs) Bipolar I Disorder (≥10 yrs), Schizophrenia (≥13 yrs) Irritability in Autistic Disorder (6-17 yrs), Bipolar I Disorder (≥10 yrs), Schizophrenia (≥13 yrs) None |
As a group – psychotic disorders, Tourette’s syndrome, aggression |
IR = immediate release, ER = extended release
ADHD, Attention Deficit Hyperactivity Disorder, OCD, Obsessive –Compulsive Disorder
There has also been an increased interest in the perceived safety of commonly prescribed psychotropic agents in children. Although short-term efficacy studies have often demonstrated safety, post-marketing studies have raised some concerns: for example, data suggesting growth suppression with stimulants [MTA, 2004; Swanson et al., 2006] and antidepressants [Nilsson et al., 2004; Weintrob et al., 2002]; increased risk of suicidal ideation in youth [Hammad et al., 2006] and young adults [Stone et al., 2009] with antidepressants; and weight gain and metabolic syndrome with antipsychotics [Fraguas et al., 2010; Correll, 2008]. These adverse events and public concern about the use of medications, particularly in children, have reinforced the importance of on-going research to elucidate the efficacy and safety of psychotropic medications.
The decision about whether to use pharmacologic interventions mandates careful consideration of the benefits and the risks of treatment and of the ability to monitor treatment safely [AACAP, 2009]. To justify the use of medications, the child must first have a disorder or target symptoms with the potential for pharmacologic responsiveness. Second, the child’s level of impairment must cross a threshold of severity such that failure to treat with medication, given all the potential risks, would cause more harm. Third, the child’s symptoms must be unresponsive or insufficiently responsive to nonpharmacologic interventions, or these interventions are not readily available in the community. Finally, the clinician must have the time available to monitor patients adequately – not only for common, and also for rare and important adverse events (e.g., suicidal ideation or behavior). Safe prescribing of medications for children also requires detailed documentation of the decision-making process and an active monitoring plan for outcome and adverse events.
The likelihood of a child with a neuropsychiatric disorder or symptoms presenting to a pediatric neurology practice is high. To treat these children effectively, the pediatric neurologist must have the ability to collect and integrate information from multiple sources (i.e., child, family, school, and other agencies) and to make a diagnostic formulation and treatment plan that addresses the neuropsychiatric symptoms and psychosocial factors that affect the delivery of care and the assessment of outcome. Given the rapidly changing nature and increasing complexity of modern clinical care, pediatric neurologists need to define their comfort level in assessing and treating neuropsychiatric disorders and to determine how this may influence the scope of their practice. For neurologists who treat neuropsychiatric disorders, it is critical to keep abreast of this evolving field, especially new safety data and data on the efficacy of nonpharmacological treatment, e.g., behavioral treatment for tics [Piacentini et al., 2010], that influence the standard of care. This may require a team of colleagues, including psychologists and psychiatrists, who can be involved in the assessment and treatment of these children with complex neuropsychiatric needs.
Stimulants
This section briefly describes the use of stimulants and nonstimulants in the treatment of ADHD (Table 49-2; also see Chapter 47).
Table 49-2 Stimulant and Nonstimulant Medications for Attention-Deficit-Hyperactivity Disorder: Preparations, Pharmacology, and Dosing
Clinical Applications
Stimulants have been in clinical use since 1937, when it was observed that a group of children in residential treatment showed marked improvement in their behavior with benzedrine (d– and l-amphetamine) [Bradley, 1937]. Since then, the criteria for ADHD have been refined, and other stimulant medications have been evaluated and consistently found efficacious in numerous placebo-controlled studies [Jensen et al., 2001]. Approximately 70–80 percent of school-age patients with ADHD have a positive response to stimulant medication. Although behavioral treatment may be considered, in head-to-head studies medication alone is more beneficial than behavioral therapy alone in children 5 years of age and older. The combination of medication and behavioral therapy is specifically helpful for oppositional behavior and children with ADHD and anxiety [Jensen et al., 2001].
Based on clear evidence of efficacy, the stimulant medications have been used to address attention, hyperactivity, and impulsivity in those with pervasive developmental disorders and in younger children. For many years, stimulant medications were viewed as poorly effective or contraindicated for hyperactivity in children with autism and pervasive developmental disorders. However, in the first large, randomized, controlled trial in this population, methylphenidate demonstrated efficacy. The response rate was less robust than in typically developing children, and rates of adverse events were higher, with nearly 1 in 5 youngsters having to stop treatment [RUPP, 2005]. A single test dose of stimulant may be useful to identify children for whom a longer stimulant trial is contraindicated [Di Martino et al., 2004]. Children who experience a significant worsening of ADHD (e.g., hyperactivity and irritability) or other symptoms (i.e., tics or stereotypies) with a single dose may be excluded from further stimulant treatment [Di Martino et al., 2004].
Preschoolers with ADHD represent another specialized population for whom the use of stimulants may be considered. The Preschoolers with ADHD Treatment Study (PATS), a large randomized, placebo-controlled trial of methylphenidate in children of ages 3–5 years, demonstrated that methylphenidate at doses greater than 2.5 mg three times a day were effective in reducing ADHD in youngsters unresponsive to psychosocial intervention. Again, response rates were less robust than that observed in school-age children, and adverse effects were more common [Greenhill et al., 2006]. Furthermore, methylphenidate may reduce growth rates, even in short-term treatment, and requires careful monitoring of weight and height [Swanson et al., 2006].
Despite substantial data supporting the efficacy of stimulants, their use in children remains controversial. The lay public and media have expressed concerns about the potential for overdiagnosis of ADHD and overuse of stimulant medications in children. However, despite the dramatic increases in stimulant use in the past 10 years [Zito et al., 2003], there is little evidence to support this claim. According to the U.S. Surgeon General, most children with psychiatric disorders are not assessed or treated [Satcher, 2001], and the ratio of stimulant use to prevalence of ADHD is less than 1:1, suggesting that undertreatment is a more prevalent and important issue [Jensen et al., 1999]. Stimulant medications have also come under public scrutiny because of concerns about safety. Concerns about worsening tics, growth suppression, enhancing risk for addiction and, more recently, sudden death, although not substantiated by the evidence, remain important issues for families considering stimulant medications in their child. Some studies actually suggest that children with ADHD who are treated with stimulant early in life have a lower risk of substance abuse than children with ADHD who are not treated [Wilens et al., 2003], but such evidence may not be as reassuring to parents as one would hope. Prudent practice therefore necessitates an evaluation that leads to confidence in the diagnosis, fully informed consent, and use of appropriate doses with close monitoring, combined with effective and available psychosocial treatments. Detailed discussion, in the assessment and treatment phases, with the family and teachers, backed up by full documentation in the medical record, is essential. During the dose adjustment phase, children often are monitored for side effects, including blood pressure, pulse, height, and weight. After a maintenance dose is achieved, visit intervals can vary from 1–4 months.
Pharmacology
Stimulants are sympathomimetic drugs that directly stimulate α- and β-adrenergic receptors. They also stimulate the release of dopamine from presynaptic nerve terminals and inhibit dopamine reuptake. The exact mechanism for efficacy on attention and hyperactivity in ADHD is unknown. Stimulant medications are available in immediate-release and sustained-release preparations (see Table 49-2).
Clinical Management
Assessment
A neuropsychiatric assessment of inattention, impulsivity, and hyperactivity involves gathering information from multiple sources, including the child, parents, teacher, therapist, or other individuals involved with the child (e.g., day-care providers and coaches). Information can be gathered through clinical interview; patient, parent, and teacher rating scales; neuropsychological testing; and medical evaluation, including laboratory screening [AACAP, 1997]. The diagnostic criteria for ADHD are detailed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR [APA, 2000]). A thorough neuropsychiatric assessment is necessary because inattention, impulsivity, and hyperactivity can be complications of medical conditions, and they are commonly caused by other neuropsychiatric disorders. Children with ADHD often have co-occurring neuropsychiatric disorders, which can make it difficult to determine accurately whether ADHD symptoms are attributable to ADHD or to the co-occurring conditions. Medical and developmental problems in the differential include vision or hearing deficits, seizures, chronic medical illnesses, sleep deprivation, and poor nutrition [Pliszka, 2007]. Children who have unidentified intellectual deficits, learning disabilities, speech and language problems, or substance abuse may appear to exhibit ADHD symptoms. Neuropsychiatric conditions, such as anxiety disorders, depressive disorders, and bipolar disorder, have disturbances in attention, impulse control, and activity level that can be especially difficult to distinguish from ADHD.
Identification of co-occurring conditions and risk factors for adverse effects is essential because some medications may be contraindicated, or medication management may require dosing modification or closer monitoring. For example, a patient with co-occurring ADHD and anxiety or depression may prompt the clinician to initiate treatment with an antidepressant first rather than a stimulant, depending on which of the two conditions is more impairing. A child with a pervasive developmental disorder may have limited response to stimulants or may have an adverse behavioral reaction that can be severe. Similarly, despite evidence that stimulants are unlikely to cause tic worsening relative to placebo [Kurlan, 2003], a patient with a personal or family history of tic disorders may develop tics de novo or experience a worsening of existing tics during an initial stimulant trial.
A medical evaluation to “clear” a child before initiating most psychotropic medications, including stimulants, is prudent. The evaluation should include a recent medical history and a physical examination completed by the primary care provider. Any significant change in health during treatment requires repeat evaluation. Choice of laboratory screening procedures and imaging studies is guided by the medical history and findings on physical or neurologic examination. These may include lead level, thyroid function tests, genetic screening, metabolic studies, magnetic resonance imaging, sleep studies, and electroencephalography (EEG). Other assessments may be indicated, including occupational therapy, physical therapy, speech and language evaluation, and neuropsychology [AACAP, 1997]. For stimulant medications, baseline height, weight, family or personal history of a tic disorder, and family or personal history of cardiac disease, including nonvasovagal syncope and sudden death, are also important. Although baseline electrocardiograph (EKG) screening for all children has been advocated by some, at present the American Academy of Pediatrics and the American Heart Association do not recommend EKG screening of all patients, but rather that the need for an EKG be considered by the treating clinician based on physical exam and history [Vetter et al., 2008].
Initiating medication and dose titration
The starting dose of methylphenidate is 5 mg, given twice daily and dispensed after breakfast and lunch to minimize appetite-suppressant effects. The dose is increased at weekly intervals by increments of 5–10 mg until the therapeutic effect is achieved or side effects are encountered. The manufacturer recommends a maximum daily dose of 60 mg [Ritalin, 2004]; however, some clinicians exceed this figure if higher doses are necessary to control symptoms and the patient is not experiencing adverse effects. Detailed informed consent and adequate monitoring and documentation are essential for safe prescribing. Severity of symptoms, after-school activities, or homework demands may warrant a late-afternoon dose. An alternative method is to calculate the dose by weight [Dulcan, 1990]. The target dose falls between 0.3 and 0.7 mg/kg, administered 2–3 times each day (total dose of 0.6–2.1 mg/kg/day).
With d-amphetamine and mixed salts preparations, the starting dose for children between the ages of 3 and 5 years is 2.5 mg/day, with incremental increases of 2.5 mg weekly until a therapeutic response is achieved. For children 6 years or older, the starting dose is 5 mg given once or twice each day, with weekly increases of 5 mg until a therapeutic response is achieved. The manufacturer does not recommend exceeding 40 mg/day [Adderall, 2004; Green, 2007]. As with methylphenidate, some clinicians use higher doses if clinically indicated. Dosing by weight, the optimum dose may fall between 0.15 and 0.5 mg/kg, administered twice or three times daily, with a maximum daily dose of 0.3–1.5 mg/kg/day [Dulcan, 1990].
Sustained-release preparations have been around for a long time but the options were limited until the mid 1990s. Earlier sustained-release preparations of methylphenidate and d-amphetamine were viewed clinically as less reliable than their immediate-release counterparts [Birmaher et al., 1989; Fitzpatrick et al., 1992; Pelham et al., 1987], and head-to-head comparisons of their efficacy compared to their immediate-release counterparts were lacking. Over the past decade, new and novel delivery systems have developed, which has significantly increased the range of available sustained-release preparations. In clinical practice, many patients experience comparable or greater benefit from sustained-release preparations because of the convenience of once-daily dosing, avoiding dosing at school, increasing compliance, and reducing rebound effects.
Monitoring stimulants
Some clinicians consider the use of “drug holidays” on weekends or during the summer to limit children’s exposure to stimulants and minimize possible long-term adverse effects, such as low weight and growth suppression. However, the practice of drug holidays is controversial because it may result in the rapid return of symptoms and accompanying impairment [Martins et al., 2004; Spencer et al., 2006]. To identify patients who may do well with drug holidays, clinicians can review symptoms and impairment from times of the day when children are not benefiting from stimulants, such as early morning or later in the evening. If patients do well during these times, it may be reasonable to consider more extended time off stimulants. Drug holidays should be planned for times when there are no important school or social activities and they should be reserved for patients whose families can provide adequate structure, behavior management, and supervision during these periods.
Although hyperactive symptoms tend to improve as children mature, inattention and impulsivity often persist. Long-term stimulant treatment may be necessary, as up to 80 percent of ADHD children continue to have symptoms into adolescence and 65 percent into adulthood [Barkley, 1996; Weiss and Hechtmann, 1993].
Adverse Effects
Although most children tolerate stimulant medications well, some do not. The most common side effects of stimulants are insomnia and nervousness [Ritalin, 2004]. Some children with ADHD experience sleep disturbance before exposure to stimulants. The child’s pre-existing sleep history should be obtained, including other factors that may contribute to sleep disturbance (e.g., poor sleep hygiene, caffeine use, oppositional behavior, separation anxiety). Ironically, some children experience difficulty falling asleep related to hyperactivity, and they may actually benefit from a small dose of stimulant to help them stay in bed and fall asleep. In group comparisons, dosing three times daily with short-acting stimulants versus dosing two times daily was not found to increase sleep disturbance [Kent et al., 1995; Stein et al., 1996]; however, new-onset sleep delay after starting stimulants may be associated with a stimulant dose that is too high overall or with dosing stimulants too late in the day. Difficulty with falling asleep because of stimulants can be addressed with a combination of dose adjustment, improved sleep hygiene (i.e., straightforward ritual for falling asleep, and removal of distractions, such as televisions, video games, homework, and night lights, from the room), cooler room temperatures, room-darkening shades, avoidance of late-afternoon or evening doses of stimulants, switching to a different stimulant, or addition of a sedating medication with ADHD treatment effects, such as clonidine [Brown and Gammon, 1992; Prince et al., 1996] or guanfacine.
Short-term reductions in expected weight gain and height have been reported in many studies [MTA, 2004; Swanson et al., 2006], although this has not been universally reported [Spencer et al., 2006; Zeiner, 1995]. Overall, the risk of growth suppression appears mild in school-age children but is moderate in preschool-age children. The Preschool ADHD Treatment Study (PATS) reported an annual reduction in growth rate of 20 percent for height and 50 percent for weight in preschoolers treated with methylphenidate compared to those that were not on stimulants [Swanson et al., 2006]. Because the impact on weight is likely mediated by stimulant-induced appetite suppression, administering stimulant doses immediately after meals [Swanson et al., 1983], allowing the child to eat later in the evening after the appetite suppressant effect of the stimulant has abated, or allowing drug holidays on weekends or evenings may mitigate these effects.
The possibility of growth suppression with long-term use of stimulants remains a controversial topic. Longitudinal studies of children with ADHD treated with stimulants followed into adulthood have not revealed any reduction in height or weight compared to adults who were never exposed to stimulants [Hechtman et al., 1984; Klein and Mannuzza, 1988]. The apparent lack of impact on adult height was thought to result from the discontinuation of stimulants in adolescence. An alternative theory proposes that this pattern of growth is inherent in children with ADHD and not related to stimulant treatment. The dysregulation of several neurotransmitter systems associated with ADHD may alter neuroendocrine function, including those involving growth [Spencer et al., 1998]. It is not clear whether growth suppression identified in the NIMH Multimodal Treatment Study of ADHD (MTA) or PATS studies will continue and have a long-term impact, resolve with stimulant discontinuation, or resolve on its own [Spencer et al., 1998].
Historically, stimulant treatment has been associated with the emergence of tics [Borcherding et al., 1990] or the exacerbation of pre-existing tics [Law and Schachar, 1999]. Children at risk appeared to be those with a personal history or family history of tic disorders. However, the effect on tics is not absolute. In placebo-controlled trials, low to moderate doses of methylphenidate improve attention and behavior in children with chronic tic disorders without significantly worsening tics [Castellanos et al., 1997; Gadow et al., 1995, 1999]. In the Treatment of ADHD in Children with Tics (TACT) study, tic increases categorized as an adverse event occurred in nearly equal numbers of subjects on placebo (22 percent), clonidine (26 percent), and methylphenidate (20 percent). These data suggest that 20–26 percent of youngsters with tics will experience tic worsening shortly after initiation of any medication treatment, including placebo, lending support to the hypothesis that tic increases observed after starting stimulants reflect the natural waxing and waning of tic severity.
Although the product information for the stimulants warns of possible decreases in seizure threshold, no increase in seizure frequency was observed in children treated with stimulants who had co-occurring ADHD and seizure disorder [Feldman et al., 1989; Wroblewski et al., 1992]. There is no increased risk of addiction from appropriate treatment with stimulants for ADHD. Adolescents with ADHD treated with stimulants were less likely to abuse stimulants [Faraone and Wilens, 2003; Hechtman, 1985].
Concerns that stimulants may increase the risk of sudden unexplained death in children followed the publication of case reports and small case series in the early 1990s [Nissen, 2006]. A recently published case-control study comparing 564 cases of sudden death in children of 7–19 years with matched controls who died as passengers in motor vehicle traffic accidents over an 11-year period in the U.S. revealed an association between unexplained sudden death and use of stimulants [Gould et al., 2009]. This finding has enhanced concern that sudden death may be a rare side effect of stimulant use in children. However, the study design does not permit the establishment of causality. The possibility that having ADHD itself confers additional risks for sudden death must be considered, as should the co-occurring increased incidence of risk-taking behavior and substance abuse [Vitiello and Towbin, 2009]. Strategies for managing the cardiac risk of stimulants have been published [Vetter et al., 2008].
Despite the impact on a broad range of ADHD symptoms, including irritability, stimulant medications can be associated with undesirable changes in mood and behavior [Gadow et al., 1992]. Some of these changes occur when the stimulant is reaching peak serum concentrations, or they may occur when serum concentrations are waning – so-called rebound effects. Effects associated with peak concentrations include dysphoria, anxiety, agitation, or the “zombie” effect (i.e., over-focused and passive). Rebound effects include overactivity, talkativeness, excitability, irritability, and insomnia [Rapoport et al., 1978; Zahn et al., 1980]. It is often difficult to determine whether such rebound symptoms are the re-emergence of ADHD symptoms once the patient is off stimulants or true withdrawal or rebound symptoms. These adverse behavioral effects can be managed in a variety of ways, including dose reduction or medication discontinuation, and by improving late-afternoon coverage by adding a low dose of immediate-release stimulant or by switching to a long-acting stimulant [Pliszka, 2007]. Youngsters who experience these side effects on one of the stimulants do not necessarily have the same behavioral effects on another stimulant, and switching to another stimulant or alternative medication can be useful. Clinicians should be comfortable using all stimulant preparations to optimize treatment effects and minimize side effects.
Pemoline (Cylert©), a long acting stimulant with a novel structures has been associated with rare cases of acute hepatic failure [Shevell, 1997]. In 2005, the FDA withdrew labeling of pemoline for use in the treatment of ADHD, and subsequently the pharmaceutical companies voluntarily agreed to stop sales and manufacture of pemoline [Hogan, 2000].
Drug Interactions
The safety of combining stimulants, especially methylphenidate, with clonidine has been controversial. Clonidine has been helpful in managing sleep disturbance related to ADHD or stimulant treatment [Wilens et al., 1994]. The combination appears to help children with ADHD and co-occurring oppositional and conduct disorder [Hunt et al., 1990]. The combination also appears useful in the treatment of ADHD in children with tic disorders [TSSG, 2002; Wilens et al., 2003]. Concerns about the interaction developed after the report of four deaths of children who apparently received clonidine and methylphenidate, as well as other medications in some cases [Fenichel, 1995]. Although the cases did not have a clear pattern of causality [Sallee et al., 2000a; Wilens et al., 1999], clinicians are more cautious about prescribing this combination. When combining clonidine and stimulants, careful screening is recommended for a personal and family history of cardiac abnormalities, arrhythmias, and nonvasovagal syncope, and a baseline and follow-up EKG may be warranted.
Nonstimulant Medications
Atomoxetine
Clinical Applications
Atomoxetine potentially offers several advantages over stimulant medications: longer duration of action, lower misuse or abuse potential, lower risk of rebound effects, lower risk of precipitating tics or psychosis, and ease of prescribing because duplicate or paper prescriptions are not required and multiple refills are possible. Effectiveness of atomoxetine in children has been supported by placebo-controlled trials [Kelsey et al., 2004; Spencer et al., 2002]. Atomoxetine doses of 1.2 and 1.8 mg/kg/day administered in divided doses were superior to placebo and atomoxetine in a dose of 0.5 mg/kg/day; there was no clear superiority of 1.8 versus 1.2 mg/kg/day. Early clinical trials used twice-daily dosing, but once-daily dosing also appears effective [Michelson et al., 2004]. Longer-term treatment (9 months) with atomoxetine appears to be safe and well tolerated [Michelson et al., 2004]. Children maintained therapeutic effect and demonstrated superior psychosocial functioning compared to children who received placebo [Kratochvil et al., 2002]. When compared with methylphenidate treatment, atomoxetine was associated with comparable therapeutic effects [Michelson et al., 2003]. Efficacy of atomoxetine in adults with ADHD was demonstrated at doses of 60–120 mg/day [Strattera, 2010].
Pharmacology
Atomoxetine is well absorbed through the gastrointestinal tract and is metabolized by the liver, predominantly by cytochrome P-450 2D6 (CYP2D6). A small percentage of the population (approximately 7 percent of whites and 2 percent of African Americans) has reduced activity of the cytochrome P-450 isoenzyme system. These individuals are considered to be “poor metabolizers” of medications whose predominant method of metabolism is this isoenzyme. Poor metabolizers can be expected to achieve higher than expected plasma concentrations on a given dose and a prolonged half-life compared with those with normal CYP2D6 activity. The half-life of atomoxetine in poor metabolizers is 21.6 hours, compared with 5.2 hours in normal metabolizers. Atomoxetine is 98 percent bound to plasma proteins, primarily serum albumin [Strattera, 2010].
Clinical Management
Children should undergo standard psychiatric and medical assessment for ADHD (see “Clinical Management of Stimulant Medication”). No laboratory screening is required, although obtaining baseline and follow-up liver function studies should be considered in view of reports of severe acute liver dysfunction [Lim et al., 2006]. Baseline values for weight, heart rate, and blood pressure should be obtained. Concomitant use of medications with cardiovascular effects and medications that inhibit cytochrome P-450 may necessitate dosage adjustment. Although the determination of cytochrome P-450 metabolizer status is available, it appears to be unnecessary because regular dosing parameters provide the opportunity for assessment of outcome and adverse events that may be experienced by poor metabolizers.
In children, the usual starting dose of atomoxetine is 0.5 mg/kg/day, given in the morning or divided into morning and late-afternoon doses. Starting with a split dosing regimen may decrease gastrointestinal side effects and irritability. Decreasing side effects on initiation will ultimately lead to better compliance. The dose can be consolidated after a target dose is achieved. The dose may be increased every 3 days to a target dose of 1.2 mg/kg/day. For adults or for children and adolescents weighing more than 70 kg, atomoxetine may be initiated at 40 mg/day. The dose may be increased gradually every 3 days to a maximum dose of 80 mg. If there is an inadequate response after a 2- to 4-week trial, the dose may be increased to 100 mg/day. Patients taking atomoxetine concomitantly with potent inhibitors of CYP2D6 should be maintained at the initial dose for at least 4 weeks before a dosage increase is considered. Dosage reduction is required in patients with hepatic impairment [Strattera, 2010].
In clinical practice, combination therapy may be used during initiation and titration of atomoxetine, especially in children with severe ADHD symptoms. The effectiveness and tolerability of combining atomoxetine with methylphenidate in children who have not responded to monotherapy have been reported in a few patients [Brown, 2004]. Discontinuation of atomoxetine does not require dose tapering. Abrupt discontinuation of atomoxetine has not been associated with an acute discontinuation syndrome [Wernicke et al., 2003].
Adverse Effects
The most common side effects of atomoxetine in children and adolescents are upset stomach, decreased appetite, nausea, vomiting, dizziness, tiredness, and mood swings. Atomoxetine was associated with increases in heart rate of 6 beats per minute, and increases in systolic and diastolic blood pressure of 1.5 mmHg compared with placebo. In an analysis of short-term and long-term treatment with atomoxetine, increased systolic blood pressure was observed in adults, and increased diastolic blood pressure occurred in children and adolescents. Heart rate increased in both groups, and no prolongation of the QTc interval was observed [Strattera, 2010]. Seizures and prolonged QTc intervals were reported after an overdose with atomoxetine [Sawant and Daviss, 2004]. During post-marketing experience, several cases of significant liver injury in children treated with atomoxetine have been reported [Lim et al., 2006; Stojanovski et al., 2007]. Lilly Research Laboratories subsequently reviewed all hepatobiliary events during clinical trials and through post-marketing voluntary adverse events reporting, and identified three cases of probable severe, reversible liver injury related to atomoxetine use [Bangs et al., 2008]. Strattera labeling now warns that severe liver injury is possible and states that atomoxetine should be discontinued and not restarted when laboratory tests show liver injury or when there is clinical evidence of jaundice. Use in patients with liver disease probably should be avoided.
Drug Interactions
Inhibitors of CYP2D6 may increase serum concentrations of atomoxetine. Atomoxetine does not have significant effects on the cytochrome P-450 system. Combination with monoamine oxidase inhibitors may precipitate a hypertensive crisis. Atomoxetine has potential interactions with cardiovascular agents and adrenergic agonists. Albuterol’s tendency to increase heart rate and blood pressure may be potentiated by atomoxetine. No increase in the cardiovascular effects of methylphenidate was observed when atomoxetine was added, and no interactions between atomoxetine and other protein-bound medications have been observed [Strattera, 2010].
Alpha2-Agonists
Clinical Applications
Clonidine is available in immediate-release and extended-release (ER) formulations. Immediate-release clonidine has been shown to improve behavior of children with ADHD; however, the degree of its effect in a meta-analysis was less than that of stimulants, and it was associated with many side effects [Connor et al., 1999]. The largest randomized controlled study to compare clonidine, methylphenidate, and the combination directly confirmed this earlier analysis [Palumbo et al., 2008]. Greatest improvement is seen with hyperactivity and impulsivity [Hunt, 1987; Hunt et al., 1982] and with frustration tolerance [Hunt, 1987] than with distractibility [Palumbo et al., 2008]. Children have been maintained on immediate-release clonidine for up to 5 years with continued benefit [Hunt et al., 1990, 1991]. Recently, clonidine ER was found effective in 2 randomized controlled trials (RCTs) in patient age 6-17 years (Kapvay, 2010, Kollins et al, 2011). One RCT used clonidine ER monotherapy and one RCT used clonidine ER as adjunctive therapy to a stimulant. To date, only the RCT with adjunctive therapy has been published in a peer reviewed journal (Kollins et al, 2011).
The combination of clonidine and methylphenidate has been helpful in adolescents with co-occurring ADHD and oppositional or conduct disorder [Hunt et al., 1990]. This combination allowed the dose of methylphenidate to be reduced by 40 percent [Hunt et al., 1990]. In children with co-occurring ADHD and tic disorders, those treated with clonidine experienced improvements in both conditions [Steingard et al., 1993]. A randomized controlled trial of clonidine, alone and in combination with methylphenidate, in children with ADHD and tics (TACT Trial) showed that clonidine was equally effective as methylphenidate but that the combination was most effective for treating ADHD symptoms [TSSG, 2002]. Clonidine has been used to treat sleep disturbances in children with ADHD [Wilens et al., 1994], and it appears to be helpful in managing severe aggression [Kemph et al., 1993]. Studies of clonidine in youngsters with Tourette’s syndrome show mixed results [Leckman et al., 1982], but significant improvements in tics and behavior have been reported [Cohen et al., 1980; Comings et al., 1990; Leckman et al., 1991].
Guanfacine is available in immediate-release and extended-release (ER) formulations through different manufacturing companies. Limited data exist on immediate-release guanfacine in children. One open trial demonstrated its effectiveness in ADHD [Hunt et al., 1995]. Findings for patients with ADHD and Tourette’s syndrome have been mixed [Chappell et al., 1995; Horrigan and Barnhill, 1995]. Results of more recent studies have been more promising [Scahill et al., 2001]. More data are available on the extended-release formulation (Intuniv®). Randomized, double-blind, placebo-controlled studies have demonstrated efficacy of guanfacine ER for treatment of symptoms of ADHD in short-term treatment [Biederman et al., 2008; Sallee et al., 2009b]. Continued efficacy is seen in longer-term treatment of up to 24 months [Sallee et al., 2009a]. Review of data suggests that guanfacine ER may be most effective in younger children and children with ADHD, combined type [Biederman et al., 2008].
Pharmacology
Clonidine and guanfacine exert agonist effects on presynaptic α2-adrenergic receptors in the sympathetic nuclei of the brain, resulting in decreased release of norepinephrine from presynaptic nerve terminals. In the central nervous system (CNS), α2-adrenergic agonists are thought to regulate noradrenergic activity in the locus ceruleus [Arnsten et al., 1988].
Clinical Management
Clonidine is initiated at a 0.05-mg dose taken at bedtime, gradually titrating the dose over several weeks to 0.15–0.3 mg/day in divided doses. Clonidine is also available in a transdermal patch, which may have the advantage of increased medication compliance and more stable blood levels. After a therapeutic dose of oral clonidine is achieved, the equivalent patch can be substituted [Catapres, 2010]. Clonidine ER is initiated at 0.1 mg at bedtime and increased weekly by 0.1 mg to a maximum dose of 0.4 mg divided twice daily (Kapvay, 2010).
Guanfacine immediate release offers the advantage over clonidine of a longer half-life and therefore less frequent dosing, and it may cause less sedation than clonidine [Hunt et al., 1995]. It is initiated at 0.5 mg at bedtime and is titrated up to a maximum of 3 mg/day. Guanfacine ER has the greatest ease of administration and allows once-daily dosing. It is initiated at 1 mg daily and increased weekly to a maximum daily dose of 4 mg/day [Intuniv, 2011].
Adverse Effects
The most common side effects of clonidine and guanfacine include sedation, dizziness, fatigue, dry mouth and eyes, nausea, hypotension, and constipation [Catapres, 2010; Iintuniv, 2011]. Syncope has been reported in 1 percent of children on guanfacine ER [Intuniv, 2011]. Clonidine in patch form may be associated with contact dermatitis, which may be reduced by changing its location on the body. Because of the risk of rebound hypertension with abrupt discontinuation, these medications should be prescribed only to patients with reliable medication compliance. Likewise, the dose should be tapered gradually when discontinuing the medication [Catapres, 2010; Intuniv, 2011].
Case reports of sudden death in children treated with clonidine has raised concerns about the cardiovascular safety of clonidine by itself or in combination with methylphenidate [Fenichel, 1995]. The most commonly reported cardiovascular side effect is bradycardia in patients taking clonidine either alone or in combination with methylphenidate [Chandran, 1994; Connor et al., 2000; Daviss et al., 2008], although this has not been universally reported [Kofoed et al., 1999; Leckman et al., 1991; Wilens et al., 2003]. One study reported prolongation of the PR interval that was not clinically significant [Connor et al., 2000], and one study reported bradycardia accompanied by a variety of EKG changes, which was confounded by concomitant treatment with other medications with potential for cardiovascular side effects [Chandran, 1994]. Some studies have suggested that the risk for bradycardia is higher when clonidine is given concomitantly with methylphenidate [Connor et al., 2000], but others have shown no additional risk [Daviss et al., 2008; Leckman et al., 1991]. To date, studies of guanfacine ER have not reported any EKG abnormalities considered to be serious adverse events, although a few subjects have been noted with clinically asymptomatic bradycardia [Biederman et al., 2008; Sallee et al., 2009a]. Practitioners should monitor bradycardia in patients taking clonidine.
Drug Interactions
Clonidine may potentiate the CNS-depressant effects of alcohol and sedating medications. The manufacturer advises caution in combining clonidine with medications that affect cardiac conduction and sinus node function because of potential additive effects, such as bradycardia and atrioventricular block [Catapres, 2010].
Antidepressants
Tricyclic Antidepressants
Clinical Applications
Tricyclic antidepressants are approved for the treatment of depression in adults and adolescents (Table 49-3). Placebo-controlled studies have demonstrated the efficacy of tricyclic antidepressants in the treatment of depression in adults, but studies enrolling children and adolescents have yielded inconsistent results. Some open studies show no significant response to tricyclic antidepressants [Kashani et al., 1984; Kramer and Feiguine, 1981]. Others suggest efficacy of desipramine, imipramine, and nortriptyline [Boulos et al., 1991; Geller et al., 1986; Ryan et al., 1986]. Placebo-controlled studies, however, do not support efficacy [Geller et al., 1989, 1990; Puig-Antich et al., 1987]. The lack of efficacy in placebo-controlled trials may be related to methodological problems, such as a small number of subjects, types of subjects enrolled (with depression that is either too mild or too severe), and the high placebo response rates in many studies. The use of tricyclic antidepressants for the treatment of depression in children and adolescents has declined because of their equivocal efficacy and safety in this population and the availability of antidepressants with a more favorable side-effect profile (i.e., selective serotonin reuptake inhibitors). Clomipramine has been approved for use in children 10 years of age or older for OCD, following publication of several randomized, controlled trials [DeVeaugh-Geiss et al., 1992; Leonard et al., 1989]. However, clomipramine is used less commonly for OCD than selective serotonin reuptake inhibitors and is considered second-line treatment in clinical practice, in part because of a less favorable side-effect profile.
