Psychopharmacology

GENERAL ISSUES AND PRINCIPLES

In considering medications for behavioral and emotional problems, it is important to keep in mind the entire range of treatment options—not just pharmacologic ones. Child and adolescent psychiatrists, the medical specialists with the greatest expertise in this area, are the ones least frequently likely to use them, especially as first interventions. Additional information is provided in other chapters as it relates to specific conditions. An understanding of more basic issues of neurochemistry and drug metabolism is important, but is beyond the scope of this introductory chapter (see Anderson & Martin, 2018 for a comprehensive review). Keep in mind that knowledge changes, and always check on current best practices! In this chapter, we will review some of the issues and principles in pharmacologic treatments and the major drug classes commonly used. Given the nature of the topic, for example, the stimulants, we focus almost entirely in their use in attention-deficit hyperactivity disorder (ADHD). For the other classes of medications, we will discuss specific disorders in relation to the medication class.

That certain drugs derived from plants, for example, opium, have psychoactive effects has of course been known for millennia (Braslow & Marder, 2019). Modern interest in the scientific study of psychoactive medications on children and adolescents began with the clinical trial conducted by Charles Bradley (1937) who examined the effects of Benzedrine (a mix of levo- and dextroamphetamine) in an open trial of children with behavioral emotional problems and observed that the children became more manageable. About the same time, a placebo-controlled study of Benzedrine was done in a large group of delinquent boys who then showed improved learning and memory (Molitch & Eccles, 1937) These studies mark the beginning of psychopharmacology in children an area of research that now includes many placebo-controlled studies showing the efficacy of stimulants in the treatment of ADHD (Bloch, Beyers, Scahill, et al., 2018b; Multimodal Treatment Study of Children with ADHD [MTA] Group, 1999, 2004). In other areas like autism, important studies like those done by the Research Units on Pediatric Psychopharmacology (RUPP) group (McDougle et al., 2000) on risperidone and on stimulants in autism have been done and are helpful but are few and far between, and the core social dysfunction of autism has, to date, been resistant to drug treatment. Similarly, despite their demonstrated safety, efficacy, and widespread use in adults, the use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescent rests on a much less extensive database, although research with adolescents has notably increased.
Pharmacologic agents are routinely prescribed in primary care practice for disorders like ADHD and anxiety (Chen et al., 2016). Often these practitioners are well able to manage cases that are uncomplicated. However, as cases increase in complexity, for example, due to side effects, associated comorbid conditions, and unusual clinical presentations, specialists tend to get involved. Finding good ways to support primary care providers in their use of these agents remains an important area of work (Meyers & Roth, 2018)

Although research in pediatric psychopharmacology has lagged behind that in adults (for a number of reasons), there have been some noteworthy and important initiatives that we will discuss subsequently. Recent congressional and governmental initiatives have also encouraged drug companies to study the use of agents in children and adolescents as well as adults (Oesterheld et al., 2018).

As Martin et al. (2004) have observed, there are some important considerations in prescribing psychoactive medications for children. They note seven major principles that guide work in this area (see Box 29.1).

BOX 29.1 Guiding Principles in Medication Management

Developmental differences in metabolism and elimination often result in shorter drug half-life in children.
Realization that comorbidity is common and that childhood disorders are complex and heterogenous. These issues may be relevant in deciding which issues are most important to target and what the impact of drug treatments may be on other conditions/problems that are present.
Identification of specific target symptoms (and their measurement) and the ability to integrate information from multiple informants (child, parents, teachers) is important. This creates some important practical problems in ongoing monitoring and dose adjustment.
Monitoring risks and benefits is important. Various methods can be used but is always important to weigh potential risks and benefits and to be sure all involved are aware of potential side effects and drug interactions.
Parents/caregivers must be engaged in treatment. As with all medications the most usual reason they don’t work is that they are not taken (or not taken correctly). It is important to engage with children and youth as well as parents to ensure that drugs are taken appropriately and that all concerned are engaged in the treatment process. Discussion of the onset of benefit as well as of potential side effects is important; some drugs will have a more or less immediate effect, whereas others will take some time to be effective. Discussion of the meaning of the medicine to the child is important. Consideration can be given to use of longer acting agents to prevent children from feeling stigmatized by being called off to the nurses’ office for mid-day mediations!
Usually medications are combined with other intervention methods. These may be as simple as ongoing special education or special services or more complex like participation in special psychotherapies or other treatments. It is important to be cognizant of these treatments. More information, particularly from practice parameters and guidelines, is now available as are guide clinicians for use in combination treatments. There are now good data on several combination treatment approaches.
Treatment should be evidence based and guided by the available data. The treatment plan is clearly individualized for the particular child or youth but should be based in a realization of the levels of strength of evidence for the treatments proposed taking into account the myriad individual family, cultural, and other factors that impact the given child.

Adapted from Martin, A., Oesterhed, J. R., Bloch, M. H., et al. General principle and clincal practice. In A. Martin, M. Bloch, & F. R. Volkmar (Eds.), Lewis’s child and adolescent psychiatry: A comprehensive textbook (5th ed., pp. 715-716). Wolters Kluwer.

In considering the use of medications, it is important to understand if there are alternatives to medication and whether these have been given an adequate trial. As part of considering medication, the prescriber will want to understand whether any medical conditions or life changes have contributed to the difficulties. Other considerations include problem severity, the degree to which it impacts across settings (e.g., both school and home) or is more limited, and the history of the problem and its impact on the child or adolescent’s life functioning. The potential risks of pharmacologic intervention must be weighed against possible benefits. Sometimes problems are of recent onset and at other times issues arise in the context of long-standing issues and concerns. Often a careful behavioral assessment is helpful. Medications can be used with behavioral interventions, but once multiple interventions occur simultaneously, it gets more difficult to understand why things change; so a careful and thoughtful approach is needed trying, if at all possible, to change just one thing at a time.

There are important developmental changes that impact the use and efficacy of medications in children. These include changes both in drug absorption, metabolism, and excretion as well as in specific mechanisms of action (see Anderson & Martin, 2018). The term “pharmacokinetics” describes how the body deals with a drug, whereas pharmacodynamics refers to the effect of a drug on the body (see Figure 29.1).

There can be important differences in the effect of medication at different ages as brain regions develop at different rates. This can impact both the hoped-for treatment response as well as side effects. These issues are reflected, for example, in different side-effect profiles of the neuroleptic medications, developmental differences in responses to agents like antidepressants and SSRIs and so forth (Oesterheld et al., 2018). An understanding of pharmacokinetics as well as pharmacodynamic factors is important and may be relevant in issues of choice of specific agent within a drug class.

Several different issues are involved in pharmacokinetic effects. These include absorption and distribution that impact onset of effects, whereas metabolism and excretion help determine duration of drug effects (Oesterheld et al., 2018). Some drugs follow a linear pattern of drug kinetics so there is essentially a linear relationship between dose and plasma concentration. For drugs with this pattern, dose-response relationships are often easiest to interpret. In other situations nonlinear (also called zero-order) kinetics occur when a given amount of the agent is metabolized per unit time (i.e., without respect to plasma level). In drugs with this pattern, dose-response relationships are more complicated to interpret (see Oesterheld et al., 2018). A range of factors impact the bioavailability of any drug including its absorption, its initial clearance (first-pass effects) by gastrointestinal and liver metabolism, and conjugation. For some agents, for example, lithium, urinary excretion is the major path for elimination of the drug, whereas for others metabolism in the liver occurs. Drugs vary in the efficiency with which this first-pass mechanism impacts bioavailability, with some very efficiently metabolized and others much less so. Although oral administration of a drug is most common, it is also less predictive in terms of bioavailability. Many psychoactive agents are absorbed just after they pass through the stomach. Our understanding of drug absorption and distribution in the body has greatly advanced over the last decades (Oesterheld et al., 2018).

FIGURE 29.1. Pharmacokinetics and pharmacodynamics of a central nervous system (CNS) drug. Reprinted with permission from Oesterheld, J., Shader, R., & Martin, A. (2018). Clinical and developmental aspects of pharmacokinetics and drug interactions. In A. Martin, F. R. Volkmar, & M. Bloch (Eds.), Lewis’s child and adolescent psychiatry: A comprehensive textbook (5th ed., p. 703). Wolters Kluwer.

STIMULANTS AND OTHER MEDICATIONS FOR ADHD

As noted earlier, the stimulants were some of the first medications used in the treatment of behavioral and emotional difficulties and now have become the first-line treatments for ADHD. These medications (methylphenidate and various forms of amphetamine) have been shown to be generally effective and exist both in short and longer acting forms. As discussed in Chapter 10, ADHD is one of the most common child mental health problems in school-age children, primarily boys. Longitudinal studies have shown the persistence of the condition into adolescence and adulthood in many cases (Spetie & Arnold, 2018). Although the effectiveness of these (and other) medications is clear, it is also clear that many children do not receive treatment (Scahill et al., 1999).

Stimulant Medications

Methylphenidate- and dextroamphetamine-related agents and mixed preparation of dextroand levo-amphetamine are most frequently used. Table 29.1 summarizes many of the features of these medications that have now been shown to be effective in literally hundreds of studies going back many decades. More recent and technologically sophisticated work has clarified important issues of dose-response as well as potential differences in these agents and their potential side effects. One study (Rapport & Denney, 1997) of dose-response found that all

levels of medication were better than placebo. Similarly, meta-analyses have shown that the most common side effects include (given the nature of stimulants) problems with insomnia, appetite, and sometimes obsessive thinking and behavior, among others (see Bloch, Beyer, Martin, et al., 2018a).

TABLE 29.1 Stimulant Medications for Attention-Deficit Hyperactivity Disorder

Drug Name (Brand)	Active Ingredient	Onset of Action	Duration of Effect	Required Number of Doses/Day	Suggested Dosing and Titration
Short Acting
Ritalin^® Methylin^® Focalin^® Metadate^®	Methylphenidate	20-60 minutes peak effect: 2 hours	3-6 hours	2-3 doses; occasionally 4 doses	Start with one 5-mg tablet (2.5 for Focalin^®) 2-3× a day. Increase by 5 mg (or 2.5 mg for Focalin^®) until target behavior controlled, maximum dose is 60 mg per day
Dexedrine^® Dextrostat^®	D-amphetamine	20-60 minutes peak effect: 1-2 hours	4-6 hours	2-3 doses	Start with one 5-mg tablet 2-3× per day^a
Adderall^®	D,L-amphetamine	30-60 minutes peak effect: 1-2 hours	4-6 hours	2-3 doses	Start with one 5-mg tablet 2-3× per day^a
First Generation: Long Acting
Ritalin SR^® Metadate ER^® Methylin ER^®	Methylphenidate	60-90 minutes peak effect: 8 hours	5-8 hours	1-2 doses	Start with one 10-mg tablet 1-2× per day^a
Dexedrine Spansules^®	D-amphetamine	60-90 minutes peak effect: 8 hours	6-8 hours	1-2 doses	Start with one 5-mg capsule 1-2× per day^a
Second Generation: Long Acting
Concerta^®	Methylphenidate	30 minutes-2 hours	12 hours	1 tablet	Start with one 18-mg tablet once per day^a
Metadate CD^® Ritalin LA^®	Methylphenidate	30 minutes-2 hours	6-8 hours	1-2 capsules	Start with one 10-mg capsule once per day^a
Daytrana^®	Methylphenidate	20-60 minutes peak effect: 10 hours after single application, 8 hours after repeat applications	8-12 hours	1 patch	Start with 10-mg patch worn 9 hours daily. Maximum dose: 30 mg patch worn 9 hours daily
Focalin XR^®	Dexmethylphenidate	1-4 hours	8-12 hours	1 capsule	Start with one 5-mg capsule once per day^a
Quillivant XR^®	Methylphenidate	30 minutes peak effect: 5 hours	8-12 hours	1 liquid dose	Start with 20 mg liquid suspension once per day^a
Adderall XR^®	D,L-amphetamine	1-2 hours	10-12 hours	1 capsule	Start with one 5- or 10-mg capsule once per day^a
Vyvanse^®	L-lysine-dextroam-phetamine	2 hours peak effect: 3-4 hours	10-12 hours	1 capsule	Start with one 30-mg capsule once daily^a
^aTitrate upward until target behavior controlled. Reprinted with permission from Bloch, M., Beyer, C., & Martin, A. (2018). ADHD: Stimulant and nonstimulant agents. In A. Martin, M. H. Bloch, & F. R. Volkmar (Eds.), Lewis’s child and adolescent psychiatry: A comprehensive textbook (5th ed., p. 719). Wolters Kluwer.

The two stimulant agents appear to be about equally as effective (Elia, 1991). One of the major problems with methylphenidate has been the short duration of action so that the advent of extended-release forms has been welcome (Pelham et al., 2001). It is important to note that only a handful of studies have addressed long-term use, although data available suggest fewer overall side effects of methylphenidate (Greenhill et al., 1996). The large Multimodal Treatment Study (MTA) of ADHD in children provided powerful evidence of the superiority of this agent (sometimes in combination with other treatments) over behavioral treatment alone and to a community care group (the latter generally providing less frequent doses of the agent; see MTA, 1999 for details). Issues in the community care group were noted to include discontinuation of the medication, possibly reflecting undertreatment. The two research groups (medication alone and medication with behavioral intervention) had more frequent visits and intensive follow-up, including teacher reports. Overall, this study suggested that in the community, medication may be underdosed and not followed sufficiently closely. It is the case that individual differences are noted, and some children and youth do respond better to one over the other agents.

The mechanism of action of the stimulants remains the focus of some debate (Solanto, 1998). It is clear that methylphenidate and amphetamine work, in slightly different ways, to impact the dopamine system in the brain (and some other systems as well). Within the brain these effects are centered in the striatum and, to some degree, in the prefrontal cortex. Both kinds of agents also impact the norepinephrine (NE) system (Biederman & Spencer, 1999) via the locus coeruleus. It is interesting that the drugs like guanfacine (see next section) are more selective in their action but with smaller clinical impact.

The immediate-release forms of these agents (see Table 29.1) are readily absorbed and generally have behavioral effects within 30-60 minutes and reach peak levels within 90-150 minutes. The clinical benefit lasts several hours. Both drugs are metabolized in the liver, although through different pathways (see Oesterheld et al., 2018). The mixed amphetamine preparations have a somewhat longer period of action (Swanson, Wigal, Greenhill, et al., 1998). The sustained release (SR) forms provide the option of once-daily dosing and more flexibility and convenience.

There has been some disagreement about best approaches to dosing, for example, by weight or fixed dose; in one well-designed study, a linear dose-response relationship was noted (Rapport & Denney, 1997). Dosing of methylphenidate is usually done multiple times during the day to achieve optimal benefit without side effects, for example, on appetite or sleep (see Bloch, Beyer, Martin, et al., 2018a, for additional dosing information). The input of parents and teachers on effectiveness is important. Information from both sources is helpful to clinicians in management.

With D-amphetamine and D,L-amphetamine, the approach is similar. Usually, only twice-daily dosing is needed: in the morning and then again at noon to achieve maximum benefit at school. The extended-release preparations are also effective with similar side-effect profiles but with the advantage of less frequent administration. They may improve compliance and avoid some of the problems of rebound effects seen in shorter acting forms. A patch form is also now available to provide extended release for children who have difficulties with oral medications.

There has been concern, given their effect on appetite suppression, that growth retardation may be an adverse effect. The data on this issue are mixed (see Bloch, Beyer, Martin, et al., 2018a). One approach is to give stimulant medications with food or just after eating and monitor weight and height on a regular basis. By their very nature stimulants have the potential to cause sleep disturbance (one of the common reasons they are abused by college students attempting to “pull all-nighters”). Changes in mood, tics, headaches, and other problems can also occur. Taking a careful sleep history prior to use of these agents is important, and use of extended-release forms may avoid rebound phenomena and minimize some side effects. When methylphenidate is used, it is frequently the case that the end-of-day dose, if needed at all, is lower than other doses. The association of tics and stimulant administration has been controversial. One complexity is that many children with tics also have ADHD and the latter responds to stimulants (Bloch et al., 2009). A major meta-analytic study failed to suggest increased rates of tics with stimulants (Cohen et al., 2015).

Nonstimulants for ADHD

Given the concerns regarding possible side effects of stimulants, a number of other agents have been developed for use in treatment of ADHD. Table 29.2 provides a summary of these agents. The drug atomoxetine (Strattera) was approved by the Food and Drug Administration (FDA) as a treatment for ADHD (and comorbid oppositional defiant disorder following placebo-controlled trials, e.g., Michelson et al., 2002; Newcorn et al., 2005). Both once- and twice-daily dosing have been used (Michelson et al., 2002). Although better than placebo, the degree of improvement is less than that of the more traditional stimulants (Wigal et al., 2005). Some of the side effects include gastrointestinal (GI) problems, fatigue, mood swings, and dizziness. There is a black box warning relative to liver problems, higher levels of aggression/hostility, as well as suicidal thinking.

The drug bupropion (Wellbutrin) has been approved for the treatment of depression and smoking cessation in adults. Its exact mechanism of action is unclear, but it does seem to have both dopaminergic and noradrenergic effects. In one large placebo-controlled trial, it was effective for ADHD, although again the magnitude of the effect was less than that for stimulants (Conners et al., 1996). Side effects can include GI problems and agitation and a reduced seizure threshold. A SR preparation is available.

The shorter acting adrenergic agents—clonidine (Catapres, Kapvay) and guanfacine (Tenex)—have been used for many years in the treatment of tics and ADHD, although they were only FDA approved for hypertension. More recently, the extended-release forms of both clonidine (Kapvay) and guanfacine (Intuniv) have been approved for ADHD as have the shorter acting forms. A meta-analysis of the efficacy of alpha-2 agonists for ADHD (Hirota et al., 2014) has shown reduction in overall ADHD as well as specific individual symptoms generally, with a moderate effect size for the major symptoms of hyperactivity,
impulsivity, and inattention. These agents may be particularly useful for children with both tics and ADHD (Weisman et al., 2013). The presumed mechanism of actions relate to central noradrenergic activity. Starting doses are small and gradually increased, patch and extended-release forms are available. Side effects of both clonidine and guanfacine are rather similar and include sedation, irritability, sleep problems. At doses usually given to children and adolescents, hypotension is not a problem although blood pressure should be monitored. Rapid withdrawal may be associated with rebound hypertension.

TABLE 29.2 Nonstimulant Medications for Attention-Deficit Hyperactivity Disorder

Medication	Drug Name	Frequency	Daily Dose Range
Atomoxetine	Strattera^®	Daily or twice daily	0.5-1.2 mg/kg/day (<70 kg) 40-80 mg/day (≥70 kg)
Clonidine	Clonidine IR^®	Twice daily to 4× per day	0.05-0.4 mg/day
	Clonidine ER (Kapvay^®)	Daily	0.1-0.4 mg/day
Guanfacine	Guanfacine IR^®	Twice daily to 4× per day	0.5-0.4 mg/day
	Guanfacine ER (Intuniv^®)	Daily	1-4 mg/day
Desipramine	Norpramin^®	Twice daily to 3× per day	2-5 mg/kg/day
Bupropion	Wellbutrin^®	Twice daily	50-150 mg
Reprinted with permission from Bloch, M., Beyer, C., & Martin, A. (2018). ADHD: Stimulant and nonstimulant agents. In A. Martin, M. H. Bloch, & F. R. Volkmar (Eds.), Lewis’s child and adolescent psychiatry: A comprehensive textbook (5th ed., p. 722). Wolters Kluwer.

THE ANTIDEPRESSANT MEDICATIONS

The various antidepressant medications are a rather diverse set of drugs, all of which have been shown to be effective in the treatment of depression in adults as well as for some other conditions, notably obsessive compulsive disorder, various anxiety disorders, autism, and posttraumatic stress disorder, among others (see Chapters 12, 13, and 23). These agents have somewhat different chemical structures and mechanisms of action. Some are SSRIs, whereas others are selective norepinephrine reuptake inhibitors (SNRIs), or inhibitors of monoamine oxidase inhibitors. There are some newer agents with different mechanisms of action as well (Bloch, Beyer, Martin, et al., 2018b). Of all of these, the SSRIs are the most extensively used and studied. This group of agents strongly inhibit reuptake of the neurotransmitter into presynaptic neurons. This is in contrast to other agents like the older tricyclics, which inhibit reuptake both of NE and serotonin. The group of SSRIs have been FDA approved for the treatment of obsessive compulsive disorder (OCD) in adults and, except for fluvoxamine, are all approved for use in adult depression as well. Table 29.3 summarizes features of these agents.

Research has been much more extensive in adults than in children, although these medications are frequently used with children. When these agents were first introduced they had a major impact on pediatric drug treatments because they were easier to use than the older tricyclic antidepressants (TCAs), did not have the same cardiac side effects of the TCAs,
generally were well tolerated, and, in a series of studies, proved superior to the TCAs for the treatment of depression as well as OCD (Riddle et al., 2001).

TABLE 29.3 Clinical Guidance for Antidepressant Medications Utilized in Pediatric Practice

	Pediatric		Adult
	Starting Dose (mg/day)	Typical Dose Range (mg/day)	Starting Dose (mg/day)	Typical Dose Range (mg/day)	Half-Life
Selective Serotonin Reuptake Inhibitors
Citalopram	10	20-40	20	40	20 hours
Escitalopram	5	10-40	10	20-40	27-32 hours
Fluoxetine	10-20	20-80	20	20-80	4-6 days
Fluvoxamine	25-50	5-0	100-300	100-300	16 hours
Paroxetine	10	20-60	10-20	40-60	21 hours
Sertraline	25-50	100-200	50	150-250	26 hours
Serotonin Norepinephrine Reuptake Inhibitors
Venlafaxine	37.5	150-225	37.5-75	75-375	10 hours
Duloxetine	40	40-60	20-60	20-80	12.5 hours
Desvenlafaxine	10	10-100	50	50-400	11 hours
Atypical Antidepressants
Bupropion	100	150-300	100-150	150-300	21 hours
Mirtazapine	7.5	15-45	15	15-45	20-40 hours
Vilazodone	Not studied		10	10-40	25 hours
Vortioxetine	Not studied		10	10-80	66 hours
Trazodone	25-50	100-150	150	150-300	3-9 hours
Tricyclic Antidepressants
Clomipramine	25	50-200	25	100-250	32 hours
Desipramine	25	50-200	100-200	150-300	12-27 hours
Nortriptyline	30-50	30-150	100	75-150	18-44 hours
Reprinted with permission from Bloch, M., Beyer, C., & Martin, A. (2018). Antidepressants. In A. Martin, M. H. Bloch, & F. R. Volkmar (Eds.), Lewis’s child and adolescent psychiatry: A comprehensive textbook (5th ed., p. 727). Wolters Kluwer.