Medication Summary
Although health care providers, parents, and teachers have hoped for effective therapies and methods that do not involve medications for children with attention deficit hyperactivity disorder (ADHD), evidence to date supports that the specific symptoms of ADHD are poorly treated without medication. Perhaps the mildest cases of ADHD can be treated with moderate success with environmental restructuring and behavioral therapy, but other than these limited situations, pharmacotherapy often is needed.
Compliance issues with medications for ADHD in children and adults is common. [47] Therefore, the use of long-acting medications at once-a-day dosing to treat ADHD has been shown to have advances over the shorter acting drugs. They have led to higher rates of remission. Their use has been marked to better adherence and they have been demonstrated to be less stigmatizing. [48] Another benefit of the long-acting medications is time of effectiveness (ie, full-day coverage). [49]
In 2015, the FDA approved a once-daily extended-release oral liquid for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years and older. [50] In the same year, the FDA approved a chewable tablet form of extended-release methylphenidate, to be sold as QuilliChew ER, for treatment of ADHD in patients aged 6 years or older. The tablet comes in strengths of 20, 30, and 40 mg and are scored so they can be split easily. The product is to be taken once daily in the morning. [51] In June 2017, the FDA approved 2 new ADHD medications, Cotempla XR-ODT and Mydayis. Cotempla XR-ODT is approved for the treatment of ADHD in children and adolescents aged 6-17 years. It is an oral disintegrating tablet form of extended-release methylphenidate, given once every morning, and is available as an 8.6 mg, 17.3 mg, and 25.9 mg tablet. [52] Mydayis is also approved for the treatment of ADHD in adolescents and adults aged 13 years or older. It is an extended-release capsule of mixed amphetamine salts, administered each morning. It is available as a 12.5 mg, 25 mg, 37.5mg, and 50 mg capsule.
The first bedtime methylphenidate (Jornay PM) was approved by the FDA in 2018. It is indicated for ADHD patients aged 6 years or older. It is administered at 8 PM, although the administration time may be adjusted between 6:30 PM and 9:30 PM to optimize tolerability and efficacy the next morning and throughout the day. The capsule contains 2 functional film coatings that act synergistically to achieve a unique pharmacokinetic profile. The first layer delays the initial release of drug for up to 10 hours, and the second layer helps to control the rate of release of the active pharmaceutical ingredient throughout the day. Compared with placebo, Jornay PM achieved significant improvements in ADHD symptoms as measured by the ADHD rating scale IV (p = 0.002) and the parent rating of evening and morning behavior (revised) scale (p < 0.001). [53]
ADHD has been associated with traffic accidents. Chang et al demonstrated that not only are persons with ADHD involved in more accidents but patients who adhere to their medication have reduced rates of such accidents. [54] The association between ADHD and accidents was estimated with Cox proportional hazards regression. The authors conclude that this should lead to increased awareness about the association between serious traffic accidents and ADHD medication.
No link between current or new use of ADHD medications and an increased risk of serious cardiovascular events in healthy young and middle-aged adults has been found. [55] However, it is recommended to avoid use of CNS stimulants with patients who have cardiac structural abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery disease, and other serious heart problems. [52, 56]
The FDA has warned that methylphenidate may rarely cause prolonged and painful erections, known as priapism. Because priapism may cause permanent damage to the penis, patients taking methylphenidate who develop an erection lasting longer than 4 hours should seek immediate medical attention. [57]
Prescription practices
Webb JR et al report a high prevalence of stimulant use among medical students when compared with a larger, general population. More than 83% of students who took stimulants used them to stay awake, specifically for cognitive performance enhancement. The study suggests that this could impact attitudes towards prescribing such medications to patients with ADHD. [58]
Numerous studies have shown a link between patients with ADHD and criminal activity. Lichtenstein and colleagues found that patients receiving ADHD medication had a significant decline in criminal activity. They found a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63-0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50-0.70) during medicated periods compared with nonmedication periods. [59]
Medication compliance
The compliance rate of youngsters on stimulant medication has always been an issue. Biederman et al studied electronic medical records of 2206 patients with prescriptions for CNS stimulant medication. They found that 46% of the prescriptions were refilled within the timeframe necessary for the patient to be considered consistently medicated. Rates of medication adherence were worse among patients receiving care from a primary care provider than among those receiving care from a psychiatrist, in older patients, and in female patients, and did not appear to be influenced by racial-ethnic group, economic class, stimulant type, or medication formulation (short or long acting). [60]
Stimulants
Class Summary
These agents are known to treat ADHD effectively.
Methylphenidate (Ritalin, Metadate CD, Methylin ER, Ritalin SR, Cotempla XR-ODT, Jornay PM)
Methylphenidate is the drug of choice approved by FDA for ADHD in children aged 6 years or older. It is the most commonly used drug. Methylphenidate is available in sustained-release forms. It is also available as a delayed-release bedtime dosage form.
Dexmethylphenidate (Focalin, Focalin XR)
Dexmethylphenidate contains the more pharmacologically active d-enantiomer of racemic methylphenidate. It blocks norepinephrine and dopamine reuptake into presynaptic neurons and increases the release of these monamines into extraneuronal spaces. To allow once-daily dosing, each extended-release (XR) capsule contains half the dose as immediate-release capsules and half as enteric-coated, delayed-release capsules.
Dextroamphetamine and amphetamine mixtures (Adderall, Mydayis)
Dextroamphetamine and amphetamine mixtures produce CNS and respiratory stimulation. The CNS effect may occur in the cerebral cortex and reticular activating system. This combination may have direct effects on both alpha- and beta-receptor sites in the peripheral system, as well as release stores of norepinephrine in adrenergic nerve terminals.
The mixture contains various salts of amphetamine and dextroamphetamine. It is available as 5-, 7.5-, 10-, 12.5-, 15-, 20-, and 30-mg scored tablets. The extended release form is also available as 12.5 mg, 25 mg, 37.5mg, and 50 mg capsules.
Dextroamphetamine (Dexedrine)
Dextroamphetamine is commonly used first or in case of methylphenidate failure. It is approved by the FDA for use in children aged 3 years or older. It is available in sustained-release forms, which may allow for daily dosing.
Lisdexamfetamine (Vyvanse)
Lisdexamfetamine is an inactive prodrug of dextroamphetamine. It elicits CNS stimulant activity. Lisdexamfetamine blocks norepinephrine and dopamine reuptake in presynaptic neurons and increases release of these monoamines in extraneuronal spaces. It is indicated for initial and maintenance treatment of ADHD for children aged 6-17 years and adults.
Amphetamine (Dyanavel XR, Evekeo)
Noncatecholamine, sympathomimetic amine that elicits CNS stimulant activity. The precise mechanism by which amphetamines produce mental and behavioral effects are unclear. Available as short-acting tablets (Evekeo) that need 2-3 doses/day in children aged 3 years or older. It is also available as a long-acting, once daily oral suspension (Dyanavel XR) or extended release oral disintegrating tablets (Adzenys XR-ODT) for patients aged 6 years or older.
Serdexmethylphenidate/methylphenidate (Azstarys)
Fixed dose combination of the prodrug of dexmethylphenidate, serdexmethylphenidate, and immediate-release dexmethylphenidate. This combination provides extended drug levels. It is indicated for ADHD in adults and children aged 6 years and older.
Dextroamphetamine transdermal (Xelstrym)
The first transdermal amphetamine patch indicated for ADHD. The transdermal system (patch) contains dextroamphetamine. The mechanism of action in ADHD is unknown. The patch is applied 2 hr before an effect is needed and removed within 9 hr after application.
Norepinephrine Reuptake Inhibitors, Selective
Class Summary
Selective norepinephrine reuptake inhibitors have been shown to be effective in the treatment of ADHD.
Atomoxetine (Strattera)
Atomoxetine elicits selective inhibition of the presynaptic norepinephrine transporter. It is used to improve symptoms of ADHD.
Viloxazine (Qelbree)
The mechanism of action by which viloxazine affects ADHD is unclear; however, it may be by selectively inhibiting norepinephrine reuptake. Indicated for treatment of ADHD in children and adolescents aged 6-17 years.
Atypical antidepressants
Class Summary
Recent studies support efficacy of venlafaxine and bupropion in ADHD. They may have a slower onset of action than stimulants but potentially fewer adverse effects.
Bupropion (Wellbutrin)
Bupropion inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake. It is also available in sustained-release preparations (Wellbutrin SR).
Venlafaxine (Effexor)
Venlafaxine may inhibit neuronal serotonin and norepinephrine reuptake. In addition, venlafaxine causes beta-receptor down-regulation. It is available in sustained-release preparations (Effexor XR).
Tricyclic antidepressants
Class Summary
See article entitled Depression. Patients may require lower doses for ADHD. They may have a quicker onset of action.
Imipramine (Tofranil)
Imipramine inhibits the reuptake of norepinephrine or serotonin (5-hydroxytryptamine, 5-HT) at presynaptic neurons. It may be useful in pediatric ADHD.
Alpha2 agonists, central-acting
Class Summary
Centrally acting antihypertensives clonidine and guanfacine have been used to treat children with ADHD. Inhibition of norepinephrine release in the brain may be the mechanism of action.
Guanfacine (Intuniv)
Guanfacine has a similar mechanism of action to clonidine but has a longer half-life and may be less sedative. The extended-release formulation (Intuniv) is indicated for children with ADHD aged 6-17 years as monotherapy or as adjunctive therapy to stimulant medications.
Clonidine (Kapvay)
Clonidine is a central alpha2 agonist. Its mechanism of action for ADHD is unknown. It is indicated for ADHD as adjunctive therapy to stimulants or as monotherapy. It is available as an extended-release tablet.
