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(PSYCHIATRIC TIMES) - Educational Objectives:

After reading this article, you will be familiar with:

* The signs and symptoms of adult ADHD.
* The tools available to help clinicians establish a diagnosis of adult ADHD.
* The therapies available to manage ADHD in adults.

Who will benefit from reading this article?

Psychiatrists, primary care physicians, neurologists, nurse practitioners, psychiatric nurses, and other mental health care professionals. Continuing medical education credit is available for most specialties. To determine if this article meets the continuing education requirements for your specialty, please contact your state licensing board.

Dr Doyle is clinical instructor in psychiatry at the Harvard Medical School in Boston. He is on the speakers bureau for Ortho-McNeil Inc, Lilly, Shire, Novartis, and Celltech.

Anne is a 46-year-old woman who never attended college because her high school counselor told her she was not "college material." Given her lackluster academic performance, she never thought to question this advice until her 9-year-old son was evaluated for attention deficit hyperactivity disorder (ADHD). Although she never had the hyperactive/impulsive symptoms that prompted his referral, she did relate to many, if not most, of the symptoms of inattention that were discovered during his evaluation. Anne asked the pediatrician whether adults can have ADHD, because she recalled seeing an advertisement on television about adult ADHD. The pediatrician assured her that ADHD does exist in adults and that treatment is available. He sheepishly added, "I always suspected that you might have ADHD. My reception staff notices too. They place bets on how late you will be for each appointment. Jennie won today."

Most pediatricians and pediatric psychiatrists are familiar with this scenario and with the frustration of finding referral sources for adults with ADHD. This article is intended to help clinicians accurately diagnose and treat ADHD in adults. Scientific evidence supports the validity of diagnostic criteria as well as the safety of treatments for this condition. Seeing a person thrive as ADHD symptoms remit can be one of the most rewarding experiences for physicians.

Epidemiologic studies suggest that 40% to 70% of children with ADHD continue to meet the criteria for ADHD as they age.1-3 These findings are consistent with a recently reported prevalence rate of 2.9% in 966 randomly selected adults who completed a telephone survey.4 Because of the high prevalence for adult ADHD (2%-6%),5 clinicians should be careful not to overlook symptoms of ADHD, especially if patients present for evaluation of other symptoms.

To appreciate why recognition of adult ADHD has taken so long, it is helpful to look back at the development of the diagnosis of ADHD. The precursor to the present notion of the disorder was hyperkinetic disorder of childhood.6 Because most hyperactive/ impulsive symptoms tend to attenuate or abate as persons with ADHD approach adulthood, the youngsters, mainly boys, in whom hyperkinetic disorder was diagnosed seemed to be growing out of their illness.

In the early 1970s, the relationship between inattention and impulsive behaviors in hyperactive children became recognized.7 In DSM-III,8,9 the nomenclature was changed to attention deficit disorder (ADD) with or without hyperactivity to acknowledge the core problems with attention. Although still considered a childhood condition, inattentive symptoms appeared to persist into adulthood.

With DSM-IV,10 the hyperactive/impulsive symptoms of hyperkinetic disorder and the inattentive symptoms of ADD were brought together under the diagnosis of ADHD with its 3 subtypes: hyperactive (at least 6 hyperactive/impulsive symptoms), inattentive (at least 6 inattentive symptoms), and combined (at least 6 hyperactive/impulsive and 6 inattentive symptoms).11 To complete the diagnosis, a patient must have impairment in 2 or more settings and symptoms must be chronically present for at least 6 months with some symptoms causing impairment earlier than age 7.11

In children and adults, the hyperactive subtype is the least prevalent. The combined subtype is most common in childhood, whereas the inattentive subtype is the predominant diagnosis for adults. In childhood, two thirds of those in whom ADHD is diagnosed are boys, but the ratio in adults is approximately equal between men and women.12

Of course, hyperactive/impulsive symptoms may be present in adults, but these seem easier to accommodate in the daily life of an adult. For example, a child who was frequently scolded for leaving his desk at school grows up to find a sales job in which moving about becomes an asset in making frequent calls on his clients. Even though hyperactivity enhances his performance in some ways, the inattentive symptoms, such as late paperwork, inaccurate sales reports, and the like, seldom lead to positive outcomes.

Some adults with ADHD have developed the discipline to dampen the hyperactive/impulsive symptoms in certain situations, and they appear to be successful at this. For instance, an individual will focus on staying still during a business meeting because shifting and squirming disturbs others; however, a good portion of his limited attention will be on the task of staying still rather than on the information presented during the meeting. Therefore, in diagnosing ADHD and monitoring adults with the disorder, the clinician should not only ask whether a symptom is present but also whether the person is making a significant effort to compensate. Obtaining corroborating information from a spouse, significant other, or someone else close to the patient can clarify a patient's true level of impairment. Family members frequently help establish onset of symptoms when patients cannot recall their own early behaviors.

Adults with ADHD are at higher risk for divorce than those without the disorder.13 Divorce frequently increases financial burdens, consequently adding to the family's emotional turmoil. Financial burdens may increase because the individual with ADHD may be overlooked for promotion because of the frequent problem with follow-through. People with ADHD do not earn as much as people without ADHD who have the same level of education.14 They often switch jobs and are at higher risk for unemployment.13

The criteria for diagnosing ADHD in children and adolescents are well established, but a few caveats should be kept in mind when applying them to adults. The current criteria stipulate that many of the symptoms must occur often to be counted toward the diagnosis. For adults, symptoms might be infrequent, yet the disorder can be significantly disruptive. For instance, a successful salesman with ADHD might be delinquent on his sales reports only once a month, and his household bills and mortgage payments are always on time. With further probing, one might find that his sales reports are due only once a month and that his wife handles the family finances.

Because an amalgamation of compensation and chronic frustration may cause ADHD symptoms to manifest differently in adults than in children, several rating scales have been developed specifically for adults with ADHD. These include older instruments, such as the Wender Utah Rating Scale and the Copeland Symptom Checklist for Adult Attention- Deficit Disorders, as well as newer ones, including the Conners' Adult ADHD Rating Scale, the Brown Attention Deficit Disorder Scales, and the Adult ADHD Self-Report Scale.15-19 A high score on the Adult ADHD Self-Report Scale indicates the need for a more complete evaluation of ADHD symptoms.15 Although rating scales are helpful in establishing the diagnosis and tracking treatment response, they are not a substitute for a careful clinical examination and history, which remain the gold standard for diagnosing ADHD.
Imaging studies

Neuroimaging studies provide valuable information about the anatomic and functional differences in the brains of persons with ADHD, yet neuroimaging remains a research tool rather than a clinical one. Two neuroimaging studies have documented a smaller posterior inferior cerebellar vermis in persons with ADHD compared with normal controls.20,21 Various neuroimaging studies showed structural differences, such as a smaller cortex,22 right prefrontal cortex,23 right frontal cortex,24 and corpus callosum. 22,25-27 One study demonstrated that persons with ADHD had smaller caudate nuclei,23 while another found the opposite.28 Abnormalities in the right prefrontal cortex have also been documented.29

Functional MRI studies using a modified Stroop test have demonstrated differences between adults with ADHD and normal controls.30,31 Those with ADHD showed activity in the frontal striatal networks while persons without the disorder engaged the anterior cingulate gyrus during the same task.30,31

Positron emission tomography (PET) studies provide evidence of decreased frontal cortical activity in adults with ADHD.32 PET imaging studies also elucidate the mechanism by which methylphenidate increases extracellular dopamine (DA) by blocking the DA transporter.32

A study using single photon emission computed tomography (SPECT) with results corrected for age demonstrated a 70% increase in DA receptor density in 6 individuals with ADHD compared with 30 normal controls.33 SPECT imaging employing highaffinity ligands, such as 123I altropane, as well as other neuroimaging technologies, currently play an important role in illustrating that ADHD is a biologically based disorder, and they hold promise as diagnostic tools in the future.

Cognitive-behavioral therapy (CBT) may help some adults with ADHD improve functionality. One type of CBT with a more behavioral basis strives to develop alternative strategies, such as using noise-cancelling headphones to eliminate distractions and to compensate for core deficits so that the patient experiences less functional impairment.34 The therapist may also devise positive rewards that improve motivation in finishing a task (eg, balancing a checkbook) that a patient may be putting off. Another type of CBT with a more cognitive approach addresses the effects that a history of academic, employment, and interpersonal relationship problems has on a patient's problem-solving style.34 This type of CBT attempts to change the dysfunctional thinking patterns that often develop in persons with ADHD. For instance, a life of frustration related to ADHD can result in a "why try" attitude in the individual that leads to further procrastination and a self-defeating cycle of behaviors. Safren and colleagues35 showed that CBT can be a useful adjunctive therapy for adults who have residual ADHD symptoms despite pharmacologic interventions. Thirty-one men and women with ADHD, who were on stable medication regimens, were randomly assigned to pharmacotherapy alone or pharmacotherapy with CBT. More treatment responders were found in the group that received CBT (56%) than in the group that received medication alone (13%) (p<0.2).

Genetic studies contribute to our understanding of ADHD as a neurodevelopmental disorder. Studies of family members and twins demonstrate that ADHD has one of the highest familial factors (0.8) of any psychiatric disorder.36 Someday, a genetic test may guide pharmacologic management of ADHD; today, however, clinicians must rely on a somewhat empiric approach to treating a person with ADHD.

A review of the data from 9 double-blind, placebocontrolled trials of stimulants used to treat adults with ADHD showed response rates between 25% and 78%.37 Given their proven efficacy and tolerability, stimulants remain the mainstay of treatment.

Immediate-release stimulants include methylphenidate, D-methylphenidate, dextroamphetamine, and amphetamine mixed salts. Immediate-release methylphenidate products provide an approximate 4-hour duration of action, while immediate-release D-amphetamine's duration of action varies between 3 and 6 hours.

Although intermediate-duration stimulants such as sustained-/extended-release methylphenidate last longer than immediate-release formulations, these medications are not as widely used for the treatment of ADHD. The pharmacokinetics of sustained-/extended-release methylphenidate does not show the ascending profile necessary to provide continuous coverage of ADHD symptoms.38,39 The plateau in plasma levels limits its use in treating ADHD.

During the past several years, the new generation of long-acting stimulant medications (oralrelease osmotic system [OROS] methylphenidate, methylphenidate, D-methylphenidate extendedrelease, methylphenidate continuous delivery, and amphetamine mixed salts) have offered the convenience of once-daily dosing, which improves adherence to the treatment regimen by providing an ascending pharmacokinetic profile without the inconvenience of multiple daily dosing.

The first of the longer-acting stimulants, OROS-methylphenidate provides 12-hour coverage of ADHD symptoms by delivering methylphenidate with an ascending pharmacokinetic profile. Two methylphenidate products that use immediaterelease and delayed-release beads (Metadate CD and Ritalin LA) provide approximately 8-hours' duration of action.

D-Methylphenidate extended-release delivers immediate- and delayed-release action in a 50:50 ratio. The amphetamine mixed salts is a long-acting amphetamine-based stimulant that also delivers immediate-release and delayed-release beads in a 50:50 ratio; its duration of action is about 10 hours.

The methylphenidate patch is the most recent advance in the ADHD treatment armamentarium. It delivers methylphenidate through a patch technology that incorporates the medication in the adhesive so that the potential for misuse or abuse is very low. The methylphenidate patch allows the patient to control the duration of action based on wear time. It eliminates the need for swallowing pills for those patients who have trouble with this.40

Pemoline is another class of stimulant that is no longer available, due to the rare risk of liver toxicity, which has outweighed its benefit. Abbott pharmaceuticals decided to discontinue pemoline marketed as Cylert, and all generic producers have agreed to stop sales and marketing their pemoline products.

Atomoxetine is the only other medication approved for the treatment of adult ADHD. It is a nonstimulant drug that works primarily by blocking the reuptake of norepinephrine into the presynaptic neuron. Stimulants, on the other hand, predominantly block the reuptake of DA, and, to a lesser extent, norepinephrine. However, animal data suggest that atomoxetine may increase both norepinephrine and DA levels, especially in the prefrontal cortex. In contrast to methylphenidate, animal studies show that atomoxetine does not increase DA in striatum or nucleus accumbens, suggesting it should not have strong motoric or drug abuse liabilities.41

Atomoxetine is not a controlled substance and it can provide all-day coverage with once-daily dosing; however, the FDA recently issued a warning about liver dysfunction in 2 patients treated with atomoxetine. Recently, the FDA issued an alert regarding reports of suicidal thinking in children and adolescents treated with atomoxetine. Analysis of adult patients treated with atomoxetine for either

ADHD or major depression found no increase in suicidal ideation or behaviors in this population.42

Although not approved for ADHD, studies suggest that catecholaminergic antidepressants may be considered second-line agents. Nortriptyline, which mainly modulates noradrenergic receptors, improved symptoms in 68% of patients in a 6-week, doubleblind, placebo-controlled trial.43 A 1-year retrospective chart review showed that nortriptyline and desipramine were moderately helpful in controlling symptoms.44 Bupropion, which influences dopaminergic and noradrenergic receptors, showed benefit in an open-label study and a 6-week, double-blind, placebo-controlled trial in which 52% of the patients responded well.45 Open studies of pargyline and selegiline showed moderate reduction of ADHD symptoms in adults.46 Venlafaxine modulates serotonergic and noradrenergic receptors and has been shown to reduce ADHD symptoms in study subjects; however, high rates of intolerance were reported.47 With a variety of medications available to treat ADHD, clinicians now have the tools to optimize treatment in adults (Table).

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