Attention-deficit hyperactivity disorder (ADHD) medications

DEFINITION: Pharmacologically produced agents used in the treatment of the syndrome of disruptive behavior known as attention-deficit/hyperactivity disorder.

SIGNIFICANCE: Medication management of attention-deficit/hyperactivity disorder targets the areas of the disorder that contribute to the patient’s impairment: inattention, hyperactivity, and impulsivity. These conditions can, at times, lead persons with the disorder to involvement with legal authorities. Researchers who have studied attention-deficit/hyperactivity disorder in prison populations have estimated its prevalence from as low as 20 percent to as high as 45 percent.

Most medications used in the treatment of attention-deficit/hyperactivity disorder (ADHD) are rudimentarily separated into stimulant and nonstimulant categories; further distinctions are made between those that are approved for treatment of the disorder by the US Food and Drug Administration (FDA) and those that are nonapproved or used “off-label” by prescribing physicians. FDA-approved medications in the stimulant category comprise amphetamine preparations (brand names include Adderall and Dexedrine) and methylphenidate preparations (brand names include Ritalin, Concerta, and Focalin). Although many nonstimulant medications primarily intended for other conditions (such as depression or narcolepsy) are used to treat ADHD, there are only several nonstimulants approved by the FDA specifically for ADHD, atomoxetine (brand name Strattera), guanfacine (brand names Intuniv and Tenex), and clonidine (brand name Kapvay). Bupropion (brand name Wellbutrin) is used as a third-line treatment for ADHD. New medications in the treatment of ADHD are being researched and developed. Qelbree is the newest nonstimulant ADHD medication approved for children and adults in 2021 and 2022, respectively. In 2019, two new stimulant medications, Jornay PM and Adhansia XR were also approved for children and adults. In 2022, the FDA announced a nationwide shortage of Adderall, which caused a widespread inability for prescriptions of the medication to be filled.

Stimulants

Although it may seem counterintuitive to treat a patient experiencing hyperactivity with a stimulant, a simple explanation regarding the theory of ADHD is as follows: In the patient with ADHD, the frontal lobe of the brain, which is responsible for executive functions (such as planning, organizing, and focusing attention) and other tasks (including controlling impulses, motivation, and movement), is deficient in the neurotransmitters that are restored to a more normative state with the use of stimulant medications. The main catecholamine neurotransmitters that are affected by the use of stimulants are dopamine and norepinephrine. These transmitters are involved in focusing attention, motivation, learning, and other cognitive functions that are adversely affected in patients with ADHD.

In general, the use of methylphenidate and amphetamine medications with patients who have ADHD leads to an approximation of a normal neurochemical state, both by blocking the reuptake of dopamine into and promoting the release of dopamine out of the nerve cells in the brain wherein dopamine is produced, stored, and released. The net effect is an increase in the amount of dopamine available to communicate between nerve cells. This area of communication between the cells is termed the synapse. Amphetamine preparations have the added effect of promoting the release and blocking the reuptake of norepinephrine.

When treatment is optimized, between 77 and 90 percent of patients with ADHD will have a favorable response to stimulant medications. This may be reflected in improvements in academic accuracy and grades, interpersonal relations, and social functioning. However, although stimulant medications have well-documented usefulness in the treatment of ADHD and are generally well tolerated, they may also be associated with side effects. These side effects include but are not limited to insomnia, weight loss, headaches, irritability, loss of appetite, stomach upset, and increases in blood pressure and heart rate. Other less common but potentially serious side effects include the development of undesired movements called tics, slowing of growth, the possibility of seizures, and the risk of developing psychotic symptoms such as hallucinations and paranoia. Often, side effects can be minimized or eliminated through the reduction of the medication dosage or through a change to a different type of stimulant that may be better tolerated.

Nonstimulants

Atomoxetine is a selective norepinephrine reuptake inhibitor that is approved by the FDA for treatment of ADHD in children and adults. It is thought that atomoxetine blocks the norepinephrine transporter in nerve cells in the brain, thereby increasing the amount of norepinephrine in the synapse between nerve cells. It is further hypothesized that in the brain’s frontal lobe, norepinephrine transporters may, to some extent, also be responsible for the reuptake of dopamine, not just norepinephrine. Research indicates that atomoxetine may be as effective in the treatment of ADHD as the stimulant methylphenidate, but atomoxetine may take a longer period of time to reach its full benefit.

Atomoxetine’s side effects may include stomach upset, constipation, decreased appetite, headache, fatigue, irritability, and an inability to empty the bladder completely when urinating. More serious side effects include rare cases of liver toxicity and the concern, given that the chemical structure of atomoxetine is similar to that of certain antidepressants, that it could promote suicidal thinking and behavior in children and adolescents such as that seen clinically in 3 to 4 percent of patients in the population taking traditional antidepressants.

Guanfacine acts as an agonist for adrenergic receptors in the prefrontal cortex and activates norepinephrine autoreceptors in the central nervous system. It is approved by the FDA for ADHD treatment in adults and children over the age of six. The exact mechanism by which it alleviates ADHD symptoms is unknown, although its interaction with the prefrontal cortex is thought to be related. Guanfacine is often prescribed in combination with a stimulant.

Common side effects of guanfacine include drowsiness, fatigue, dizziness, dry mouth, headache, nausea, and constipation. As it is also used to lower blood pressure, it may cause hypotension. It can also cause heart problems, such as high, low, or irregular heart rate and chest pain.

Clonidine (brand names Catapres and Disarit) is an alpha-2 adrenergic agonist, like guanfacine. These drugs have been used to treat high blood pressure and, through their effects on the central nervous system mediated by norepinephrine-containing nerve cells, are helpful in diminishing impulsivity, hyperactivity, and even aggression in patients with ADHD. They may also help with sleep disturbance and motor (movement) tics that are seen in some patients. The main side effects are dry mouth, headache, sedation, constipation, slowing of heart rate, and lowering of blood pressure.

The nonstimulants atomoxetine, guanfacine, and clonidine are considered second-line treatments for ADHD. Bupropion is a third-line agent because it has not been approved by the FDA for the treatment of ADHD but has shown promise in several small trials.

Bupropion is an alternative and structurally chemically different antidepressant with usefulness in treating ADHD. It is thought that bupropion helps patients with ADHD through its effects on norepinephrine and dopamine. In high doses, this medication may make patients more prone to seizures. The suicide risk warnings for children and adolescents are the same as those applied to tricyclic antidepressants.

Other Treatments

Typically, alternative medications have been used as second or third-line options to treat ADHD. Although these approaches are not approved by the FDA for the treatment of ADHD, they still have use for those patients who cannot tolerate or do not benefit from more traditional treatments. Further, these medications may be used in conjunction with other treatments to augment or boost a patient’s response.

Tricyclic antidepressants, such as imipramine (brand names include Tofranil and Antideprin) and nortriptyline (brand names include Aventyl and Pamelor), have been used in the treatment of ADHD with some success. It is theorized that the beneficial effects of these antidepressants on ADHD symptoms are related to the blockade of norepinephrine reuptake into nerve cells. Use of these medications, however, has fallen out of favor with most treatment providers because of the limiting side effects associated with the drugs, the most concerning of which is the risk of sudden cardiac death if the medications are taken in overdose or if the blood levels of the medications get too high. Concerns also exist regarding an increase in suicidal thoughts and behaviors in child and adolescent patient populations. Nevertheless, in experienced hands and with proper monitoring, these medications can be prescribed safely and effectively for treatment of ADHD.

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