Key aspects of clinical pharmacology will affect the overall outcome of psychotropic drug use in children and adolescents. These include absorption and bioavailability, distribution, metabolism, pharmacogenetics, drug interactions, and elimination. Dosing considerations are particularly important for children. Because clearance rates per kilogram of body weight in children can be faster for some, but not all, drugs, such as paroxetine (1), it is evident that optimal dosing in children cannot be achieved solely by reduction in adult dosage on the basis of weight. Renwick showed that clearance of drugs adjusted for body weight can be twice as high in children as in adults (2). This could be because in children, clearing organs, such as liver and kidney, represent a higher fraction of body weight (3). According to Edwards (3), the average drug concentration with chronic administration under steady-state conditions is given by the following equation:

where Cl is clearance and γ is the dosing interval. In the pediatric literature, there is, however, a paucity of information on the relationship between drug concentration and effect. When only bioavailability is taken into consideration, the following formula can contribute to guide dosing in children:

These formulas, however, cannot be precise indicators of treatment, as clearance rates for specific drugs and dose/effect relationships in children are often not known. In view of the limitations of available data on polymorphic metabolism, drug interactions, clearance, and defined target plasma concentration, children treated with psychoactive medication should be closely monitored (3). With the advent of BPCA (Best Pharmaceuticals for Children Act), FDAMA (FDA Modernization Act), and the Pediatric Rule, more studies on medications including psychotropic medications have been performed in children and adolescents. One such study of the pharmacokinetics of aripiprazole shows that in this trial the pharmacokinetics were linear and close to that of adults (4).

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by impairments in attention and concentration with or without hyperactivity and impulsivity (5). Current diagnostic regimens require onset of symptoms before the age of 7 and impairment in two of three settings, home, school/work, and social (6).

The rates of ADHD vary across the life span with elementary school children ranging from 6% to 10%,
adolescents 4% to 6%, and adults up to 4.4% (5,7). In childhood, ADHD seems to be more common in boys, but as one passes through adolescence and into adulthood, the ratio becomes closer to 1:1 (5,7). Long-term consequences of ADHD include school and occupational failure, substance abuse, divorce, car accidents, legal problems, and a variety of comorbid psychiatric disorders (8,9). Despite these grim statistics, a recent study of young men with ADHD treated with stimulants compared with those without stimulant treatment showed that treatment reduced the rates of comorbid psychiatric disorders and grade retention at 10-year follow-up, meaning that treatment had short- and long-term consequences on quality of life and psychiatric sequelae (10).

First-line treatment is now primarily the long-acting agents in stimulant and nonstimulant categories (5). Positive trials for a variety of long-acting stimulants (methylphenidate and amphetamine) and the norepinephrine reuptake inhibitor atomoxetine have led to labeling for pediatric and adolescent use, and all three categories can be used as first-line treatment (11). It should be noted that atomoxetine carries a black box labeling for suicidality at rates lower than those seen in the antidepressants. Other agents have been seen as superior to placebo in clinical trials but not FDA approved due to issues around safety including modafinil (Stevens–Johnson syndrome) and bupropion (seizures and suicidality) (12,13). The latest agents studied have been the α-adrenergic agents clonidine in a NINDS trial and long-acting guanfacine in several industry-sponsored trials that led to FDA approval and labeling in 2009 (14,15).

Having this selection of agents stimulants, norepinephrine reuptake inhibitors, and α agonists makes it unlikely that one would need to go to combination therapy or nonlabeled medications, but both options may be necessary if a child fails FDA-approved medications (11). Even with the lack of systemic long-term trials, there is some prospective information on long-term effects on growth with both stimulants and atomoxetine (16,17). Concerns about cardiovascular issues with stimulants have led to a variety of warnings and scared clinicians away from using these medications (18,19).

Autism is a pervasive developmental disorder with an onset by the age of 3 years, characterized by impairments in reciprocal social interactions and communications and by unusually restricted, repetitive, and stereotyped patterns of behaviors and interests (6). The sex ratio is 4:1 male to female, and the prevalence of autism spectrum disorders (ASD) is as high as 60 per 10,000 births and full symptom autism at 10 to 20 per 10,000 live births (20). For many families, there seems to be a genetic aspect to the disorder and an increased risk of developing autism with increasing paternal age and presence of a sibling with the disorder (21). A variety of etiologies and genetic causes seem to exist for those with ASD.

To date, no medications have been found to correct the underlying deficits in communication seen in children with autism. Pharmacologic agents are used to target the comorbid psychiatric disorders including ADHD, anxiety, and depression that can impair a child’s functioning in the classroom and are discussed in other sections of this chapter. This section on autism will focus on the treatment of irritability and aggression seen in youth with autism that frequently disrupts school and home placements, leading to hospitalizations or placements in residential settings. The best evidence for the use of pharmacologic agents to treat aggression and irritability in children with autism and ASD is seen with risperidone and aripiprazole (22,23,24,25). Risperidone is currently FDA approved for the indication, and aripiprazole submitted two large positive trials and is FDA approved for the irritability autism indication. Other antipsychotics and mood stabilizers have been studied in smaller open-label trials for the treatment of aggression and irritability in autism (26). At low doses, these medications can reduce irritability and lead to improved attention and concentration, decrease stereotypies, and improve academic and social functioning.

Other interventions that have been tried for the treatment of autism are gluten and/or casein-free diets, chelation, secretin, and avoidance of childhood immunizations. None have been proven in double-blind trials to improve functioning and all may lead to health difficulties. Parents and clinicians should stay with proven treatments.

Anxiety disorders affect 10% to 20% of youth throughout childhood and adolescence (27,28). The practice parameters for the treatment of anxiety recommend the use of multimodal treatment, which includes psychotherapy, especially cognitive behavioral therapy (CBT), and pharmacotherapy (27). The anxiety disorders include simple phobia, generalized anxiety disorder, panic disorder, separation anxiety disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD). The best-studied therapy modality for anxiety disorders is CBT for all of anxiety disorders with some benefit from desensitization or more simple behavioral therapy proving effective in simple phobias. Two large groupings of trials have examined the treatment of anxiety disorders in children and adolescents. The first group is monotherapy industry-funded trials and the second group is the NIH-funded medication monotherapy and combination trials.

For the treatment of OCD, several medications are FDA approved in pediatrics including clomipramine, fluoxetine, fluvoxamine, and sertraline (29,30,31,32). Studies in paroxetine were also positive but not FDA approved (33). Positive treatment trials for generalized anxiety disorder and social phobia were also done with venlafaxine, paroxetine, and sertraline, however, these trials while providing efficacy and safety information did not lead to additional FDA labeling (34,35,36,37). The largest trial for posttraumatic stress disorder with sertraline did not lead to FDA labeling because the medication arm did not separate from placebo in the trial (38). The two National Institute of Mental Health (NIMH) trials of pediatric anxiety disorders examined a trio of anxiety disorders frequently seen together in children—generalized anxiety disorder, separation anxiety disorder, and social phobia. The first trial showed that fluvoxamine was superior to placebo in the reduction of anxiety symptoms (39). In the more recent trial of these three anxiety disorders, the investigators
showed that a combination of sertraline plus manualized CBT produced the greatest reduction in anxiety symptoms followed by sertraline and CBT which were both superior to placebo (40). The NIMH combination trial for OCD showed that combining sertraline and CBT produced the largest reduction in OCD symptoms followed by CBT then sertraline which were both superior to placebo (41). The main finding from the NIMH multimodal trials in anxiety was that combining medication and CBT led to larger reductions in symptoms than placebo and CBT or medication monotherapy. Risk–benefit analysis of the antidepressant trials for anxiety showed that the number needed to treat (NNT) for improvement was 6 for OCD and 3 for non-OCD anxiety disorders and the number needed to harm (NNH) regarding suicidality was 200 for OCD and 143 for non-OCD anxiety (42). This meta-analysis clearly outlines the superiority of benefit over risk in the FDA anxiety registration trials.