Attention Deficit/Hyperactivity Disorder (ADHD)
The traditional treatment strategy for ADHD is two-pronged, involving both medication and psychological support (Antshel 2011).
The most widely used drugs to treat ADHD are brain stimulants, of which there are several available (Chavez 2009). Although these drugs have long been used in clinical medicine, their mechanisms of action have only recently started to be better understood. These drugs change the levels and signaling by neurotransmitters (eg, norepinephrine and dopamine) in the brain (Berridge 2011).
Methylphenidate. Methylphenidate is the most common stimulant medication used to treat ADHD. Many different forms of methylphenidate are available, including Ritalin®, Methylin®, Metadate®, Concerta®, and Daytrana®, which vary in dosage, delivery system (capsule, tablet, or patch), and rate of drug delivery. Dexmethylphenidate (Focalin®) consists of a specific structural form of methylphenidate thought to be better absorbed and more chemically active in the brain (Greydanus 2009; Liu 2006).
Daytrana®, the methylphenidate patch first released in the United States in 2006, is a relatively new development in ADHD treatment. It releases the drug through the skin, giving it the advantage of once-daily administration, flexibility in its removal, and suitability for children who cannot swallow pills; however, it can cause skin reactions where applied (Elia 2011).
Methylphenidate Drugs Induce Oxidative Stress
Aside from known side effects such as heart problems and growth suppression, methylphenidate also causes oxidative stress. Oxidative stress is the metabolic process by which reactive molecules damage cells and tissues. Oxidative stress is implicated as a contributing factor in several diseases and the aging process (Wang 2013; Kim 2013).
Animal studies have shown that methylphenidate treatment leads to an increase in the production of tissue-damaging reactive oxygen species in certain brain regions (Schmitz, Scherer, Machado 2012). Alarmingly, one animal experiment showed that brains of young animals were especially prone to the increased oxidative stress caused by methylphenidate, suggesting children may be more susceptible to this phenomenon than adults (Martins 2006).
Ironically, although methylphenidate is used as a treatment for ADHD, some evidence suggests that oxidative stress actually contributes to the development and progression of several psychiatric disorders, including ADHD (Ceylan 2012; Ng 2008; Kawatani 2011).
This is concerning, especially considering that evidence shows methylphenidate exposure during development likely has lasting neurological consequences that may impact brain health in later life. Conventional physicians are often quick to prescribe methylphenidate to children with ADHD despite a lack of thorough understanding of its long-term developmental effects (Urban 2013).
Amphetamines. Amphetamine drugs including dextroamphetamine (Dexedrine®) and Adderall® (a combination of amphetamine and dextroamphetamine) are also popular, and some people with ADHD may respond better to these alternatives (Chavez 2009).
Another amphetamine, lisdexamfetamine (Vyvanse®), is a relatively recent addition to the arsenal of stimulant drugs for ADHD. It was first approved by the Food and Drug Administration (FDA) for the treatment of ADHD in children in 2007 and is currently also approved for adolescents and adults. Unlike other stimulants prescribed for ADHD, lisdexamfetamine is a "prodrug," an inactive precursor converted to the active form of the drug after ingestion. This property is claimed to give the drug a smoother effect throughout the day with fewer rebound symptoms. It may also help prevent addiction or abuse (Madaan 2013).
Side Effects of Stimulant ADHD Medications
Up to 30% of children with ADHD either do not respond to stimulants or cannot tolerate their side effects (CDC 2013b; Akhondzadeh 2003). The side effects of stimulant use can range from mild to severe. Adverse effects include headache, insomnia, decreased appetite, rapid heart rate, abdominal pain and growth suppression (long-term use) (Medscape 2013; ePOCRATES 2013). They should not be used in people with hypertension, heart or vascular disease, hyperthyroidism, glaucoma, psychosis, or those taking monoamine oxidase inhibitors (MAOIs), which are sometimes prescribed for depression. Because of their potential for abuse and effects on addiction-related pathways in the brain (through dopamine), they are also not suitable for people with substance abuse disorders. Stimulants can worsen tics in people with Tourette’s syndrome (three-fourths of whom also have ADHD), and some of them induce tics in people who did not have them previously. They can also induce mania or psychosis in people who have not previously shown signs of bipolar disorder or schizophrenia (Greydanus 2009). In rare cases, sudden death has been reported after the use of methylphenidate and amphetamines. Especially before taking stimulants, individuals should be screened for a history of cardiovascular risks.
In light of incidents of sudden death after taking ADHD medication, in 2008 the American Heart Association went so far as to recommend that all children have an electrocardiogram to rule out any undetected developmental defects to the heart before beginning stimulant medication for ADHD (Perrin 2008).
Non-stimulant ADHD medications are an effective alternative for some individuals. There are only a few non-stimulant ADHD drugs approved by the FDA. The first is atomoxetine (Strattera®), which inhibits reuptake of the neurotransmitter norepinephrine. Others include clonidine (Catapres®, Kapvay®) and guanfacine (Tenex®, Intuniv®), which counter the effects of the sympathetic nervous system (Cruz 2010; Antshel 2011; Christman 2004).
Use of atomoxetine avoids some of the complications associated with stimulants, notably tics and sleep disturbances, but there is an increased risk of suicidal thinking in children and adolescents given the drug, so people in these age groups should be carefully monitored for the first few months after beginning treatment or changing dosage (Purper-Ouakil 2005; FDA 2005).
Antidepressants. Although not FDA-approved for the treatment of ADHD, antidepressants, including venlafaxine (Effexor®) and the tricyclic antidepressant bupropion (Wellbutrin®), have also shown some promise in treating ADHD (Greydanus 2009; NIH 2013b). In one double-blind randomized trial, bupropion was found to be comparable in effect to methylphenidate (Jafarinia 2012).
Other agents. Modafinil (Provigil®), a wakefulness- and cognition-promoting drug, has also been used to treat ADHD and has shown promise in clinical trials on both children and adults with ADHD (Greydanus 2009; Kumar 2008). It is not FDA-approved for ADHD treatment as of the time of this writing (Spiller 2013).