Wednesday, May 31, 2023
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Instructor in Psychiatry, Harvard Medical School, Boston, Massachusetts; Scientific Coordinator, Adult ADHD Research Program, Massachusetts General Hospital, Cambridge, Massachusetts
Adjunct Professor of Psychiatry, University of North Carolina, Chapel Hill; Adjunct Associate Professor of Psychiatry, Duke University, Durham, North Carolina
Attention-deficit/hyperactivity disorder (ADHD) appears to affect 4.4% of adults between the ages of 18 and 44 in the United States.[1] Studies suggest that adults with ADHD often experience impairment in academic, occupational, and social functioning, along with high rates of comorbidities that compound their distress. Several presentations at the 2006 American Psychiatric Association meeting in Toronto, Ontario, Canada, highlighted ongoing efforts to mitigate the effects of ADHD in adults.
During 2 weeks in May 2003, 400 primary care physicians completed a Harris Interactive online survey exploring their comfort diagnosing and treating ADHD in adults. Participants indicated that they were more comfortable with their knowledge of depression and generalized anxiety than with their knowledge of ADHD. In all, 65% of survey respondents were uncomfortable diagnosing ADHD without referring to a specialist, and only 5% reported that they "make the final determination to treat ADHD with medication."[2] Although these data are 3 years old, they highlight the importance of improved mechanisms for identifying and treating ADHD in primary care settings, particularly given that access to mental health specialists is limited.
The Adult Symptom Rating Scale (ASRS) is a self-report survey that clinicians can administer to identify adults who are likely to have ADHD.[3] Answers to 6 items on the ASRS screener version have been validated as highly predictive of expert clinical identification of ADHD. The ASRS instruments are publicly available at www.med.nyu.edu/psych/psychiatrist/adhd.html. Researchers from New York University in New York City reported on a 2-year follow-up of participants identified as likely to have ADHD according to the ASRS, during an ADHD Screening Day conducted in May 2004. At that time, 85% of the 33 adults screened positive for ADHD; they then discussed these results and referral options with trained clinicians. Of 51 subjects who completed a follow-up survey 2 years later, 47% had sought ADHD diagnosis or treatment, 74% of whom were diagnosed by a specialist and 4% of whom were diagnosed by a primary care physician (PCP). The 53% of individuals who did not seek diagnosis of ADHD reported that ADHD symptoms contributed to their not obtaining a diagnosis.[4] The findings of this study are consistent with those of larger epidemiologic surveys and suggest that a large percentage of adults with ADHD remain untreated. As the investigators suggest, because of the very symptoms they are trying to address, patients may benefit from active involvement by clinicians during the referral process.
An emerging body of research is demonstrating the efficacy and safety of agents used to treat ADHD in adults. Methylphenidate treatment trials for adult ADHD that included doses ≥ 1.0 mg/kg/day have demonstrated higher response rates than trials involving lower doses. Recent data suggest that, when necessary and tolerated, such robust stimulant treatments can be safe in adults.[5]
For example, in a 6-month study that demonstrated continued efficacy and tolerability of MAS XR treatment in adults with titration up to 60 mg daily, 28% of subjects completed the study at 40 mg/day and 56% completed it at 60 mg/day.[6] To date, however, the only ADHD treatments approved for use in adults by the US Food and Drug Administration are d-methylphenidate extended release at dosages up to 20 mg daily, mixed amphetamine salts extended release (MAS XR) at dosages up to 20 mg daily, and atomoxetine at up to 100 mg/day.
Evidence from pharmacy claim records shows that adherence to prescriptions for ADHD treatment may be low.[7] At the APA 2006 meeting, researchers reported an analysis of pharmacy database records cataloguing filled prescriptions for psychostimulants, diabetes agents, and hypercholesterolemia treatments from the fall of 2003 through the fall of 2004. Subjects entering the observation period had filled a prescription for the first time in 90 days. Subjects were considered persistent with a medication at a given time point when the current fill date was within 2 months of the previous fill date. By Month 2 of the observation period, persistence rates were similar for psychostimulants, antidiabetic agents, and statins. By Month 7, persistence rates for MAS-XR (22.9%) and methylphenidate modified release (23.5%) were similarly low, whereas persistence rates were slightly higher for rosiglitazone (an antidiabetic agent) (33.4%) and the statins (26.0%-30.1%), and similar or slightly lower for insulin treatments (17.6% for insulin glargine).[8] This study suggests, from a pharmacy claims perspective, that adherence to long-acting stimulant agents may be similar to adherence to treatments for other chronic illnesses. Because adequacy of ADHD treatment often depends on adherence to prescriptions, this study highlights that adherence to treatment is a potential barrier to adequate management of ADHD. Because stimulant efficacy, which may require robust dosing in adults, may contribute to prescription adherence, it is possible that subadequate treatment practices contribute to these findings of low adherence to stimulants.
Little investigation has examined the longer-term effects of methylphenidate treatment in adults with ADHD. A recent extension study, however, followed 65 adults with ADHD treated with methylphenidate administered 3 times daily (59 subjects) or placebo (6 subjects) under double-blind conditions for up to 30 weeks. Participants had previously completed a 6-week study of short-term efficacy in which subjects were randomized at a ratio of 2.5 to 1 to receive methylphenidate or placebo. Subjects who experienced at least a 30% reduction in ADHD symptoms during this 6-week study were eligible to enter the extension study. Symptoms were measured by the clinician-rated ADHD Rating Scale (ADHD RS, an instrument that captures symptoms of ADHD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]). In the 24-week extension phase, responders were assessed every 4 weeks.
The mean dose remained between 1.0 and 1.1 mg/kg/day for methylphenidate and between 1.2 and 1.3 mg/kg/day for placebo during the 24-week study. Compared with results of the earlier, short-term study, mean improvement in the ADHD RS and clinician-rated Global Assessment of Functioning remained stable for subjects on methylphenidate and those on placebo. Worsening of ADHD symptoms, as defined by loss of at least 25% improvement in ADHD RS score from baseline, occurred in 15% of methylphenidate-treated subjects and 43% of placebo-treated subjects by the end of the 24-week maintenance period. Adverse events were typical of stimulant treatments, and no significant changes in vital signs or blood pressure were observed in this maintenance study.[9] Although comparisons are limited by the small size of the placebo group, this study offers important evidence for the longer-term efficacy and safety of methylphenidate treatment in adults.
Although longer-acting stimulants have been designed to mimic, and even improve upon, the daytime coverage of multiple doses of shorter-acting formulations, few studies have compared the safety and efficacy of short- and long-term treatments. A recent analysis of pooled data from 2 independently conducted, 6-week, placebo-controlled, randomized methylphenidate adult clinical trials compared 2 forms of methylphenidate. In 1 trial, osmotic oral release system-methylphenidate (OROS mph) was administered once daily and was titrated to optimize effect up to a maximum of 1.3 mg/kg/day. The second trial, of immediate-release methylphenidate (IR-mph) administered 3 times daily, involved titration up to a maximum of 1.0 mg/kg/day. By data pooling, 3 treatment groups were created for study: placebo (n = 116), IR-mph (n = 102), and OROS-mph (n = 67). The Adult ADHD Investigator Symptom Report Scale (AISRS, a scripted version of the ADHD RS) was the main outcome measure, and at the end of 6 weeks of treatment, AISRS scores were significantly higher in the placebo group than for both the IR-mph (P < .001) and the OROS-mph (P < .001) groups. No statistically significant difference in AISRS scores was found between the OROS-mph and IR-mph groups. In all, 66% of subjects receiving OROS-mph, 70% of subjects receiving IR-mph, and 31% of subjects receiving placebo were considered much or very much improved on the Clinical Global Improvement Scale.
Both methylphenidate treatments were well tolerated, with adverse events similar in nature to and occurring at rates typical of those observed in stimulant studies and no serious adverse events. Subjects receiving OROS-mph did report dry mouth, reduced appetite, and gastrointestinal complaints slightly but significantly more often than subjects treated with IR-mph. Small but statistically significant increases in diastolic blood pressure and heart rate were noted for both methylphenidate treatments.[10] This analysis suggests that daytime coverage of ADHD with robust dosing of methylphenidate can be effective and well tolerated, although conclusions comparing the different forms of methylphenidate are limited by the pooled study design.
Some clinicians prescribe more than 1 agent to manage ADHD symptoms for particular patients, but this practice has not been systematically studied. At the 2006 APA meeting, 2 retrospective reviews offered a preliminary perspective on such treatment combination approaches. Because adults often have activities that span beyond the 8-12 hours that long-acting stimulants last, short-acting stimulants are sometimes prescribed to cover the hours following the wear-off of a long-acting agent. One chart review examined the efficacy of prescribing afternoon d-methylphenidate (d-mph) to 27 individuals aged 8 to 51 years (mean age, 18) to augment a morning dose of OROS-mph or MAS-XR. Whereas all subjects were receiving extended-release stimulants, 8 of the subjects also received d-mph in the morning as well as the afternoon, and 9 were also taking atomoxetine. Subjects receiving d-mph in the afternoon reported benefit lasting 3-6 hours (4 on average), and tolerated it well; 2 subjects experienced dose-limiting side effects (agitation, early insomnia).[11] This review of afternoon treatment augmentation suggests that the practice of combining agents can be helpful in some cases, but it does not allow us to draw conclusions about the efficacy and tolerability of this approach.
Another review of an augmentation strategy retrospectively assessed the treatment records of 29 patients with ADHD, ranging in age from 10 to 60 years (mean age, 32 years), who received atomoxetine concurrently with a stimulant. This was a heterogeneous sample, with 11 subjects having comorbid dysthymia or depression, 7 subjects having anxiety disorders, and 1 subject with bipolar disorder. In all, 76% of the study sample tolerated the combination of atomoxetine and MAS XR, and rates of discontinuation appeared similar for subgroups with and without comorbidity.[12] Structured measures were not used to assess effect or tolerability. This study offers a preliminary perspective on the tolerability of combining stimulant and atomoxetine treatments, but highlights the importance of prospective systematic study of this clinical practice before it can be widely recommended.
Although patients with ADHD often have residual ADHD-related challenges despite optimization of medication regimens, there is little science to guide clinicians in making recommendations for nonpharmacologic approaches to these challenges. Some studies have suggested, however, that some forms of nonpharmacologic therapy are useful for ADHD patients.[13] One uncontrolled study, for example, demonstrated that subjects with ADHD who were stabilized on medication, but had residual symptoms, benefited from a manualized modified cognitive behavioral therapy.[14] The protocol from this study was developed into a clinician guide with companion patient workbook,[15] and may be useful for structuring clinical interventions.
Recently, 48 patients at 5 sites were randomized to receive a manualized problem-focused therapy (PFT) and either d-amphetamine (up to 20 mg twice daily) or placebo. Participants were assessed 10 and 20 weeks into the interventions. The PFT included education about ADHD and training in coping strategies for symptoms associated with ADHD, and involved flexibility in that some modules were selected to address the particular challenges faced by individual subjects, such as substance use or financial management. Both groups showed improvements in ADHD-RS scores. By 20 weeks, subjects receiving both PFT and d-amphetamine showed greater maintenance of gains in the Clinical Global Impression of ADHD Improvement and Global Assessment of Functioning scores than subjects receiving PFT and placebo. Significant improvements in the Sheehan Disability Scale occurred for both treatment groups (P < .05) but did not statistically differ between the groups. Overall, investigators found that individuals who received PFT and stimulant experienced a trend toward greater and more persistent benefit than subjects receiving PFT and placebo treatment.[16]
This study design does not control for the placebo effect of participation in therapy, and thus it is unclear whether benefits apparently associated with PFT treatment might be nonspecific to this particular intervention. Larger, systematic, controlled studies of nonpharmacologic therapies will be needed before clinicians can utilize them as proven strategies for management of ADHD.
Because ADHD can have a broad impact on quality of life, researchers have been interested in capturing change in these effects during the course of a clinical trial. At this year's APA meeting, researchers reported on measurements from 2 different instruments designed to capture changes in quality of life, during the first 10 weeks of a large open-label trial of MAS-XR treatment. Analyses were conducted on an intent-to-treat population consisting of 702 adults from 81 community practice sites in North America; mean age was 36.9 years in the intent-to-treat population. Participants received 10 to 60 mg of MAS XR daily. Investigators administered the 36-item Short Form Health Survey version 2 to study subjects. Compared with 1998 US normative data, adults with untreated ADHD had lower scores at pretreatment baseline for Mental Health Component summary score by 1 standard deviation, but similar scores for components reflected in the Physical Component summary score. After 10 weeks of MAS-XR, the scores for mental health subdomains significantly improved such that the Mental Health Component summary score became comparable to the US norms.[17]
Subjects in the same study also completed the ADHD Impact Module, a quality-of-life measure that was developed to capture more ADHD-specific aspects of functioning. This self-report instrument was developed on the basis of findings from a literature review and clinician and patient interviews. The module asks subjects to rate overall quality of life and to complete subscales titled Living with ADHD; General Well-Being; Performance and Daily Functioning; Relationships and Communication; Bothersomeness and Concern; and Daily Interference. By the tenth week of the study, statistically significant improvements occurred, compared with baseline, in self-ratings of overall quality of life and all 6 subscales (P values all < .001). Strongest improvements were reported for Performance and Daily Functioning, Bothersomeness and Concern, and Daily Interference subscales.[18]
These 2 scales, administered in the same study, demonstrate how different aspects of the functioning of ADHD patients may be captured using general vs disease-specific survey instruments. Given the lack of a control group, this study does not demonstrate to what degree the quality-of-life improvements were related to medication vs a placebo effect. The validity of such quality-of-life measures as tools for assessing the well-being of patients might be strengthened by proven correlations with actual outcomes in an ADHD population. We hope that a more extensive validity study will reveal the full relevance of such instruments for use in research and clinical practice.
Although many medication treatments are available to manage ADHD, much remains to clarify their efficacy and safety in adults. The sample of studies presented here offers further evidence, however, that ADHD can be safely and effectively treated in adults, and that the scope of research on ADHD treatments is expanding to address unmet needs and capture the impact of treating more than core ADHD traits.
