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Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications

Attention deficit hyperactivity disorder in children and adolescents: Treatment with medications
Literature review current through: May 2024.
This topic last updated: Sep 19, 2023.

INTRODUCTION — Attention deficit hyperactivity disorder (ADHD) is a disorder that manifests in childhood with symptoms of hyperactivity, impulsivity, and/or inattention. The symptoms affect cognitive, academic, behavioral, emotional, and social functioning [1].

This topic review focuses on the treatment of ADHD in children and adolescents with medications. The pharmacology of the drugs used to treat ADHD in children and adolescents, the epidemiology, pathogenesis, diagnosis, and prognosis of ADHD in children and adolescents, and ADHD in adults are discussed separately.

(See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents".)

(See "Attention deficit hyperactivity disorder in children and adolescents: Epidemiology and pathogenesis".)

(See "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis".)

(See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis".)

(See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder".)

(See "Attention deficit hyperactivity disorder in adults: Epidemiology, clinical features, assessment, and diagnosis".)

ROLE OF PHARMACOTHERAPY — (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Pharmacotherapy'.)

PREREQUISITES — Certain criteria should be met before pharmacotherapy is initiated (table 1). In addition:

A comprehensive, cardiovascular-focused patient history, family history, and physical examination should be completed. (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder", section on 'Pretreatment clinical evaluation'.)

Screening for risk factors for bipolar disorder (eg, personal or family history of depression or mania) – Stimulant medications and atomoxetine have been associated with the development of mania or mixed episodes. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)

The child's baseline height, weight, blood pressure, and heart rate should be measured.

A pretreatment baseline should be established for common side effects associated with pharmacotherapy for ADHD (eg, appetite, sleep pattern, headaches, abdominal pain). Baseline sleep problems do not appear to predict stimulant-related sleep problems and may actually improve with stimulant therapy [2].

Adolescent patients should be assessed for substance use or abuse [3]. Those with signs and symptoms of substance abuse should undergo evaluation and treatment for addiction before treatment for ADHD (if possible) [4].

Contraindications to specific medications are discussed separately. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents".)

PRETREATMENT EDUCATION — Before initiation of medication for ADHD, it is important for the clinician to schedule a visit specifically to discuss treatment with medications. Topics to be addressed at this visit include [5,6]:

An explanation (to the patient) that the medication is being prescribed by the clinician to help the patient with self-control and ability to focus. Acceptance of the medication by the child/adolescent has been associated with long-term adherence [7].

An explanation of the benefits and potential risks of medication, emphasizing the uncertainty about a causal association between cardiovascular risks (including sudden unexpected death) and stimulant medications for children with cardiac symptoms or a positive family history of heart disease [8]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents" and "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder".)

In the discussion of potential risks, it is important to discuss the common side effects including loss of appetite/excessive weight loss, insomnia, and possibly tics. For males who will be treated with methylphenidate or atomoxetine, it is also important to discuss the signs and symptoms of priapism (which is a rare adverse effect) and the importance of seeking immediate medical attention if priapism occurs [9]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Tics' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Priapism' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects' and "Priapism".)

An explanation of the process and expected length of time (ie, one to three months) involved in determining the best medication, dose, and frequency of administration; this includes (see 'Dose titration' below):

The frequency of follow-up

The information that will be needed at follow-up visits or phone calls

Behaviors that the caregivers should monitor and report

The American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry have developed a medication guide for ADHD to help educate caregivers about the medications used to treat ADHD. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects'.)

CHOICE OF AGENT

General considerations — The choice of the initial medication depends upon a number of factors, including (table 2) [3,10,11]:

The duration of desired coverage (completion of homework or driving may require coverage into the evening)

The ability of the child to swallow pills or capsules

The time of day when the target symptoms occur

The desire to avoid administration at school

Coexisting tic disorder (use of alpha-2 adrenergic agonists may be warranted)

Coexisting emotional or behavioral condition (an alpha-2-adrenergic agonist may be useful for patients who are over-aroused, easily frustrated, highly active, or aggressive) [10]

Potential adverse effects

History of substance abuse in patient or household member: Avoid stimulants or use stimulants with less potential for abuse (eg, lisdexamfetamine, osmotic-release preparation methylphenidate, or dextroamphetamine patch) (see "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulants')

Preference of the child/adolescent and their caregiver or guardian

Expense (in general, short-acting stimulants are least expensive; among long-acting stimulants, pulse formulations are less expensive than bead preparations, osmotic-release preparations, and the methylphenidate or dextroamphetamine patch)

Generic drugs are less expensive than brand-names but not available for all formulations [12,13]; generic medications may be used as long as they are systematically titrated. Dose equivalence with the brand-name drug cannot be assumed [14]. (See 'Dose titration' below.)

Genetic testing — We do not recommend performing pharmacogenetic testing before prescribing medication for ADHD. Although this is an active area of research and variants in some candidate genes have demonstrated promise as clinical predictors of response or tolerability, prospective studies confirming benefits (eg, improved initial or dose titration, decreased adverse events or cost) are lacking [15-20].

We agree with the US Food and Drug Administration and the American Academy of Pediatrics that results of pharmacogenetic tests that are directly marketed to consumers (eg, for genetic variants that may be associated with medication metabolism) should not be used to make decisions about the appropriateness of a particular medication or dosing of a particular medication [3,21]. (See "Overview of pharmacogenomics", section on 'Use of genomic biomarkers to guide therapy'.)

Stimulants versus other medications — When the clinician and patient or caregivers agree to a trial of medication for ADHD in a school-aged child or adolescent (≥6 years), we suggest a stimulant as the first-line agent (table 3A-B) [3,10,22]. However, the preferences of the patient and caregivers must be taken into consideration [10,23]. (See 'General considerations' above.)

Stimulants are preferred to other medications because stimulants have a rapid onset of action and long record of safety and efficacy [11,12,23-28].

Selective norepinephrine reuptake inhibitors (eg, atomoxetine, viloxazine) are alternatives to stimulants and may be more appropriate for patients with a history of illicit substance use or household members with a history of illicit substance use, concern about abuse or diversion, or a strong caregiver preference against stimulant medication [10,29]. Atomoxetine is less effective than stimulants but well tolerated [30]. Trials comparing viloxazine and stimulants or other medications for ADHD are lacking. However, in a small nonrandomized crossover study (35 children, 15 of whom remained on concurrent psychostimulant treatment), participants had a greater reduction in both inattention and hyperactivity/impulsivity scores after four weeks of viloxazine than after four weeks of atomoxetine, with reduced time to response [31]. Additionally, participants reported fewer side effects with viloxazine, and an overwhelming majority preferred viloxazine.

Alpha-2-adrenergic agonists (eg, guanfacine, clonidine) usually are used when children respond poorly to a trial of stimulants or selective norepinephrine reuptake inhibitors, have unacceptable side effects, or have significant coexisting conditions. As a class, they are less effective than stimulants.

In randomized trials, systematic reviews, and meta-analyses, stimulants [25,30,32-39], atomoxetine [30,37,40-52], and alpha-2-adrenergic agonists [30,53-58] are more effective than placebo in reducing the core symptoms of ADHD. However, stimulants typically have a slightly larger treatment effect size (standardized mean difference) than nonstimulants (approximately 1.0 versus approximately 0.7 for both atomoxetine and alpha-2-adrenergic agonists) [3,10,37,52,53,58-62]. The standardized mean difference describes the number of standard deviation units the mean performance of the treatment group differed from that of the control group; by consensus, differences of 0.2, 0.5, and 0.8 are considered small, moderate, and large, respectively [63].

In a systematic review and network meta-analysis that included 81 published and unpublished randomized trials in >10,000 children, amphetamines and methylphenidate were more effective than atomoxetine in reducing clinician-rated core symptoms of ADHD [30].

In head-to-head comparisons in a network meta-analysis of randomized trials, amphetamines were more efficacious than guanfacine, but the efficacy of methylphenidate, guanfacine, and clonidine was similar [30].

The response rate to a specific stimulant (ie, reduction in hyperactivity or increase in attention as rated by caregivers, teachers, and/or research raters) is approximately 70 percent [32,64,65]. At least 80 percent of school-aged children and adolescents will demonstrate a response in core symptoms with stimulants if the stimulants are tried in a systematic way.

In addition to improvement in core symptoms of ADHD, treatment with stimulants also improves caregiver-child interactions, aggressive behavior, and academic productivity and accuracy [66,67]. The effect on academic performance is less strong [35].

Stimulant medications do not significantly improve learning problems, social skills, oppositional behavior, or emotional problems that are secondary to or coexist with ADHD [68]. However, stimulant medications may facilitate the psychological or behavioral treatment of these problems by controlling the core symptoms of ADHD. In addition, the use of stimulant medications may improve self-esteem in children with ADHD and comorbid conditions [69].

There are few controlled studies of long-term therapy for ADHD; however, ADHD symptoms appear to improve with time regardless of treatment modality [36,70]. Systematic reviews have found few high-quality studies assessing the long-term effectiveness of treatment with stimulants or atomoxetine [30,63]. Nonetheless, one concluded that medications continue to be effective and well-tolerated over at least 12 months [63], with a single study suggesting effectiveness for five years [71].

Choosing among stimulants — Individual preferences of the clinician and caregiver determine the choice of the initial stimulant medication [10,29]. In choosing among the various stimulants, duration of action is a primary consideration [26]. Another consideration is whether the child can swallow pills (since some formulations cannot be crushed, split, or opened) (table 2).

Although amphetamines may be slightly more efficacious, methylphenidate is better tolerated. In a systematic review and meta-analysis that included 81 published and unpublished randomized trials in >10,000 children, amphetamines were slightly more efficacious than methylphenidate in reducing clinician-rated core symptoms of ADHD at approximately 12 weeks (standardized mean difference -0.24, 95% CI -0.44 to -0.05) [30]. However, amphetamines were less tolerable than placebo while methylphenidate was not.

Short-acting forms – Short-acting forms of medication (table 3A) are often used as the initial treatment in children <6 years, who are more sensitive to dose-dependent adverse effects and should be started at low doses [10,28]. Long-acting formulations generally are not available at doses small enough for young children. Short-acting forms also may be used to determine the optimal daily dose before switching to a comparable long-acting agent (table 3B) [72]. However, in children older than six years, a longer-acting preparation may be used initially, starting at the lowest dose and titrating up [10]. (See 'Dose titration' below.)

Intermediate- or long-acting forms – Intermediate or long-acting preparations generally are indicated for children who require a duration of action longer than four hours or in whom the administration of medication every four hours is inconvenient, stigmatizing, or impossible [10,28,29,73]. Long-acting medications may improve adherence and are potentially less likely to be misused or diverted [28,74].

Combination of short- and long-acting forms – A combination of a long-acting and late-afternoon short-acting medication may be necessary to provide adequate coverage in the evening hours for homework completion or driving [29].

Preschool children — Medication may be helpful for preschool children (age four through five years) who have failed an adequate trial of behavior therapy [3,10]. When the clinician and caregivers agree that medication is warranted for a preschool child, we suggest methylphenidate rather than amphetamines or nonstimulant medication.

A systematic review found only one good quality study of stimulant medication in preschool children with ADHD [63]. In the multicenter Preschool ADHD Treatment Study (PATS), treatment with immediate release methylphenidate improved ADHD symptoms in children (3 to 5.5 years) with ADHD who were unresponsive to psychosocial interventions (effect size [standardized mean difference] 0.4 to 0.8) [75]. However, the effect size was smaller than that generally seen in older children (approximately 1.0) [10,60]. The standardized mean difference describes the number of standard deviation units the mean performance of the treatment group differed from that of the control group; by consensus, differences of 0.2, 0.5, and 0.8 are considered small, moderate, and large, respectively [63]. Among the 206 children reassessed three years after completion of the controlled study (mean age 7.4 years), 65 percent were receiving medication for ADHD. Among the 179 children reassessed six years after completion of the controlled study (mean age 10.4 years), 71 percent were receiving medication for ADHD [76]. Although the pharmacotherapy course was variable, 85 percent of children being treated with stimulants at year 3 continued to receive stimulants at year 6. A subsequent trial of 153 children (three to five years) treated with an educational intervention plus either immediate release methylphenidate or placebo demonstrated a reduction in ADHD symptoms (effect size -0.55 [95% CI -0.99 to –0.10]) and improvement in global functioning with methylphenidate [77].

Randomized trials comparing methylphenidate with other medications for preschool children are lacking. In a retrospective review of health records of children <6 years with ADHD who were treated in seven developmental-behavioral pediatrics practices, 497 children received medication; 65 percent received stimulants (predominantly methylphenidate) and 35 percent received alpha-2-adrenergic agonists (predominantly guanfacine) [78]. Symptoms improved in the majority of children (78 percent in the stimulant group, 66 percent in the alpha-2-adrenergic agonist group; difference 12 percent, 95% CI 2-22). Most adverse effects were more common with stimulants: moodiness/irritability (50 versus 29 percent), appetite suppression (38 versus 7 percent), and difficulty sleeping (21 versus 11 percent); daytime sleepiness was more common with alpha-2-adrenergic agonists (38 versus 3 percent). Although these findings support the effectiveness of methylphenidate in preschool children, the adverse effect profile must be considered. Additional studies are necessary to determine the efficacy and safety of stimulants and alpha-2-adrenergic agonists in the treatment of ADHD in preschool children.

In a randomized trial published after the systematic review, atomoxetine improved core caregiver- and teacher-reported symptoms of ADHD in preschool children but did not improve overall clinical function [48]. Controlled studies comparing methylphenidate with atomoxetine for preschool children are lacking.

Initiation and titration of methylphenidate for preschool children is discussed below. (See 'Dose titration for preschool children' below.)

DOSE TITRATION — Pharmacotherapy for ADHD has three stages: titration, maintenance, and termination [5].

Titration of stimulants — During the titration stage, the optimal dose and frequency of medication are determined. The titration phase typically lasts from one to three months [5]. It requires close monitoring (usually weekly) by the clinician, some of which can be done by phone or telemedicine.

The dose-response relationship for stimulant medication varies by child (perhaps related to genetic polymorphisms) and within the child may vary by domain of function or target symptoms of interest [15,79,80]. Individual differences in metabolism preclude weight-based dosing of stimulant medications [5].

The optimal dose is the dose at which target outcomes are achieved with minimal to tolerable side effects. Many side effects can be managed to be well tolerated by patients.

It is helpful to start ADHD medication on a weekend day so that caregivers can watch for adverse effects with the first doses. It is also helpful to write prescriptions so that the pharmacy will provide a separate bottle of medication, with appropriate instructions, for administration at school (if administration at school is necessary). Children should not be allowed to administer their own medication. Adolescents may administer their own medication; however, it is important for caregivers to monitor adherence (through pill counting and observation of behavior).

Stimulant medications usually are started at the lowest dose that may produce an effect and increased gradually (every three to seven days) until core symptoms improve by 40 to 50 percent compared with baseline or adverse effects become unacceptable [5,28,29]. The maximum daily dose for stimulant medications is provided in the tables (table 3A-B). However, doses exceeding the recommended maximum doses may be necessary for adult-sized adolescents [81].

At a therapeutic dose, the effects of stimulant medications on core symptoms usually are apparent 30 to 40 minutes after administration and continue for the expected duration of action [82-84]. Administration with a high-fat meal may delay the onset and increase peak concentrations of some formulations (eg, Metadate CD, Methylin chewable tablets or oral solutions, Adderall XR) [85]. See methylphenidate drug information and dextroamphetamine drug information. Appetite suppression may be another indicator of treatment response [5]. Inadequate dose may be indicated by a shorter-than-expected duration of action.

The decision regarding the frequency of stimulant medication (both times per day and days per week) is based upon the presentation of ADHD and the domains of function in which improvement is desired. As an example, a child with the predominantly inattentive presentation of ADHD may need medication only on school days, whereas a child who has difficulty with peer relationships may need medication every day. Children who participate in after-school sports or activities on certain days of the week may require longer-acting preparations or more frequent dosing on those days. Dosing schedules that change from day to day have not been studied in controlled trials.

Dose titration for preschool children — The metabolism of methylphenidate is slower in preschool children than in older children and adolescents. Preschool children usually are started at a lower dose that is increased in smaller increments. In the Preschool ADHD Treatment Study (PATS), the authors concluded that it may be best to begin methylphenidate at 2.5 mg orally twice per day, and during the course of one week, increase the dose as necessary up to 7.5 mg orally three times per day. We agree with this regimen.

Titration of atomoxetine and viloxazine — Titration of atomoxetine and viloxazine are discussed separately (table 3B). (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Selective norepinephrine reuptake inhibitors'.)

Monitoring response and adverse effects — During the titration stage, the child's core symptoms and adverse effects should be assessed weekly and the medication dose adjusted as indicated (table 3A-B) [72,86-88]. Core symptoms and adverse effects can be monitored through caregiver and teacher feedback and/or ADHD rating scales (table 4) (via telephone, fax, or secure electronic system) [29,89]. Patients generally are seen at least once per month to monitor weight, height, heart rate, and blood pressure [10,29,86]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)

Teacher feedback is essential. Many caregivers choose a medication regimen for their child that has maximal effects during the school day. In such cases, caregivers may not be in a position to observe medication effects on core ADHD symptom and reports from the caregivers alone are not sufficient to make a determination of treatment failure.

Managing stimulant adverse effects — When children or adolescents who are being treated with stimulant medications develop adverse effects, it is important to determine the timing of the effect in relation to medication administration and whether the effect is related to a coexisting disorder or environmental stressor [5,90]. Mild adverse effects may resolve with time or can be addressed by adjusting the dose, time of administration, or formulation of stimulant [10,86]. Tips for initial management of common adverse effects of stimulant medications are provided below [90-92].

Decreased appetite – Administer the medication at or after a meal; encourage the child to eat nutrient dense foods before those with "empty calories"; offer food that the child likes for the noon meal, which is often affected [5,85,90,92,93]. When making these changes, an important caveat is that meals with high fat content may delay the onset and increase peak concentrations of some formulations (eg, Metadate CD, Methylin chewable tablets or oral solutions, Adderall XR). See methylphenidate drug information and dextroamphetamine drug information.

Poor growth – Drug holidays may be beneficial for children in whom stimulant therapy is associated with a growth trajectory that crosses two major percentiles (ie, the 5th, 10th, 25th, 50th, 75th, 90th, and 95th) [10]. Drug holidays should only be undertaken if they can be tolerated without marked impairment in functioning. Poor growth that does not respond to drug holidays should be discussed with caregivers to determine preferences for continued treatment. Nutritional consultation to facilitate growth while taking medications may also be warranted. (See 'Drug holidays' below.)

Dizziness – Monitor blood pressure and pulse; ensure adequate fluid intake; if associated only with peak effect, try a longer-acting preparation (table 3A-B) [90].

Insomnia/nightmares – Establish a bedtime routine and good sleep hygiene habits; omit or reduce the last dose of the day, or, if using a long-acting preparation, change to a short-acting preparation (table 3A-B) or administer earlier in the day [26,90,92,94].

Mood lability – If mood lability occurs at the time of peak concentration, try reducing the dose or switching to a longer-acting preparation; irritability, sadness, and increased activity as the medication wears off is particularly common when short-acting medication is used on a morning and noon twice-a-day schedule – try adding an afternoon dose or switching to long-acting form; evaluation for coexisting mood disorder or anxiety disorder may be warranted [5].

Rebound – "Rebound" refers to symptoms or adverse effects that occur as the medication is wearing off; rebound effects may improve by increasing the dose of the long-acting agent administered in the morning or adding a smaller dose of short-acting medication at the end of the day, before rebound symptoms typically occur [10,90,91].

Tics – Given the frequency of comorbid tic disorders and ADHD, and the typical waxing and waning pattern of tics, new or worsening tics may be coincidentally rather than causally associated (even if the tics appear to improve when the child is not taking stimulants) [95,96]. If tics begin or are worsened in children taking stimulants, a brief trial off of medication or at a lower dose may be warranted. The trial is most informative if the tics persist when the medication is discontinued; improvement off of medication or at a lower dose may be coincidental. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Tics'.)

Suicidality and psychosis – If children taking stimulant medications develop severe psychiatric symptoms (eg, suicidality, hallucinations, or increased aggression), verify that the dose is appropriate and that the medication is being administered as prescribed [90]. If so, reduce the dose or discontinue the stimulant [92]; stimulant medications can be discontinued abruptly, without tapering. If symptoms persist, referral to a qualified mental health specialist or psychopharmacologist may be warranted to assess for bipolar disorder or a thought disorder [90].

Diversion and misuse – It is important for clinicians to monitor symptoms and prescription refills for evidence of misuse or diversion of ADHD medication [3,97]. Stimulant diversion and misuse can be prevented, to some extent, by prescribing long-acting stimulants (table 3B) with less potential for abuse and by keeping track of prescription dates [26,74,97]. It is also helpful to have an open discussion about stimulant diversion and misuse with patients and caregivers so that students can be prepared if they are approached by peers to sell or misuse medications and so that caregivers can remain vigilant in monitoring medications [26]. Clinicians should be especially cautious if a member of the child's household has a history of substance use.

Discussion points include [97]:

Taking the medication exactly as prescribed (both the dose and the frequency)

Letting the clinician know if the medication does not seem to be working

Avoiding alcohol, tobacco, marijuana, and other illicit substances (may interact with stimulants and exacerbate attentional problems)

Administering medication at school in a safe location with adult supervision (eg, school nurse's office)

Keeping the medication in a safe location – and not being coerced/tempted into selling it or giving it away

A plan for transition of responsibility for administering stimulant medication from the caregiver to the child or adolescent; the adolescent should be fully responsible for managing their medication before leaving home (eg, for college) [98] (see 'Adherence' below)

Managing atomoxetine adverse effects — When children or adolescents who are being treated with stimulant medications develop adverse effects, it is important to determine the timing of the effect in relation to medication administration and whether the effect is related to a coexisting disorder or environmental stressor. Mild adverse effects may resolve with time or if the single daily dose is divided into two doses per day. Discontinuation of atomoxetine may be warranted for emergence of psychotic or manic symptoms (eg, hallucinations, delusional thinking, mania) or suicidal ideation in children with no previous history [99]. Atomoxetine can be discontinued by stopping all doses at once [100].

Treatment failure — Treatment failure is defined by lack of satisfactory improvement in core symptoms of ADHD at the maximum dose or the occurrence of intolerable adverse effects [101].

It is important to differentiate lack of response from "rebound" effects as the medication wears off [5]. With lack of response there is no improvement in core symptoms; with "rebound" there is an initial improvement in core symptoms, but near the end of the expected duration of action, there may be a recurrence or worsening of symptoms. (See 'Managing stimulant adverse effects' above.)

Children who fail to have improvement in core symptoms at the maximum recommended dose (table 3A-B) or who have intolerable side effects with one class of stimulant medication can be tried on a medication from the other class of stimulants (with a similar titration process) [36,89]. At least one-half of children who do not respond to one type of stimulant will respond to the other [29,36,61]. Side effects may occur with one type of stimulant but not another [61,102]. For children who have onset or exacerbation of tics with the first stimulant, a trial of reduced dose or a second stimulant may be warranted before switching to a different class of medication. Children who do not respond to a second stimulant may respond to nonstimulant medications or the addition of extended release clonidine or guanfacine [22,103].

Review of the initial presentation and diagnosis is warranted for children who do not respond to a second stimulant at the maximum dose [26]. The following possibilities must be considered:

Lack of adherence to the medication regimen

The possibility of medication diversion (eg, giving or selling the medication to others)

Whether the expectations are realistic

Whether there is a comorbid psychiatric diagnosis (see "Attention deficit hyperactivity disorder in children and adolescents: Clinical features and diagnosis", section on 'Differential diagnosis')

Changing from one medication to another — Changing from one medication is warranted for children who do not have improvement in core symptoms at the maximum recommended dose or who have intolerable side effects.

From one stimulant to another – Dosing guidelines for switching from one stimulant to another are provided in the table (table 5).

From a stimulant to atomoxetine or viloxazine – When switching from a stimulant to atomoxetine or viloxazine, stimulant medication should be continued for the first few weeks (unless stimulant treatment was associated with concerning side effects) to allow atomoxetine or viloxazine to reach full effect [104].

From atomoxetine or viloxazine to a stimulant – When switching from atomoxetine or viloxazine to stimulants for lack of response, atomoxetine or viloxazine can be stopped abruptly.

MAINTENANCE THERAPY — The maintenance stage begins once the optimal dose and frequency of medication have been determined. During the maintenance stage, regular monitoring is necessary to review progress, adjust the dose if necessary (according to response in core symptoms, not the child's weight), monitor adverse effects of therapy, and review the child's understanding of the medication as they mature [10,72]. Regular (eg, annual) screening for possible emergence of comorbid psychiatric conditions should also be conducted [105].

Frequency of follow-up — The frequency of follow-up during the maintenance phase may range from every three to six months depending upon adherence, coexisting conditions, and the persistence of symptoms [29]. More frequent visits generally are necessary for children with coexisting conditions. In addition to office and/or telemedicine visits every three to six months, telephone monitoring should occur at the time of medication refill requests. Communication with teachers or other school personnel can be tailored to individual patient and caregiver needs. (See "Attention deficit hyperactivity disorder in children and adolescents: Overview of treatment and prognosis", section on 'Care coordination'.)

Monitoring adverse effects — The child's height, weight, blood pressure, and pulse should continue to be monitored during the maintenance stage. Additional adverse effects must be monitored closely because stimulant medication may be used for many years. Structured monitoring can be performed with the use of a side effects profile. One such symptom rating scale for evaluating side effects of medications is included in the National Institute for Children's Healthcare Quality sample management plans. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects' and "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine adverse effects'.)

Adherence — Adherence to the treatment regimen can be monitored by documenting the dates of prescription refills, pill counts, or electronic monitoring. Caregivers, adolescents, and young adults may overestimate adherence to therapy when adherence is reported subjectively [106,107]. Adolescents may be more likely to disclose nonadherence if they are asked to "tell me how many pills have been missed this month" rather than "have you missed any pills this month?" [98].

College students living away from home are at risk for nonadherence. In an observational study of 51 undergraduate students with ADHD, overall adherence was 54 percent, ranging between 34 and 68 percent, depending on year of study and time of semester [98]. Strategies to improve adherence include incorporating ADHD medications into daily routines (eg, brushing teeth), using smartphone reminder applications, and periodic caregiver check-ins.

Dose adjustments — Maintenance doses typically are similar to the doses demonstrating optimal efficacy during the titration period [61,108,109]. However, medication adjustments may be necessary to accommodate changes in the child's lifestyle or activities. Long-acting medications may interfere with sleep onset in adolescents who sleep later on weekend mornings than they do during the week [26]. In such patients, the use of a shorter-acting preparation on weekend days may be beneficial. When adjustments to the maintenance dose are necessary, they should not exceed the smallest available unit for the specific medication (table 3A-B).

DRUG HOLIDAYS — "Drug holidays" (ie, discontinuation of stimulant medication on weekends or during the summer) are not routinely recommended because ADHD is a chronic and pervasive disorder [26]. Decisions about drug holidays must be made on a case by case basis. As an example, a child with the predominantly inattentive presentation of ADHD may need medication only on school days. Drug holidays are not an option for children who are taking atomoxetine, viloxazine, or alpha-2-adrenergic agonists (eg, extended release guanfacine, extended release clonidine) because of the gradual onset and prolonged effect of these medications [100].

Drug holidays, if they can be tolerated without marked impairment of functioning, may be beneficial for children in whom stimulant therapy is associated with an aberrant growth trajectory (eg, a growth trajectory that crosses two major percentiles; the major percentiles are the 5th, 10th, 25th, 50th, 75th, 90th, and 95th) [10]. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulant adverse effects'.)

The effects of a weekend drug holiday were evaluated in a controlled study in which 40 children and adolescents were randomly assigned to receive methylphenidate twice per day, seven days per week or twice per day on weekdays and placebo on weekends [110]. There were no differences between groups on Monday teacher ratings or weekend caregiver ratings, but those in the drug holiday group had significantly less insomnia [110].

TERMINATION OF THERAPY — The duration of pharmacologic therapy is highly individualized. Ongoing evaluation of the risks and benefits of medication is necessary for each patient [6,10]. At the 36-month follow-up of participants in a multicenter randomized trial of ADHD treatments (medication; behavioral/psychological therapy; combination medication and behavioral/psychological therapy; and community care), the treatment groups had similar clinical and functional outcomes (all substantially improved compared with baseline) [70]. Thus, after several years of medication, it is reasonable to offer children and adolescents who have had stable improvement in ADHD symptoms and target behaviors a trial off of medication to determine whether medication is still necessary [29]. Such a trial should be undertaken with close monitoring of core symptoms and function at home, school, and in the community.

To prevent unsupervised termination of medication, the procedures for a trial period off medicine should be discussed routinely with patients. Regular assessment and monitoring of behavior through formal ratings appears to decrease the rate of unsupervised termination of medications [111]. Although controlled studies are lacking, occasional trials off medication may assist in determining whether continuation of medication is necessary.

If conducted, trials off medication should be timed so as not to interfere with academic and/or vocational efforts. Because long-term side effects and drug dependence do not occur with stimulant medications, atomoxetine, or viloxazine, they can be discontinued by stopping all doses at once [79,100,111]. However, the discontinuation of alpha-2-adrenergic agonists and tricyclic antidepressants should follow established guidelines (ie, tapering off over several weeks) [112,113].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Attention deficit hyperactivity disorder".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

Beyond the Basics topic (see "Patient education: Treatment of attention deficit hyperactivity disorder in children (Beyond the Basics)")

Basics topic (see "Patient education: Medicines for attention deficit hyperactivity disorder (ADHD) in children (The Basics)")

SUMMARY AND RECOMMENDATIONS

Pretreatment considerations – Certain criteria should be met before pharmacotherapy is initiated (table 1). In addition, a comprehensive, cardiovascular history and examination should be completed; baseline height, weight, blood pressure, and heart rate should be established; and adolescent patients should be assessed for substance use or abuse. In addition, a pretreatment baseline should be established for common side effects (eg, appetite, sleep, headaches, abdominal pain, etc). (See 'Prerequisites' above and "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder".)

Pretreatment education includes an explanation of the rationale for medication treatment, the benefits and potential risks of medication, and the process of determining the optimal regimen. (See 'Pretreatment education' above.)

Choice of agent – When the clinician and patient or caregivers agree to a trial of medication for ADHD in a school-aged child or adolescent, we suggest a stimulant as the first-line agent (Grade 2B); for preschool children we suggest methylphenidate rather than amphetamines or nonstimulant drugs (Grade 2B). However, the preferences of the patient and caregiver must be taken into consideration. Selective norepinephrine reuptake inhibitors (eg, atomoxetine) are an alternative. Other medications (eg, alpha-2-adrenergic agonists) usually are used when children respond poorly to a trial of stimulants or selective norepinephrine reuptake inhibitors, have unacceptable side effects, or have significant coexisting conditions. (See 'Choice of agent' above.)

Individual preferences of the clinician and caregiver determine the choice of the initial stimulant medication. In choosing among the various stimulants, duration of action is a primary consideration (table 3A-B). Another consideration is whether the child can swallow pills (table 2). (See 'Choosing among stimulants' above.)

Dose titration and monitoring – During the titration stage, the optimal dose and frequency of medication are determined. The optimal dose is the dose at which target outcomes are achieved with minimal to tolerable side effects. The titration stage lasts from one to three months and requires close monitoring of core symptoms, target outcomes, and adverse effects by the clinician. Guidelines for the initial dose and dose advancement are provided in the tables (table 3A-B). (See 'Dose titration' above and 'Monitoring response and adverse effects' above.)

Treatment failure – Treatment failure is defined by lack of satisfactory improvement in core symptoms of ADHD at the maximum dose (table 3A-B) or the occurrence of intolerable adverse effects. Children who fail treatment with one class of stimulant medication can be tried on the other (with a similar titration process). Dosing guidelines for switching from one stimulant to another are provided in the table (table 5). (See 'Treatment failure' above.)

Review of the initial presentation and diagnosis is warranted for children who do not respond to a second stimulant at the maximum dose. The following possibilities must be considered (see 'Treatment failure' above):

Lack of adherence to the medication regimen

The possibility of medication diversion (eg, giving or selling the medication to others)

Whether the expectations are realistic

Whether there is a comorbid psychiatric diagnosis

Maintenance therapy – The maintenance stage begins once the optimal dose and frequency of medication have been determined. Continued monitoring of treatment progress and adverse effects is necessary during the maintenance phase. The frequency of follow-up depends upon adherence, coexisting conditions, and the persistence of symptoms and functional impairment. During the maintenance phase, decisions regarding discontinuation of stimulant medication on weekends or school vacations must be made on a case by case basis. (See 'Maintenance therapy' above.)

Termination of therapy – The duration of pharmacologic therapy is highly individualized; ongoing evaluation of the risks and benefits of medication is necessary for each patient. After several years of medication, it is reasonable to offer children and adolescents who have had stable improvement in ADHD symptoms and target behaviors a trial off of medication to determine whether medication is still necessary. Such a trial should be undertaken with close monitoring of core symptoms and function at home, school, and in the community. (See 'Termination of therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kevin Krull, PhD, who contributed to earlier versions of this topic review.

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Topic 16927 Version 54.0

References

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