Pediatric Psychopharmacology for Treatment of ADHD, Depression, and Anxiety
Abstract
The pediatric practitioner is often the first point-of-contact for children and adolescents suffering from mental illness. Part of the treatment planning for psychiatric diagnoses includes consideration of medication. Attention-deficit/hyperactivity disorder, one of the most common diagnoses, is very responsive to stimulant medications; for children who are unable to tolerate stimulants or who do not achieve satisfactory symptom management, central α-agonists and atomoxetine are effective and generally well-tolerated alternative or augmentative agents. Depression and anxiety disorders are also frequently encountered in the pediatric office setting. The use of selective serotonin reuptake inhibitors is considered first-line psychopharmacology for depression and anxiety symptoms. Despite concerns for suicidal ideation related to this medication class, the benefits typically outweigh the risks. This review provides basic clinical pharmacology of stimulant and nonstimulant attention-deficit/hyperactivity disorder medications and selective serotonin reuptake inhibitors intended to serve as a primer for the general pediatrician.
- AACAP —
- American Academy of Child and Adolescent Psychiatry
- AAP —
- American Academy of Pediatrics
- ADHD —
- attention-deficit/hyperactivity disorder
- ER —
- extended release
- FDA —
- Food and Drug Administration
- PHQ-9 —
- 9-item Patient Health Questionnaire
- qAM —
- every morning
- qHS —
- at bedtime
- SSRI —
- selective serotonin reuptake inhibitor
Approximately 1 in 5 children in the United States suffers from some form of mental illness, yet 80% of these children do not receive treatment.1,2 It is estimated that 75% of children and adolescents with psychiatric disorders are seen in primary care.3 Furthermore, 7.5% of children and adolescents are prescribed a psychiatric medication, and 85% of psychopharmacologic prescribing is by pediatric providers.4,5 Consistent with the American Academy of Pediatrics’ (AAP’s) mission to enhance pediatric care in a medical home, the AAP charges the following: “Pediatric primary care providers have unique opportunities and a growing sense of responsibility to prevent and address mental health and substance abuse problems in the medical home.”6
The purpose of this review article is to empower primary care pediatricians as basic psychopharmacologists for the common mental health diagnoses of attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety. Mental health care involves an array of interventions, including psychological education, and, contingent on the needs of the child, neuropsychological testing to assess for learning and other comorbid disorders, school accommodations, and psychotherapy. These treatment modalities are important aspects of care but are outside the scope of this article.
ADHD Medications
Case Vignette
Joey, a 6-year-old, 20-kg boy, presents to his pediatrician, Dr Smith, with complaints of significant hyperactivity, impulsivity, and defiance that are problematic in the classroom and at home. Presentation in the office and parent and teacher Vanderbilt rating scale scores* are consistent with a diagnosis of ADHD, and other medical, psychiatric, and learning issues are ruled out. Dr Smith provides psychological education about ADHD, refers for parent management training, and recommends school accommodations for classroom symptoms. After ensuring no contraindications, he prescribes dexmethylphenidate extended release (ER) (Focalin XR) 5 mg every morning (qAM).
At subsequent weekly or biweekly follow-ups, the dose is titrated to 10, 15, and 20 mg qAM based on parent and teacher Vanderbilt scores demonstrating little or no improvement. At the fourth follow-up, Dr Smith switches to amphetamine/dextroamphetamine ER (Adderall XR) 20 mg, after which parent and teacher report notable improvement in hyperactivity and impulsivity, although Joey experiences appetite suppression. Dr Smith counsels on high-protein and high-calorie nutrition, but Joey’s weight decreases to the point of crossing a weight percentile. The amphetamine/dextroamphetamine ER dose is decreased to 15 mg then to 10 mg over subsequent visits; although Joey’s appetite and weight improve toward baseline, Vanderbilt scores demonstrate return of hyperactivity and impulsivity, although not to the degree of severity of initial presentation. Dr Smith augments amphetamine/dextroamphetamine ER 10 mg qAM with guanfacine ER (Intuniv) 1 mg at bedtime (qHS).
Three weeks later, parent and teacher Vanderbilt scores endorse satisfactory ADHD symptom management, which is maintained through the remainder of the school year, and Joey’s weight gain follows an age-appropriate trajectory.
Stimulants
Indications
ADHD diagnosis and stimulant medication prescription have steadily increased over time.7–9 The AAP and the American Academy of Child and Adolescent Psychiatry (AACAP) practice guidelines endorse stimulant medications, methylphenidate and amphetamine, as first-line treatment10–12 (see Table 1 for effect sizes). Recommendations are robustly evidence based. Specifically, the Multimodal Treatment of ADHD trial showed improvement in inattention, hyperactivity, and impulsivity and amelioration of general disruptive behavior and, to a lesser degree, academic achievement and appropriate peer relations.13–16 Off-label prescription indications for stimulant medications include defiance, aggression, depression, and narcolepsy.17–19
ADHD Medication Effect Size
Prescribing Practice
Before stimulant prescription, the AAP and the American Heart Association recommend careful physical examination and patient and family histories of heart disease, as follows: patient history of palpitations, syncope, or chest pain and family history of sudden death or cardiac disease in children or young adults.20 Any concerning signs or symptoms warrant cardiac workup before beginning medication. The various formulations of methylphenidates and amphetamines are generally considered to be equally efficacious, although a meta-analysis and more recent randomized controlled trial suggest superiority of lisdexamfetamine over methylphenidates.21,22 Amphetamines, however, may have a greater risk of side effects.23–25 The Food and Drug Administration (FDA)–approved minimum age for most stimulants is 6 years, with the exception of immediate-release mixed amphetamine salts and dextroamphetamine, both approved to age 3 years. Despite this FDA age approval, methylphenidate was the medication treatment arm selected for use in the landmark Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study, which influenced current clinical practice in preschool-aged children with ADHD.26 General dosing recommendations favor initiation at the lowest dose and titration as expeditiously as 1-week intervals (see Table 2 for dosing parameters) Long-acting stimulants are generally preferred over short-acting stimulants to minimize dosing frequency. Morning medication should be administered after breakfast. Although some long-acting stimulants claim up to 12 hours of medication effect, some children metabolize the medication more quickly, potentially warranting the addition of a short-acting stimulant dose in the afternoon. The Texas Children’s Medication Algorithm Project for pharmacotherapy of ADHD advises prescription of a stimulant medication titrated to effect. If response is unsatisfactory, it is recommended that the clinician trial the other stimulant class at an equivalent dose (2 mg methylphenidate to 1 mg dexmethylphenidate to 1 mg amphetamine) titrated to effect.27 Of note, it is important for pediatricians to discuss the risks of stimulant recreational abuse and diversion with adolescent patients and their families when initiating stimulant medications (see Table 3 for common and serious side effects).
Stimulant Dosing Parameters
Stimulant Side Effects
Nonstimulant ADHD Medications
Although stimulants are first-line treatment of ADHD based on established robust efficacy, there are various indications for the use of FDA-approved nonstimulant medications for children aged ≥6 years (see Table 1 for effect sizes.) These include failed trials of methylphenidate and amphetamine (secondary to unsatisfactory symptom response at maximum dosage or intolerable side effects), underlying medical conditions lending to greater concern for potential stimulant side effects (including underweight or hypertension), comorbid substance abuse, or family preference. An α-agonist or atomoxetine may be prescribed as monotherapy or, in cases of partial stimulant response, ER clonidine and guanfacine are also FDA-approved as augmentative to stimulant medication.
Indications: Central α2-Agonists
Initially indicated for management of hypertension, the central α2-agonist medications guanfacine and clonidine are now formulated as ERs (Intuniv and Kapvay, respectively). These are FDA-approved for ADHD treatment in the pediatric population down to age 6 years, and efficacy has been corroborated by a recent meta-analysis.28 In addition to reduction in distractibility, hyperactivity, and impulsivity, off-label uses include defiance and, with clonidine, sleep-onset insomnia.29
Prescribing Practice: α2-Agonists
Because of the antihypertensive effects of guanfacine ER and clonidine ER, strict adherence to prescribing instructions is critical; overdosing could lead to dangerous hypotension and inconsistent dosing might lead to rebound hypertension. Because of potential sedation, it is recommended that dosing initially be at bedtime. Efficacy is observed between 1 and 3 weeks after initiation, and dosing titration may be weekly. Clonidine ER is administered twice daily beginning with the first titration step (see Table 4 for dosing parameters.) When resuming α-agonist medication administration after a period off of medication (≥2 days), the dosing should start at the initiation dose and titrated as before. Because abrupt discontinuation of these α-agonists can lead to rebound hypertension, these drugs should be tapered in stepwise intervals weekly until complete discontinuation (see Table 5 for common side effects).
Nonstimulant ADHD Medication Dosing Parameters
Nonstimulant ADHD Medication Side Effects
Atomoxetine
Indications
Atomoxetine (Strattera) is a norepinephrine reuptake inhibitor medication that is also FDA- approved for use in children and adolescents with ADHD down to age 6 years. A recent positive meta-analysis corroborates efficacy; however, studies suggest that atomoxetine is inferior to stimulants and guanfacine ER.30 There is evidence for unique benefit in children with comorbid anxiety. As with the aforementioned ADHD medications, there is some medication benefit for defiance.31
Prescribing Practice
Atomoxetine is titrated in no sooner than 3 days to the target dose (see Table 4 for dosing parameters.) Twice-daily dosing may be associated with a decrease in defiance and less gastrointestinal side effects.32,33 Slower titration is indicated when prescribed concurrently with CYP2D6 inhibitors such as fluoxetine. Medication effect is slower-acting than stimulant and α-agonist medications so families should be advised that it may take 2 to 6 weeks before effects are noticed (see Table 5 for common and serious side effects).
SSRIs
Case Vignette
Emma, a 13-year-old girl, presents to Dr Smith with parent complaints of irritability and withdrawal. Her responses on the 9-item Patient Health Questionnaire† (PHQ-9) screening tool score positive for severe depression, and she describes pervasive and significant mood and neurovegetative symptoms secondary to numerous school and home stressors. After establishing safety as well as screening for bipolar disorder in Emma and her family and other comorbid or confounding conditions, such as substance abuse or trauma, Dr Smith provides psychological education, refers for cognitive behavioral therapy, and discusses initiation of an SSRI. The family agrees to initiate fluoxetine 10 mg daily. One week later, Emma describes mild gastrointestinal distress; Dr Smith recommends symptomatic treatment and continuation of the medication. By week 2, Emma reports resolution of gastrointestinal symptoms and denies any notable positive or negative medication effects. On office follow-up in 4 weeks after medication initiation, Emma’s PHQ-9 reveals very mild improvement in depressive symptoms, and she reports scheduled intake with a therapist in 1 week. Dr Smith titrates fluoxetine to 20 mg daily. Thereafter, monthly office follow-ups reveal little change in Emma’s PHQ-9 scores. The pediatrician titrates fluoxetine by 10 mg at each monthly visit to a maximum dose of 40 mg daily. At follow-up in another month, there is reported mild improvement, but symptoms remain overall moderate so the pediatrician discontinues fluoxetine and initiates escitalopram 10 mg daily. At primary care follow-up, now 4 months since the initiation of psychopharmacologic intervention, Emma reports marked improvement of symptoms (of mild-moderate severity on the PHQ-9). She graduates out of cognitive behavioral therapy and endorses depressive symptom remission in monthly then in every 3-month follow-ups. Ten months later, Emma, her parents, and Dr Smith discuss tapering off of escitalopram over summer break, which she does without difficulty.
Indications
SSRIs are important treatment tools for moderate- severe depression and anxiety disorders. A review of published and unpublished data on SSRI treatment of pediatric depression suggests that the risks and benefits of SSRI use in pediatrics should be carefully considered within the context of each patient.34 However, the published literature supports the AAP and AACAP position statements of SSRI efficacy for pediatric depression and anxiety.35–42 Three of the most significant trials include the Treatment of Adolescents with Depression Study, the Pediatric Obsessive Compulsive Disorder Treatment Study, and the Child/Adolescent Anxiety Multimodal Study; these are multisite, placebo-controlled studies that concluded that combination SSRI and psychotherapy is superior to either alone.43–46 Only a few medications are FDA-approved for use in the pediatric population, so that much of the psychopharmacologic prescribing for pediatric depression and all of the prescribing for non–obsessive-compulsive disorder anxiety are considered off-label. Although most SSRIs are considered equivalent, paroxetine is disfavored in the pediatric population because of its efficacy and side-effect profile47–49 Research does not support the use of SSRIs as first-line treatment of symptoms of posttraumatic stress disorder, although, in practice, they are commonly used as an adjunctive therapy.50,51 Despite the conflicting adult literature and an even smaller pediatric evidence base, some clinicians have found anecdotal success with the use of SSRIs to target core eating disorder symptoms of anorexia or bulimia nervosa.52
Prescribing Practice
Specific dosing for SSRIs for depression and anxiety can be found in Table 6. Management algorithms for pediatric depression and anxiety exist to further guide providers.41,42,53,54 When initiating SSRI treatment, early effects may be seen at 1 to 2 weeks, but patients should be advised that efficacy may not be seen for 4 to 8 weeks. Follow-up with the patient in the office or via telephone should be scheduled at 1 and 2 weeks after starting the medication; titration may be made at 3- to 4-week intervals to the effective dose as tolerated or to a maximum dosage. If a patient experiences absent or partial response with the maximum dosage of first SSRI, the pediatrician should discontinue and initiate a different SSRI.40,55 Failure of a second SSRI at the maximum tolerated or recommended dose constitutes treatment nonresponse to first-line medication and warrants referral to a child psychiatrist. Once remission has been achieved, patients should be monitored every 3 months, and the medication should be continued for at least 6 to 12 months of stability.53,54 When discontinuing the medication, the clinician should slowly taper over a minimum of 1 to 2 months.56,57 Abrupt discontinuation may cause flulike symptoms including agitation, dizziness, feeling “spaced out,” lightheadedness, drowsiness, poor concentration, nausea, headache, and fatigue. These effects can be reversed by resuming the preceding SSRI dose and tapering at a more gradual rate57 (see Table 7 for common SSRI side effects).
SSRI Dosing Parameters
SSRI Side Effects
Safety Risk
After the FDA and UK Medicine Healthcare Products Regulatory Agency released warnings about increased suicidal thoughts and suicidal behaviors among children taking antidepressants, the use of these medications decreased worldwide.58,59 The literature calculates the risk of suicidality in children and adolescents taking an SSRI to be low: 1% to 2% of children experience the emergence of suicidal thoughts and behaviors but not completed suicides.60,61 The highest risk is seen during the first 9 days of treatment and with higher than usual starting doses.61–63 There does not appear to be a significant difference between the various antidepressants despite historical data incriminating paroxetine.64,65 The nature of the association between SSRI use and suicidality is unclear. Pediatricians need to be vigilant of the possibility of increased suicidality among patients for whom they are prescribing SSRIs; however, concerns for suicidal ideation are outweighed by the positive, protective effects of an overall decrease in the burden of disease morbidity and suicide mortality. Informed consent should include the discussion of the relative risk of increased suicidal thinking with antidepressant medications versus the risk of suicide without psychopharmacologic treatment. Consent also includes discussion of the mutually agreed upon threshold for referral to a psychiatric specialist, such as worsening safety concerns, adverse medication reactions that include emergence of mania or psychosis, and lack of response to first-line treatments (see Table 8 for comparison of benefit to suicidality risk61).
SSRI Benefit to Suicidal Risk Comparison
Conclusions
The management of the common diagnoses of ADHD, depression, and anxiety, by way of psychological education, psychotherapy referral, basic psychopharmacology, and appropriate child psychiatry referral, is within the scope of general pediatric practice. Indications for referral include symptoms refractory to first-line treatment, psychotherapy, and aforementioned medications (whether secondary to limiting adverse side effects or to lack of optimal response to maximum dosage) or severe symptoms, including significant and ongoing suicidal ideation or attempt or symptoms of mania or psychosis. Clinicians are encouraged to develop a practical management algorithm within their practice that includes appropriate referral resources and comfort with the use of stimulants and nonstimulants in treatment of ADHD and of the use of SSRIs for depression and anxiety. The reader is directed to AAP and AACAP practice guidelines for further direction.41,42,53,54
Acknowledgments
We thank Drs Rachel Moon, MD, and Adelaide Robb, MD, for their mentorship and insight in the development of this manuscript.
Footnotes
- Accepted February 26, 2015.
- Address correspondence to Kristine Schmitz, MD, General and Community Pediatrics, Children’s National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010. E-mail: kschmitz{at}childrensnational.org
Drs Southammakosane and Schmitz conceptualized the manuscript, drafted the initial manuscript, and reviewed and revised the manuscript. Both authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
↵* The Vanderbilt ADHD Rating Scale is widely available, including at http://www.chadd.org/.
↵† The 9-item Patient Health Questionnaire is widely available, including at http://PHQscreeners.com.
References
- Copyright © 2015 by the American Academy of Pediatrics
