Treating Adults With Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is often underappreciated and inadequately treated in adults.¹ Long thought to be a disorder of childhood, ADHD is now believed to persist into adulthood in approximately half of all cases.² Current epidemiological data suggest an estimated prevalence of 4.4% in adults.³ However, this may be an underestimation; a recent study questioned the requirement that symptoms be present before age 7 and suggested that the criteria for age of onset be raised, possibly to 12 years.¹ Further research is needed in this area.

The importance of adequately treating ADHD in adults is underscored by evidence of significant impairment secondary to untreated ADHD, including significant deficits in educational, occupational, and social functioning.⁴ Poor driving skills have been reported in this population and are of particular concern given the increased morbidity and mortality associated with traffic accidents.^5,6

By definition, adults have lived with symptoms of ADHD longer and may have a higher degree of sequelae than children. These sequelae include poor self-esteem, temper issues, mood reactivity, anxiety, decreased motivation, and other symptoms associated with depression and anxiety.⁷ Along these lines, the rates of comorbidity in adult ADHD are striking, with estimates as high as 90%.⁸ Common comorbidities include disruptive and antisocial behaviors, learning disorders, tic disorders, anxiety disorders, personality disorders, substance abuse disorders, and mood disorders.⁸ It remains unclear how much comorbidity is the result of adults living with untreated ADHD for many years. Studies suggest that adults with ADHD who have comorbid conditions are often treated for the coexisting disorder but not ADHD, further emphasizing the need for adequate detection and treatment of ADHD.⁹

Integrated treatment
Although the treatment of ADHD in adults has received little attention-particularly in comparison with the treatment of children and adolescents-some general guiding principals are evident.

First, the importance of integrating psychosocial intervention is underscored.^2,10,11 There is strong evidence that core deficits of inattention, hyperactivity, and impulsivity can be treated effectively with standard ADHD medication. However, without adequate psychosocial treatment, the improvement in these core symptoms may not translate into improved functioning.

Children who are typically in a school setting have a built-in system for addressing the deficits inherent with ADHD, but this is not the case with adults and medication may not alleviate all the symptoms of adult ADHD.⁸ Adults may be particularly good candidates for psychosocial intervention since they are typically self-referred, as opposed to children, who are brought in by their parents.¹⁰

Specific psychosocial interventions that hold promise include psychoeducation; behavioral modification; social skills training; academic/occupational intervention; and psychotherapy,^2,8 including cognitive-behavioral therapy, which has recently been adapted for the treatment of adults with ADHD.¹⁰

All adults who are being treated for ADHD should receive basic psychoeducation regarding the symptoms and course of the disorder.⁸ The importance of medication compliance should be integrated into the overall treatment plan.¹² Furthermore, patients may be referred to various self-help books or support organizations such as Children and Adults With Attention-Deficit/Hyperactivity Disorder (CHADD).²

Fostering the development of coping skills and helping the patient to better structure his or her environment are also important in the psychosocial treatment of ADHD.⁸ Cognitive-behavioral therapy in adults with ADHD focuses on improving coping skills that are impaired by many years of distractibility, disorganization, and impulsivity, and holds particular promise as an adjunct to medication; however, controlled trials are needed to confirm efficacy.¹⁰

Pharmacotherapy of ADHD
Just as with children, stimulants and atomoxetine are the mainstay treatment for adults with ADHD. FDA-approved medications for ADHD treatment in adults include mixed amphetamine salts, dexmethylphenidate, and atomoxetine. Please see the Table for a summary of specific FDA-approved medications for adults with ADHD. Package inserts should be reviewed for complete prescribing details. All other medications discussed here are off-label. The mechanism of action for medications used to treat ADHD is thought to involve the neurotransmission of dopamine and/or norepinephrine. Nicotinic agonists may hold some promise and histaminergic systems have been hypothesized to be involved in the pathophysiology of ADHD.

Stimulants
Amphetamine salts and methylphenidate preparations have established efficacy in adults with ADHD.^2,13,14 The mechanism of action for stimulants is thought to be primarily mediated through dopaminergic neurotransmission.¹⁵ Effective dosages in adults should be based on weight and may be significantly higher than the dosages known to be effective in children. For example, a recent study on the use of osmotic-release oral system methylphenidate in adults suggested an optimal dosage of 1.3 mg/kg/d.¹³ Adults in this study had a higher incidence of anorexia, dry mouth, moodiness, anxiety, insomnia, cardiovascular complaints, and dizziness.¹³

Cardiovascular complaints may be of concern in adults more so than in children. Because of the higher incidence of cardiovascular disease, including hypertension, routine monitoring is strongly recommended.^2,13 In addition, the high rate of comorbidity in adults with ADHD is a factor, because stimulants can worsen psychosis, mood, and anxiety. The use of stimulant medication in adults with comorbid substance use disorders is particularly problematic given the potential for abuse. However, long-acting formulations are a reasonable option with less potential for abuse.¹³

Atomoxetine
Multiple studies have confirmed the efficacy of atomoxetine in treating adults with ADHD. Atomoxetine is primarily a norepinephrine reuptake inhibitor, although it may secondarily affect dopamine levels.¹⁵ It may be particularly useful in adults with ADHD, because it can alleviate anxiety symptoms and has no abuse potential.¹⁵ Atomoxetine may be considered first in adults with comorbid substance use disorders, anxiety disorders, or mood disorders.¹⁶ It is generally well tolerated; common adverse effects observed in adults include insomnia and GI and genitourinary symptoms.¹⁵ Increases in blood pressure and pulse have been observed in adults; therefore, atomoxetine should be used with caution in the context of cardiovascular risk factors such as hypertension.¹⁵

Antidepressants
Numerous antidepressant medications have been used to treat ADHD. However, there is limited data supporting their use and published trials typically involved small numbers and high dropout rates.¹⁷

Perhaps the strongest evidence supports the use of desipramine, which has been found to have similar efficacy to stimulants.¹⁷ The results of a 6-week, double-blind, placebo-controlled trial showed desipramine to be effective in the treatment of adult ADHD; however, adverse effects and potential for overdose lethality limit its usefulness.¹⁸

Bupropion is frequently used to treat ADHD. A few small studies support its use in adults. Bupropion's mechanism of action is unclear but may be related to indirect agonism of norepinephrine and dopamine.¹⁹

A double-blind, placebo-controlled, randomized trial of 40 adults with ADHD²⁰ and a recent, larger study involving 162 adults over an 8-week treatment period²¹ supported its use. The latter study used once-daily dosing of bupropion extended-release (XL) and demonstrated effect sizes similar to those seen with atomoxetine for the treatment of adult ADHD.²¹ The study excluded adults with comorbid mood or anxiety disorders, suggesting that the benefit attained with bupropion was independent of any antidepressant or anxiolytic effect, and bupropion-XL was generally well tolerated with no serious adverse events.²¹ The demonstrated efficacy of bupropion in the treatment of depression suggests that it may be used as monotherapy in patients with comorbid ADHD and depression.

In a preliminary study, venlafaxine was shown to effectively treat ADHD in adults with comorbid ADHD and depression.²² Venlafaxine alone was found to be comparable in efficacy to a combination of stimulants and antidepressants, suggesting that venlafaxine may also be an option as monotherapy for patients with comorbid depression and ADHD.²² There are no controlled studies using venlafaxine for the treatment of ADHD and more research is needed.

Monoamine oxidase inhibitors and other tricyclic antidepressants besides desipramine have been used to treat ADHD with varying levels of success, but their use is limited by problematic adverse effects. There is little evidence supporting the use of SSRIs, possibly because of their lack of activity on norepinephrine and dopamine systems.²

α-Adrenergic agonists
The central α-agonists clonidine and guanfacine are often used in the treatment of ADHD, but there is little data to support their use, particularly in adults. Potential adverse effects include rebound hypertension, dizziness, and transient sedation.^2,23 Cardiovascular monitoring is recommended.

Modafinil
Modafinil was efficacious in 2 placebo-controlled studies in children and adolescents^24,25 and in 2 small studies with adults.^26,27 The apparent efficacy of modafinil is particularly interesting in that it is not thought to enhance noradrenergic or dopaminergic transmission. It has been suggested that the mechanism of action of modafinil in the treatment of ADHD might involve selective activation of histaminergic wakefulness.²⁶ Unfortunately, in recent trials modafinil was associated with one suspected case of Stevens-Johnson syndrome; this has hindered further efforts to seek approval of the medication for ADHD treatment.²⁸

Nicotinic agonists
Dysregulation in the nicotinic system has also been suggested in the pathophysiology of ADHD, and cholinergic agonists have been postulated for ADHD treatment. A pilot study of a cholinergic agonist, ABT-418, in a population of adults with ADHD demonstrated that ABT-418 was well tolerated and efficacious, although it was not as robust as stimulant medication.²⁹

However, a recent double-blind, placebo-controlled, randomized trial of the acetylcholinesterase inhibitor galantamine failed to show efficacy.³⁰ The dosages in this study were based on the treatment of geriatric patients with dementia and may have been too low in healthy adults with ADHD.³⁰ More studies are needed to clarify the role of nicotinic agonists in the treatment of adult ADHD.

Oxcarbazepine
Oxcarbazepine was found to be relatively well tolerated and effective in the treatment of adult ADHD in a small pilot study (N = 9).³¹ Adverse effects included dizziness, sedation, and nausea. The authors hypothesized that the clinical effect of oxcarbazepine on ADHD may be through enhanced dopaminergic transmission.³¹

Light therapy
A recent open trial of light therapy as an adjunctive treatment to medication in adults with ADHD resulted in improvements not only in mood but also in core ADHD symptoms and objective measures of attention.³²

Combination pharmacotherapy
There is little evidence supporting the use of combination pharmacotherapy in the treatment of adult ADHD, although it is common practice.³³ Circumstances in which combination pharmacotherapy may be advised include a partial response to one agent, dose-limiting adverse effects, and comorbid disorders.³³ Perhaps the most common combination strategy is to use a central α-agonist in combination with a stimulant.² This is an attractive strategy, given the complementary therapeutic effects of α-agonists (noradrenergic) and stimulants (dopaminergic), as well as the potential to lessen the adverse effects of stimulants (eg, insomnia).

The Texas Children's Medication Algorithm Project has advocated combining stimulant medication and atomoxetine in children who are partially responsive to either agent.³⁴ A recent chart review supported the use of dexmethyl-phenidate in combination with another stimulant to increase the duration of efficacy and the use of mirtazapine to reduce stimulant-induced insomnia.³³ Combining medications can be associated with a greater adverse-effect burden, and there have been negative reports on the use of combination treatment.

In a study on the use of paroxetine in combination with dextroamphetamine, adults with ADHD who received both paroxetine and dextroamphetamine showed little improvement over the monotherapy group that was treated with dextroamphetamine alone. The group receiving combination therapy exhibited a greater degree of adverse events.³⁵ Of note, there was no improvement in ADHD symptoms with paroxetine alone.³⁵

Conclusion
Adult ADHD is an increasingly recognized public health problem for which we currently have a multitude of treatment options. Adults with ADHD are likely to respond as well as or better than children to psychosocial interventions combined with pharmacotherapy because of increased motivation and lack of inherent psychosocial supports. The choice of pharmacotherapy for adults is similar to that for children, although there may be a greater focus on substance abuse, cardiovascular adverse effects, and comorbidity.

Stimulant medication should be considered first. However, in the context of comorbid substance abuse, anxiety, or mood symptoms, atomoxetine may be the first choice. Combination pharmacotherapy or alternative medications, such as antidepressants that affect norepinephrine and/or dopamine systems, as well as central α-agonists, may be considered in nonresponders. Newer agents such as modafinil, nicotinic agents, and oxcarbazepine hold promise as future treatments for ADHD and may help shed light on the pathophysiology of ADHD.