The ADHD adolescent and young adult is at risk for school failure, emotional difficulties, poor peer relationships, and trouble with the law. Factors identifiable in younger youth that predict the persistence of ADHD into adulthood include familiality with ADHD and psychiatric comorbidity—particularly aggression or delinquency problems. Although the literature provides compelling evidence that the diagnosis of ADHD in childhood predicts persistent ADHD and poor outcome in adolescence, these findings also suggest that such a comprised outcome is not shared by all ADHD children. The discussion thus far has not addressed a related clinical question: Can the functioning of ADHD children normalize in the context of persistent ADHD? We analyzed data from a 4-year longitudinal study of referred children and adolescents with ADHD, to assess normalization of functioning and its predictors among boys with persistent ADHD.
Using indices of emotional, educational, and social adjustment, we found that 20% of children with persistent ADHD functioned poorly at follow-up in all three domains, 20% did well in all three domains, and 60% had intermediate outcomes. These findings suggested that the syndromatic persistence of ADHD is not associated with a uniform functional outcome but leads instead to a wide range of emotional, educational, and social adjustment outcomes that can be partially predicted by exposure to maternal psychopathology, larger family size, psychiatric comorbidity, and impulsive symptoms.
Medications remain a mainstay of treatment for children, adolescents, and adults with ADHD. In fact, recent multisite studies support that medication management of ADHD is the most important variable in outcome in context to multimodal treatment. For example, in a large prospective and randomized long-term trial of ADHD youth, those receiving stimulants alone were observed to have similar improvement in core ADHD symptoms at 14 months follow-up compared to those randomized to receive stimulants plus psychotherapy. Of interest, both medicated groups had a better overall outcome than those receiving extensive psychotherapy without stimulants. The stimulants, specific norepinephrine reuptake inhibitors (SNRIs), certain antidepressants, and certain antihypertensives comprise the available agents for ADHD. Stimulants, SNRIs, and antidepressants have been demonstrated to have similar pharmacological responsivity across the lifespan including school-aged children, adolescents, and adult groups with ADHD.
The stimulants are the most commonly prescribed agents for pediatric and adult groups with ADHD. The most commonly used compounds in this class include methylphenidate (Ritalin, Concerta, Metadate, Focalin, and others) and amphetamine (Dexedrine, Adderall). Stimulants are sympathomimetic drugs, which increase intrasynaptic catecholamines (mainly dopamine) by inhibiting the presynaptic reuptake mechanism and releasing presynaptic catecholamines. Whereas methylphenidate specifically blocks the dopamine transporter protein, amphetamines also release dopamine stores and cytoplasmic dopamine directly into the synaptic cleft. Recent data suggests that acute tolerance to stimulants may develop rapidly necessitating an ascending- or pulsing-pharmacokinetic profiles for ADHD efficacy.
Methylphenidate and d-amphetamine are both short-acting compounds, with an onset of action within 30–60 minutes and a peak clinical effect usually seen between 1 and 2 hours after administration lasting 2–5 hours. The amphetamine compounds (Adderall) and sustained release preparations of methylphenidate and dextroamphetamine are intermediate-acting compounds with an onset of action within 60 minutes and duration of 6–8 hours.
Given the need to additionally treat ADHD outside of academic settings (i.e., social, homework) and to reduce the need for in school dosing and likelihood for diversion, there has been great interest in extended release preparations of the stimulants. Extended release preparations greatly reduce untoward peak adverse effects of stimulants such as headaches and moodiness, as well as essentially eliminating afternoon wear off and rebound.
A new generation of highly sophisticated, well-developed, safe and effective long-acting preparations of stimulant drugs has reached the market and revolutionized the treatment of ADHD. These compounds employ novel delivery systems to overcome acute tolerance termed “tachyphylaxis.” There are several long-acting methylphenidate formulations and a long-acting methylphenidate formulation. While Concerta is a 12-hour formulation, Metadate-CD and Ritalin LA are 8-hour methylphenidate formulations. In addition Adderall XR is a 12-hour amphetamine formulations. Methylphenidate as a secondary amine gives rise to four optical isomers: d-threo, l-threo, d-erythro, and l-erythro. Recently the active stereoisomer, d-threo-methylphenidate compound has been available in an immediate release and long-acting form as Focalin and Focalin XR.
Stimulants appear to work in all age groups of individuals with ADHD. Studies in preschoolers report improvement in ADHD symptoms, structured tasks as well as mother–child interactions; however, there may be a higher side effect burden compared to other age groups. Similarly, in adolescents response has been reported as moderate to robust, with no abuse or tolerance noted. In addition, stimulant treatment has been found to be effective in adults with ADHD.
Predictable short-term adverse effects include reduced appetite, insomnia, edginess, and GI upset. In adults, elevated vital signs may emerge necessitating baseline and on-drug monitoring. There are a number of controversial issues related to chronic stimulant use. Although stimulants may produce anorexia and weight loss, their effect on ultimate height remains less certain. While initial reports suggested that there was a persistent stimulant-associated decrease in growth in height in children, other reports have failed to substantiate this finding, and still others question the possibility that growth deficits may represent maturational delays related to ADHD itself rather than to stimulant treatment. Stimulants may precipitate or exacerbate tic symptoms in ADHD children. Recent work suggests that the majority of ADHD youth with tics can tolerate stimulant medications; however, up to one third of children with tics may have worsening of their tics with stimulant exposure. Current consensus suggests that stimulants can be used in youth with comorbid ADHD plus tics with careful monitoring for stimulant-induced tic exacerbation.
Despite case reports of stimulant misuse, there is a paucity of scientific data supporting that stimulant-treated ADHD individuals abuse their medication; however, data suggests that diversion of stimulants to non-ADHD youth continues to be a concern. Families should closely monitor stimulant medication and college students receiving stimulants should be advised to carefully store their medication. Despite the findings on efficacy of the stimulants, studies have also reported consistently that typically one third of ADHD individuals do not respond or cannot tolerate this class of agents.
Specific Norepinephrine Reuptake Inhibitors (Atomoxetine)
Atomoxetine (Strattera) is one of a new class of compounds, known as SNRIs. Currently atomoxetine is the only nonstimulant that is FDA approved for ADHD. Atomoxetine may be particularly useful in stimulant failures, or when oppositionality, anxiety, or tics co-occur within ADHD. After extensive testing, atomoxetine has been found to be generally safe and well tolerated. However, there have been rare (2 out of 3 million patients) reports of liver injury.
A subgroup of antidepressants are second-line drugs of choice for ADHD. The tricyclic antidepressants (TCAs) as well as bupropion (Wellbutrin) block the reuptake of neurotransmitters including norepinephrine. In contrast, the serotonin reuptake inhibitors are not useful for ADHD. The TCAs are effective in controlling abnormal behaviors and improving cognitive impairments associated with ADHD, but less so than the majority of stimulants. As minor increases in heart rate and the ECG intervals are predictable with TCAs, ECG monitoring at baseline and at therapeutic dose is suggested, but not mandatory.
The antihypertensives clonidine (Catapress) and guanfacine (Tenex) are alpha-adrenergic agonists, which have been primarily used in the treatment of hypertension. These compounds have been shown to be useful in the treatment of ADHD. Guanfacine is longer acting and less sedating than clonidine. The antihypertensives have been used for the treatment of ADHD as well as associated tics, aggression, and sleep disturbances, particularly in younger children.
Modafinil is an antinarcoleptic agent, which is structurally and pharmacologically different than other agents approved to treat ADHD. Testing in children has reported effectiveness in ADHD. While generally safe and well-tolerated there has been concerns about uncommon occurrences of a severe rash possibly related to Stevens Johnson syndrome.
The largest-scale study examining the relative and combined effectiveness of medical and nonmedical interventions for ADHD is the NIMH Multimodal Treatment Study for ADHD Study (MTA). In this 5-year, 6-site project, 579 elementary-age children with ADHD were randomly assigned to one of four 14-month treatment conditions: behavioral treatment, medication management (mostly methylphenidate), combined behavioral treatment and medication management, and a community comparison group. Children in the Behavioral Treatment arm received a very intensive combination of treatments, including school consultation, a classroom aide, an 8-week summer treatment program, and 35 sessions of parent management training. Findings from the MTA study at 14 months indicate that medical intervention was significantly more effective than behavioral and community treatments; that behavioral treatment only modestly enhanced the effect of medication alone; and that behavioral treatment alone was no more effective than the treatment received by children in the community comparison group on core symptoms of ADHD.