Self-management skills are widely promoted by health plans and specialty societies with the expectation that they will improve care. The 1997 National Heart, Lung, and Blood Institute guidelines on treating asthma emphasize self-management,¹ although they do not recommend specific programs. To maximize therapeutic effectiveness, it would be useful to know which components of patient self-management improve outcomes. Written action plans and peak flow meters are commonly used in asthma self-management programs. While these are simple, low-cost interventions for an individual, the aggregate cost for the entire population of asthmatics may be high.²

Much literature has accumulated on the effectiveness of providing asthma education alone and on programs that actively engage patients in their own care.Several systematic reviews have found that providing educational information alone has had little effect on asthma outcomes.^3-5 There is evidence, though, that self-management activities are more effective than educational information alone. A recent Cochrane review of 24 trials found that self-management with regular practitioner review reduces hospi-talizations and emergency room visits.⁶ This review did not identify specific components contributing to improved outcomes. In contrast to the aforementioned studies on patient education, a large case-control study of children in the Kaiser Permanente System,⁷ found that written action plans were associated with lower rates of hospitalization and emergency room use. However, such observational studies often include confounding factors and are not sufficient to establish a cause-effect relationship between written action plans and improved outcomes.

We report on a systematic review that attempts to isolate the independent effect of a written action plan on asthma outcomes. We address two key questions:

1. Compared with medical management alone, does the addition of a written asthma action plan (with or without peak flow meter use) improve outcomes?
2. Compared with a written action plan based on symptoms, does a written action plan based on peak flow monitoring improve outcomes?

Methods

This study is part of a broader evidence report on the management of chronic asthma prepared for the Agency of Health Care Research and Quality⁸. Complete details of the methodology are available in the full report⁸ (http://www.ahcpr.gov/clinic/epcix.htm).

Literature search and study selection

We performed a comprehensive literature search from 1980 to August 2000 using MEDLINE, Embase, the Cochrane Library, and a hand search of recent bibliographies. The search was limited to full-length, peer-reviewed articles with an English abstract. Two independent reviewers carried out each step of study selection and data abstraction. Disagreements were resolved by consensus of the two reviewers or, if necessary, by the decision of a third reviewer.

Initial study selection was limited to comparative full-length reports or abstracts in peer-reviewed medical journals, with at least 25 evaluable children or adults per arm, treated for at least 12 weeks. Relevant comparisons included a written action plan and no written action plan; a written action plan based on peak flow readings and a written action plan based on symptoms. Study designs varied: clinical trials, cohort comparisons, case-control analyses, cross-sectional evaluations, and before-after comparisons. Specific components of the management plan had to be described.

Relevant outcomes included measures of inpatient and outpatient utilization, lung function, symptoms, rescue medication or oral steroid use, and quality of life. Outcomes of greatest interest were utilization parameters, as the goals of self-management usually focus on improving these outcomes.

These initial selection criteria yielded many studies that were confounded by multiple asthma management interventions and thus did not isolate the comparisons of interest. Therefore, the research team collectively determined the study design features that would best isolate the effects of written action plans and used them as new criteria in a second round of study selection. The studies thus selected satisfied 4 criteria: 1) randomization of patients; (2) delivery of the same interventions to experimental and control groups, except that the experimental group also received a written action plan; (3) delivery of the same interventions to experimental and control groups, except that one group received a written action plan based on peak flow meter readings, and the comparison group received a written action plan based on symptom monitoring; and 4) inclusion of a written action plan that met our specified definition.

A written action plan, by our definition, had two components: an algorithm that identified specific clinical indicators signaling the need for adjustments in medication; and specific instructions on how to adjust medications in response to such indicators. Many publications lacked sufficient detail on the written plan, so a brief survey was sent to the primary author of each of the 36 studies. If no response was obtained (36%), the article was excluded only when it was clear from the publication that our definition was not met.

Assessment of study quality

High-quality studies were randomized controlled trials that met the 3 domains of study quality that have been demonstrated empirically to impact effect size: concealment of treatment allocation; double-blinding; and minimization of exclusion bias.^9,10 However, we doubted the feasibility of double-blinding a written asthma plan intervention, and so relaxed this requirement. We considered exclusion bias to be minimized when a study either reported intent-to-treat analysis or excluded fewer than 10% of subjects from analysis, with the ratio of subjects excluded from each arm being less than 2:1.

To more fully evaluate study design issues that may be particularly important in asthma research,^11,12 we constructed asthma-specific quality indicators in consultation with an expert panel. Controls for potential confounders of treatment effect included establishing reversibility of airway obstruction, controlling for other medication use, reporting compliance, and addressing seasonality. In addition, a priori reporting of power calculations and accounting for exclusions and withdrawals were judged to be study quality characteristics pertinent to this body of evidence.

Data analysis

We constructed evidence tables for the outcomes of interest, and performed a qualitative synthesis of the data. Meta-analysis was not appropriate due to wide discrepancies in the patient populations studied, the interventions employed, and measurement and reporting of outcomes.

Results

Our literature search yielded a total of 4578 citations. Of these, 36 studies met the initial selection criteria. Many of these qualifying studies, however, were confounded by multiple asthma management interventions applied inconsistently across treatment arms. For example, a common confounder was review of and change in long-term medication use in the treatment group, but not in the control group. This necessitated a refinement in our selection criteria to focus on studies that largely isolated the effect of written action plans.^13-21 This step yielded a final evidence base of 9 randomized controlled trials with a total enrollment of 1501 patients.

Table 1 summarizes the characteristics, interventions, and outcomes of the 9 studies. Two studies were 3-arm trials,^16,17 which raised the total number of comparisons among the 9 studies to 11. The largest study was the Grampian Asthma Study of Integrated Care (n=569),¹⁴ a community study conducted in the UK. Enrollment in the other 8 studies ranged from 43 to 64 patients per arm. Treatment duration ranged from 24 to 52 weeks.

None of the studies met our definition of high quality. In fact, no study met any of the generic quality criteria—none was blinded, none described concealment of allocation, and all excluded more than 10% of subjects. Furthermore, none reported an intention-to-treat analysis. Thus these trials were prone to withdrawal bias as well as overestimation of treatment effect due to lack of allocation concealment.

No study met the majority of asthma-specific indicators (Table 1). Of the 9 studies, only 5 met any asthma-specific indicator. Three reported prospective power calculations,^13-15 but 2 of these substantially overestimated the expected effect.^13,15 Two studies established reversibility;^14,17 2 controlled for other medication use;^13,15 and 2 reported compliance.^17,21 Thus, the studies were also prone to a type II error (failing to detect a true effect) and to potential confounding of outcomes.

We performed sample power calculations for hospitalizations (Table 2), derived from baseline rates reported in 4 studies^14,16-18 and standard deviations reported in 2.^14,17 A study with 250 patients per arm could detect a reduction of 50% or more in hospitalization, given a control rate of at least 0.2 hospitalizations/patient/year. In actuality, GRASSIC,14 which is the largest available trial (N=569), had baseline hospitalization rates of 0.12 and 0.13. With this baseline rate, over 700 patients per arm are required, higher than the actual enrollment in GRASSIC. The other studies in this review would be adequately powered to detect a 50% difference only in the setting of even higher baseline utilization (eg, 0.30 hospitalizations/patient/year).

Table 3 displays utilization outcomes for the 11 comparisons in the 9 trials. In 5 studies (N=1019), medical management with a written action plan was compared with medical management without a written action plan.^13-17 Two trials (N=185) compared a peak flow meter plus a written action plan with a peak flow meter and no written action plan^18,19 In 4 studies (N=393), a written action plan based on peak flow monitoring was compared with a written action plan based on symptoms.

TABLE 1

Study characteristics

TABLE 2

Power calculations for hospitalizations per patient per year

Written action plan versus no written action plan

All 5 studies used a peak flow meter based written action plan. All reported utilization outcomes, but the types and units of measurement were not consistent across studies (Table 2). Additionally, 4 studies reported on symptoms,^13-16 and 3 reported lung function outcomes.^13-15

With one notable exception, there were no statistically significant differences in outcomes among groups. Cowie et al¹⁶ reported an 11-fold decrease in total emergency room visits for the group using a peak-flow action plan (5 vs 55, P = .02), and also reported a reduction in hospitalizations of a similar magnitude (2 vs 12) that did not reach statistical significance. However, this study suffers from notable flaws that diminish confidence in the results. It is a post-intervention comparison among groups, which does not compare change from baseline, or incorporate baseline values as covariates in the analysis. Moreover baseline utilization data were provided by patient recall and not corroborated by medical records. There was a substantially larger variability in the baseline utilization rates for the peak flow group compared with the control group. This suggests that a subset of very high frequency users may have been over-represented in the peak flow group, and the reduction in emergency room visits may be concentrated in this subset.

Peak-flow meter-based written action plan versus peak flow meter with no written action plan

Two studies^18,19 addressed the independent effect of a written action plan when added to peak flow self-monitoring (Table 3). Charlton¹⁹ reported no significant group differences for main outcomes, while Ignacio-Garcia¹⁸ reported large and statistically significant differences in most of the outcomes, favoring the group that used the written action plan.

The Ignacio-Garcia study, however, suffers from notable flaws suggesting the results may be attributable to bias. The sole participating physician, not blinded to treatment assignment, was highly involved in all phases of patient assessment, monitoring, and treatment. There was evidence of baseline differences between the two groups. A total of 25% of patients were withdrawn after randomization, and an unexplained decline in lung function occurred in the control group. Thus, the potential for selection bias, withdrawal bias, and ascertainment bias limits confidence in the results of this study

Symptom-based written action plan compared with peak flow-based written action plan

In 4 studies,^16,17,20,21 reported outcomes were generally equivalent between groups and comparisons were not statistically significant, with one exception (Table 3). The 3-arm study by Cowie et al¹⁶ reported a striking reduction in the total number of emergency room visits with a peak flow meter-based written action plan compared with a symptom-based written action plan (5 versus 45, P

Discussion

The objective of this systematic review was to assess the independent effects of 2 specific components commonly included in asthma self-management plans—a written action plan and a peak flow meter. Few studies, however, are designed to permit reviewers to isolate the effects of these components. Moreover, the studies we reviewed did not clearly identify the population expected to benefit from interventions or specify the primary outcomes of interest; nor was the level of clinically meaningful improvement prospectively defined.

Most of the trials we reviewed, including the largest community study of 569 patients, did not demonstrate improved outcomes. The 2 trials that reported statistically significant results favoring a peak flow-based written action plan suffer from notable flaws suggesting the results may be attributable to bias. In the other 7 trials, there was little difference in outcomes between groups. However, these studies had insufficient power to detect group differences or confidently conclude equivalence between groups.

Thus, available evidence is insufficient to demonstrate that asthma outcomes are improved by use of a written asthma action plan, with or without peak flow monitoring. While this body of literature does not establish that these interventions are ineffective, it suggests they will not have a large effect on outcomes when applied to the general asthmatic population. The application of written action plans to all asthmatics indiscriminately may be a wasteful use of resources. This systematic review also questions the validity of written action plans as an indicator of asthma quality of care, or as a means to achieve quality improvement.

This analysis also highlights several obstacles to assessing the effects of disease management interventions. First, while the impact of whole intervention programs can be evaluated in controlled trials, it may be unfeasible to isolate each component of such programs and subject it to a rigorous analysis. Furthermore, as a behavioral intervention, the general principle of engaging patients in self-management may be more important that the specific components of these programs. Finally, regarding the optimization of medications (most obviously initiation of inhaled steroids) the impact of written action plans is likely to be relatively small, particularly on lung function or symptom control.

Future clinical trials should be done selectively, aimed at producing rigorous results that can improve the effectiveness of self-management interventions. Further study is warranted for specific subpopulations, such as those with higher baseline severity of illness or those with high baseline utilization rates. Available data suggest that, if there is benefit to be gained from self-management interventions, it will most likely be seen among these patients. Specific components of self-management that might be tested individually are those that are relatively high-cost, resource intensive, or risky for the patient.

Existing trials have tended to over-estimate the effects of action plan-based interventions, thus having invested resources for results inadequate for optimizing self-management strategies. Careful consideration needs to be taken in future trials to realistically estimate the expected impact of each intervention, and to specify the primary outcomes of interest and their baseline frequencies. Future trials should be large enough to detect a difference if one exists, or to confidently conclude that the intervention is ineffective.

Attention to these principles will help to advance our knowledge in this area most efficiently and to ultimately improve the quality of care for the entire population of patients with asthma.

· Acknowledgments ·

We acknowledge Kathleen Ziegler, Pharm.D, and Claudia Bonnell, RN, MSL, for their assistance in the research and preparation of this manuscript.

Self-management skills are widely promoted by health plans and specialty societies with the expectation that they will improve care. The 1997 National Heart, Lung, and Blood Institute guidelines on treating asthma emphasize self-management,¹ although they do not recommend specific programs. To maximize therapeutic effectiveness, it would be useful to know which components of patient self-management improve outcomes. Written action plans and peak flow meters are commonly used in asthma self-management programs. While these are simple, low-cost interventions for an individual, the aggregate cost for the entire population of asthmatics may be high.²

Much literature has accumulated on the effectiveness of providing asthma education alone and on programs that actively engage patients in their own care.Several systematic reviews have found that providing educational information alone has had little effect on asthma outcomes.^3-5 There is evidence, though, that self-management activities are more effective than educational information alone. A recent Cochrane review of 24 trials found that self-management with regular practitioner review reduces hospi-talizations and emergency room visits.⁶ This review did not identify specific components contributing to improved outcomes. In contrast to the aforementioned studies on patient education, a large case-control study of children in the Kaiser Permanente System,⁷ found that written action plans were associated with lower rates of hospitalization and emergency room use. However, such observational studies often include confounding factors and are not sufficient to establish a cause-effect relationship between written action plans and improved outcomes.

We report on a systematic review that attempts to isolate the independent effect of a written action plan on asthma outcomes. We address two key questions:

1. Compared with medical management alone, does the addition of a written asthma action plan (with or without peak flow meter use) improve outcomes?
2. Compared with a written action plan based on symptoms, does a written action plan based on peak flow monitoring improve outcomes?

Methods

This study is part of a broader evidence report on the management of chronic asthma prepared for the Agency of Health Care Research and Quality⁸. Complete details of the methodology are available in the full report⁸ (http://www.ahcpr.gov/clinic/epcix.htm).

Literature search and study selection

We performed a comprehensive literature search from 1980 to August 2000 using MEDLINE, Embase, the Cochrane Library, and a hand search of recent bibliographies. The search was limited to full-length, peer-reviewed articles with an English abstract. Two independent reviewers carried out each step of study selection and data abstraction. Disagreements were resolved by consensus of the two reviewers or, if necessary, by the decision of a third reviewer.

Initial study selection was limited to comparative full-length reports or abstracts in peer-reviewed medical journals, with at least 25 evaluable children or adults per arm, treated for at least 12 weeks. Relevant comparisons included a written action plan and no written action plan; a written action plan based on peak flow readings and a written action plan based on symptoms. Study designs varied: clinical trials, cohort comparisons, case-control analyses, cross-sectional evaluations, and before-after comparisons. Specific components of the management plan had to be described.

Relevant outcomes included measures of inpatient and outpatient utilization, lung function, symptoms, rescue medication or oral steroid use, and quality of life. Outcomes of greatest interest were utilization parameters, as the goals of self-management usually focus on improving these outcomes.

These initial selection criteria yielded many studies that were confounded by multiple asthma management interventions and thus did not isolate the comparisons of interest. Therefore, the research team collectively determined the study design features that would best isolate the effects of written action plans and used them as new criteria in a second round of study selection. The studies thus selected satisfied 4 criteria: 1) randomization of patients; (2) delivery of the same interventions to experimental and control groups, except that the experimental group also received a written action plan; (3) delivery of the same interventions to experimental and control groups, except that one group received a written action plan based on peak flow meter readings, and the comparison group received a written action plan based on symptom monitoring; and 4) inclusion of a written action plan that met our specified definition.

A written action plan, by our definition, had two components: an algorithm that identified specific clinical indicators signaling the need for adjustments in medication; and specific instructions on how to adjust medications in response to such indicators. Many publications lacked sufficient detail on the written plan, so a brief survey was sent to the primary author of each of the 36 studies. If no response was obtained (36%), the article was excluded only when it was clear from the publication that our definition was not met.

Assessment of study quality

High-quality studies were randomized controlled trials that met the 3 domains of study quality that have been demonstrated empirically to impact effect size: concealment of treatment allocation; double-blinding; and minimization of exclusion bias.^9,10 However, we doubted the feasibility of double-blinding a written asthma plan intervention, and so relaxed this requirement. We considered exclusion bias to be minimized when a study either reported intent-to-treat analysis or excluded fewer than 10% of subjects from analysis, with the ratio of subjects excluded from each arm being less than 2:1.

To more fully evaluate study design issues that may be particularly important in asthma research,^11,12 we constructed asthma-specific quality indicators in consultation with an expert panel. Controls for potential confounders of treatment effect included establishing reversibility of airway obstruction, controlling for other medication use, reporting compliance, and addressing seasonality. In addition, a priori reporting of power calculations and accounting for exclusions and withdrawals were judged to be study quality characteristics pertinent to this body of evidence.

Data analysis

We constructed evidence tables for the outcomes of interest, and performed a qualitative synthesis of the data. Meta-analysis was not appropriate due to wide discrepancies in the patient populations studied, the interventions employed, and measurement and reporting of outcomes.

Results

Our literature search yielded a total of 4578 citations. Of these, 36 studies met the initial selection criteria. Many of these qualifying studies, however, were confounded by multiple asthma management interventions applied inconsistently across treatment arms. For example, a common confounder was review of and change in long-term medication use in the treatment group, but not in the control group. This necessitated a refinement in our selection criteria to focus on studies that largely isolated the effect of written action plans.^13-21 This step yielded a final evidence base of 9 randomized controlled trials with a total enrollment of 1501 patients.

Table 1 summarizes the characteristics, interventions, and outcomes of the 9 studies. Two studies were 3-arm trials,^16,17 which raised the total number of comparisons among the 9 studies to 11. The largest study was the Grampian Asthma Study of Integrated Care (n=569),¹⁴ a community study conducted in the UK. Enrollment in the other 8 studies ranged from 43 to 64 patients per arm. Treatment duration ranged from 24 to 52 weeks.

None of the studies met our definition of high quality. In fact, no study met any of the generic quality criteria—none was blinded, none described concealment of allocation, and all excluded more than 10% of subjects. Furthermore, none reported an intention-to-treat analysis. Thus these trials were prone to withdrawal bias as well as overestimation of treatment effect due to lack of allocation concealment.

No study met the majority of asthma-specific indicators (Table 1). Of the 9 studies, only 5 met any asthma-specific indicator. Three reported prospective power calculations,^13-15 but 2 of these substantially overestimated the expected effect.^13,15 Two studies established reversibility;^14,17 2 controlled for other medication use;^13,15 and 2 reported compliance.^17,21 Thus, the studies were also prone to a type II error (failing to detect a true effect) and to potential confounding of outcomes.

We performed sample power calculations for hospitalizations (Table 2), derived from baseline rates reported in 4 studies^14,16-18 and standard deviations reported in 2.^14,17 A study with 250 patients per arm could detect a reduction of 50% or more in hospitalization, given a control rate of at least 0.2 hospitalizations/patient/year. In actuality, GRASSIC,14 which is the largest available trial (N=569), had baseline hospitalization rates of 0.12 and 0.13. With this baseline rate, over 700 patients per arm are required, higher than the actual enrollment in GRASSIC. The other studies in this review would be adequately powered to detect a 50% difference only in the setting of even higher baseline utilization (eg, 0.30 hospitalizations/patient/year).

Table 3 displays utilization outcomes for the 11 comparisons in the 9 trials. In 5 studies (N=1019), medical management with a written action plan was compared with medical management without a written action plan.^13-17 Two trials (N=185) compared a peak flow meter plus a written action plan with a peak flow meter and no written action plan^18,19 In 4 studies (N=393), a written action plan based on peak flow monitoring was compared with a written action plan based on symptoms.

TABLE 1

Study characteristics

TABLE 2

Power calculations for hospitalizations per patient per year

Written action plan versus no written action plan

All 5 studies used a peak flow meter based written action plan. All reported utilization outcomes, but the types and units of measurement were not consistent across studies (Table 2). Additionally, 4 studies reported on symptoms,^13-16 and 3 reported lung function outcomes.^13-15

With one notable exception, there were no statistically significant differences in outcomes among groups. Cowie et al¹⁶ reported an 11-fold decrease in total emergency room visits for the group using a peak-flow action plan (5 vs 55, P = .02), and also reported a reduction in hospitalizations of a similar magnitude (2 vs 12) that did not reach statistical significance. However, this study suffers from notable flaws that diminish confidence in the results. It is a post-intervention comparison among groups, which does not compare change from baseline, or incorporate baseline values as covariates in the analysis. Moreover baseline utilization data were provided by patient recall and not corroborated by medical records. There was a substantially larger variability in the baseline utilization rates for the peak flow group compared with the control group. This suggests that a subset of very high frequency users may have been over-represented in the peak flow group, and the reduction in emergency room visits may be concentrated in this subset.

Peak-flow meter-based written action plan versus peak flow meter with no written action plan

Two studies^18,19 addressed the independent effect of a written action plan when added to peak flow self-monitoring (Table 3). Charlton¹⁹ reported no significant group differences for main outcomes, while Ignacio-Garcia¹⁸ reported large and statistically significant differences in most of the outcomes, favoring the group that used the written action plan.

The Ignacio-Garcia study, however, suffers from notable flaws suggesting the results may be attributable to bias. The sole participating physician, not blinded to treatment assignment, was highly involved in all phases of patient assessment, monitoring, and treatment. There was evidence of baseline differences between the two groups. A total of 25% of patients were withdrawn after randomization, and an unexplained decline in lung function occurred in the control group. Thus, the potential for selection bias, withdrawal bias, and ascertainment bias limits confidence in the results of this study

Symptom-based written action plan compared with peak flow-based written action plan

In 4 studies,^16,17,20,21 reported outcomes were generally equivalent between groups and comparisons were not statistically significant, with one exception (Table 3). The 3-arm study by Cowie et al¹⁶ reported a striking reduction in the total number of emergency room visits with a peak flow meter-based written action plan compared with a symptom-based written action plan (5 versus 45, P

Discussion

The objective of this systematic review was to assess the independent effects of 2 specific components commonly included in asthma self-management plans—a written action plan and a peak flow meter. Few studies, however, are designed to permit reviewers to isolate the effects of these components. Moreover, the studies we reviewed did not clearly identify the population expected to benefit from interventions or specify the primary outcomes of interest; nor was the level of clinically meaningful improvement prospectively defined.

Most of the trials we reviewed, including the largest community study of 569 patients, did not demonstrate improved outcomes. The 2 trials that reported statistically significant results favoring a peak flow-based written action plan suffer from notable flaws suggesting the results may be attributable to bias. In the other 7 trials, there was little difference in outcomes between groups. However, these studies had insufficient power to detect group differences or confidently conclude equivalence between groups.

Thus, available evidence is insufficient to demonstrate that asthma outcomes are improved by use of a written asthma action plan, with or without peak flow monitoring. While this body of literature does not establish that these interventions are ineffective, it suggests they will not have a large effect on outcomes when applied to the general asthmatic population. The application of written action plans to all asthmatics indiscriminately may be a wasteful use of resources. This systematic review also questions the validity of written action plans as an indicator of asthma quality of care, or as a means to achieve quality improvement.

This analysis also highlights several obstacles to assessing the effects of disease management interventions. First, while the impact of whole intervention programs can be evaluated in controlled trials, it may be unfeasible to isolate each component of such programs and subject it to a rigorous analysis. Furthermore, as a behavioral intervention, the general principle of engaging patients in self-management may be more important that the specific components of these programs. Finally, regarding the optimization of medications (most obviously initiation of inhaled steroids) the impact of written action plans is likely to be relatively small, particularly on lung function or symptom control.

Future clinical trials should be done selectively, aimed at producing rigorous results that can improve the effectiveness of self-management interventions. Further study is warranted for specific subpopulations, such as those with higher baseline severity of illness or those with high baseline utilization rates. Available data suggest that, if there is benefit to be gained from self-management interventions, it will most likely be seen among these patients. Specific components of self-management that might be tested individually are those that are relatively high-cost, resource intensive, or risky for the patient.

Existing trials have tended to over-estimate the effects of action plan-based interventions, thus having invested resources for results inadequate for optimizing self-management strategies. Careful consideration needs to be taken in future trials to realistically estimate the expected impact of each intervention, and to specify the primary outcomes of interest and their baseline frequencies. Future trials should be large enough to detect a difference if one exists, or to confidently conclude that the intervention is ineffective.

Attention to these principles will help to advance our knowledge in this area most efficiently and to ultimately improve the quality of care for the entire population of patients with asthma.

· Acknowledgments ·

We acknowledge Kathleen Ziegler, Pharm.D, and Claudia Bonnell, RN, MSL, for their assistance in the research and preparation of this manuscript.

Self-management skills are widely promoted by health plans and specialty societies with the expectation that they will improve care. The 1997 National Heart, Lung, and Blood Institute guidelines on treating asthma emphasize self-management,¹ although they do not recommend specific programs. To maximize therapeutic effectiveness, it would be useful to know which components of patient self-management improve outcomes. Written action plans and peak flow meters are commonly used in asthma self-management programs. While these are simple, low-cost interventions for an individual, the aggregate cost for the entire population of asthmatics may be high.²

Much literature has accumulated on the effectiveness of providing asthma education alone and on programs that actively engage patients in their own care.Several systematic reviews have found that providing educational information alone has had little effect on asthma outcomes.^3-5 There is evidence, though, that self-management activities are more effective than educational information alone. A recent Cochrane review of 24 trials found that self-management with regular practitioner review reduces hospi-talizations and emergency room visits.⁶ This review did not identify specific components contributing to improved outcomes. In contrast to the aforementioned studies on patient education, a large case-control study of children in the Kaiser Permanente System,⁷ found that written action plans were associated with lower rates of hospitalization and emergency room use. However, such observational studies often include confounding factors and are not sufficient to establish a cause-effect relationship between written action plans and improved outcomes.

We report on a systematic review that attempts to isolate the independent effect of a written action plan on asthma outcomes. We address two key questions:

1. Compared with medical management alone, does the addition of a written asthma action plan (with or without peak flow meter use) improve outcomes?
2. Compared with a written action plan based on symptoms, does a written action plan based on peak flow monitoring improve outcomes?

Methods

This study is part of a broader evidence report on the management of chronic asthma prepared for the Agency of Health Care Research and Quality⁸. Complete details of the methodology are available in the full report⁸ (http://www.ahcpr.gov/clinic/epcix.htm).

Literature search and study selection

We performed a comprehensive literature search from 1980 to August 2000 using MEDLINE, Embase, the Cochrane Library, and a hand search of recent bibliographies. The search was limited to full-length, peer-reviewed articles with an English abstract. Two independent reviewers carried out each step of study selection and data abstraction. Disagreements were resolved by consensus of the two reviewers or, if necessary, by the decision of a third reviewer.

Initial study selection was limited to comparative full-length reports or abstracts in peer-reviewed medical journals, with at least 25 evaluable children or adults per arm, treated for at least 12 weeks. Relevant comparisons included a written action plan and no written action plan; a written action plan based on peak flow readings and a written action plan based on symptoms. Study designs varied: clinical trials, cohort comparisons, case-control analyses, cross-sectional evaluations, and before-after comparisons. Specific components of the management plan had to be described.

Relevant outcomes included measures of inpatient and outpatient utilization, lung function, symptoms, rescue medication or oral steroid use, and quality of life. Outcomes of greatest interest were utilization parameters, as the goals of self-management usually focus on improving these outcomes.

These initial selection criteria yielded many studies that were confounded by multiple asthma management interventions and thus did not isolate the comparisons of interest. Therefore, the research team collectively determined the study design features that would best isolate the effects of written action plans and used them as new criteria in a second round of study selection. The studies thus selected satisfied 4 criteria: 1) randomization of patients; (2) delivery of the same interventions to experimental and control groups, except that the experimental group also received a written action plan; (3) delivery of the same interventions to experimental and control groups, except that one group received a written action plan based on peak flow meter readings, and the comparison group received a written action plan based on symptom monitoring; and 4) inclusion of a written action plan that met our specified definition.

A written action plan, by our definition, had two components: an algorithm that identified specific clinical indicators signaling the need for adjustments in medication; and specific instructions on how to adjust medications in response to such indicators. Many publications lacked sufficient detail on the written plan, so a brief survey was sent to the primary author of each of the 36 studies. If no response was obtained (36%), the article was excluded only when it was clear from the publication that our definition was not met.

Assessment of study quality

High-quality studies were randomized controlled trials that met the 3 domains of study quality that have been demonstrated empirically to impact effect size: concealment of treatment allocation; double-blinding; and minimization of exclusion bias.^9,10 However, we doubted the feasibility of double-blinding a written asthma plan intervention, and so relaxed this requirement. We considered exclusion bias to be minimized when a study either reported intent-to-treat analysis or excluded fewer than 10% of subjects from analysis, with the ratio of subjects excluded from each arm being less than 2:1.

To more fully evaluate study design issues that may be particularly important in asthma research,^11,12 we constructed asthma-specific quality indicators in consultation with an expert panel. Controls for potential confounders of treatment effect included establishing reversibility of airway obstruction, controlling for other medication use, reporting compliance, and addressing seasonality. In addition, a priori reporting of power calculations and accounting for exclusions and withdrawals were judged to be study quality characteristics pertinent to this body of evidence.

Data analysis

We constructed evidence tables for the outcomes of interest, and performed a qualitative synthesis of the data. Meta-analysis was not appropriate due to wide discrepancies in the patient populations studied, the interventions employed, and measurement and reporting of outcomes.

Results

Our literature search yielded a total of 4578 citations. Of these, 36 studies met the initial selection criteria. Many of these qualifying studies, however, were confounded by multiple asthma management interventions applied inconsistently across treatment arms. For example, a common confounder was review of and change in long-term medication use in the treatment group, but not in the control group. This necessitated a refinement in our selection criteria to focus on studies that largely isolated the effect of written action plans.^13-21 This step yielded a final evidence base of 9 randomized controlled trials with a total enrollment of 1501 patients.

Table 1 summarizes the characteristics, interventions, and outcomes of the 9 studies. Two studies were 3-arm trials,^16,17 which raised the total number of comparisons among the 9 studies to 11. The largest study was the Grampian Asthma Study of Integrated Care (n=569),¹⁴ a community study conducted in the UK. Enrollment in the other 8 studies ranged from 43 to 64 patients per arm. Treatment duration ranged from 24 to 52 weeks.

None of the studies met our definition of high quality. In fact, no study met any of the generic quality criteria—none was blinded, none described concealment of allocation, and all excluded more than 10% of subjects. Furthermore, none reported an intention-to-treat analysis. Thus these trials were prone to withdrawal bias as well as overestimation of treatment effect due to lack of allocation concealment.

No study met the majority of asthma-specific indicators (Table 1). Of the 9 studies, only 5 met any asthma-specific indicator. Three reported prospective power calculations,^13-15 but 2 of these substantially overestimated the expected effect.^13,15 Two studies established reversibility;^14,17 2 controlled for other medication use;^13,15 and 2 reported compliance.^17,21 Thus, the studies were also prone to a type II error (failing to detect a true effect) and to potential confounding of outcomes.

We performed sample power calculations for hospitalizations (Table 2), derived from baseline rates reported in 4 studies^14,16-18 and standard deviations reported in 2.^14,17 A study with 250 patients per arm could detect a reduction of 50% or more in hospitalization, given a control rate of at least 0.2 hospitalizations/patient/year. In actuality, GRASSIC,14 which is the largest available trial (N=569), had baseline hospitalization rates of 0.12 and 0.13. With this baseline rate, over 700 patients per arm are required, higher than the actual enrollment in GRASSIC. The other studies in this review would be adequately powered to detect a 50% difference only in the setting of even higher baseline utilization (eg, 0.30 hospitalizations/patient/year).

Table 3 displays utilization outcomes for the 11 comparisons in the 9 trials. In 5 studies (N=1019), medical management with a written action plan was compared with medical management without a written action plan.^13-17 Two trials (N=185) compared a peak flow meter plus a written action plan with a peak flow meter and no written action plan^18,19 In 4 studies (N=393), a written action plan based on peak flow monitoring was compared with a written action plan based on symptoms.

TABLE 1

Study characteristics

TABLE 2

Power calculations for hospitalizations per patient per year

Written action plan versus no written action plan

All 5 studies used a peak flow meter based written action plan. All reported utilization outcomes, but the types and units of measurement were not consistent across studies (Table 2). Additionally, 4 studies reported on symptoms,^13-16 and 3 reported lung function outcomes.^13-15

With one notable exception, there were no statistically significant differences in outcomes among groups. Cowie et al¹⁶ reported an 11-fold decrease in total emergency room visits for the group using a peak-flow action plan (5 vs 55, P = .02), and also reported a reduction in hospitalizations of a similar magnitude (2 vs 12) that did not reach statistical significance. However, this study suffers from notable flaws that diminish confidence in the results. It is a post-intervention comparison among groups, which does not compare change from baseline, or incorporate baseline values as covariates in the analysis. Moreover baseline utilization data were provided by patient recall and not corroborated by medical records. There was a substantially larger variability in the baseline utilization rates for the peak flow group compared with the control group. This suggests that a subset of very high frequency users may have been over-represented in the peak flow group, and the reduction in emergency room visits may be concentrated in this subset.

Peak-flow meter-based written action plan versus peak flow meter with no written action plan

Two studies^18,19 addressed the independent effect of a written action plan when added to peak flow self-monitoring (Table 3). Charlton¹⁹ reported no significant group differences for main outcomes, while Ignacio-Garcia¹⁸ reported large and statistically significant differences in most of the outcomes, favoring the group that used the written action plan.

The Ignacio-Garcia study, however, suffers from notable flaws suggesting the results may be attributable to bias. The sole participating physician, not blinded to treatment assignment, was highly involved in all phases of patient assessment, monitoring, and treatment. There was evidence of baseline differences between the two groups. A total of 25% of patients were withdrawn after randomization, and an unexplained decline in lung function occurred in the control group. Thus, the potential for selection bias, withdrawal bias, and ascertainment bias limits confidence in the results of this study

Symptom-based written action plan compared with peak flow-based written action plan

In 4 studies,^16,17,20,21 reported outcomes were generally equivalent between groups and comparisons were not statistically significant, with one exception (Table 3). The 3-arm study by Cowie et al¹⁶ reported a striking reduction in the total number of emergency room visits with a peak flow meter-based written action plan compared with a symptom-based written action plan (5 versus 45, P

Discussion

The objective of this systematic review was to assess the independent effects of 2 specific components commonly included in asthma self-management plans—a written action plan and a peak flow meter. Few studies, however, are designed to permit reviewers to isolate the effects of these components. Moreover, the studies we reviewed did not clearly identify the population expected to benefit from interventions or specify the primary outcomes of interest; nor was the level of clinically meaningful improvement prospectively defined.

Most of the trials we reviewed, including the largest community study of 569 patients, did not demonstrate improved outcomes. The 2 trials that reported statistically significant results favoring a peak flow-based written action plan suffer from notable flaws suggesting the results may be attributable to bias. In the other 7 trials, there was little difference in outcomes between groups. However, these studies had insufficient power to detect group differences or confidently conclude equivalence between groups.

Thus, available evidence is insufficient to demonstrate that asthma outcomes are improved by use of a written asthma action plan, with or without peak flow monitoring. While this body of literature does not establish that these interventions are ineffective, it suggests they will not have a large effect on outcomes when applied to the general asthmatic population. The application of written action plans to all asthmatics indiscriminately may be a wasteful use of resources. This systematic review also questions the validity of written action plans as an indicator of asthma quality of care, or as a means to achieve quality improvement.

This analysis also highlights several obstacles to assessing the effects of disease management interventions. First, while the impact of whole intervention programs can be evaluated in controlled trials, it may be unfeasible to isolate each component of such programs and subject it to a rigorous analysis. Furthermore, as a behavioral intervention, the general principle of engaging patients in self-management may be more important that the specific components of these programs. Finally, regarding the optimization of medications (most obviously initiation of inhaled steroids) the impact of written action plans is likely to be relatively small, particularly on lung function or symptom control.

Future clinical trials should be done selectively, aimed at producing rigorous results that can improve the effectiveness of self-management interventions. Further study is warranted for specific subpopulations, such as those with higher baseline severity of illness or those with high baseline utilization rates. Available data suggest that, if there is benefit to be gained from self-management interventions, it will most likely be seen among these patients. Specific components of self-management that might be tested individually are those that are relatively high-cost, resource intensive, or risky for the patient.

Existing trials have tended to over-estimate the effects of action plan-based interventions, thus having invested resources for results inadequate for optimizing self-management strategies. Careful consideration needs to be taken in future trials to realistically estimate the expected impact of each intervention, and to specify the primary outcomes of interest and their baseline frequencies. Future trials should be large enough to detect a difference if one exists, or to confidently conclude that the intervention is ineffective.

Attention to these principles will help to advance our knowledge in this area most efficiently and to ultimately improve the quality of care for the entire population of patients with asthma.

· Acknowledgments ·

We acknowledge Kathleen Ziegler, Pharm.D, and Claudia Bonnell, RN, MSL, for their assistance in the research and preparation of this manuscript.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.

Attention-deficit/hyperactivity disorder (ADHD) may be the only mental disorder that was discovered in children and later acknowledged in adults. Although controlled studies of adults with ADHD are few, we know that ADHD is common in adults, it can be diagnosed reliably, and 75% of those treated respond to treatment.¹

The hallmark symptom of ADHD in children—hyperactivity—is usually attenuated in adults. In fact, some adults prefer the term ADD to ADHD because they are not hyperactive. This may be especially true of women, as their attention problems during childhood often were not recognized as ADHD (Box 1).

Box 1

Characteristics of adult ADHD

Adults with ADHD visit a psychiatrist for a variety of reasons. Often they are parents of children diagnosed with ADHD, and the possibility that they are similarly affected has arisen during their children’s evaluation and treatment. Sometimes they have recognized themselves in consumer articles about ADHD, or others have seen them in this light.

Adults with ADHD continue to experience their childhood difficulties in sustaining attention, listening, following instructions, and organizing tasks; inattention to details; lack of sustained mental effort; losing things; distractibility, and forgetfulness. Typical complaints include underachievement and poor adjustment at work or home. Comorbid ADHD may also be identified in patients who present with depression, anxiety, substance misuse, and mood swings.

The cognitive impairment of ADHD continues into adulthood, even in adults without hyperactive symptoms. It may be that adults are not hyperactive because the basal ganglia, which control motor activity in the brain, have over the years accommodated the problem through behavior modification or neurodevelopmental changes in late adolescence.²

Children with ADHD have abnormal cerebrospinal fluid (CSF) and blood levels of the dopaminergic metabolite homovanillic acid (HVA), but adults with ADHD may not. The primary origin for CSF HVA is the nigrostriatum, which suggests that subcortical dopaminergic nuclei are more often affected in children than adults.² This may mean that compensatory changes occur as persons with ADHD mature, or perhaps the forms of ADHD that persist into adulthood have a different pathology or pathophysiology.

Comorbidities with ADHD

Rarely does one see pure ADHD; comorbidity is the rule. ADHD can be diagnosed quickly if you know what to look for. But a facile diagnosis may overlook a comorbidity that must be treated first—especially if you plan to use stimulants. Many patients with ADHD also have bipolar disorder, and a smaller proportion of patients with bipolar disorder have undetected ADHD. Placing a patient with undetected bipolar disorder on a stimulant could precipitate mania.

Table 1

COMMON COMORBIDITIES WITH ADHD

From the initial assessment, your treatment plan must address comorbid conditions (Table 1). This means taking a good history that includes corroborating information from relatives and data from the past, if possible. The case will then be much easier to manage, and quality of care greatly enhanced.

Stimulants: Usual first-choice therapy

In most cases, adult ADHD responds well to stimulant medications, although most available evidence is limited to studies in children. Several nonstimulant medications are also available, and the FDA is considering a new-drug application for a medication indicated for adult ADHD. Stimulants produce significant improvement in 30% of patients and mixed results in another 40%. Comorbidities may account for the 10 to 30% of patients who do not respond to stimulant therapy.

Methylphenidate, taken multiple times daily, is the most common treatment for ADHD. Dextroamphetamine and mixed salts of amphetamine also are used (Table 2).³ Patients usually respond to either methylphenidate or an amphetamine, and typically 25% of those who do not respond to one will respond to the other. When the clinical efficacy of amphetamines diminishes over time, many psychiatrists rotate medications. Replacing one amphetamine with another often eliminates the need to slowly increase the dosage and allows the clinician to maintain a relatively stable regimen.

When administering stimulants to adults, consider the individual’s total dosage requirement and daily schedule. Will he or she fare better with multiple daily dosing or a sustained-release form? How long is his or her average day? Does the patient have to be alert for 12 hours—or longer?

Some patients cannot sleep unless they take their last stimulant dose at bedtime. Others will have insomnia if a last dose is taken too late in the afternoon, especially with a sustained-release formulation.

When starting a patient on stimulants, begin with a 12-hour day and titrate the dosage—usually up, sometimes down—depending on response and side effects. Educating patients about their medications enables them to participate in decision-making.

Common side effects of stimulants include insomnia, decreased appetite, upset stomach, headache, anxiety, agitation, and increased pulse rate and blood pressure. The increase in blood pressure is usually less than 10%, but patients with poorly controlled hypertension should not be treated with stimulants until their blood pressure is well controlled. Until more is known about long-term effects, periodic assessment of blood pressure may be warranted.

Table 2

STIMULANT THERAPY FOR ADULTS WITH ADHD

Box 2

Adults with ADHD have been treated with mixed amphetamine salts with positive results. In a 7-week controlled, crossover study, 27 adults with ADHD received an average of 54 mg/d administered in two doses. Symptoms improved significantly—a 42% decrease on the ADHD Rating Scale. The medication was well-tolerated, and 70% of those receiving mixed amphetamine salts improved, compared with 7% of those who received a placebo.⁴

Duration of action of mixed salts of amphetamine has been measured at 3.5 hours with a 5-mg dose and 6.4 hours with a 20-mg dose.⁵ With methylphenidate, a dose of 12.5 mg worked for 4 hours. The maximum recommended dosage of mixed salts of amphetamine is 40 mg/d in divided doses.

Stimulant medications are well-tolerated. Addiction and the need for increased dosages can occur over long-term use (months to years). Reducing the dosage or switching from methylphenidate to an amphetamine variant can usually prevent these problems.

The FDA recently approved a single-enantiomer form of methylphenidate. It contains only the active “d” enantiomer, whereas the racemic mixture contains both the “d” and “l” enantiomers. Because the “l” enantiomer is inert, the resulting medication is more potent and may be prescribed at half the dosage of the racemic mixture.

Pemoline, a once-daily stimulant, is considered a second-line treatment because of reports of hepatic failure in some patients. Its use requires written informed consent and liver function tests at baseline and every 2 weeks. In a controlled trial, pemoline at high dosages (120 to 160 mg/d) was found moderately effective in adults with ADHD.⁶

Newer options: Longer-acting stimulants

Newer forms of slow-release methylphenidate and mixed amphetamine salts with sophisticated delivery systems are available.

Metadate CD is delivered in capsules containing beads with polymer coatings that dissolve and release their contents at different times. The capsules contain a 30:70 ratio of immediate- and extended-release beads.

Metadate CD has not been tested for adults in controlled clinical trials. In children ages 6 to 15, a single morning dose has been shown to be clinically effective in the morning and afternoon. A supplemental immediate-release capsule can be given in the morning if a patient’s medication levels need to be increased quickly. Dosage supplementation may also be required later in the day.

Concerta is delivered in 18-mg and 36-mg tablets. The immediate-release coating on the tablets delivers medication within the first hour. The drug inside then dissolves in the GI tract and is released at a controlled rate by osmotic pressure. The indigestible tablet is passed in the stool.

Concerta was investigated in children ages 6 to 12 and provides 10 to 12 hours of sustained medication. From child studies, we know that when a patient takes a 36-mg tablet at 6 AM, blood levels decline in late afternoon. An 18-mg dose at noon covers the 4 to 6 hours needed for evening chores.

Adderall XR is an extended-release, once-daily form of mixed amphetamine salts. No controlled trials of this formulation are available in adults with ADHD. Its efficacy was established after two clinical trials of children aged 6 to 12 who met DSM-IV criteria for ADHD.

Individualized and flexible dosing improves symptom control and compliance when treating adults with ADHD. For some patients, once-daily dosing is more convenient than multiple doses, while others prefer the immediate-release form because they like its midday “pause” and bid dosing. The immediate-release tablet allows the flexibility of bid or tid dosing, depending on the day’s requirements.

Antidepressants: Another choice

Antidepressants are usually considered second-line treatment for ADHD because of concerns about efficacy and side effects. The few available studies show antidepressants work as well as stimulants but more slowly. It is good practice, therefore, to advise patients that—unlike feeling the effect of a stimulant in 60 minutes—they will not feel an effect from an antidepressant for days or weeks, and that achieving an optimal effect may take 4 to 6 weeks.

Antidepressants have several advantages over stimulants. They are not classified as narcotics, work without the on-off effects of stimulants, and can treat comorbid depression and anxiety. For adult ADHD, the most effective agents work on the catecholamine systems—norepinephrine and/or dopamine. This includes the tricyclic antidepressants, MAO inhibitors, bupropion, and venlafaxine. The serotonin reuptake inhibitors have not shown promise in ADHD, nor have mirtazapine or nefazodone demonstrated much effect.

Desipramine, a tricyclic antidepressant, is a strong inhibitor of norepinephrine reuptake. In a double-blind, controlled study in 41 adults with ADHD, 68% of patients receiving desipramine, 200 mg/d, responded positively, compared with no patients who took a placebo.⁷

When venlafaxine was given in standard dosages to 10 adults with ADHD in an open, 8-week clinical trial, an effect was seen by week two. Of the nine patients who completed the study, seven were considered responders. Symptoms were reduced significantly with venlafaxine treatment, and most side effects were mild.⁸

In an open study, bupropion treatment resulted in moderate to marked response in 74% of 19 patients. Ten of those patients who responded chose to continue bupropion rather than their previous medication.⁹ In a 6-week controlled study of 40 patients, bupropion use was associated with a 42% reduction in ADHD symptoms in the 38 patients who completed the study. Patients who received a placebo showed only a 24% reduction in symptoms. According to the CGI, 52% of patients who received bupropion reported being “much improved” or “very improved” compared with 11% of those receiving a placebo.¹⁰

Other treatment options that have shown mixed results include modafinil, alpha-2a agonists, acetylcholinesterase inhibitors, and the histaminergic agents.

Managing adverse effects

Substance abuse Stimulant abuse has been a concern, but it has not become the problem many feared. In fact, some studies have found that methylphenidate may help stanch the craving for cocaine in adults with ADHD.^11,12 Treating ADHD with pharmacotherapy also has been shown to reduce the risk for substance abuse in adolescence by 85%.¹³

With careful screening, you can usually identify drug-seeking behavior in adult patients. For patients with substance abuse problems, you can prescribe the nonstimulants.

Tics that can occur with stimulant medications usually can be suppressed by reducing the dosage, being vigilant, and waiting it out. Tics may ameliorate over weeks to months.

Cardiac and cognitive effects Long-term use of stimulant medications at high dosages has been associated with cardiac and cognitive toxicity, as noted in the 1998 NIH consensus statement on diagnosis and treatment of ADHD. It is important to provide patients with this information as part of their informed-consent briefing. (See “Related resources,” to view the consensus statement.)

Nonpharmacologic management

Nonpharmacologic treatments such as EEG biofeedback; psychoeducational approaches; and individual, family, and group psychotherapy are widely used to treat adults with ADHD. Clinicians and patients often perceive these interventions as beneficial, although none have been tested in randomized, placebo-controlled studies.

Patients often function better when their home and work environments are thoughtfully organized, with a designated work/study space and regularly scheduled times for meals, sleep, and exercise. An ADHD coach may facilitate such structure and discipline (Box 2).

New agents in the pipeline

Efforts are being made to increase awareness of adult ADHD and to improve its treatment. For example, the National Institute of Mental Health is funding research on adult ADHD and displays on its Web site a PET scan of an adult brain with ADHD (see “Related resources”).¹⁴ Several medications also are being developed to treat ADHD.

Atomoxetine, a nonstimulant medication awaiting FDA approval for adult ADHD, is a selective norepinephrine reuptake inhibitor. In a double-blind, placebo-controlled, crossover study of adults with well-characterized ADHD, 11 of 21 patients improved with use of atomoxetine, compared with 2 of 21 who improved with use of a placebo. The average dosage of 76 mg/d was well-tolerated.¹⁵ The 52% response rate is similar to the 54% average improvement rate reported for methylphenidate in previous studies of adult ADHD.

In clinical trials, atomoxetine was given bid. Insomnia was not a side effect, so bid dosing does not interfere with sleep. Approximately 10 to 15% of patients experienced weight loss as a side effect.

Other treatment options under development include:

• a transdermal system for delivery of methylphenidate¹⁶
• a novel nicotinic analogue
• glutamate AMPA receptor modulation
• omega-3 fatty acids.

Related resources

• Hallowell EM, Ratey JJ. Driven to distraction: Recognizing and coping with attention deficit disorder from childhood through adulthood. New York: Simon and Schuster; Reprint edition 1995.
• Solanto MV, Arnstein AFT, Castellanos FX, eds. Stimulant drugs and ADHD: Basic and clinical neuroscience. New York: Oxford University Press; 2001.
• Weiss M, Trokenberg-Hechtman L, Weiss G. ADHD in adulthood: A guide to current theory, diagnosis, and treatment. Baltimore: Johns Hopkins University Press; 1999.
• National Institute of Mental Health. http://www.nimh.nih.gov

Drug brand names

• Atomoxetine • (investigational)
• Bupropion • Wellbutrin
• Desipramine • Norpramin
• Dextroamphetamine • Dexedrine, Dextrostat
• Methamphetamine • Desoxyn
• Methylphenidate • Focalin, Ritalin
• Methylphenidate SR • Concerta, Metadate CD, Metadate ER, Methylin ER, Ritalin SR
• Mixed salts of amphetamine • Adderall, Adderall XR
• Modafinil • Provigil
• Pemoline • Cylert
• Venlafaxine • Effexor

Disclosure

The author reports that he serves as a consultant to Eli Lilly and Company and is on the speaker’s bureaus of Wyeth Pharmaceuticals and AstraZeneca.