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Risks and Benefits of Available Treatments for Adult ADHD

Jeffrey H. Newcorn, MD

Division of Child and Adolescent Psychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York

Why treat ADHD in adults? Implicit in that question is the idea that not all ADHD has to be treated. For instance, someone who is minimally distracted and is in a setting that does not require constant vigilance may be able to manage without treatment. However, for those individuals requiring treatment, therapy is intended to reduce the impairment resulting from symptoms rather than the symptoms themselves. Adult ADHD is associated with a predominance of inattention-related impairment, and treatment targets include academic or occupational problems related to attention, task completion, and time management, as well as relationship or self-esteem problems.

Comorbidity is common in adults with ADHD. Typical comorbidities include mood and anxiety disorders, substance use disorders, and, in some cases, personality disorders. When ADHD occurs with comorbidity, selected treatments have the potential to alter the course of the comorbid disorder as well.

Pharmacotherapy in Adults With ADHD

A variety of FDA-approved medications are available for treating adults with ADHD, including the stimulants methylphenidate and amphetamine. Within the methylphenidate stimulant class, OROS methylphenidate and extended-release dexmethylphenidate are approved for use in adults. Extended-release mixed amphetamine salts and lisdexamfetamine are the approved amphetamine stimulants. The only nonstimulant approved for use in adults is atomoxetine.

Off-label treatments for adult ADHD include the nonstimulant medications bupropion and extended-release guanfacine (the latter is approved for ADHD in children and adolescents), and modafinil, an atypical (schedule 4) stimulant approved for the treatment of excessive sleepiness associated with sleep disorders. Other medications sometimes used, although much less frequently than those previously mentioned, include clonidine, the tricyclic antidepressants, and venlafaxine.

Patients with ADHD usually need medication coverage throughout the day, but this is particularly true for adults, since an adult’s work day lasts longer than a child’s school day. When attempting to dose stimulant medications adequately in adolescents and adults, it may be useful to consider milligram-per-kilogram dosing guidelines—not because the medications are administered according to a weight-based dose schedule, but because this calculation can provide a reference for evaluating absolute dose.

Mechanisms of action. All medications used for the treatment of ADHD affect catecholamine neurotransmission in the anterior and posterior attention centers of the brain. The catecholamines dopamine and norepinephrine suppress irrelevant signals and enhance relevant signals, respectively. A variety of other neuromodulators also interface with these neurotransmitters.

Stimulant medications bind to dopamine and norepinephrine transporters, while the nonstimulant medication atomoxetine binds relatively selectively to the norepinephrine transporter. These transporters, located on presynaptic neurons, are involved in the reuptake of neurotransmitter from the synaptic cleft. Amphetamine also facilitates neurotransmitter release by blocking reuptake into synaptic vesicles. The above processes result in an accumulation of dopamine and norepinephrine in the synaptic cleft,1,2 which is then available to potentiate postsynaptic neuronal impulses.

Pharmacotherapy for ADHD changes the way the brain processes information by altering the functioning of neural networks. For instance, fMRI scans of untreated children with ADHD obtained while performing a neuropsychological test of response inhibition showed decreased activation in the striatum compared with healthy controls.3 After administration of methylphenidate, the fMRI profile showed increased striatal activation in patients with ADHD. A variety of other medication-related changes have also been observed.

Stimulants. Each of the stimulant drugs approved for treating adult ADHD have demonstrated a clear separation from placebo and, when dosed comparably, probably have similar efficacy. However, there are differences in effect sizes across multiple studies. When studied in a forced-dose titration design, OROS methylphenidate
(AV 1AV 1),4 extended-release dexmethylphenidate,5 extended-release mixed amphetamine salts,6 and lisdexamfetamine (AV 2AV 2)7 each showed a decline in symptoms, but generally no appreciable difference across dose ranges.

Stimulants have black box warnings for abuse potential. Longer-acting formulations have a gradual onset and offset and may cause less euphoria, thereby reducing the risk of abuse. Lisdexamfetamine is metabolized in such a way that it has less abuse liability than other amphetamine formulations.7 Responsible stimulant use is safe and well tolerated, but common adverse effects that may complicate treatment include dry mouth, insomnia, nausea and abdominal pain, appetite suppression, headache, edginess or irritability, and changes in a variety of cardiovascular indices that are not necessarily robust at the group level but can be significant for individuals.4–8 Individuals may experience significant differences in tolerability or in efficacy with methylphenidate and amphetamine even though the average response across groups is relatively similar.

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Atomoxetine. Atomoxetine has demonstrated efficacy in the treatment of adult ADHD (AV 3AV 3).9 The time course to response shows incremental improvement over time.10 Side effects of atomoxetine in adults include dry mouth, insomnia, nausea, dizziness, and increased blood pressure and heart rate. Decreased appetite due to gastrointestinal distress (most often seen early in treatment) and decreased libido and erectile difficulty (generally seen in older men) may also occur.9,10 Hepatotoxicity has been reported in a few cases. Atomoxetine does not carry a risk for abuse liability in animals; it does not bind to receptors associated with abuse potential, nor does it increase dopamine in the striatum or nucleus accumbens.2 Atomoxetine is also not associated with euphoria and abuse liability in humans when administered at usual doses.11 Atomoxetine has a black box warning for suicidality in children and adolescents.

Bupropion. Bupropion is an antidepressant that has been studied as an off-label treatment for adults with ADHD and has shown a moderate degree of response. For example, Wilens et al12 found a 30% reduction in ADHD Rating Scale scores (the pre-determined response threshold in this study) in 53% of patients taking extended-release bupropion compared with 31% of those taking placebo (AV 4AV 4), with no occurrence of serious adverse events. The most common side effects were headache, dry mouth, and insomnia. Bupropion has a black box warning for suicidality in children, adolescents, and adults younger than 25 years old.

Pharmacotherapy for Adults With ADHD and Comorbid Disorders

Because data specific to comorbidity in adults with ADHD are unavailable, recommendations are extrapolated from the few extant child and adolescent studies. Atomoxetine treatment reduced both ADHD and anxiety symptoms in patients with ADHD and comorbid anxiety disorders13 and has been shown to reduce tics in a subgroup of ADHD patients with Tourette’s syndrome and tic disorders.14 In individuals with comorbid substance use disorder, atomoxetine may be a good treatment selection because of its decreased abuse potential. In patients with ADHD and comorbid depression, bupropion (an approved antidepressant) may be effective in treating both disorders.15 Alternatively, patients with ADHD and comorbid depression might be prescribed a stimulant and an SSRI antidepressant.

Cardiovascular Assessment

Safety considerations are similar for children and adults with ADHD. It is important to assess the risk of adverse cardiovascular effects in people of all ages at baseline and after treatment initiation. The caveat for adults is that pulse and blood pressure are higher than in children and adults have increased risk for cardiovascular disease, so cardiovascular safety considerations take on even greater significance in the adult population. Clinicians should take a medical history and screen patients for (1) personal, congenital, or acquired cardiac disease; (2) a family history of premature cardiac disease at less than 30 or 40 years of age; and (3) a history of palpitations, chest pains, syncope, seizures, and post-exercise symptoms that might indicate cardiovascular problems. It is also important to inquire about the use of other medications that could exacerbate the cardiovascular effects of ADHD treatments, including over-the-counter stimulant formulations such as decongestant medications and caffeine.16 Often, adults may have had an ECG or stress test as part of their routine medical check-up, so those results may be available.

Nonpharmacologic Treatment for ADHD

Psychosocial and psychoeducational interventions and environmental modifications can be very useful in treating ADHD and should be combined with pharmacotherapy when possible,17 especially when treating adults, as the need for self-management strategies is greater for adults than for children. Clinicians should help patients identify and avoid distracting environments, organize their physical space, and establish automated methods for managing tasks. Individuals with ADHD do better when they are given short, focused directions rather than detailed instructions that attempt to cover multiple content points. Patients also respond to a focus on motivation and interest because attentional dysfunction is highest in tasks that are not intrinsically motivating or rewarding. Therefore, instructing patients in the use of external aids such as electronic calendars with planners, tape recorders, notepads, checklists, and reminder alarms can be helpful. To target time management and organization, teach patients to break down complex tasks into a series of smaller ones, to effectively use planning aids, and to implement contingent self-reinforcement and positive and negative visualization.

Summary

Pharmacotherapy with either stimulants or nonstimulants can be effective for the treatment of adult ADHD. This is true whether or not the patient has a comorbid disorder. Strategies for treating adult ADHD and comorbidities are generally not evidence-based; the recommended strategy is to use monotherapy as an initial approach before moving to combination therapy. It is important to monitor symptoms of ADHD and comorbid disorders because treatment in one domain can affect symptoms across multiple domains. Adults may require higher absolute doses of stimulants than children, but not necessarily higher milligram-per-kilogram doses. Treatment should be tailored to fit the duration of the impairment over the course of the day. In addition, cardiac screening and monitoring is recommended. Although the evidence base for psychosocial intervention in adults is sparse, it is logical to combine medication with psychosocial management. Patients should be trained in a variety of self-management techniques, but treatment plans should also emphasize the patient’s strengths.

For Clinical Use

  • Screen adults with ADHD for comorbid disorders, and tailor treatment accordingly
  • Screen patients for cardiovascular risks at baseline, and regularly reassess after treatment initiation
  • Target the patient’s work day for full treatment coverage, and use milligram-per-kilogram calculations if necessary to reach a therapeutic adult dose
  • Combine pharmacotherapy with psychosocial interventions when possible

Drug Names

amphetamine (Adderall and others), atomoxetine (Strattera), bupropion (Aplenzin, Wellbutrin, and others), clonidine (Catapres, Duraclon, and others), dexmethylphenidate (Focalin and others), guanfacine (Intuniv, Tenex, and others), lisdexamfetamine (Vyvanse), methylphenidate (Daytrana, Ritalin, and others), modafinil (Provigil), venlafaxine (Effexor and others)

Abbreviations

ADHD=attention-deficit/hyperactivity disorder, ADHD-RS=Attention-Deficit/Hyperactivity Disorder Rating Scale, AISRS=Adult ADHD Investigator System Report Scale, CAARS-INV=Conners’ Adult Attention Rating Scale-Investigator rated, CGI-I=Clinical Global Impressions-Improvement scale, CGI-S=Clinical Global Impressions-Severity scale, ECG=electrocardiogram, FDA=US Food and Drug Administration, fMRI=functional magnetic resonance imaging, ITT=intent-to-treat, OROS=osmotic-controlled release oral delivery system, SSRI=selective serotonin reuptake inhibitor, XL=extended release

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References

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