Introduction

Although attention-deficit/hyperactivity disorder (ADHD) starts in childhood, the diagnosis is often delayed until adulthood,^[1] leaving behind a trail of academic underachievement, lost jobs, and fractured relationships. Comorbidities are common; a majority of adults with ADHD struggle with anxiety, depressive disorders, and substance abuse as well as other psychiatric problems.^[2,3] The behavior of adults with ADHD directly affects others around them; parenting skills can be compromised because of the adult's inattention, impulsivity, and overall impatience.^[4] Treatment can be helpful in all of these domains of impairment.

Once diagnosed, adults with ADHD are eager to realize benefit. Their doctors can be equally committed to quick gains. Indeed, symptom improvement will enhance overall medication compliance in this patient population. However, adults with ADHD are no more compliant with their medication regimen than other patients with chronic disorders; one study found that adults with ADHD take only half the medication prescribed to them.^[5]

Four long-acting stimulant drugs are approved to treat ADHD in adults and all are rapidly efficacious: mixed amphetamine salts extended release (MAS XR); extended-release dexmethylphenidate; lisdexamfetamine; and osmotic-release oral (OROS) methylphenidate. One nonstimulant, atomoxetine, is indicated for adults. All 5 of these medications have been proven superior to placebo (Table 1).^[6-10]

Table 1. FDA-Approved Medications for Adult ADHD

Chemical Name	Brand Name	Usual Starting Dose	Duration	Dosage Range
Extended-release mixed amphetamine salts	Adderall XR®	10 mg/morning	8-12 hours	10-30 mg/day
Lisdexamfetamine	Vyvanse™	30 mg/morning	12 hours	20-70 mg/day
OROS methylphenidate	Concerta®	18-36 mg/morning	10-12 hours	18-72 mg/day
Extended-release d-methylphenidate	Focalin® XR	5-10 mg/morning	6-10 hours	10-40 mg/day
Atomoxetine	Strattera®	40 mg/morning	Steady state	40-100 mg/day

ADHD = attention-deficit/hyperactivity disorder; FDA = US Food and Drug Administration; OROS = osmotic-release oral
Data from Young J. ADHD Grown Up: A Guide to Adolescent and Adult ADHD. 2007.^[11]

Short-acting stimulants have been available for decades, but their use as first-line treatment is not advised. These agents require 3-4 daily doses to sustain effectiveness throughout the day. This is a tall order for patients with preexisting struggles with time management and organization. Furthermore, because behavioral response is linked to drug metabolism and these agents have a therapeutic effect that wanes within hours of administration, it is difficult for a clinician to assess efficacy in patients with rapidly shifting blood levels. For these reasons, the use of short-acting stimulants delays significant and consistent improvements in symptoms.^[12]

Reviewing Basic Patient Information

Medications play a paramount role in the treatment of ADHD throughout the life cycle. Before choosing a particular medication, the clinician needs to review the patient's medical and psychiatric history, including relevant comorbidities. Of particular note is heart health because stimulants and atomoxetine are associated with an elevated risk for cardiovascular events. The prescriber should take note of previous ADHD medication trials, if any, and how the patient perceived his or her response. The patient's current work and sleep schedule are factors in treatment selection, as is the patient's weight. The appetite-suppression effect of stimulants may promote adherence in some and have the opposite effect in others. In addition, past and current substance abuse should be considered because concerns over misuse and diversion may also influence choice of medication. None of the medications have been proven safe during pregnancy, and this potential should be weighed as well.

Diagnosis

Adults with ADHD typically present with complaints of inattention, distractibility, and impulse dyscontrol. Many times patients are overwhelmed by the intensity of their symptoms, and frequently this pervasive frustration is inaccurately diagnosed as depression or anxiety. Many patients are given trials of antidepressant medication, resulting in a suboptimal outcome. This inappropriate use of medications delays recovery. The diagnosis of ADHD always should be considered when evaluating psychologically distressed nonpsychotic, nondemented individuals.^[13] The common ADHD rating scales reflect the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and help quantify the level of symptomatology (Table 2).

Table 2. Common Rating Scales for Adult ADHD

Name of Scale	For Adolescents	For Adults	Self-rater	Clinician-Administered	Other Raters (Teachers, Parents, Spouses, etc)
Adult Self-Report Scale V.1.1		✓	✓
Adult ADHD Self-Report Scale (ASRS) Symptom Checklist		✓	✓	✓ (Clinician scores and interprets)
Brown ADD Scale		✓	✓
Brown Attention-Deficit Disorder Rating Scale for Adults		✓		✓
Conners Adult ADHD Rating Scale (CAARS)	✓	✓	✓	✓	✓
Wender Utah Rating Scale		✓	✓ (To determine ADHD in childhood retrospectively)

ADHD = attention-deficit/hyperactivity disorder
Data from Young J. ADHD Grown Up: A Guide to Adolescent and Adult ADHD. 2007.^[11]

Looking at Comorbidities

Consideration of ADHD from the outset ensures that anxiety and depression are not default diagnoses. However, anxiety and mood disorders often co-occur with ADHD. In this scenario, treatment choice is dictated by symptom severity. In the presence of suicidal ideations or severe panic, mood symptoms should be addressed first. If the patient has a history of mania, these episodes should be controlled before stimulants are introduced. In other circumstances, ADHD symptoms cause greater difficulty for the patient than other issues, and ADHD medication can be introduced early in the treatment process. Directly treating the underlying ADHD often improves these associated symptoms. In the absence of clear empirical data, the hierarchical approach to ADHD and comorbidities requires extensive clinical judgment (Figure).^[14]

Figure. Pharmacotherapy: how to prioritize treatment in a patient with multiple diagnoses.
Adapted with permission from: Goodman D. In: Biederman J, ed. ADHD Across the Lifespan: An Evidence-Based Understanding From Research to Clinical Practice. Veritas Inc.; Hasbrouck Heights, NJ. 2005.^[14]

Past Patient Experience With ADHD Medications

Most newly diagnosed adult patients will have little experience with ADHD medications other than those they have read about or possibly given to their children. Most patients will be receptive to a medication option, but others may have reservations. Many patients are concerned that the medications are controlled substances and thus are potentially addictive. Others question whether the medications are safe. The clinician needs to anticipate and respond to these concerns. The patient may have had a poor outcome with a previous medication trial. Effective questioning of the patient may reveal simple explanations for this lack of success. The patient may have been underdosed or may not have adhered to the prescribed regimen, particularly if the patient was ambivalent about treatment (as many adolescent are) or the previous medication was a short-acting agent. A long-acting drug and a higher therapeutic dose may make a marked difference. If the patient is resistant to one agent, then trying a different medication might be more effective and elicit better adherence.

Considering Work and Sleep Schedules

The clinician should also review patients' daily work and sleep schedules. For the majority of adults who work in the daytime and sleep at night, morning dosing of stimulants is appropriate. Dose timing is more challenging for adults who work unconventional shifts. Patients who work at night, eg, hospital-based nurses, can be advised to take the medication an hour before starting their work shifts. Medical residents or long-haul truckers may work longer shifts that exceed the duration of the stimulant effect. In these circumstances, adding a short-acting stimulant at the end of the long-acting dose can be helpful. All recipients of stimulants should be aware, however, that with these agents, proper sleep hygiene is essential.

If Overweight or Obesity Is an Issue

The patient's current body mass index should also be considered. One side effect of ADHD medications is appetite loss, and many adults welcome this "adverse effect." Some of the commonly used ADHD medications were previously marketed for the treatment of obesity. This particular feature may help foster adherence, but some individuals may be tempted to escalate their dose of stimulants, reasoning that higher doses may accelerate a desired weight loss. The anorectic effects may not persist, and only a comprehensive modification in diet and exercise will allow meaningful weight loss.

However, ADHD treatment may contribute to healthy lifestyles in other ways. Stimulants help control impulsive behavior, and many patients report less overeating or emotional eating. Furthermore, control of ADHD symptoms assists patients to more firmly adhere to a behaviorally based weight loss program.

Reviewing Substance Abuse and Diversion Issues

All stimulants carry a warning about potential dependence on the product label. For this reason, it is also important to ascertain whether a patient has a history of substance abuse. However, having even a recent history of substance abuse may not preclude treatment with stimulants; some evidence supports that stimulants reduce the likelihood of future substance abuse behavior.^[15] It is important for physicians to anticipate that patients may be pressured to divert their medications to friends or family. The purpose of this diversion typically is not to obtain a psychological high, but rather for help with studying or other performance enhancement. This behavior should be discouraged. Short-acting agents are more popular for this purpose, and this social trend is another reason to minimize the use of these agents. In general, young adults, particularly college students, have a higher risk of diverting ADHD drugs.^[16]

Evaluating Any Risk for Pregnancy

Women of childbearing ages should be advised that stimulants and nonstimulants are contraindicated for pregnant and breast-feeding women.^[17] Clinicians should advise patients who are planning pregnancy of this finding, although little data exist on the teratogenicity of stimulant medications. Clinicians should discuss methods of birth control with any women who are not planning a pregnancy.

Starting Treatment Medications

As soon as these pressing non-ADHD psychiatric and medical issues have been considered, a choice of drug and dose must be made. In general, stimulants are more effective at treating ADHD symptoms than atomoxetine.^[12,18] Up to 70% of patients with ADHD are responsive to the first stimulant that they are prescribed, and that percentage increases to 90% for patients who must be prescribed a second stimulant.^[18-20]

Few head-to-head studies between long-acting stimulants have been published, but some information about relative compliance is available. Using pharmacy data of 60,010 patients taking ADHD medications (41.6% adults), researchers found that adherence and persistence were best with long-acting stimulants, with long-acting amphetamines having the advantage over long-acting methylphenidate.^[21]

In another study, Lasser and colleagues^[22] used a post hoc analysis of 2 studies comparing the efficacy of stimulants vs placebo. In the first study, 239 adults with ADHD were given lisdexamfetamine in advancing doses from 50 to 70 mg daily and were compared with 62 adults who had been randomly assigned to receive placebo. In the second study,^[22] 83 adults received MAS XR in an escalating dose from 20 to 40 mg and were compared with 45 adults who had been randomly assigned to receive placebo. Standard ADHD and clinician assessment scales were used to evaluate outcomes. Individuals in both studies performed significantly better on stimulants vs placebos on the ADHD Rating Scale-IV (ADHD RS-IV) total scores as well as the Clinical Global Impressions (CGI) ratings.

Starting With Long-acting Drugs and Titrating Upward as Needed

As with other psychiatric drugs, ADHD medications are best started at low doses and titrated up. Clinicians may choose to make the titration from the lowest possible dosage to the next highest dosage within a few weeks (assuming that the drug is well tolerated), so that patients will begin to experience benefit, slowing the titration thereafter to monthly changes until the optimal dosage is achieved.

Higher doses of medications may be needed. In a unique study of 23 mothers and their 6- to 12-year-old children, in which both mothers and children were diagnosed with ADHD, the study mothers were treated with OROS methylphenidate.^[4] Among other objectives, the study was designed to look at parenting skills as an outcome measure. During the first week, all mothers were treated with placebo. In the second phase of the study, lasting 2 weeks, mothers were randomly assigned to either the optimal dose or placebo. The maximum dose given was 90 mg/day.

The mothers' scores improved on various parenting rating scales in which lower scores corresponded with better skills or behaviors. For example, the higher scores on the Alabama Parenting Questionnaire in categories, such as inconsistent discipline and poor monitoring/supervision, dropped significantly in mothers given OROS methylphenidate at doses of 54 mg or greater. The Conners Adult ADHD Rating Scale reported significant improvement in hyperactivity/impulsivity and inattention. The CGI-Severity of Illness scale was also used, and increasing dosages were associated with improved scores.

Of interest, the researchers tracked children who were medicated and compared them with the medicated mothers. When both mothers and children were medicated, the parenting scores also improved, suggesting a synergistic effect.^[4]

If Atomoxetine Is Used

Some patients are disinclined to take stimulant medications; others may have experienced untoward side effects or have been assessed and found to be at high risk for abuse or diversion. In such cases, the nonstimulant medication atomoxetine may be considered. In contrast with the rapid response to stimulants, the onset of action for atomoxetine may take several weeks, although once at steady state the benefits last throughout the day.^[10] Although atomoxetine is perceived as a safer alternative to stimulants, clinicians should be fully aware of its properties. Atomoxetine has been associated with increases in heart rate and blood pressure.^[23] As with the stimulants, caution should be exercised when using atomoxetine in patients with hypertension or preexisting cardiac disease. Although atomoxetine is not an antidepressant, it is mechanistically similar in that it is a selective norepinephrine reuptake inhibitor. Both atomoxetine and such antidepressants carry a black box warning alerting of increased suicide risk in early therapy.

The risk for diversion is much lower with atomoxetine than with the stimulant medications; however, it should be used cautiously in the substance use disorder population. For example, in a retrospective study of the medication in adults with ADHD with and without alcohol abuse and dependence, adverse events were more common among drinkers vs nondrinkers.^[24] Heavy drinkers had the greatest occurrence of treatment-emergent adverse events in both the atomoxetine and the placebo groups. Despite the risks, these researchers found that atomoxetine was a useful drug among patients with no major hepatotoxicity.^[24] Table 3 provides a basic comparison of the pros and cons between stimulants as a group and atomoxetine.

Table 3. Pros and Cons of Stimulants vs Atomoxetine

	Pros	Cons
Stimulants	Rapid onset of action Good medication adherence if long-acting stimulants used Many years of research on effects in children and adolescents Not associated with sexual side effects	Schedule II drugs with risk with warnings for abuse and diversion Possible intensification of symptoms at end of dose Not recommended for pregnant or breast-feeding women May cause anorexia and insomnia
Atomoxetine	Not a scheduled drug and poses no risk for abuse or diversion Refills available without hard copy prescription An option for individuals who fail to respond to stimulants 24-hr control once therapeutic serum drug levels are established	May have delayed onset of action May have poorer adherence than stimulants Risk for suicidal thoughts[25] Can cause erectile dysfunction in middle-aged men[26]

Helping Patients With Expectations

Patients may be unclear about what they can expect from ADHD treatment, and clinicians should help strike a balance between hopeless nihilism and an unfettered belief that the medication will solve all problems. Because each individual with ADHD experiences unique challenges, the goal of treatment should be carefully elucidated from the outset. For example, if a particular patient has problems with blurting out statements that she later regrets, the medication may offer her a new-found self-censoring ability; the questions at the next medication review visit should center on impulsive behavior. Similarly, the patient who complains about chronically missing appointments or forgetting to pay bills should be followed for changes in organization and working memory.

Adverse effects, such as insomnia, headache, and appetite loss, are common among adults taking any form of methylphenidate or amphetamine.^[27] Patients should be advised to report any troubling treatment-emergent problems immediately, particularly significant heart palpitations or disturbing thoughts. Fortunately, most of the common initial side effects (diarrhea, dry mouth, and even anxiety) dissipate within a week or so.

Following Patients Once They Start Their Medications

A return visit should be scheduled 2-4 weeks after the patient begins taking the medication. This allows for an early adjustment of dosing that is based on adverse events and clinical progress. Some patients may report little difference either because none is evident or because they are not psychologically minded. Oftentimes the patient is not the first to observe positive or negative effects. Obtaining collateral input from family members may yield a different response. In the absence of family participation, patients should be specifically asked what input they have received from coworkers, friends, and family members.

Monitoring Progress

Symptomatic improvement should be monitored at least monthly until the proper regimen is established. Once stabilized, return visits every 3 months are recommended.^[28] Recent recommendations published by the National Committee for Quality Assurance suggest that individuals with ADHD be seen for a minimum of 4 medication management and/or psychotherapy visits in 6 months, and that the interval between initial evaluation and first follow-up be 30 days or less.^[28]

In each session, inquiries about the patient's physical and emotional health should be included. It is particularly important to obtain blood pressure information and any symptoms of cardiac problems because both stimulants and atomoxetine can have cardiovascular effects.

Cardiovascular and metabolic issues become more important with age. In a study of 917 patients with ADHD and preexisting cardiovascular symptoms,^[3] more than half of the patients between 46 and 64 years of age had preexisting cardiovascular disease (54.3%); by contrast, patients between 21 and 29 years of age represented roughly 8% of all with preexisting cardiovascular conditions (Table 4). Patients also should be asked about diabetes; in this study,^[3] 10.9% of patients with preexisting cardiovascular conditions before receiving ADHD treatment had diabetes, compared with 3.5% of the entire cohort. The study authors advise cautious use of stimulants and atomoxetine in adults with serious preexisting cardiovascular conditions.^[3]

Table 4. Descriptive Characteristics for Privately Insured 21- to 64-Year-Old Adults With a New ADHD Treatment Episode During the Period From 2006 to 2007^a

	Full Cohort (N = 8752)	No Preexisting CV Condition (N = 7835)	Any Preexisting CV Condition (N = 917)	P Valueb
Age (mean, SD)	37 (10)	36 (10)	45 (10)	< .0001
Age (Percentage)				< .0001
21-29	2350 (26.9)	2278 (29.1)	72 (7.9)
30-45	4245 (48.5)	3898 (49.8)	347 (37.8)
46-64	2157 (24.7)	1659 (21.2)	498 (54.3)
Sex (male)	4410 (50.4)	3912 (49.9)	498 (54.3)	.012
CV Condition (percentage)	917 (10.5)
Congenital abnormalities	20 (0.2)	N/A	20 (2.2)	N/A
Atherosclerosis	36 (0.9)	N/A	36 (3.9)	N/A
Cardiac disease	845 (9.7)	N/A	845 (92.2)	N/A
Cerebrovascular disease	78 (0.9)	N/A	78 (8.5)	N/A
Diabetes	303 (3.5)	203 (2.6)	100 (10.9)
Mental comorbidities (any) (percentage)	3439 (39.3)			< .0001
Anxiety disorders	1175 (13.4)	2994 (38.2)	445 (48.5)	< .0001
Bipolar disorder	351 (4.0)	305 (3.9)	46 (5.0)	.101
Depressive disorder	1807 (20.7)	1555 (19.9)	252 (27.5)	< .0001
Schizophrenia and related disorders	66 (0.8)	52 (0.7)	14 (1.5)	.004
Substance-related disorders	166 (1.9)	144 (1.8)	33 (2.4)	.239
Other mental disorders	166 (1.9)	144 (1.8)	22 (2.4)	< .0001
Other psychotropics (any) (percentage)	3706 (42.3)	3147 (402.)	559 (60.7)	< .0001
Antidepressants	2985 (34.1)	2521 (32.2)	464 (50.6)	< .0001
Antipsychotics	226 (2.6)	174 (2.2)	52 (5.7)	< .0001
Mood stabilizers	522 (6.0)	423 (5.4)	99 (10.8)	< .0001
Anxiolytics/hypnotics	1874 (21.4)	1537 (19.6)	337 (36.8)	< .0001
Mental Health Services (Percentage)
Inpatient mental health care	97 (1.1)	78 (1.0)	19 (2.1)	.003
Emergency mental health care	120 (1.4)	203 (1.3)	17 (1.9(q	.184
Psychotherapy	1889 (21.6)	1641 (20.9)	248 (27.0)	< .0001
Mental health assessment	1481 (17.0)	1301 (16.6)	183 (20.0	.011
Care provider at index				< .0001
Inpatient hospital	174 (2.0)	133 (1.7)	41 (4.5)
Psychiatrist	2331 (26.6)	2087 (26.6)	244 (26.6)
Other specialty	6247 (71.4)	5615 (71.7)	632 (68.9)

ADHD = attention-deficit/hyperactivity disorder; CV = cardiovascular
^aTable presents N, column percentage for 12-month period prior to index date if not otherwise specified.
^bChi-squared or t test as appropriate
From Gerhard T, et al. Pharmacoepidemiol Drug Saf. 2010;19:457-464.^[3]

If the Initial Agent Causes Reported Adverse Events

In most cases, any initial adverse events will resolve, but if side effects persist, it may be necessary to switch to another medication. For example, if the patient finds the anorectic effect of amphetamine to be unacceptable, switching to a long-acting methylphenidate may be helpful. If methylphenidate is found to flatten the patient's affect or cause a sensation of hyperfocus, other agents can be introduced. Most adverse events are transient and essentially common to all stimulants, and if the patient complains of a rapid heartbeat and increased nervousness, it is easier to lower the dosage of the initial drug rather than switching to another stimulant.

If patients complain of insomnia, they should be asked whether they had a problem with insomnia before taking the medication. If not, the patient should be asked about when he or she takes the drug. If the patient has a routine daytime schedule and is taking the long-term stimulant at or after noon, then he or she should be advised to take the drug earlier in the day, such as 7:00 or 8:00 AM. Patients who complain about nervousness or jitteriness should be queried about their caffeine intake. Cutting back on caffeinated drinks may resolve this issue and allow continuation of the medication.^[29]

Sometimes age increases the risk for some side effects. For example, one study showed that the risk for diminished libido (6.6%) and erectile dysfunction (10.9%) in patients taking atomoxetine was higher among men 25 years of age and older compared with men between the ages of 18 and 25 years who had no such trouble with atomoxetine.^[26] The average age of the 55 younger adults in the study was 21.7 years, whereas the average age of the 481 older adults was 43.4 years. These factors may play a role in determining the drug of choice in middle-aged men with ADHD.

Conclusion

Research on ADHD drugs, in terms of many areas of functioning and patient medical and mental health histories, makes it clear that treatment should be individualized to the patient's needs, taking into account whether the patient has cardiovascular disease, sleep disorders, and mental health comorbidities. In addition, the patient's past experience with ADHD medications as well as his or her current expectations for ADHD drugs should be considered. In most cases, long-acting ADHD medications are best because they can provide a more rapid response, which further increases the likelihood of medication adherence.

Supported by an independent educational grant from Shire.