SPECIAL ISSUES FOR CHILDREN AND ADOLESCENTS
In the treatment of psychiatric disturbances in children and adolescents, psychopharmacology may be a key part of a multimodal treatment plan, the primary intervention, or an adjunct to other forms of treatment. The clinician must educate the family regarding the disorder, treatment options, and the child’s needs at each developmental stage. The clinician also must consider the meaning of the prescription and administration of a drug to the child, the family, and the child’s teachers and peer group.
Evidence-based clinical practice of pediatric psychopharmacology is impeded by the relative lack of double-blind randomized placebo-controlled trials (RCTs). Many medications that initially appeared to be effective in anecdotal reports, case series, and open trials were not shown to be more effective than placebo in double-blind studies. In evaluating the medical literature on drug effects, it is important to distinguish between statistically significant and clinically significant effects: to know whether the target symptoms are reduced to near-normal levels or merely changed and to determine the clinical meaning of the change. Within a heterogeneous sample, some patients’ conditions may improve and others may worsen, resulting in nonsignificant change as a group. On the other hand, statistically significant group changes may translate into only modest improvement in individual patient functioning and may not be worth the effort, expense, and potential risk of the treatment.
Simultaneous use of more than one medication (“polypharmacy”) should be cautious, judicious, and as rare as possible because of the increased risk of significant side effects, toxic drug interactions, and difficulty assessing effectiveness of each drug. It is important to give a medication an adequate trial of long enough duration for that drug and at a sufficient dose to determine effectiveness before switching to or adding another drug.
The interactions between drug treatment and physical, cognitive, social, and emotional development may produce unique or especially severe side effects. All psychotropic medications have the potential for cognitive toxicity. Because some drug treatments last for years, there is a risk of chronic and cumulative effects. Cognitive blunting can impair developing academic skills, social skills, and self-esteem even before physical side effects are observed, especially in young children. Young patients may have behavioral toxicity (i.e., the worsening of preexisting behaviors or affective states or the development of new symptoms). Behavioral toxicity typically abates after dose adjustments or change of drug.
Indications and Dosing
Once a drug is approved for any indication, the U.S. Food and Drug Administration (FDA) regulates only the company’s advertising of the drug, not the prescribing behavior of physicians. Because in the past, pharmaceutical companies had little incentive to test drugs in children, the majority of psychopharmacological agents and indications (and most drugs used in pediatrics as well) lack pediatric labeling and are “unapproved” or “off-label” for children. For preschool-age children, even fewer drugs have FDA psychiatric indications. As a result, the FDA guidelines as published in the Physicians’ Desk Reference (PDR) cannot be relied on for appropriate indications, age ranges, or doses for children. Although lack of approval for an age group or a disorder does not imply improper or illegal use, it is prudent to inform the family of these labeling issues, as well as of evidence in the literature for safe and effective use. The physician should make clinical judgments based on the medical literature rather than the PDR.
Dose may be determined by titration using effectiveness and side effects; within guidelines based on age, weight, or blood levels; or by extrapolation from adult doses. Although it is ideal for pediatric drug doses to be derived from data on children, such dosing studies are rare. A useful general principle is “start low and go slow.”
The age-dependent processes of drug absorption, distribution, protein binding, metabolism, and elimination influence optimal dose size and schedule (Vitiello 2017). Young children absorb some drugs more rapidly than do adults, leading to higher peak levels. Age-related factors that may influence distribution include uptake by actively growing tissue and proportional size of organs and tissue masses. Prior to puberty, children have, compared with adults, relatively more body water and less fat (which serves as a reservoir for lipid-soluble compounds). In children, drugs such as lithium (which are primarily distributed in body water) have a proportionally larger volume of distribution and therefore a lower concentration. By age 1 year, glomerular filtration rate and renal tubular secretion mechanisms reach adult levels. Hepatic enzyme activity develops early, and the rate of drug metabolism is then related to liver size. Both kidney and liver parenchyma in children are larger than in adults, relative to body size. Therefore, compared with adults or older adolescents, children generally require a larger dose per kilogram of body weight of drugs that are primarily metabolized by the liver. They may also require divided doses to minimize fluctuations in blood level. Compared with adults, children also tend to have less protein binding of drugs, leaving a greater proportion of the drug biologically active.
Children often differ from adults in both effectiveness and adverse effects of a medication. Assessing the risk–benefit ratio, especially for long-term treatment, is particularly complicated in children and adolescents. Many scientific unknowns persist regarding drug effects during development. Evaluation is complicated by a variety of nonpharmacological effects, including nonspecific therapeutic effects of evaluation and treatment; expectancy in the patient, parent, or teacher; changes in the environment; and the natural course of the disorder (e.g., the waxing and waning of symptoms in Tourette’s disorder).
The clinician must specify target symptoms and obtain emotional, behavioral, cognitive, and physical data at baseline and during treatment. Treatment effects can be assessed by interviews of and standardized symptom rating scales by the patient, the parent, and other caregivers (e.g., teachers, inpatient nurses); direct observation in the office, waiting room, or classroom; physical examination; and, as appropriate, specific cognitive, learning, or laboratory tests. The clinician must actively question regarding both therapeutic and adverse effects because many young patients will not report them spontaneously, and parents may not notice.
The interactions between treatment and the environment raise complex issues for children and adolescents. To assess medication effects, the clinician must evaluate and monitor the adult and peer environments as well as the patient. It is important to know what the therapeutic contacts and any clinical change mean to the patient and to family members. The adults (parents, teachers, or staff in an inpatient unit or residential treatment setting) who care for children may misinterpret the youngster’s response to the environment as indicating a need for medication or an improvement that is a result of medication. Some of these adults mistakenly seek to use psychotropic medication alone to control or eliminate a child’s troublesome behavior, instead of investigating the family or institutional dynamics that may be provoking and maintaining such behavior or implementing more time-consuming, difficult, and expensive therapeutic or behavioral management strategies or changes in living situation.
Adherence to Treatment
Effective treatment requires a therapeutic alliance and the cooperation of the patient, parents, school personnel, and often other caregivers. Adherence to a treatment regimen can be reduced by factors such as lack of perceived need for treatment, failure to understand the disorder, poor organization, lack of money, misunderstanding of instructions, or refusal to cooperate. Overly complex schedules of drug administration may make accurate administration nearly impossible. Media attention to alleged inappropriate use of medications has made some families and teachers highly resistant to pharmacotherapy.
Some children cannot or will not swallow pills. Some drugs are available in elixir or dissolving tablet form or can be dissolved in juice or sprinkled on pudding or applesauce. Problems with this method of administration may include unpleasant taste, chemical interaction resulting in precipitation of the medication, and inaccurate dosing. Information on shaping the ability to swallow pills is available on the Web at www.massgeneral.org/children/assets/pdf/Lurie-Center-Teaching%20Your%20Child%20to%20Swallow%20a%20Pill.pdf.
The careful clinician attempts to balance the risks of medication, the risks of the untreated disorder, and the expected benefits of medication relative to other treatments. With the exception of drugs used for attention-deficit/hyperactivity disorder (ADHD), it is generally preferable that there be substantial clinical experience with a new drug in adults before it is used with children and young adolescents.
Consent for pharmacotherapy in children is a complex issue that can be made even more difficult if the parents or guardians are in conflict (e.g., in angry divorces or with children in the custody of child welfare). Informed consent is best considered an ongoing process rather than a single event. “Assent” to medication use is considered possible to obtain from a patient older than 7 years, with more complex understanding at older ages. Formal consent forms are less useful than a documented discussion of therapeutic options with potential risks and benefits and an opportunity for questions and answers. Published information sheets for parents and teachers are available to supplement discussions with the prescribing clinician about specific medications (Dulcan and Ballard 2015).
The number of available stimulant preparations (Table 17–1) has increased dramatically, which enhances the clinician’s ability to tailor the medication regimen to the patient. They include a variety of forms of methylphenidate and amphetamine. Unfortunately, increasingly narrow payor formularies often drastically limit available choices.
Generic (IR) (3–4 hours)
5, 10, 20
5 mg/5 mL, 10 mg/5 mL
2.5, 5, 10
Methylin (IR) (3–4 hours)
Oral solution (grape)
5 mg/5 mL, 10 mg/5 mL
Ritalin (IR) (3–4 hours)
5, 10, 20
Aptensio XR (10–12 hours)
Capsule with beads
Ratio of IR:LA = 40:60
10, 15, 20, 30, 40, 50, 60
Metadate ER (6–8 hours) and generic
Wax matrix tablet
Ritalin LA (8–9 hours) and generic
Capsule with beads (sprinkle)
Ratio of IR:LA = 50:50
10, 20, 30, 40
Metadate CD (6–8 hours)
Capsule Diffucap with beads (sprinkle)
Ratio of IR:LA = 30:70
10, 20, 30, 40, 50, 60
Concerta (10–12 hours) and generics
Oros Osmotic Controlled Release
Ratio of IR:LA = 4:14
18, 27, 36, 54
18 mg Oros = 5 mg IR bid or tid
Quillivant XR (8 hours)
Extended release oral suspension
Ratio of IR:LA = 20:80
25 mg/5 mL–60 mL, 120 mL, 150 mL, 180 mL
Bottles: 300 mg (60 mL), 600 mg, 750 mg, 900 mg
QuilliChew ER (8 hours)
20, 30, 40
Transdermal system (patch)
Worn for 9 hours for 12-hour duration
10, 15, 20, 30
Dexmethylphenidate (only the dextro isomer of methylphenidate)
Focalin (3–4 hours) and generic
2.5, 5, 10
Focalin XR (10–12 hours)
Capsule with beads (sprinkle)
Ratio of IR:LA = 50:50
5, 10, 15, 20, 25, 30, 35, 40
Generic XR (10–12 hours)
See Focalin XR
5, 10, 15, 30, 40
Generic (IR) (3–5 hours)
Dextroamphetamine sulphate (3–5 hours)
Oral solution (bubblegum)
2.5, 5, 7.5, 10, 15, 20, 30
Dexedrine Spansule (6–8 hours) and generic
Capsule with beads (sprinkle)
5, 10, 15
Dyanavel XR (8–10 hours)
Vyvanse (lisdexamfetamine dimesylate) (12 hours)
Prodrug (may open capsule—dissolve in water or orange juice or mix in yogurt and give immediately; do not divide capsules)
20, 30, 40, 50, 60, 70
Mixed salts amphetamine
Adderall (IR) (3–5 hours) and generic
Ratio of isomers d:l = 3:1
5, 7.5, 10, 12.5, 20, 30
Adderall XR (10–12 hours) and generic
Capsule with beads (sprinkle)
Ratio of IR:LA = 50:50
5, 10, 15, 20, 25, 30
Adzenys XR-ODT and generic (10–12 hours)
Orally disintegrating tablet
Dissolve in mouth (fruit flavor)
Ratio of isomers d:l = 3:1
Ratio of IR:LA = 50:50
3.1, 6.3, 9.4, 12.5, 15.7, 18.8
3.1 mg Adzenys = 5 mg Adderall XR
Evekeo (4–6 hours)
Ratio of isomers d:l =1:1
Note. CD = extended-release; ER = extended-release; IR = immediate-release; LA = long-acting; ODT = orally disintegrating tablet; XR = extended-release.
Long-acting capsules may not be chewed, crushed, or divided. A chart with color pictures of medications that have FDA approval for ADHD is available online from www.adhdmedicationguide.com.
Indications and Efficacy
Stimulant medications, including various formulations of methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine mixed salts, and lisdexamfetamine (see Table 17–1), are the first-line treatment for ADHD. Stimulants retain their effectiveness for ADHD treatment in adolescents (and adults). In preschool children, stimulant effect is more variable, and the rate of side effects is higher, especially sadness, irritability, clinging, insomnia, anorexia, and repetitive behaviors (Greenhill et al. 2006). Stimulants can improve attention and reduce excessive distractibility in patients with ADHD, whether or not hyperactivity is present. Many children whose symptoms respond positively to stimulants, however, continue to have deficits such as specific learning disabilities and gaps in knowledge and skills caused by inattention, poor social skills, and family problems. Intensive behavior modification may add to stimulant effect or permit the use of a lower dose of medication, but it is often difficult to implement and sustain behavioral treatment and to transfer improvements from one setting to another. The National Institute of Mental Health (NIMH) Multimodal Treatment of ADHD (MTA) study showed that optimally titrated methylphenidate was more effective for core ADHD symptoms than intensive behavioral therapy, optimal methylphenidate treatment plus behavioral treatment was more effective than behavioral treatment alone, and each of the MTA treatments was more effective than treatment as usual in the community (mostly stimulants, but at lower doses, fewer doses per day, shorter duration of treatment, and less close monitoring) (MTA Cooperative Group 1999).
When conduct disorder or oppositional defiant disorder coexists with ADHD, stimulant medication can reduce defiance, negativism, and impulsive verbal and physical aggression. In children and adolescents with intellectual disability, stimulants are effective in treating ADHD target symptoms, although the amount of improvement is smaller and side effects are more common. Stimulants may also reduce symptoms of inattention, impulsivity, and overactivity when ADHD is present along with autism spectrum disorder (ASD) or intellectual disability.
Boys and adults, with or without ADHD, have similar cognitive and behavioral responses to comparable doses of stimulants, except that children report feeling “funny,” whereas adults report euphoria (Donnelly and Rapoport 1985). Stimulants act in the brain by inhibiting the dopamine transporter, thereby increasing the amount of dopamine available in the synapse. Norepinephrine reuptake from the synapse is also blocked. Amphetamine also releases dopamine into the synapse. Stimulants may preferentially increase neurotransmitter activity at inhibitory synapses and in inhibitory brain areas. Stimulants are absorbed rapidly from the gut and metabolized rapidly. Stimulant medication effects on ADHD occur primarily as the drug is being absorbed and as the plasma (and brain) concentration is rising.
There are no useful predictors of whether an individual patient with ADHD will respond to a specific medication. Neurological soft signs, electroencephalogram (EEG), brain scans, neurochemical measures, or genetic tests are not useful predictors of response to stimulants. Although prior studies were mixed, the NIMH MTA study showed that children who have anxiety comorbid with ADHD do not have a reduced response to stimulants. More than 90% of patients with ADHD have some positive response to at least one of the stimulant medications. A substantial number of children respond to one stimulant but not another (Ramtvedt et al. 2013). Stimulant effects on individual target symptoms (Table 17–2), however, vary greatly from child to child and even from one symptom to another in a single patient. A given dose may produce improvement in some areas but no change or worsening in others. Therefore, if one stimulant is ineffective, another should be tried before using another drug class. Methylphenidate is the most commonly used and best-studied stimulant. Amphetamine disadvantages include negative attitudes of pharmacists and higher potential for abuse. Compared with methylphenidate, amphetamine may have a slightly greater incidence of side effects such as growth retardation, appetite suppression, and compulsive behaviors.
Reduce activity to level that fits the context
Decrease excessive talking, noise, and disruption
Decrease fidgeting and finger-tapping
Improve fine motor control
Reduce off-task behavior
Improve ability to play and work independently
Decrease intensity of behavior
Reduce verbal and physical impulsive aggression
Improve (but not normalize) peer social status
Reduce noncompliance and defiance with adults
Improve parent–child interactions
Parents and teachers respond with less controlling and more positive behavior
Improve effort and attention, especially to boring tasks
Increase on-task behavior
Increase quantity and accuracy of academic work
Dexmethylphenidate (Focalin) contains only the dextro isomer of methylphenidate. Compared with conventional d,l-methylphenidate, half the dose of dexmethylphenidate is just as effective, with fewer side effects, and perhaps longer duration. Longer-acting stimulant preparations are now most commonly used. They are especially appealing for children in whom the duration of action of the standard formulations is very short (2.5–3.0 hours); when severe rebound occurs; or when administering medication every 4 hours (or at school) is inconvenient, inconsistent, stigmatizing, impossible, or insufficiently supervised to prevent diversion of the drug. The many different formulations of methylphenidate and amphetamine (see Table 17–1) are useful in tailoring treatment to each patient.
Although short-term efficacy of stimulants has been clearly demonstrated, it is much more difficult to demonstrate long-term effects. Existing studies have had methodological problems (e.g., naturalistic treatment assignment; comorbidity; premature termination of drug; doses too high, too low, or poorly timed; inconsistent adherence to medication; individual variation in response; insensitive outcome instruments). A long-term prospective randomized controlled trial assigning children with ADHD to stimulant medication or placebo or other treatment is neither ethical nor feasible.
Initiation and Ongoing Treatment
The decision to medicate a child with ADHD is based on the child’s inattention, impulsivity, and often hyperactivity that are not due to another treatable cause and that are persistent and severe enough to cause functional impairment at school and usually at home and with peers. For safety reasons, parents must be willing to monitor the medication and to attend appointments with the child. An important part of treatment is education of the child, family, and teacher, including explicitly debunking common myths about stimulant treatment. Stimulants do not have a paradoxical sedative action, do not lead to drug abuse, and do continue to be effective after puberty.
Multiple outcome measures that use more than one source and setting are essential. The clinician obtains baseline data from the school on behavior and academic performance before initiating stimulant medication. The physician should work closely with parents on adjusting the size and timing of doses and obtain frequent reports from teachers and annual academic testing. Brief symptom checklists, such as the Child Attention Problems (CAP) Rating Scale (see Tables 3–5 and 3–6) or the IOWA Conners Scale (see Chapter 3, “Neurodevelopmental Disorders”), are useful in gathering weekly data from teachers.
Many experts recommend a systematic stimulant titration using the full range of doses—for example, 5, 10, 15, and 20 mg of methylphenidate (highest dose omitted for very young or small children). Body weight serves only as a rough guide. Doses of amphetamine or dexmethylphenidate (Focalin) are half the milligrams of methylphenidate. A strategy that is preferred by many clinicians and parents is to start stimulant medication at a low dose and increase by half (if necessary and if pill is scored) or whole pills (within the usual recommended range) every week or two, monitoring response (ideally including teacher ratings) and side effects. By age 3 years, children’s absorption, distribution, protein binding, and metabolism of stimulants are similar to those of an adult, although adults may experience more side effects than do children at equivalent therapeutic doses.
The onset of clinical effect for immediate-release methylphenidate and amphetamine is within 30 minutes after each dose. A single dose is usually effective for 3–4 hours. Of the immediate-release forms, amphetamine typically has about an hour longer therapeutic duration compared with methylphenidate. A typical regimen for the immediate-release preparations would be thrice-daily dosing, with medication given after breakfast, after lunch, and after school. Starting with only a morning dose may be useful in assessing drug effect, by comparing morning and afternoon school performance. The need for an after-school dose or for medication on weekends is individually determined by considering target symptoms. A third dose after school has been shown to improve behavior without increasing sleep problems (Kent et al. 1995). Most children with moderate or severe symptoms of ADHD need full coverage, all day and all week. The long-acting formulations are typically given once a day, in the morning, with supplementation with immediate release if necessary, timed according to target symptoms.
If the initial stimulant drug choice is not effective or not well tolerated, more than half of nonresponders to methylphenidate or amphetamine respond to the other stimulant.
Medical monitoring includes, at a minimum, pulse rate and blood pressure initially and at times of dose change; weight at baseline, during titration, and two to three times a year; and height at baseline and then several times a year. Prior to prescribing stimulant medication, the clinician should take a cardiac history, including any patient structural abnormalities, chest pain, palpitations, fainting, and reduced exercise tolerance and family history of arrhythmias, early cardiac death, or sudden unexplained death. Electrocardiogram (ECG) monitoring prior to and during stimulant treatment has been controversial. Following the FDA warnings in 2006 regarding sudden death in patients with structural cardiac abnormalities or other serious heart problems, the American Heart Association issued a statement that recommended obtaining an ECG prior to stimulant treatment (Vetter et al. 2008). This recommendation lacked specific supporting evidence, and soon after, the American Academy of Pediatrics (supported by the American Academy of Child and Adolescent Psychiatry) issued a statement (Perrin et al. 2008) concluding that routine pretreatment cardiac tests are not indicated unless there is known or suspected cardiac disorder or symptoms. If there are such findings on history or pediatric examination, an ECG and often a pediatric cardiology consultation are indicated. Several large naturalistic studies have not found increased cardiac risk when stimulants are used for ADHD in youth. The clinician should look for and inquire about tics at baseline and at every visit. Periodic reevaluation of the need for a dose increase or decrease or a change in timing of administration will optimize improvement.
Although pharmacological tolerance has been reported occasionally, medication administration is often irregular, and lack of adherence should be considered when medication appears to become ineffective. The child should not be responsible for his or her own medication, because youngsters with ADHD are impulsive and forgetful at best, and most dislike the idea of taking medication, even when they can verbalize its positive effects and report few if any side effects. They will often avoid, “forget” to take, surreptitiously spit out, or simply refuse to take a dose of medication. Apparent decreased drug effect may be caused by a reaction to a stressful change at home or school, lower efficacy of a generic preparation, or abatement of an initial positive placebo effect. If tolerance does occur, the other stimulant may be substituted.
The duration of medication treatment is individually determined by whether drug-responsive target symptoms are still present. Treatment may be required through adolescence and into adulthood. If behavioral symptoms are not severe outside of the school setting, the young person may have an annual drug-free trial of at least 2 weeks, or even the whole summer if symptoms are mild. If school behavior and academic performance are stable, a carefully monitored trial off medication during the school year (but not at the beginning) will provide data on whether medication is still needed.
Risks and Side Effects
Most side effects are similar for all stimulants (Table 17–3). Giving medication after meals reduces appetite suppression. Difficulty falling or staying asleep may be due to ADHD symptoms, oppositional refusal to go to bed, separation anxiety, stimulant effect or rebound, or excess environmental stimulation (especially electronic devices). Preexisting sleep problems are common in patients with ADHD. Stimulants may either worsen or improve irritable mood. Other than mildly elevated blood pressure, cardiovascular side effects are exceedingly rare. Adverse effects may result if a child chews one of the long-acting forms instead of swallowing it.
Common side effects (try dose reduction)
Weight loss or slowed weight gain (may be worse with amphetamine)
Irritability (may be worse with amphetamine)
Less common side effects
Mildly elevated blood pressure
Insomnia (may be worse with amphetamine)
Dysphoria (may be worse with amphetamine)
Impaired cognitive test performance (especially at very high doses)
Decrease in expected weight gain
Rebound overactivity and irritability (try adding small afternoon or evening dose)
Habits such as skin picking and nail biting
Allergic rash, hives, or conjunctivitis
Transient motor tics (may be worse with amphetamine)
Infrequent side effects
Anxiety and fearfulness
Rare but potentially serious side effects (usually reversible)
Exacerbation or precipitation of tics (may be worse with amphetamine)
Psychosis with hallucinations
Stereotyped activities or compulsions
Reported with Concerta only
Capsule lodged in throat
Reported with Daytrana only
Skin irritation under patch
Allergy to methylphenidate
The use of stimulants in patients with a personal or family history of tics has been controversial because of concern that new, persistent tics might be precipitated, especially in those children who are at genetic risk. The physician must balance the impairment resulting from tics with that from ADHD symptoms, considering the efficacy and side-effect profile of alternative medications. With appropriate informed consent and careful clinical monitoring, a stimulant (methylphenidate) may remain the first choice (Friedland and Walkup 2015). Tics are extremely common in children with ADHD, with or without stimulant medication, and tend to wax and wane. A comprehensive review of controlled trials concluded that new onset or worsening of tics is no greater while taking stimulant medication than with placebo (Cohen et al. 2015). There is some evidence that very high doses of amphetamine can increase tic severity, which may persist (Kurlan 2002).
Although stimulant-induced growth retardation has been a concern, and weight and height should be monitored, any decreases in expected weight gain and growth are small and rarely clinically significant (Faraone et al. 2008). The magnitude may be dose related and may be greater with dextroamphetamine than with methylphenidate. Attenuation of effect has been reported. Medication-free summers (if clinically appropriate) may facilitate height or weight normalization.
Rebound effects such as increased excitability, activity, talkativeness, irritability, and insomnia, beginning 3–15 hours after a dose, may be seen as each dose or the last dose of the day wears off or for up to several days after sudden withdrawal of high daily doses of stimulants. These effects may resemble a worsening of the original symptoms. Management strategies include increasing structure after school, giving a dose of medication in the afternoon that is smaller than the midday dose, or using a long-acting formulation. If the rebound effect is severe, an alternative agent (atomoxetine, guanfacine, or clonidine) can be added to or substituted for the stimulant.
Clinically relevant contraindications to the use of stimulant medication are schizophrenia or other acute psychosis, glaucoma, or recent stimulant drug abuse. When potential abuse of stimulant medication by the patient—or, more often, by peers or family members—is a concern, Concerta may be a good choice, as its once-a-day administration is easier to supervise, and the physical characteristics of the capsule contents (methylphenidate mixed with an osmotic “sponge”) make it impossible to crush and snort or inject. Vyvanse is also not abusable, because of the need for enzyme cleavage of the amino acid before the amphetamine is active.
No evidence indicates that stimulants as clinically prescribed decrease the seizure threshold or precipitate bipolar disorder.
A selective serotonin reuptake inhibitor (SSRI) may be added to a stimulant for the treatment of comorbid ADHD and depression or anxiety (for symptoms remaining after stimulant treatment).
Stimulants are used in combination with atomoxetine, clonidine, or guanfacine to treat symptoms resistant to a stimulant alone. This is theoretically appealing because of complementary actions and nonoverlapping side-effect profiles.
Atomoxetine (Strattera) is a specific norepinephrine reuptake inhibitor with minimal affinity for other receptors or transporters.
Indications and Efficacy
Atomoxetine was the first nonstimulant approved by the FDA for the treatment of ADHD. RCTs have shown efficacy in inattentive and hyperactive-impulsive symptoms of ADHD in preschoolers through adolescents as reported by parents and teachers (Kelsey et al. 2004; Michelson et al. 2001). Atomoxetine is effective in some youth who have not responded to stimulant treatment. In RCTs, about half of subjects are atomoxetine responders (Newcorn et al. 2009). In responders, the effect size is lower than that typically seen with stimulants. Atomoxetine improves comorbid oppositional symptoms (improvement greater at higher doses) (Newcorn et al. 2005) and comorbid anxiety symptoms. In addition to having a different side-effect profile, which is useful for patients who do not tolerate stimulants, atomoxetine provides 24-hour coverage, which is especially helpful with the evening and early-morning symptoms not covered by stimulants. Atomoxetine might be the first choice for patients with ADHD if stimulants (which are controlled substances) are refused or not feasible or for patients with preexisting severe early-morning behavior problems, insomnia, or low weight.
Initiation and Ongoing Treatment
Atomoxetine may be given once a day (morning or evening) or divided into two doses (with breakfast and dinner) to reduce side effects. The starting dose is 0.3 mg/kg/day (usually in a single daily dose) for a week, with the dosage then increased over 1–3 weeks to an initial target dose of 1.2 mg/kg/day. The FDA maximum dose is 1.4 mg/kg/day or 100 mg, whichever is less, but the off-label maximum dose (demonstrated safe in clinical trials) is 1.8 mg/kg/day. The maximum response at a particular dose may be delayed several weeks or even months, requiring patience (especially when compared with the immediate effects of the stimulants). Tapering is not required when discontinuing this medicine. Atomoxetine is metabolized via the cytochrome P450 2D6 pathway. Some patients are poor metabolizers because of genetic makeup or drug interactions, but there are no adverse clinical consequences and genotyping is not recommended.
Atomoxetine may be combined with a stimulant in patients who are partially responsive to each.
Risks and Side Effects
Side effects are generally mild and include sedation, decreased appetite, nausea, abdominal pain, and dizziness. Taking the medication with food improves tolerability. There are slight increases in blood pressure and pulse (rarely clinically significant), but no QTc prolongation on the ECG. Atomoxetine does not increase tics (Allen et al. 2005) or lower the seizure threshold. The capsules must not be opened, as the contents are caustic to the eye. Rare side effects include syncope, vomiting, constipation, irritability, and, very rarely, priapism and (in patients with comorbid bipolar disorder) manic activation. Atomoxetine has two FDA black box warnings: one regarding extremely rare severe liver injury and one (based on weak evidence) of increased hostility and aggression or suicidal ideation. Routine liver function monitoring is not recommended, but parents should be instructed that if jaundice, unexplained abdominal symptoms, pruritus, or dark urine appear, the medication should be stopped and the physician should be called so that liver function tests can be obtained. Atomoxetine does not have a physiological withdrawal syndrome if stopped suddenly, although symptoms of ADHD are likely to return.
GUANFACINE AND CLONIDINE
Guanfacine hydrochloride and clonidine are α-adrenergic agonists developed for the treatment of hypertension. They have been used as second- or third-line treatments for ADHD, despite relatively sparse supporting research. More recently, extended-release formulations of guanfacine (Intuniv) (once a day) and clonidine (Kapvay) (twice a day) have been studied in RCTs and given FDA indications for the treatment of ADHD, either alone or in addition to a stimulant medication. These longer-acting formulations have more research to support their use, and they avoid daily rebound of symptoms or gaps in effectiveness as well as the inconvenience of needing to be given three or four times a day. Also, like atomoxetine, they provide coverage for symptoms of ADHD in the early morning and the evening, when stimulants are not active. Comparing the two drugs, in general, guanfacine has more evidence for treatment effect in inattention, and clonidine is more sedating.
Indications and Efficacy
Clonidine improves frustration tolerance and compliance and reduces emotional outbursts in ADHD. It may be used at bedtime to decrease ADHD overarousal or oppositional behavior or to ameliorate insomnia caused by stimulant effect or rebound.
In a study comparing immediate-release methylphenidate and clonidine, the combination, and placebo, methylphenidate was most effective by teacher report and class observation, with the fewest adverse effects of the active treatments. Clonidine was less effective for ADHD symptoms and caused sedation, but it demonstrated improvement on parent ratings. The combination showed little evidence of added benefit and no increase in side effects (Palumbo et al. 2008). A small RCT comparing immediate-release methylphenidate and clonidine and the combination in youth with ADHD plus aggressive oppositional or conduct symptoms found that all three treatment conditions were associated with significant improvement in attention, impulsivity, and oppositional and conduct symptoms on parent and teacher rating scales and laboratory measures, with few differences among groups. There were no safety findings related to the combination (Connor et al. 2000).
An RCT (Jain et al. 2011) of two doses of extended-release clonidine (0.2 mg/day and 0.4 mg/day) versus placebo in children with hyperactive/impulsive or combined type ADHD found efficacy by parent report of both doses of clonidine, starting at 2 weeks after the target dose was reached.
Two RCTs have demonstrated efficacy of extended-release guanfacine as monotherapy for both hyperactive/impulsive and inattentive symptoms of ADHD as well as for oppositional symptoms by parent, teacher, and clinician ratings (Biederman et al. 2008; Sallee et al. 2009). Extended-release guanfacine has also been shown to be effective for symptoms of ADHD when added to stimulant medication in stimulant partial responders (Wilens et al. 2012). Immediate-release guanfacine combined with dexmethylphenidate has been demonstrated to be more effective in treating ADHD than either guanfacine or the stimulant alone (McCracken et al. 2016).
A modest-sized RCT in children with tic disorders and ADHD showed that guanfacine (immediate release) significantly improved (compared with placebo) teacher and clinician ratings of ADHD symptoms, led to decreased errors on a continuous performance test (while placebo subjects had increased errors), and decreased tic severity by 31% (compared with 0% in the placebo group) (Scahill et al. 2001).
The efficacy of clonidine for Tourette’s disorder per se has been controversial. However, an RCT in children with both chronic tics and ADHD showed efficacy of clonidine in reducing both tics and impulsivity/hyperactivity (Tourette’s Syndrome Study Group 2002).
Guanfacine or clonidine may be useful in the management of aggressive behavior, impulsivity, oppositional behavior, self-injurious behavior, and agitation in a variety of conditions, including posttraumatic stress disorder and intellectual disability. Extended-release guanfacine has been shown to decrease symptoms of inattention and hyperactivity/impulsivity in children with ASD (Scahill et al. 2015).
Initiation and Ongoing Treatment
Before guanfacine or clonidine is initiated, a cardiovascular history and a physical examination (including blood pressure and pulse rate) are needed. An ECG may be advisable for preschool children, although the American Heart Association guidelines do not mandate ECG monitoring with these drugs (Vetter et al. 2008). If there is a family history of diabetes or clinical symptoms in the patient, a fasting blood glucose may be indicated. These drugs are contraindicated in patients with a history of syncope, bradycardia, or heart block.
One mg of guanfacine is equivalent to 0.1 mg of clonidine. One of these α-adrenergic agonists can be switched to the other by a gradual cross-taper.
Immediate-release guanfacine is started at 0.5 mg/day, with the dosage gradually increased by 0.5 mg every 3–4 days to a maximum daily dose of 4 mg in three divided doses. Extended-release guanfacine is given once a day, titrated from 1 mg/day, with the dosage increased by 1 mg/day each week to a maximum of 4 mg/day. The target dose is 0.05–0.08 mg/kg/day. The FDA approved maximum dose is 4 mg/day or 0.12 mg/kg/day, whichever is less, although adolescents may require up to 6 mg/day (Wilens et al. 2015). The extended-release form is not mg-to-mg equivalent with immediate-release guanfacine. Discontinuation should be by gradual taper (1 mg every 3–7 days).
Immediate-release clonidine is started at a low dose of 0.05 mg/day at bedtime and titrated gradually over 2–4 weeks to 0.15–0.40 mg/day (0.003–0.01 mg/kg/day) in four divided doses (for immediate release), in order to minimize sedation. The medication should be continued for 2–8 weeks at the maximal dose before determining effectiveness (Pliszka et al. 2000). Clonidine is available in a transdermal skin patch that may improve ability to administer medication as prescribed and may reduce effects on blood pressure by smoothing blood levels. The transdermal form is effective for only 4–5 days in children, compared with 7 days in adults (Hunt 1987). Clonidine extended-release (Kapvay) is started at 0.1 mg/day in two divided doses and the dosage increased by 0.1 mg/day each week to a target of 0.4 mg/day, divided into every-12-hour doses. Doses of immediate- and extended-release clonidine are not mg-for-mg equivalent. Any form of clonidine should be discontinued by gradual tapering to avoid withdrawal tachycardia, hypertension, headache, and nausea.
Risks and Side Effects
The extended-release forms must not be crushed, chewed, or broken.
Guanfacine has fewer and milder side effects (primarily irritability, sedation, headache, and abdominal pain) and less rebound than clonidine. Surprisingly, guanfacine used for the treatment of ADHD in children has little effect on pulse or blood pressure, although syncope has been reported rarely in patients with ADHD or Tourette’s disorder.
The most troublesome side effect of clonidine is somnolence, which is most prominent early in treatment and generally decreases after 4–8 weeks. Patients may experience daily rebound hyperactivity and irritability or insomnia when the immediate-release form is used. The extended-release formulation of clonidine may produce less somnolence and rebound. The most serious potential adverse effects of clonidine are cardiovascular and include hypotension, bradycardia, rebound tachycardia and hypertension, and asymptomatic ECG conduction changes. Clonidine may worsen symptoms of dysphoria. Less common side effects include headache, abdominal pain, irritability, nightmares, rash, and decreased glucose tolerance. The skin patch often causes a local hypersensitivity reaction and may produce allergic sensitization.
In the past, anecdotal reports of sudden death in children who at one time had been taking both methylphenidate and clonidine generated some concern, but evidence linking the drugs to the deaths is tenuous (Wilens et al. 1999). Pending further clarification, extra caution has been advised when treating preschoolers or children with cardiac disease, when combining clonidine with additional medications, or when adherence to consistent medication administration is uncertain.
Medications called antidepressants that are commonly used for the treatment of a variety of disorders in children and adolescents are listed in Table 17–4. Evidence related to their pediatric use is growing, although more research is needed, particularly studies comparing drugs of the same class. Interestingly, despite the name of the drug class, in children and adolescents, evidence is stronger for benefit in anxiety disorders than in depression. The safest and most commonly used class of antidepressants is the selective serotonin reuptake inhibitors (SSRIs). Antidepressants with other mechanisms of action are collectively referred to as atypical antidepressants. Because of problematic adverse effects and potential lethality in overdose, tricyclic antidepressants (TCAs) are very rarely used in children, with the exception of clomipramine for treatment-resistant obsessive-compulsive disorder (OCD).
Typicala daily dose < 18 years
Indications supported by RCT < 18 years
Selective serotonin reuptake inhibitors
OCD, SM, SoAD
GAD, OCD, SAD, SoAD
Depression, OCD, SoAD
Depression, GAD, OCD, SAD, SoAD
Wellbutrin (IR, SR)
150–300 mg children
150–450 mg adolescents
Effexor (IR, XR)
Depression, GAD, SoAD
Note. ADHD = attention-deficit/hyperactivity disorder; GAD = generalized anxiety disorder; IR = immediate release; OCD = obsessive-compulsive disorder; RCT = randomized controlled trial; SAD = separation anxiety disorder; SM = selective mutism; SoAD = social anxiety disorder; SR = sustained release; XL = extended release; XR = extended release. aStarting doses are lower. Within this range, children require lower doses than do adolescents. bDivided doses.
Mechanisms of Action
Selective serotonin reuptake inhibitors, as the name implies, block the presynaptic reuptake of serotonin. Chronic use of SSRIs also results in the down-regulation of serotonin receptors, which then modulates serotonergic transmission. The SSRIs differ in how they affect other neurotransmitter receptors and therefore the strength of serotonin reuptake selectivity.
The atypical antidepressants vary in mechanism of action. Bupropion (Wellbutrin) has a novel chemical structure and inhibits norepinephrine and dopamine reuptake. Venlafaxine (Effexor), and its derivative, desvenlafaxine (Pristiq), inhibit serotonin and norepinephrine reuptake and weakly inhibit dopamine uptake. Duloxetine (Cymbalta) is a selective serotonin-norepinephrine reuptake inhibitor with weak dopaminergic reuptake inhibition. Mirtazapine (Remeron) is unique in its noradrenergic and specific serotonergic mechanisms. Trazodone (Oleptro) has a distinctive mechanism of action as both a serotonin reuptake inhibitor and a mixed serotonergic agonist and antagonist.
Indications and Efficacy
SSRIs are the first-line medication treatment for youth with depression. In RCTs, the response rate for SSRIs is 50%–60%, versus 30%–50% for placebo. The high “placebo response” (more accurately described as nonspecific positive response to being in a clinical trial) has made it difficult to demonstrate superiority of antidepressants to placebo in pediatric depression.
The FDA has approved pediatric indications in major depressive disorder (MDD) for fluoxetine (age 8 years and older) and escitalopram (age 12 years and older). Fluoxetine has the best-documented clinical trial efficacy. Two RCTs of escitalopram yielded positive responses in adolescents only (thus resulting in the FDA indication only for older children) (Emslie et al. 2009; Wagner et al. 2006). Escitalopram was shown to be superior to placebo in the continuation treatment of depression (Findling et al. 2013). Paroxetine is rarely used, because of mixed evidence on efficacy and concern about side effects in youth. The results of two studies of sertraline (reported as one merged study) (Wagner et al. 2003) support efficacy in depressed youth. Data from citalopram trials are inconsistent. Fluvoxamine has not been studied in pediatric depression. Case reports suggest that duloxetine may be beneficial in adolescents with pain and depression (Meighen 2007). TCAs have not been shown to be efficacious in pediatric depression.
Research evidence is lacking with regard to comparative effectiveness among the SSRIs, so choice is based on target symptoms, comorbidity, side effects, half-life, interactions with other medications, positive familial experience with or response to the agent, patient/family preference, cost, insurance formulary, or a trial of the drug in the particular patient. For example, fluoxetine’s long half-life may be an advantage if missed doses are likely, but side effects or drug–drug interactions can persist for weeks after fluoxetine is discontinued, and fine-tuning of the dose may be difficult. If a patient does not respond well to the first one chosen, a trial with another SSRI is typically indicated. Treatment of Resistant Depression in Adolescents (TORDIA) found that in teens with MDD or dysthymia who had failed to respond to an adequate trial of an SSRI, a medication change with added cognitive-behavioral therapy (CBT) was more effective than switching medications alone. Switching to fluoxetine or citalopram was as effective as switching to venlafaxine, and venlafaxine produced more side effects (Brent et al. 2008).
Multiple SSRIs, including fluoxetine, fluvoxamine, paroxetine, and sertraline, have been shown in RCTs to be efficacious in the treatment of OCD in youth. Drugs with FDA indications for OCD in children and adolescents are sertraline (age 6 years and older), fluoxetine (7 years and older), fluvoxamine (8 years and older), and the TCA clomipramine (10 years and older), which is a third-line choice due to safety and tolerability issues. Clomipramine is generally reserved for use as an augmentation strategy to an SSRI, and is less commonly used for this purpose than are atypical antipsychotics.
The first-choice medication for treating pediatric anxiety disorders is an SSRI, although medication is considered to be only one component of a multimodal treatment plan and is recommended only when symptoms are moderate to severe with significant functional impairment. In a large RCT of 7- to 17-year-olds with separation anxiety disorder (SAD), generalized anxiety disorder (GAD), or social anxiety disorder, combination treatment (CBT plus sertraline) was more effective than either monotherapy or placebo, and each active treatment (CBT or sertraline) as monotherapy was significantly superior to placebo (Walkup et al. 2008). Consensus among experts is that there is no evidence that one SSRI is more effective than another for these disorders. Fluoxetine was shown to be effective for youth with GAD and social anxiety disorder, but not for youth with SAD (Birmaher et al. 2003). The efficacy of fluoxetine in selective mutism is suggested by one small RCT (although most subjects had remaining symptoms) (Black and Uhde 1994). A multisite RCT demonstrated efficacy of fluvoxamine in children and adolescents with social anxiety disorder, SAD, or GAD (Walkup et al. 2001). In a large study of youth with SAD, GAD, or social anxiety disorder, sertraline was superior to placebo (Walkup et al. 2008). Sertraline was also efficacious in a small RCT for GAD in children and adolescents (Rynn et al. 2001). Wagner et al. (2004) found youth with social anxiety disorder to respond favorably to paroxetine. Despite the lack of research, SSRIs are sometimes used to treat panic disorder in youth, based on extrapolation from use in adults.
There is also a growing body of evidence to support the use of the atypical antidepressants in pediatric anxiety disorders. A large RCT in youth with social anxiety disorder found venlafaxine extended release (ER) to be superior in efficacy to placebo (March et al. 2007). Venlafaxine ER also has shown efficacy in GAD (Rynn et al. 2007). Duloxetine demonstrated efficacy in pediatric GAD (Strawn et al. 2015); this resulted in FDA labeling for pediatric GAD. Duloxetine is the only medication that has FDA labeling for any pediatric anxiety disorder (excluding OCD, formerly categorized as an anxiety disorder). A very small case series of youth with chronic and cyclical vomiting showed a reduction in vomiting with use of mirtazapine (Coskun and Alyanak 2011).
Bupropion has been shown to be effective in both children and adults with ADHD, with an effect size equivalent to that of methylphenidate (Barrickman et al. 1995).
Several TCAs have demonstrated efficacy in the treatment of ADHD. Given that a variety of safer alternative drugs (stimulants in many formulations, atomoxetine, guanfacine, clonidine) have demonstrated efficacy in ADHD, a TCA (most often nortriptyline) would be a fourth- or fifth-line choice for the treatment of ADHD, used only if other drugs are ineffective or not tolerated.
Autism Spectrum Disorder
There is some evidence that the SSRIs such as fluoxetine (Hollander et al. 2005) may be useful in reducing aggression, temper problems, self-injurious behavior, and stereotyped behavior seen in patients with ASD, although other studies have negative results. An RCT of citalopram failed to show reduction in repetitive behaviors in children with ASD (King et al. 2009). The atypical antipsychotics are more commonly used to treat severe irritability or aggression in youth with ASD.
Enuresis can be addressed by the child’s primary care physician or in a multimodal treatment program that addresses any medical contributing factors and implements behavioral strategies. Imipramine has been replaced by desmopressin (DDAVP) as the drug of first choice in the treatment of enuresis.
Initiation and Ongoing Treatment
Typical therapeutic daily dose ranges are listed in Table 17–4. The general principle “start low and go slow” applies. In medication trials for anxiety disorders, often relatively high doses were used to achieve symptom reduction. Thus, for anxiety disorders, the principle can be expanded to “start low, go slow, and aim high.” Many of the medications are metabolized in the liver; thus, patients with hepatic insufficiency may require additional monitoring when antidepressants are prescribed. An especially careful assessment of all prescribed and over-the-counter (OTC) medications needs to be completed prior to treatment initiation, because many of the antidepressants have drug–drug interactions.
SSRIs do not require medical assessment prior to or during treatment other than pregnancy testing, when indicated. Particularly in patients with anxiety disorders, it is advisable to use very low initial doses and slow titration in order to minimize side effects that could lead to refusal to take medication. A useful starting strategy is to prescribe the lowest dose pill available, or half a pill, if scored. The liquid formulation of fluoxetine may be used for very gradual titration. Fluoxetine is sometimes prescribed on an every-other-day basis because it has a long half-life and active metabolites. A very long-acting form (Prozac Weekly) is available for patients who may be nonadherent with daily medication, once a therapeutic dose is found and tolerability in that patient is established.
Bupropion is available in immediate-, sustained-, and extended-release forms. The immediate-release formulation may be used to start treatment; conversion to a longer-acting formulation may be done once an adequate dose has been attained. Because of the side effect of increased seizure risk (likely dose-related), bupropion is contraindicated in youth with epilepsy, eating disorders, or other risk factors for seizures. Use of venlafaxine, desvenlafaxine, or duloxetine may result in blood pressure elevation; thus, blood pressure monitoring is necessary. Mirtazapine may cause elevation in liver enzymes and leukopenia; if a child develops flulike symptoms, checking the hepatic enzymes and complete blood count may be indicated.
The goal of treatment should be full remission of symptoms. After a child or adolescent has been asymptomatic for 6–12 months, the clinician may consider slowly tapering the medication. Timing of a discontinuation trial should avoid stressful life events or predictably difficult times such as a new school year. Many factors should be considered in determining the need for maintenance therapy in depression. These factors include the severity of the initial depressive episode (i.e., presence of suicidal thinking, psychosis, or severe functional impairment), number and severity of prior depressive episodes, chronicity, comorbidity, family psychopathology, and presence of support. It is recommended, based on extrapolation from adult data, that youth with multiple depressive episodes continue maintenance medication indefinitely.
Risks and Side Effects
With SSRI use, side effects are mild, typically emerge early in treatment, and resolve over time. Low starting doses and slow, gradual titration can limit the development of adverse effects. Common somatic side effects include headaches, anorexia, weight loss, weight gain, bruxism, nausea, tremors, drowsiness, and vivid or strange dreams. Increased activity levels can occur, perhaps related in part to akathisia. Symptoms of behavioral activation include restlessness, insomnia, social disinhibition, and agitation or aggression. Bipolar switching or manic reaction is a less common but potentially serious adverse effect of any antidepressant and can include changes in mood, sleep, behavior, and impulse control. All antidepressant medications, including SSRIs, have an FDA “black box warning” regarding risk of increased suicidal thoughts and behaviors. Although the increased risk is small, careful monitoring is necessary, especially as medication is started and following dose adjustments. In reported studies, children who reported new or increased suicidal thoughts or behaviors typically had preexisting risk factors. Some patients develop apathy or an amotivational syndrome after weeks or months of SSRI treatment, consisting of emotional blunting, decreased motivation, passivity, and loss of interest and energy. This can superficially resemble sedation or worsening of depression, and parents and patients may not identify the cause. A small decrease in dose may be helpful. Pediatric clinicians are not used to considering sexual side effects, but the sexual dysfunction commonly associated with SSRIs (i.e., decreased libido, anorgasmia, and erectile dysfunction) may be distressing for adolescents. Bleeding or bruising is very rare but possible (Lake et al. 2000).
Because SSRIs inhibit the cytochrome P450 isoenzymes, there is considerable potential for adverse drug interactions. Serotonin syndrome is a very rare, potentially fatal reaction to the addition or increase in dose of a serotonergic agent (most often in combination with another prescribed or over-the-counter medication or an herbal remedy) characterized by extreme restlessness, agitation, fever, myoclonic jerking movements, severe hyperreflexia, clonus, fasciculation, nausea, vomiting, and diarrhea. Seizures, severe hypotension, ventricular tachycardia, and disseminated intravascular coagulation can occur in severe cases.
Although the margin of safety of SSRIs is greater than for other antidepressants, deaths have been reported following large ingestions of SSRIs.
Withdrawal symptoms, including dizziness, headache, chills, tiredness, nausea, vomiting, and diarrhea, may occur after sudden discontinuation of an SSRI. This is less of a problem with fluoxetine, because of its very long half-life, and is more likely with paroxetine and fluvoxamine. Mild withdrawal symptoms can occur even with missed doses in some youth. Citalopram and escitalopram have few significant drug interactions because of their weak hepatic cytochrome P450 enzyme inhibition, and they are good options in patients who are on multiple medications. Fluoxetine’s long half-life reduces the risk of discontinuation withdrawal symptoms, but the extensive washout period required complicates a subsequent medication trial, if switching drugs is necessary. Among SSRIs, fluvoxamine likely has the lowest incidence of sexual side effects, but sleep disturbances can be a problem. Paroxetine requires exact adherence and slow taper if discontinued, because of its shorter half-life and increased risk for withdrawal symptoms.
The atypical antidepressants are also fairly well tolerated. They have the same general side-effect profile as do SSRIs, though they do not cause sexual side effects (except trazodone). Each atypical antidepressant may have distinctive side effects. Bupropion is associated with an increased seizure risk. Blood pressure elevations can be seen with venlafaxine, desvenlafaxine, and duloxetine. Trazodone is associated with the potentially serious side effect of priapism (i.e., prolonged painful erection of the penis). The atypical antidepressants, notably venlafaxine, should also be tapered slowly to avoid discontinuation symptoms. The FDA warning regarding risk of increased suicidal thinking and behavior also applies to the atypical antidepressants.
Common adverse effects of bupropion include irritability, insomnia, anorexia, and tic exacerbations. Less commonly, edema, rashes, and nocturia have been reported. Increased seizure risk was discussed above.
Lithium carbonate, a naturally occurring salt, is the oldest mood stabilizer.
Indications and Efficacy
Lithium has an FDA indication for the treatment of mania in patients 12 years and older. The Collaborative Lithium Trials (CoLT) provide the most recent data on lithium’s efficacy and safety in pediatric mania (Findling et al. 2011, 2015). Lithium may be considered in the treatment of bipolar affective disorder, mixed or manic, and for prophylaxis of bipolar disorder in children and adolescents who have a documented history of recurrent episodes. It is effective for acute stabilization in many adolescents with mania, although adjunctive antipsychotic medication is often required. Children and adolescents with mania tend to have a less dramatic response to lithium than do adults, and mania with preadolescent onset tends to have a poorer response to lithium than does adolescent-onset mania (Strober et al. 1988). The Treatment of Early Age Mania (TEAM) study found risperidone to be more efficacious than lithium (Geller et al. 2012), although the side-effect profile in long-term use of risperidone in youth is concerning.
Several small studies of youth with severe aggression, especially with impulsivity and explosive affect, showed lithium to be effective in reducing aggression, hostility, and tantrums. Lithium may be useful in intellectually disabled youth with severe aggression directed toward themselves or others.
Initiation and Ongoing Treatment
Lithium should not be prescribed unless the family is willing and able to consistently administer multiple daily doses and obtain lithium blood levels. In addition to the usual medical history and physical examination, complete blood count (CBC) with differential, electrolytes, thyroid function studies, calcium, blood urea nitrogen (BUN), and creatinine should be determined before lithium is started. A urinalysis and ECG also should be obtained. Girls of reproductive age should have a pregnancy test.
Lithium carbonate is the most commonly used formulation because of its reliable serum levels and reasonable cost. Immediate-release (lithium carbonate, 300 mg; Eskalith, 300 mg), controlled-release (Lithobid, 300 mg; Eskalith CR, 450 mg), and elixir (lithium citrate, 300 mg/5 mL) formulations are available. Because the slow-release formulations are not cleared as rapidly as regular lithium, twice-daily administration is sufficient, and more steady blood levels are achieved.
No systematic studies have been done in children to compare the efficacy and side effects of different dosing schedules. In prepubertal children, traditional practice is to start lithium at 300 mg/day for several weeks and slowly increase the dosage to 900 mg/day in divided doses. Usual child and adolescent therapeutic doses range from 900 to 1,200 mg/day, although total daily doses of up to 2,000 mg may be required. Therapeutic levels can be safely attained in a much shorter time by using a weight-based dosing guide (Weller et al. 1986). Also, published nomograms can be used to calculate doses based on blood levels after single test doses (Alessi et al. 1994; Geller and Fetner 1989). The higher glomerular filtration rate in children compared with adults usually requires a higher milligram-per-kilogram dose before puberty. A weight-based pediatric titration strategy starts with 15–20 mg/kg/day in two or three divided doses. The total daily dose is increased by 300 mg every 4–5 days, based on clinical response, side effects, and serum levels. The titration strategy recommended based on the CoLT trial is for patients weighing at least 30 kg to begin treatment with lithium at a daily dose of 300 mg tid, followed by 300-mg weekly increases (an additional 300-mg increase during the first week), with monitoring of lithium levels and positive and adverse effects. The maximum allowable lithium level is 1.4 mEq/L (Findling et al. 2011).
Lithium’s half-life (approximately 18 hours) could permit once-a-day dosing in adolescents. However, because children have more rapid lithium clearance than do adults, multiple divided doses may be necessary to maintain therapeutic levels. In addition, some patients have gastrointestinal distress when they take the entire daily dose at bedtime. Lithium is therefore usually given two or three times a day with meals, even though divided doses have the disadvantage of potentially decreasing adherence to the prescribed regimen.
Therapeutic levels in children are generally similar to those in adults: 0.6–1.2 mEq/L. Under usual circumstances, levels should not exceed 1.4 mEq/L. Peak serum levels will occur within 1–2 hours after ingestion. Steady-state serum levels are achieved after 5 days. To measure the serum level, blood should be drawn 8–12 hours after the last evening dose and before the first morning dose. Levels are obtained once or twice weekly during dose adjustment; levels are checked every 3–6 months after a stable dose has been reached. Clinical status may suggest more frequent checks of the lithium level.
The clinician should periodically check BUN and creatinine or creatinine clearance because lithium may alter kidney function. A thyroid-stimulating hormone (TSH) test should be obtained every 4–6 months. The clinician must be alert to possible clinical signs of hypothyroidism that could be mistaken for fatigue or a retarded depression.
No studies have addressed the issue of how long to continue lithium. A naturalistic study (Strober et al. 1990) found that adolescents who discontinued lithium were three times more likely to relapse compared with those who continued taking the medication. Most relapses occurred within the first year after cessation of treatment. Once lithium is started, it seems advisable to continue administration for at least 6 months, and preferably a year. If studies of lithium termination in adults are applicable to children, an even longer duration of treatment might be considered. Experience in adult patients with worsening of cycling and decreased response to treatment following intermittent lithium use suggests special caution regarding discontinuation of mood stabilizers. Lithium should be discontinued by gradual tapering. The clinician should closely follow up with the patient after lithium is discontinued and should monitor the patient for signs of relapse so that episodes can be treated early.
Risks and Side Effects
Lithium is well tolerated by many children and adolescents, but younger children are more prone to side effects, especially at higher lithium doses and serum levels. The most common side effects in children (i.e., tremor, weight gain, headache, nausea, diarrhea) rarely require discontinuation of lithium. Polydipsia and polyuria may cause enuresis and prevent attainment of a therapeutic level. Lithium may produce goiter and/or hypothyroidism, which may have more significant consequences in developing children than in adults. Lithium effects on blood glucose level are controversial, but reactive hypoglycemia is possible. Acne may be induced or aggravated. Hypokalemia is a very rare side effect that can be managed by dietary supplementation (e.g., two bananas, two large carrots, two cups of skim milk, half of a honeydew melon, or an avocado daily), which is preferable to taking potassium tablets that taste bad and can further irritate the gastrointestinal tract. Because of its teratogenic potential (highest risk in first trimester), lithium is relatively contraindicated in sexually active girls.
Toxicity is closely related to serum levels, and the therapeutic margin is narrow. The patient and the family should be told to call the doctor immediately if the patient develops a febrile or gastrointestinal illness, uses rigorous dieting to lose weight, or takes diuretics or nonsteroidal anti-inflammatory agents (often taken by adolescent girls to relieve menstrual distress). Lithium should be stopped while a patient has fever, vomiting, or diarrhea. Vigorous exercise in hot weather can lead to lithium toxicity, and parents should be cautioned to make sure the patient drinks enough water. Erratic consumption of large amounts of salty snack foods may cause wide fluctuations in lithium blood levels. Caffeine may decrease the lithium level.
“Antipsychotics” are used in children and adolescents to treat both psychotic and severe nonpsychotic mental and behavioral disorders. These medications are divided into two groups: the first-generation antipsychotics (FGAs), or “typicals” (also called “neuroleptics”), and the second-generation antipsychotics (SGAs), or “atypicals.” While all antipsychotics block dopamine D2 receptors, the two groups differ in the extent to which they affect dopamine pathways implicated in psychosis, mania, tics, and aggression, as well as dopamine-related adverse effects on motor symptoms, prolactin secretion, and cognition. Antipsychotics also bind to varying degrees to serotonergic, histaminic, muscarinic, and α-adrenergic receptors, determining the therapeutic and side-effect profile of each particular drug.
Indications, Efficacy, and Use
Atypical antipsychotics are generally preferred for most pediatric indications because of their lower risk of potentially irreversible side effects such as tardive dyskinesia. Table 17–5 outlines the current FDA indications for the SGAs and selected FGAs that have grandfathered indications extrapolated from adult data.
Typical pediatric starting dose, mg
Typical pediatric dose range, mg
Pediatric indications in the United States
↑ Lipids, risk of diabetes
Irritability associated with ASD, ages 6–17 years
Bipolar I disorder, manic or mixed, ages 10–17 years (acute monotherapy, adjunctive with lithium or valproate, maintenance)
Schizophrenia, ages 13–17 years (acute, maintenance)
Tourette’s disorder, ages 6–17 years
Bipolar I disorder, manic or mixed, ages 10–17 years (acute)
NA (adults 1 mg bid)
BD depression, autism: 20
Schizophrenia, ages 13–17 years
Bipolar I disorder, manic or mixed, ages 13–17 years (acute)
Schizophrenia, ages 13–17 years (acute)
Schizophrenia, ages 12–17 years (acute)
Bipolar I disorder, manic, ages 10–17 years (acute monotherapy and adjunctive with lithium or valproate)
Schizophrenia, ages 13–17 years (acute)
Irritability associated with ASD, ages 5–17 years
Bipolar I disorder, manic or mixed, ages 10–17 years (acute)
Schizophrenia, ages 13–17 years (acute)
Severe behavioral problems and short-term treatment of hyperactive children with accompanying conduct disorders, ages 1–12 yearse
Psychotic disorders, ages 3–17 yearse
Nonpsychotic behavior disorders and Tourette’s disorder , ages 3–17 yearse
Schizophrenia, ages 12–17 yearse
Note. Much of these data are extrapolated from adult populations, and the information may change as more pediatric data become available. 0 = none; 0/+ = minimal; + = mild; ++ = moderate; +++ = severe. ARI = aripiprazole; ASD = autism spectrum disorder; ASE = asenapine; BD = bipolar disorder; CHLOR = chlorpromazine; CLO = clozapine; EPS = extrapyramidal symptoms; HAL = haloperidol; ILO = iloperidone; LUR = lurasidone; OLA = olanzapine; PAL = paliperidone; PER = perphenazine; QUE = quetiapine; RIS = risperidone; SCZ = schizophrenia; ZIP = ziprasidone. aRelevance for development of torsades de pointes not established. bSecond-generation antipsychotics have low risk of causing tardive dyskinesia, except for CLO, which has none. The first-generation antipsychotics in this table all have moderate risk of causing tardive dyskinesia. cAripiprazole may reduce prolactin levels. dLess at higher doses than at lower doses (potential threshold ≥ 300 mg/day). eExtrapolated from adults.
Source. Adapted from Correll 2016.
Several typical and atypical antipsychotics have modest efficacy in children and adolescents with schizophrenia. Difference in efficacy among these drugs when used for schizophrenia has not been demonstrated, with the exception of clozapine, which has been shown to benefit patients who have been unresponsive to the other agents. Concerns about the development of tardive dyskinesia with long-term use of the typical antipsychotics and the prominence of negative symptoms in young patients with schizophrenia suggest preference for the atypicals, although these medications also have problematic side effects (see below). RCTs have demonstrated efficacy superior to placebo for agents in both groups of antipsychotics. Improvement in positive symptoms can be seen by the second week of treatment, but improvement in positive symptoms may not plateau for a month or longer, and negative symptoms may continue to improve for 6 months to a year.
Treatment is generally started with an SGA that has an FDA indication for schizophrenia in children and adolescents. (See Table 17–5 for indicated drugs, starting dose, and dose range.) If there is no response to a drug after a 3- to 4-week trial at adequate dose (and assured adherence), another antipsychotic may be tried. Because of its side-effect profile, clozapine is considered only after failed treatment with two or three of the other SGAs, as well as one of the typical neuroleptics.
Full efficacy may not appear for up to 6 months. Positive symptoms (delusions and hallucinations) tend to abate first, with improvements seen by the second week of treatment, plateauing after a month or longer. Improvement in cognitive symptoms (thought disorder) follows, and, very slowly, negative symptoms (apathy, anergy, withdrawal) may improve. To monitor outcome, parent and teacher reports are essential, in addition to self-reports from adolescents. Standardized clinician rating scales, such as the Positive and Negative Syndrome Scale for Schizophrenia, derived from the Children’s Psychiatric Rating Scale, are sensitive to improvement in children (Spencer et al. 1994).
Current practice for adults with schizophrenia is to continue antipsychotic treatment indefinitely; however, firm recommendations regarding children are lacking because of the difficulty in making a definitive diagnosis and the possibility of developmental toxicity. Antipsychotics should be discontinued by gradual tapering to prevent rebound symptoms or relapse.
RCTs have demonstrated efficacy of SGAs (aripiprazole, olanzapine, quetiapine, risperidone, asenapine, and ziprasidone) as monotherapy for mania or mixed episodes in pediatric patients with bipolar disorder. For bipolar depression, combined olanzapine-fluoxetine was superior to placebo, but two studies of quetiapine yielded negative findings (Correll 2016). Monotherapy is infrequently sufficient for full remission, however, and atypical antipsychotics are often used adjunctively with lithium or valproate. The effect size in youth with bipolar mania, compared with that in adults, is larger for the atypicals and smaller for lithium and anticonvulsant mood stabilizers.
Risperidone, olanzapine, and aripiprazole have been shown in RCTs to reduce severe tantrums, irritability, aggression, stereotypies, and self-injurious behavior (but not the core symptoms of autism) in children with ASD. The majority of these studies have assessed risperidone and aripiprazole in trials of 6 weeks to 6 months (Correll 2016). A single RCT of lurasidone for irritability in children ages 6–17 years with ASD did not show superiority over placebo (Loebel et al. 2016). Studies of longer-term maintenance treatment with antipsychotics in ASD suggest that risperidone is superior to placebo for relapse prevention (McCracken et al. 2002; Troost et al. 2005). Aripiprazole use has support for longer-term maintenance in ASD (Findling et al. 2014).
By 2011, as many as 1 in 6 children and adolescents with ASD and/or intellectual disability had been prescribed an SGA (Park et al. 2016). The young age at initiation of treatment in these children, the chronicity of their conditions, and the lack of long-term studies of efficacy and neurodevelopmental and metabolic effects of antipsychotics require that their use be continually reevaluated in each child, with assurance that nonpharmacological interventions to address problematic behaviors are implemented. Antipsychotic medications often increase appetite. If food-seeking behaviors become disruptive or aggressive, especially in nonverbal children, it is critical to evaluate the extent to which the medication may be actually increasing symptoms that it is meant to target.
Efficacy is often difficult to evaluate in Tourette’s disorder because of the natural waxing and waning of symptoms. If tics cause impairment, habit reversal training is effective and is a more benign alternative to medication. Alpha-adrenergic receptor agonists (guanfacine, clonidine) have a more favorable benefit–risk ratio than other classes of medications used for tics. If disabling tics do not respond to these interventions, antipsychotics may be considered. Aripiprazole, haloperidol, pimozide, risperidone, and ziprasidone have been shown to be superior to placebo in RCTs for pediatric Tourette’s disorder (Whittington et al. 2016), although all have significant side effects.
Aggressive Behavior Unresponsive to Other Interventions
Studies of hospitalized severely aggressive children ages 6–12 years have found that several typical neuroleptics are effective compared with placebo in reducing aggression, hostility, negativism, and explosiveness (Correll 2016). The risks of cognitive dulling and tardive dyskinesia place these drugs low on the list of medication options for aggression, however. Chlorpromazine leads to unacceptable sedation at relatively low doses.
Off-label use of atypical antipsychotics in youth with disruptive behavior disorders is increasingly common. Best practice dictates that antipsychotics be used for aggression or impulsivity only when nonpharmacological treatments have been employed, other appropriate medications with more benign profiles (e.g., stimulants, α agonists) have been optimally tried, and any comorbid or underlying disorders are adequately treated. Most RCTs of atypical antipsychotics for disruptive behavior disorders in children and adolescents have evaluated risperidone and found it to be superior to placebo in reducing aggression.
Initiation and Ongoing Treatment
Before an antipsychotic medication is started, a medical history (with special focus on personal and family history of obesity, hypertension, hyperlipidemia, diabetes mellitus, and cardiovascular symptoms or disease) and a physical examination (including blood pressure, pulse, height, weight, and body mass index [BMI]) should be obtained. Initial laboratory studies include CBC with differential, liver functions, fasting glucose, and lipid profile. Counseling regarding nutrition and exercise should be started immediately and refreshed at every visit, if the patient’s clinical condition permits. In addition to verbal discussion and opportunity for questions, published medication information sheets can be used (e.g., Dulcan and Ballard 2015).
Detailed informed consent is especially crucial for clozapine, and monitoring is more extensive (FDA Drug Safety Communication 2015). An ECG should be obtained before starting ziprasidone, clozapine, or pimozide. An EEG is indicated before clozapine treatment because of the potential for EEG abnormalities and seizures.
The clinician should carefully examine each patient for abnormal movements with a scale such as the Abnormal Involuntary Movement Scale (AIMS) at baseline and every 3–6 months thereafter. Especially in children with ASD or Tourette’s disorder, it may be difficult to distinguish medication-induced movements of tardive dyskinesia or withdrawal dyskinesias from those movements characteristic of the disorder itself. The clinician should explain the risk of movement disorders to parents and patients (as appropriate) before starting treatment and regularly as treatment continues.
Dose must be titrated with careful attention to reduction in target symptoms and to side effects. Age, weight, and severity of symptoms do not provide clear dose guidelines. Children generally require higher mg/kg doses than do adults, and divided doses may be preferable in younger children. The half-lives of antipsychotics vary, and the titration schedules differ between those that reach a steady state rapidly (quetiapine, ziprasidone) and those with longer half-lives. Antipsychotics should be maintained at the lowest effective dose. Regular specific queries regarding side effects are required.
As treatment continues, pulse, blood pressure, height, weight, and BMI are followed at 3-month intervals. Blood triglycerides and high-density lipoprotein cholesterol (HDL) and fasting glucose are measured every 6 months. Prolactin is measured only if the patient is symptomatic (true gynecomastia, galactorrhea, breast tenderness, or, in females, amenorrhea). Patients who have significant weight gain in the first 3 months of treatment should have liver function enzymes measured, as fatty liver infiltration may develop.
Risperidone, aripiprazole, and olanzapine are available as a disk that dissolves rapidly in the mouth, a useful formulation when quick drug action is needed or when pill swallowing is difficult or resisted. Risperidone, aripiprazole, and several of the typical neuroleptics are available as a liquid. Risperidone, olanzapine, and paliperidone (and several typical neuroleptics) are available as a long-acting injection. Quetiapine is available in an extended-release form.
If a typical neuroleptic is to be used, one of the higher-potency drugs, such as perphenazine or thiothixene, may be best. The lower-potency compounds (e.g., chlorpromazine) are best avoided for chronic use because of sedation, cognitive dulling, and memory deficits that can interfere with learning.
Risks and Side Effects
Pediatric patients are more prone to side effects from antipsychotic drugs than are adults, and they are at risk for prolonged exposure, including during key developmental stages. Common side effects of antipsychotic medications are summarized in Table 17–5. The most common problematic side effect of the SGAs is immediate and chronic weight gain, often associated, after as short a treatment period as 12 weeks, with clinically significant hyperlipidemia and insulin resistance (Correll et al. 2009). Metabolic syndrome, a common chronic complication of antipsychotic medication, is characterized by abdominal obesity, elevated fasting triglycerides, reduced HDL, elevated blood pressure, and elevated fasting glucose due to insulin resistance leading to type 2 diabetes. Weight gain and associated morbidity are highest with olanzapine, quetiapine, and clozapine. Of the SGAs, lurasidone has the least effect on weight.
Sedation and cognitive dulling may exacerbate the effect of negative symptoms and interfere with school functioning. Priapism has been reported with use of SGAs. Clozapine is associated with blood dyscrasias, seizures, and hypersalivation, as well as very rare myocarditis.
Acute EPS, including dystonic reactions, parkinsonian tremor and rigidity, drooling, and akathisia, are commonly seen with typical neuroleptic treatment and are more prevalent than initially hoped with atypical antipsychotic use. Laryngeal dystonia is potentially fatal. Acute dystonia may be treated with oral or intramuscular diphenhydramine (25 or 50 mg) or benztropine (0.5–2.0 mg). When medication is started in an outpatient, the clinician should instruct a responsible adult to watch for a dystonic reaction and may prescribe diphenhydramine or benztropine to use acutely if needed (or recommend an immediate visit to the local emergency room). Adolescent boys seem to be especially vulnerable to acute dystonic reactions, so prophylactic antiparkinsonian medication may be indicated (benztropine 1–2 mg/day in divided doses). Clinical experience suggests that prepubertal children do not respond well to anticholinergics; therefore, reduction of antipsychotic dose is preferable to adding another drug if EPS appear. Chronic parkinsonian symptoms are often underrecognized by clinicians and may impair performance of age-appropriate activities and lead to resistance to taking medication.
Akathisia may be especially difficult to identify in very young patients or those with limited verbal ability. It may be misinterpreted as anxiety or agitation and mistakenly exacerbated with an increase in antipsychotic dose. Clonazepam, beta-blockers, or mirtazapine may reduce neuroleptic-induced akathisia in adolescents.
Tardive dyskinesia or withdrawal dyskinesias are frequent in children treated with typical neuroleptics. Most withdrawal dyskinesias are transient. Very rarely, potentially irreversible tardive dyskinesia has been documented in children and adolescents after treatment as brief as 5 months. Other withdrawal-emergent symptoms include nausea, vomiting, loss of appetite, diaphoresis, and hyperactivity. Various behavioral withdrawal symptoms may appear up to several weeks after antipsychotic discontinuation and persist for as long as 8 weeks. These must be distinguished from a return of symptoms of the original disorder. Withdrawal dyskinesia has also been reported after risperidone discontinuation.
Neuroleptic malignant syndrome (NMS), a potentially fatal side effect, is manifested by hyperthermia, muscle rigidity, autonomic hyperactivity, and changes in consciousness. It has been reported to be associated with the atypicals, as well. Adolescents may present with serious medical complications or may have NMS without fever. NMS is treated by discontinuation of the antipsychotic and use of aggressive supportive measures. The use of specific medications to treat NMS has not been studied in adolescents, although case reports suggest the use of bromocriptine or dantrolene.
Anticholinergic side effects, such as hypotension, dry mouth, constipation, nasal congestion, blurred vision, and urinary retention, are uncommon but may occur. Children may develop enuresis on antipsychotics. Chlorpromazine increases the risk of sunburn.
Indications and Efficacy
Anticonvulsants are medications that were initially developed for the treatment of epilepsy. Although some anticonvulsants have FDA approval for psychiatric use in adults, none of them has an FDA indication for treatment of psychiatric conditions in children. Despite this, they are often used in clinical practice for treatment of bipolar disorder and severe aggression associated with emotional lability and irritability, with or without evidence of primary neurological findings. The pediatric research literature supporting the safety and efficacy of anticonvulsants is limited, and clinical use of these medications is largely based on extrapolation from adult studies, which may not apply in younger patients. When used for these conditions, the drugs are often called mood stabilizers, a grouping that also includes lithium. Among the anticonvulsants, divalproex sodium has the most robust data supporting its use in children. There are some limited data regarding carbamazepine and lamotrigine, but virtually no empirical data on the pediatric psychiatric use of other anticonvulsants.
Sodium valproate (valproic acid [Depakene]; divalproex sodium [Depakote]) has an FDA indication in adults for the treatment of mania in bipolar disorder. The data supporting the use of divalproex (DVP) for treatment of pediatric bipolar disorder are mixed, with both positive and negative study findings. Efficacy was demonstrated in an NIMH-sponsored RCT that found DVP to be superior to both lithium and placebo in the treatment of youth with bipolar I disorder (Kowatch et al. 2007). However, a subsequent industry-sponsored RCT failed to find divalproex extended-release to be superior to placebo in the treatment of manic or mixed episodes in youth ages 10–17 years (Wagner et al. 2009). Findling and colleagues (2005) found that after stabilization with combination lithium and divalproex treatment, neither monotherapy with divalproex nor lithium monotherapy was sufficiently effective for maintenance therapy.
Generally, studies comparing divalproex with atypical antipsychotics have demonstrated equal or greater efficacy for atypical antipsychotics. A head-to-head randomized study of quetiapine versus divalproex for adolescent mania found quetiapine to be as effective as divalproex with a more rapid onset of action (DelBello et al. 2006), and another RCT found that combination divalproex and quetiapine was more effective than divalproex alone (DelBello et al. 2002). The TEAM multisite RCT found that subjects treated with risperidone had a higher response rate (68.5%) than those treated with lithium (35.6%) or divalproex (24%), but the magnitude of this effect was influenced by site-related characteristics and the presence of ADHD (Geller et al. 2012; Vitiello et al. 2012). These findings are supported by a randomized trial comparing treatment of pediatric mania with risperidone versus divalproex that found risperidone was associated with more rapid improvement, greater efficacy, and better tolerability (Pavuluri et al. 2010). Another RCT of youth with pediatric bipolar disorder demonstrated greater improvement in manic symptoms in response to risperidone than to divalproex in the youth who had comorbid disruptive behavior disorder (DBD), whereas those without comorbid DBD responded similarly to both medications (West et al. 2011).
Carbamazepine (Carbatrol, Tegretol) is an older anticonvulsant that has demonstrated efficacy in adult mania, but lack of controlled trials and problematic side effects and drug interactions limit its use in pediatric bipolar disorder. Although some evidence supports use of this drug for aggression in conduct disorder, a controlled study did not find carbamazepine to be more effective than placebo in reducing aggression (Cueva et al. 1996). Carbamazepine has largely been replaced by the atypical antipsychotics for this use.
Lamotrigine (Lamictal) has an FDA indication for use in maintenance treatment in adults with bipolar disorder. Some open-label trials support its use in pediatric bipolar depression, both as monotherapy and as adjunctive therapy (Chang et al. 2006); in acute mania (Biederman et al. 2010); and as maintenance treatment after acute stabilization of a manic or hypomanic episode (Pavuluri et al. 2009). Other anticonvulsants have insufficient pediatric data to recommend their use for psychiatric indications.
Initiation and Ongoing Treatment
Baseline assessments prior to using anticonvulsants include a recent medical history and physical examination, menstrual and sexual history, CBC with differential, liver function tests, and a pregnancy test for postpubertal females, because both valproate and carbamazepine carry risks of teratogenicity. Prior to carbamazepine being used in patients of Asian ancestry, genetic testing is recommended for HLA-B*1502, an allele that increases risk of dangerous skin reactions. CBC with differential, serum levels of the drug, and liver function tests should be checked every 6 months.
For children and adolescents, valproate is typically started at 10–15 mg/kg/day in two or three divided doses and then titrated up gradually according to tolerance and response. Serum valproate levels are optimally measured 12 hours after the last dose. Target serum levels for treating mania are thought to be 50–125 micrograms/mL. Depakote is often the preferred formulation (over Depakene) because it is enteric-coated to reduce gastrointestinal side effects. An extended-release formulation (Depakote ER) permits fewer daily doses. A soft-gel capsule of valproic acid delayed release (Stavzor) is easier to swallow.
Coadministration of guanfacine has been shown to increase plasma levels of valproate (Ambrosini and Sheikh 1998).
Typical starting dose of carbamazepine is 15 mg/kg/day, or for children 100 mg twice a day and for adolescents 100 mg three times a day. Dose may be increased by 100–200 mg/day at weekly intervals. The maximum total daily dose of carbamazepine is 1,000 mg in children and 1,200 mg in adolescents. Usual maintenance total doses are 10–20 mg/kg/day divided into two or three doses per day. There is an extended-release form (Equetro) that permits once-a-day dosing. There are no systematic data on optimal therapeutic levels for treatment of pediatric aggression or bipolar disorder. The commonly used maintenance level is 7–10 micrograms/mL.
The risk of potentially fatal Stevens-Johnson syndrome or toxic epidermal necrolysis is increased when lamotrigine is started at a high dose or titrated too rapidly, especially in children. Educating the patient and family to closely monitor for and to report any rash is essential. If a rash occurs, stopping the medication is advised. Because coadministration with divalproex doubles the concentration of lamotrigine, lamotrigine should be started at an even lower dose and titrated more slowly when the two drugs are used together. Lamotrigine is typically started at 25 mg/day and titrated by 25 mg every 2 weeks to minimize side effects. There are starter packs available for patients who are taking divalproex and lamotrigine concurrently. Carbamazepine and some other anticonvulsants can induce the metabolism of lamotrigine so higher end-doses may be required.
Risks and Side Effects
Data on pediatric safety and tolerability of the anticonvulsants are mostly derived from experience with the use of these drugs in the treatment of epilepsy. Behavioral toxicity is possible with any of these drugs (more likely with carbamazepine and gabapentin). Topiramate may cause cognitive dulling and memory problems. Drug interactions between anticonvulsants and other medications are often problematic.
The FDA has placed a warning on all anticonvulsants of increased risk of suicidal thoughts and behavior.
Common side effects include gastrointestinal symptoms, weight gain, sedation, transient hair loss, and tremor. Rare and serious adverse effects include liver toxicity (primarily in children younger than 3 years who are taking multiple anticonvulsants and usually reversible when the drug is stopped), hyperammonemia, blood dyscrasias, thrombocytopenia, and, very rarely, pancreatitis. Patients should be monitored for nausea, vomiting, easy bruising, lethargy, disorientation, malaise, or persistent abdominal pain (possible pancreatitis). Significant concern has been raised by the connection between valproate use and polycystic ovary syndrome, manifested by obesity, insulin resistance, acne, hirsutism, and irregular or absent menstrual periods (associated with decreased fertility). Female patients should be monitored closely for these symptoms.
Valproate is contraindicated in pregnancy because of increased rates of adverse neurodevelopmental outcomes and neural tube defects in exposed babies. The drug should not be used in females of childbearing potential in the absence of highly reliable use of birth control. Some authorities have suggested that valproate is contraindicated in all females of childbearing potential.
Common side effects include nausea, vomiting, vertigo, decreased coordination, drowsiness, blurred vision, and nystagmus (reversible by lowering dose). Rare adverse events include tics, ataxia, blood dyscrasias such as aplastic anemia and agranulocytosis, decreased thyroid function, hyponatremia, hepatitis, exacerbation of seizures, and life-threatening skin reaction. Adverse behavioral reactions may occur, with mania, extreme irritability, agitation, insomnia, obsessive thinking, hallucinations, delirium, psychosis, paranoia, hyperactivity, and aggression, especially in the first month of treatment. Carbamazepine is contraindicated in females of childbearing potential because of teratogenicity. Because of its metabolism by cytochrome P450 enzyme 3A4, carbamazepine has the potential to interact with many other medications, thereby increasing or decreasing the levels of these medications.
Lamotrigine is associated with Stevens-Johnson syndrome (see “Initiation and Ongoing Treatment” above). Youth under age 16 are at a threefold greater risk of developing Stevens-Johnson syndrome compared with adults. In 2010, the FDA mandated a warning regarding association of lamotrigine with aseptic meningitis.
Melatonin is a naturally occurring neurotransmitter related to serotonin and tryptophan. It influences circadian rhythms in the anterior hypothalamus and is capable of shifting sleep phase. Melatonin is frequently recommended by clinicians or used independently by parents for initial insomnia (delayed sleep onset) in typically developing children or in youth with ADHD, ASD, and neurodevelopmental disabilities, as well as in adolescents with delayed sleep phase syndrome. In a study of currently stimulant-treated children (6–14 years old, 91% boys) with ADHD and initial insomnia (Weiss et al. 2006), the first intervention was sleep hygiene modifications for all. Those with insufficient response (the majority of subjects) entered a double-blind crossover trial of placebo versus 5 mg melatonin given 20 minutes before bedtime. Relative to placebo, melatonin decreased initial insomnia by 16 minutes. Combined sleep hygiene and melatonin resulted in a mean decrease in initial insomnia of 60 minutes. Total sleep time did not change, and improved sleep was not associated with improvement in symptoms of ADHD. Adverse events did not differ from those seen with placebo.
In the treatment of initial insomnia, melatonin is given approximately 30 minutes before desired sleep-onset time. One may start with a dose of 1.5 mg and increase in 1.5-mg increments every 4–5 days as needed, to a dose of 10–15 mg. Lower doses are used to normalize the circadian sleep-wake cycle in delayed sleep phase syndrome. Approximately 0.3 mg is given about 4–5 hours before the current habitual time of falling asleep. The same dose is gradually moved earlier as the falling asleep time is moved earlier (advanced).
Melatonin is not regulated as a drug and is sold as a food or nutritional supplement over the counter, raising concerns about variable potency of preparations and possible impurities. Side effects of melatonin per se are minimal, and melatonin may be used long-term with few, if any, adverse effects (Hoebert et al. 2009).
OMEGA-3 FATTY ACIDS
Omega-3 fatty acids are a subgroup of the long-chain polyunsaturated fatty acids (LC-PUFAs), which reduce inflammation and are implicated in cardiac health, cancer prevention, and neurodevelopment as well as regulation of mood and behavior. Omega-3 fatty acids are essential, meaning that humans cannot synthesize them but can metabolize naturally occurring plant-based α-linolenic acid into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major omega-3 fatty acids. Other sources are seafood, vegetable oils, and nuts.
Omega-3 supplementation has been shown to have a moderate effect size on symptoms in pediatric bipolar depression and ADHD (see Barragán et al. 2017; Bloch and Qawasmi 2011; Fristad et al. 2015). Children with ADHD may have low baseline levels of omega-3 fatty acids and may benefit from supplementation either as monotherapy or adjunctive therapy to stimulants. Studies of omega-3 fatty acids in autism spectrum disorder have not shown benefit.
Current recommended dose is an EPA/DHA combination at about 1,000 mg/day, generally in the form of fish oil. Side effects may include stomach upset, diarrhea, and “fish burps.” Relative contraindications include hepatic impairment and bleeding disorders. As with all supplements, it is best to purchase a product with the U.S. Pharmacopeial Convention (USP)–verified mark that indicates that the product has been voluntarily submitted for verification of federal standards of quality, purity, and potency. This includes exclusion of heavy metals such as mercury, which may accumulate in fish oil.
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