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 RESEARCH ARTICLE

OROS methylphenidate in the treatment of adults with ADHD: A 6-month, open-label, follow-up study

Barrie K. Marchant, MS

Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Frederick W. Reimherr, MD

Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Corinne Halls, MS

Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Erika D. Williams, MSW

Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

Robert E. Strong, DO

Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT, USA

BACKGROUND: This open-label trial followed a previously reported randomized, placebo-controlled trial of osmotic release oral system (OROS) methylphenidate (MPH) for the treatment of personality disorder (PD). Important findings from the double-blind phase are reexamined for long-term significance.

METHODS: Of 41 patients who completed the double-blind, placebo-controlled trial, 34 continued into this open-label phase. The Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) measured outcome. Patients were categorized using previously defined attention-deficit/hyperactivity disorder (ADHD) groups: ADHD alone, ADHD with emotional dysregulation (ADHD + ED), and ADHD plus emotional dysregulation plus oppositional symptoms (ADHD + ED + ODD); and 3 post hoc personality categories: patients with no PD (PD-negative), patients with 1 PD (PD-positive), and patients meeting criteria for 2 or more PDs (PD-plus).

RESULTS: Three WRAADDS-defined ADHD dimensions improved at similar levels (attention + disorganization, 61%; hyperactivity + impulsivity, 60%; and emotional dysregulation, 66%). All ADHD subgroups (ADHD alone, ADHD + ED, and ADHD + ED + ODD) improved. ADHD + ED + ODD patients had the highest level of social maladjustment at baseline and showed the most long-term improvement in this area. PD-plus patients were less likely to complete the study or show improvement. Sixty-five percent of treatment responders were on moderate doses (≤54 mg/d) of OROS MPH. Vital signs and ECGs did not differ from baseline.

CONCLUSIONS: Eighteen (44%) patients completed the trial. All 3 ADHD dimensions showed similar, well-maintained improvement. Patients with several PDs responded poorly to treatment in this small trial.

KEYWORDS: ADHD, adult, OROS MPH, Concerta, long-term, open-label, personality disorder

ANNALS OF CLINICAL PSYCHIATRY 2010;22(3):196-204

  INTRODUCTION

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood illness that often continues into adulthood.1,2 Although alternative treatments have proven effective, stimulants continue to be the most common treatment. Among the stimulants, methylphenidate (MPH) was the first treatment demonstrated to be effective for adults with ADHD,3 and it remains at least as effective as other treatments. Unfortunately, because of the very short half-life of immediate-release MPH, it usually requires administration at least 3 times a day, perhaps more often in adults. This regimen impairs treatment compliance and has led to the development of sustained-release formulations such as osmotic release oral system (OROS) MPH, designed to provide once-daily administration.

OROS MPH has proven successful in short-term, controlled trials for children,4,5 adolescents,6 and adults.7-9 However, because ADHD is a chronic condition requiring extended treatment, long-term studies are needed. Long-term, open-label studies for children and adolescents also have found that OROS MPH is effective.4,6 There have been only 4 reports of long-term pharmacologic treatment in adults, one using mixed amphetamine salts, extended release,10 a second using atomoxetine,11 a third using OROS MPH,12 and a fourth using dexmethylphenidate, extended release.13 All 4 studies reported well-maintained treatment effects with good safety.

None of these adult studies provided much information on participants’ type of ADHD. Studies have associated a wide array of other disorders and/or symptom clusters with ADHD. The Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA)14 presented an excellent survey of the conditions found in children with combined-type ADHD. The authors concluded that 4 clinical profiles (ADHD alone, ADHD combined with an anxiety disorder, ADHD combined with oppositional defiant disorder (ODD) and/or conduct disorder (CD), and ADHD combined with both comorbid conditions) could be detected.

As part of the initial study, we also conducted a careful assessment of personality disorder (PD) with 2 different measures and then confirmed the diagnosis with extended observation of each patient. The extent of PDs and their impact on outcome measures have been previously reported.15

This report extends these prior analyses8,15 by looking at the long-term portion of the 2007 study and examining outcomes for patients with PD and 3 ADHD subgroups: patients meeting DSM-IV criteria for adult ADHD alone (ADHD alone), patients meeting criteria for both ADHD and emotional dysregulation (ADHD + ED), and patients meeting criteria for ADHD, emotional dysregulation, and oppositional impairment (ADHD + ED + ODD).

The primary purpose of this study was to assess the long-term efficacy and safety of OROS MPH in adult ADHD as measured by the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS).

Secondary goals of this study were to determine the following:

1. Were baseline symptoms of emotional dysregulation and/or oppositional impairment associated with differing treatment effects or completion rates during this long-term, open-label treatment phase?

2. Was the response in the double-blind portion of the study predictive of long-term outcome? Specifically, did patients with an initial response continue to be responders? Did nonresponders continue to be nonresponders in the long-term portion of the study?

3. Were any differences in long-term outcome associated with PD?

4. Was there improvement in social adjustment at this long-term evaluation?

  METHODS

The University of Utah Institutional Review Board reviewed and approved the study. This 6-month, open-label trial of OROS MPH was preceded by a double-blind, placebo-controlled, crossover phase. During the double-blind crossover phase, patients were randomly assigned to either placebo or OROS MPH. After 4 weeks, patients were crossed to the other treatment arm. Following these 2 arms, patients immediately entered the open-label phase, during which they were seen monthly. The dosing was not restricted, and we attempted to adjust the dosage to maximize improvement in ADHD symptoms while limiting the number and extent of adverse events.

Study population

Participants were required to have a current diagnosis of adult ADHD using DSM-IV-TR criteria for current ADHD based on the Conners’ Adult ADHD Diagnostic Interview for DSM-IV, with at least moderate ADHD symptoms and the Utah Criteria for ADHD in adults. Inclusion and exclusion criteria have been previously reported.8

Measures

The Wender Utah Rating Scale (WURS) and the Parent Rating Scale (PRS) were used to assess childhood symptoms of ADHD.

Change on the total WRAADDS was the primary outcome variables. The WRAADDS is an interviewer-administered scale assessing the adult ADHD symptoms identified in the Utah Criteria for ADHD in adults (attention difficulties, hyperactivity/restlessness, temper, affective lability, emotional overreactivity, disorganization, and impulsivity).

The ADHD Investigator Symptoms Rating Scale (AISRS) is an 18-item scale that reflects current symptoms of ADHD based on DSM-IV-TR criteria. The scale was originally developed for children with ADHD, however, it has been revised by the inclusion of prompts applicable to adults.

The Self-Report ADHD Scale, used to assess oppositional impairment, is being developed as an adult-oriented self-report questionnaire to assess the 7 symptom areas of the WRAADDS as well as symptoms in 3 other areas: oppositional defiant symptoms, academic impairment, and social functioning. It uses a 5-point Likert-type scale ranging from 0 = none to 4 = very much. It was used at baseline for ODD assessment. (Copies of the scale are available from the corresponding author.)

The Weissman Social Adjustment Scale–Self Report (WSAS-SR)16 was used to assess social adjustment. This scale consists of 54 questions addressing work, social and leisure, marital, parental, extended family, and economic status.

An ECG was obtained at baseline and at the termination visit. Vital signs (blood pressure, heart rate, and weight) were measured at each visit, as were adverse events.

Emotional dysregulation and oppositional impairment at baseline were defined as follows: Emotional dysregulation was defined using previously published criteria17 of scores ≥7 on the 3 WRAADDS scales of temper + mood instability + emotional overreactivity. Classification of oppositional impairment was done in a 2-step process. First, patients averaging at least moderate impairment on the 8 symptoms of oppositional impairment in the Self-Report ADHD Scale were identified. Second, the history of these patients was reviewed by both the treating doctors (FWR and RES) and the staff of the Mood Disorders Clinic to confirm the assessment.

Using the categories of emotional dysregulation and oppositional impairment, 3 subgroups were developed: (1) Patients meeting criteria for adult ADHD but not meeting criteria for emotional dysregulation or oppositional impairment (ADHD alone), (2) Patients meeting criteria for both ADHD and emotional dysregulation but not criteria for oppositional impairment (ADHD + ED), and (3) Patients meeting criteria for ADHD, emotional dysregulation, and oppositional impairment (ADHD + ED + ODD). Two patients had oppositional impairment but not emotional dysregulation and were not included in the subgroup comparisons.

At the end of the study, a final diagnostic assessment was completed for each patient, using information from the Structured Clinical Interview for DSM-IV Axis-II Personality Disorders (SCID-II),18 the Wisconsin Personality Disorders Inventory IV (WISPI-IV),19 and observation of the patient. Patients were categorized into 3 post hoc PD groups: PD-negative (patients without a PD), PD-positive (patients meeting diagnostic criteria for only one PD), and PD-plus (patients meeting diagnostic criteria for 2 or more PDs).20

Data analysis and statistical procedures

Improvement in the WRAADDS and its 3 factors (attention/disorganization, hyperactivity/impulsivity, and emotional dysregulation) was assessed using paired t tests comparing the open-label endpoint with baseline scores (last observation carried forward [LOCF]). Categorical improvement was defined as improvement of ≥50% on the WRAADDS and Clinical Global Impression– Improvement scale (CGI-I) scores of 1 or 2. Between-group differences at baseline were assessed using analysis of variance (ANOVA).

Improvement in the WSAS was assessed using procedures similar to those used to analyze the ADHD symptoms.

The impact of PD group on improvement in the WRAADDS and its 3 factors was assessed using ANOVA on change from baseline. Chi-square was used for categorical variables.

All 34 patients who received at least one dose of open-label medication were included in the analysis of safety. Safety variables were analyzed using paired t tests comparing the open-label endpoint with baseline scores (LOCF).

All analyses were done using the SPSS 13.0 statistical package (SPSS, Chicago, IL). All statistics were 2-tailed, with P < .05.

  RESULTS

Baseline

Forty-seven patients met admission criteria and signed consent agreements for entry into the study. Four patients were eliminated during the baseline phase after meeting criteria for randomization but before entering the first double-blind phase. One patient dropped out of each treatment arm without contributing any efficacy data. Forty-one patients completed the full double-blind trial. Thirty-four (83%) patients entered the open-label phase; all contributed outcome data, and 18 (44%) completed the 6-month phase.

Patient characteristics at baseline for those entering the long-term, open-label phase are displayed in TABLE 1. Of the 34 patients entering the open-label phase, 4 (12%) patients were experiencing ADHD alone. Fifteen (44%) met criteria for ADHD + ED. Fifteen (44%) patients were categorized as ADHD + ED + ODD. Nineteen patients were categorized as PD-negative, 9 patients as PD-positive, and 6 patients as PD-plus.

As in our previous analysis of the double-blind phase,8 we found several differences among the 3 ADHD subgroups. Patients with ADHD alone were the least impaired and the ADHD + ED + ODD patients were the most impaired in the total WRAADDS (F[2,31] = 7.62; P = .002), but this was primarily accounted for by differences in emotional dysregulation (F[2,31] = 23.03; P < .001). In contrast, there were no significant group differences found in the ADHD Investigator Symptoms Rating Scale (AISRS). Between-group differences were significant for WURS (F[2,31] = 11.22; P < .001), PRS (F[2,23] = 3.66; P = .042), and the 17-item Hamilton Rating Scale for Depression (HAMD-17) (F[2,31] = 4.41; P = .021). Patients with ADHD alone were the least impaired and the ADHD + ED + ODD patients were the most impaired in all 3 measures.


TABLE 1

Baseline demographics for patients entering the long-term phase

  All patients (n = 34) ADHD alone (n = 4) ADHD + ED (n = 15)a ADHD + ED + ODDb (n = 15)
Male, n (%) 22 (65%) 3 (75%) 9 (60%) 10 (67%)
Age, y, mean ± SD 31.5 ± 11.6 30.8 ± 5.4 31.9 ± 15.1 31.4 ± 9.2
BMI, kg/m2, mean ± SD 28.8 ± 6.0 27.1 ± 6.4 28.6 ± 5.2 29.5 ± 6.9
Total WRAADDS total, mean ± SD 23.5 ± 3.5 19.5 ± 1.9 22.6 ± 3.4 25.0 ± 1.8
  Attention + disorganization 7.3 ± 1.0 7.8 ± 0.5 7.5 ± 1.1 7.3 ± 0.6
  Hyperactivity + impulsivity 6.5 ± 1.6 6.3 ± 1.3 5.9 ± 2.0 7.1 ± 0.6
  Emotional dysregulation 9.5 ± 2.3 5.0 ± 1.4 9.3 ± 1.5 10.5 ± 1.4
Total AISRS, mean ± SD 35.7 ± 9.2 34.3 ± 10.7 33.8 ± 9.0 38.1 ± 9.2
  Inattention 20.4 ± 4.1 21.3 ± 3.6 20.5 ± 4.7 20.6 ± 3.8
  Hyperactivity/impulsivity 15.0 ± 6.2 13.0 ± 7.2 13.3 ± 5.8 17.4 ± 6.0
WURS, mean ± SD 56.9 ± 15.9 35.8 ± 19.4 52.6 ± 11.9 66.7 ± 11.2
PRS, mean ± SD 20.2 ± 5.8 16.3 ± 7.3 18.2 ± 5.1 23.1 ± 4.7
HAMD-17, mean ± SD 11.2 ± 5.9 6.0 ± 0.8 9.6 ± 5.5 13.9 ± 5.8
Responders in crossover, n (%) 19 (56%) 2 (50%) 5 (33%) 12 (75%)
PD-negative,c n (%) 19 (56%) 4 (100%) 11 (73%) 4 (27%)
PD-positive,d n (%) 9 (27%) 0 2 (13%) 7 (47%)
PD-plus,e n (%) 6 (18%) 0 2 (13%) 4 (27%)
ADHD: attention-deficit/hyperactivity disorder; AISRS: ADHD Investigator Symptoms Rating Scale; BMI: body mass index; ED: emotional dysregulation; HAMD-17: 17-item Hamilton Rating Scale for Depression; ODD: oppositional defiant disorder; PD: personality disorder; PRS: Parent Rating Scale; WURS: Wender Utah Rating Scale.
aADHD + ED: Patients met criteria for ADHD as well as ED.
bADHD + ED + ODD: Patients met criteria for ADHD and ED, and had significant ODD symptoms.
cPD-negative: Patients did not meet criteria for personality disorder.
dPD-positive: Patients met criteria for 1 personality disorder.
ePD-plus : Patients met criteria for ≥2 personality disorders.
Efficacy

ADHD symptoms measured by average total WRAADDS scores decreased 63% over baseline (t = 14.8; df = 33; P < .001). Significant improvement was seen across all 3 dimensions and all 3 ADHD patient groupings. As seen in TABLE 2, there was a positive treatment effect for the ADHD symptoms of attention + disorganization (t = 13.0; df = 33; P < .001), hyperactivity + impulsivity (t = 9.2; df = 33; P < .001), and emotional dysregulation (t = 13.8; df = 33; P < .001). Although, as seen in TABLE 2, the 3 subgroups appeared to differ in rates of retention and treatment response, these differences did not reach statistical significance.

Twenty patients met WRAADDS criteria for improvement in the OROS MPH arm of the double-blind period, and 19 entered the open-label phase. At endpoint they had improved an average of 68% over baseline, and 17 (89%) of these continued to meet criteria for improvement at exit (last value carried forward [LVCF]). Twenty-one patients did not meet WRAADDS criteria for improvement in the OROS MPH arm of the double-blind period, and 15 entered the open-label phase. At endpoint they had improved an average of 55% over baseline, and 9 (60%) of these met criteria for improvement at exit (LVCF). Improvement during this period was significant for the total WRAADDS (P < .001), as well as the 3 groupings of attention + disorganization (P < .001), hyperactivity + impulsivity (P = .004), and emotional dysregulation (P < .001).


TABLE 2

Long-term outcome—Decrease in WRAADDS from baseline to termination (LVCF)

  All patients n = 34 ADHD alone n = 4 ADHD + EDa n = 15 ADHD + ED + ODDb n = 15
Completed long-term (%) 53% 100% 40% 53%
WRAADDS improved, n (%) 26 (76%) 4 (100%) 10 (67%) 12 (80%)
CGI-I improved, n (%)c 29 (85%) 4 (100%) 12 (80%) 13 (87%)
Total WRAADDS, mean ± SD (% improvement over baseline) 14.6 ± 5.7 (63%)d 16.3 ± 2.1 (83%)d 12.8 ± 6.3 (57%)d 15.9 ± 5.6 (63%)d
Attention + disorganization 4.5 ± 2.0 (61%)d 6.8 ± 1.9 (87%)e 3.9 ± 1.7 (52%)d 4.6 ± 2.0 (63%)d
Hyperactivity + impulsivity 3.9 ± 2.5 (60%)d 5.3 ± 1.0 (84%)f 3.0 ± 3.1 (51%)f 4.5 ± 1.7 (63%)d
Emotional dysregulation 6.1 ± 2.6 (66%)d 3.8 ± 3.2 (75%)d 6.0 ± 2.1 (64%)d 6.9 ± 2.7 (66%)d
ADHD: attention-deficit/hyperactivity disorder; CGI-I: Clinical Global Impression–Improvement scale; ED: emotional dysregulation; LVCF: last value carried forward; ODD: oppositional defiant disorder; WRAADDS: Wender-Reimherr Adult Attention Deficit Disorder Scale.
aADHD + ED: Patients met criteria for ADHD as well as ED.
bADHD + ED + ODD: Patients met criteria for ADHD and ED, and had significant ODD symptoms.
cNumber of patients “much” or “very much” improved on the CGI-I.
dP ≤ .001.
eP ≤ .01.
eP ≤ .005.
Change is measured between baseline and endpoint using paired t tests.
Personality disorder

Although all 3 PD groups demonstrated improvement over baseline, this improvement was much less for the PD-plus sample. This relationship between PD group and treatment was significant for the total WRAADDS (F[2,31] = 8.6; P = .001) as well as the 3 symptom groups: attention + disorganization (F[2,31] = 4.1; P = .025) hyperactivity + impulsivity (F[2,31] = 7.1; P = .003), and emotional dysregulation (F[2,31] = 8.2; P = .001 ). The lower response of the PD-plus group was also evident using the categorical variable of improvement as defined by a 50% improvement on the WRAADDS (χ2 = 7.61; df = 2; P = .025). As seen in TABLE 3, the PD-plus patients were least likely to complete the long-term phase; however, this difference was not statistically significant.


TABLE 3

Long-term treatment outcome for the 3 personality disorder categories

  PD-negativea n = 19 PD-positiveb n = 9 PD-plusc n = 6
Completed long-term, n (%) 12 (63%) 5 (55%) 1 (17%)
WRAADDS, n (%) improved 16 (84%) 8 (89%) 2 (33%)
CGI-I, n (%) improvedd 16 (84%) 9 (100%) 4 (67%)
Total WRAADDS, mean ± SD (%) decrease in score from baseline 14.4 ± 5.3 (67%)e 17.3 ± 4.5 (68%)e 10.8 ± 7.3 (42%)f
Attention + disorganization 4.8 ± 2.2 (65%)e 4.8 ± 1.5 (66%)e 3.2 ± 1.9 (40%)g
Hyperactivity + impulsivity 3.7 ± 2.7 (63%)e 5.1 ± 1.2 (71%)e 2.8 ± 2.9 (39%)
Emotional dysregulation 5.8 ± 2.3 (71%)e 7.7 ± 2.7 (70%)e 5.0 ± 2.8 (46%)g
CGI-I: Clinical Global Impression–Improvement scale; LVCF: last value carried forward; WRAADDS: Wender-Reimherr Adult Attention Deficit Disorder Scale.
aPD-negative: Patients did not meet criteria for personality disorder.
bPD-positive: Patients met criteria for 1 personality disorder.
cPD-plus: Patients met criteria for ≥2 personality disorders.
dNumber of patients “much” or “very much” improved on the CGI-I.
eP ≤ .001.
fP > .05.
gP ≤ .01.
Change is measured between baseline and long-term (LVCF) using paired t tests.
Social adjustment

TABLE 4 shows the changes in social adjustment for the 3 groups between baseline and open-label endpoint in several areas. Scores of 3 or higher were considered indicative of at least moderate impairment, and the “%” score was the percentage of items that were given a score of 3 or more across all patients and all questions. Social adjustment showed numerical improvement in many areas; however, few were statistically significant. Social adjustment in the area of social leisure improved for all patients (P = .017). For ADHD + ED + ODD patients, the area of work improved significantly (P = .021), and 4 other areas (social leisure, family, spouse, and financial) improved at a level approaching significance (P = .1). In summary, at baseline there was a general relationship indicating that the ADHD-alone patients had the best social adjustment, and the ADHD + ED + ODD patients had the worst social adjustment. At long-term endpoint, only the ADHD + ED + ODD group had improved at a level approaching statistical significance.


TABLE 4

Social adjustment* at baseline and long-term according to ADHD symptomatology

  All patients ADHD alone ADHD + EDa ADHD + ED + ODDb
  Baseline Long-term Baseline Long-term Baseline Long-term Baseline Long-term
All work 36% 13% 10% 0% 36% 17% 42% 14%c
Social leisure 45% 30%c 39% 11% 42% 43% 50% 26%d
Family 11% 4% 16% 0% 17% 26% 33% 12%d
Spouse 28% 19% 0% 6% 21% 29% 46% 14%d
Financial 45% 44% 40% 50% 33% 50% 55% 36%d
Conflicts 18% 13% 11% 3% 10% 21% 30% 8%
Strong feelings 23% 13% 13% 0% 20% 24% 29% 14%
ADHD: attention-deficit/hyperactivity disorder; ED: emotional dysregulation; ODD: oppositional defiant disorder.
*Percentage of patient responses indicating clinically significant problems (scores of ≥3), for all patients on all questions.
aADHD + ED: Patients met criteria for ADHD as well as ED.
bADHD + ED + ODD: Patients met criteria for ADHD and ED, and had significant ODD symptoms.
cP = .05.
dP < .1.
Change is measured between baseline and endpoint using paired t tests.
Medication dose

Medication doses were quite variable (mean value ± SD = 59.8 ± 24.9 mg/d) and comparable to the double-blind phase (64.0 ± 23.3 mg/d). Twelve (35%) patients were on high doses (64 mg/d or higher), 16 (47%) on moderate doses (45 to 54 mg/d), and 6 (18%) patients on low doses (18 to 36 mg/d). These dose levels were similar to dose levels these same patients received during the double-blind phase, when there were 17 (50%) patients on high doses, 13 (45%) on moderate doses, and 4 (12%) patients on low doses (P = .76). Although OROS MPH is approved for once-daily dosing, of the 26 treatment responders, 8 (31%) left the study using a twice-daily dosing regimen. Of the 8 on twice-daily dosing, 5 (63%) were taking 64 mg/d or more.

Vital signs and adverse events

Changes in vital signs between baseline and long-term evaluations were minimal. Systolic blood pressure changed from 123.3 ± 9.9 to 121.1 ± 9.4 mm Hg; diastolic blood pressure changed from 80.7 ± 9.4 to 81.0 ± 9.1 mm Hg; heart rate changed from 74.5 ± 9.9 to 71.9 ± 8.9 bpm; PR interval changed from 151.2 ± 14.6 to 145.5 ± 21.1 msec; QRS interval changed from 89.4 ± 10.6 to 88.7 ± 9.3 msec; QT interval changed from 394.8 ± 32.3 to 385.1 ± 36.0 msec; QTc interval changed from 408.1 ± 17.5 to 411.2 ± 19.4 msec; and weight changed from 188.6 ± 49.1 to 198.9 ± 47.6 lb. None of these changes were statistically significant. Specific adverse events experienced by patients were similar to those reported in other ADHD trials using stimulants. A total of 10 patients experienced at least one adverse event. Four patients (12%) experienced problems with sleep/insomnia. Two patients (6%) experienced a decrease in appetite. Four patients (12%) experienced 1 of 3 related problems: anxiety, tension, or agitation. Headache, nausea, and dry eyes, nose, or mouth were experienced by one patient each. Only 2 patients experienced problems that were rated as moderate or worse in severity.

  DISCUSSION

The use of OROS MPH for the treatment of adult ADHD has been reported in a study by Biederman et al,7 in a prior analysis of the patients in this report by Reimherr et al,8 and in a long-term open-label trial.12 The 2 double-blind studies and the open-label study all found OROS MPH to be effective.

As in both acute trials, OROS MPH was effective in the long-term treatment of all ADHD symptoms. Not only did the DSM-IV symptoms improve, but the symptoms of emotional dysregulation improved as well.

In the double-blind phase, most patients (83%) had symptoms of either emotional dysregulation and/or oppositional impairment. Similarly, 88% of patients participating in this follow-up phase had symptoms of either emotional dysregulation and/or oppositional impairment at baseline. These patients responded to treatment in the acute trial as well as the long-term evaluation. The ADHD + ED group improved 57% over baseline (P < .001), and the ADHD + ED + ODD group improved 63% over baseline (P < .001). These results suggest that clinicians may consider treating patients exhibiting these additional symptoms, since the patients clearly respond to treatment. Furthermore, the ADHD symptoms of emotional dysregulation improved with treatment at a rate (66%) similar to the symptoms of attention/disorganization (61%) and hyperactivity/impulsivity (60%). Given the impact that these emotional and oppositional defiant symptoms have on family and social relationships, these improvements are equally useful across the entire day, not primarily during school/work hours.

Completion rates might represent another method of comparing different treatments for adults with ADHD in long-term studies. This is essentially the primary outcome measure in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study of schizophrenia. Completion rates in the long-term phase were similar to those reported in studies of atomoxetine, mixed amphetamine salts, and dexmethylphenidate.13 Of 41 patients completing the double-blind phase, 34 (83%) contributed data in this follow-up phase and 18 (44%) completed the 6-month trial. In Adler’s atomoxetine adult ADHD trial, of 536 patients randomized, 199 (37%) remained in the study after 6 months. In the long-term mixed amphetamine salts–extended release study, 255 patients entered the double-blind phase, and 108 (42%) remained at 12 months. Finally, in Adler’s extended-release dexmethylphenidate adult trial, 221 patients were randomized and 103 (47%) completed the 6-month open-label phase. In an unpublished trial of immediate-release methylphenidate that the authors conducted several years ago, 116 patients were randomized to the double-blind phase and 64 (55%) completed at least 6 months of the open-label phase. (This last study differed from the others in that only treatment responders were allowed to enter the open-label trial, whereas all double-blind completers were invited to participate in the other 3 trials.) In our experience, 6 months is a reasonable time period to allow social adjustment changes to occur and to allow patients and families to judge the benefits of extended treatment.

Since a significant number of both double-blind treatment responders and nonresponders entered this long-term phase, we can compare their long-term treatment responses. There were 20 treatment responders and 21 treatment nonresponders during the double-blind trial. All but one treatment responder continued into the open-label phase, as did 15 of the nonresponders. Extended treatment was not associated with a change in efficacy for the double-blind responder group. In comparison, patients who did not respond during the double-blind period improved from 23.1 ± 2.8 at baseline to 20.3 ± 4.0 in the OROS MPH arm. During this open-label phase, they improved to an average of 10.3 ± 8.0 at the end of the study. For these patients, the change between double-blind and open-label was highly significant (P < .001), and 9 patients ultimately met criteria for improvement. It would appear that extended treatment was associated with increased recruitment of responders and that 4 weeks may not be sufficient time for some patients to respond to treatment.

Personality

Numerous patients in this trial suffered from 1 or more PDs. Of the 10 PD-plus patients, only 6 entered into this long-term phase. In comparison, 9 of the 11 PD-positive patients entered this phase, as did 19 of 26 PD-negative patients. In another report we noted that the PD-plus patients responded poorly to treatment.15 This poor response continued in the long-term phase. In contrast, the PD-positive patients continued to benefit from treatment at levels equivalent to the PD-negative patients. Moreover, the improvements in these groups extended across all ADHD symptoms. This response pattern based on PD confirms our double-blind report.

Social adjustment

As in the analysis of the acute trial, we combined 3 areas (work, housework, and school), as appropriate, into a single category called work. We also included 2 groupings of these questions called conflict and strong feelings. At baseline, there was a general relationship between the increasing impairment of our 3 groups and SAS-SR impairment (ADHD alone < ADHD + ED < ADHD + ED + ODD). This difference did not reach statistical significance, except that the ADHD + ED + ODD group had a higher ranking on conflict than did the other 2 groups at baseline. In contrast with previous reports, there was limited evidence of improvement in social adjustment as a result of treatment. It is unclear the extent to which this lack of significance results from the use of a self-report outcome measure. The use of an investigator-rated scale using a significant other may have provided a more complete picture of social adjustment.

Medication dose

As in the acute treatment portion of this study, medication doses were quite variable, with 6 patients on low doses (18 to 36 mg/d), 13 on moderate doses (45 to 54 mg/d), and 10 on high doses (64 mg/d or higher). These dose levels contrast with some other studies. A meta-analysis performed by Faraone et al21 indicated that studies of adults taking methylphenidate doses of 0.9 mg/kg generated larger effect sizes than did studies using lower doses. Further, in their adult OROS MPH study, Biederman et al7 reported average doses of 81 mg/d compared with the average of 69 mg/d for treatment responders during the open-label phase of this trial. These different results suggest that one should titrate doses until a response is achieved. This titration is facilitated by using interview forms like the WRAADDS and the involvement of reliable informants such as a significant other. It is not unusual for family members to describe changes in mood and temper not recognized by the patient.

Vital signs and adverse events

The long-term use of OROS MPH proved to be accompanied by relatively few side effects. In the acute trial, there were small but statistically significant differences between the OROS MPH and placebo arms in diastolic blood pressure and QT interval. In contrast, there were no significant differences between the baseline and long-term evaluations. As in the acute trial, there were no clinically significant outliers in QTc interval, blood pressure, or heart rate. As in other OROS MPH studies, the primary adverse events experienced by our patients were sleep/ insomnia, decreased appetite, and anxiety. All but 2 of the adverse events were in the mild range, and no patients discontinued treatment as a result.

  CONCLUSIONS

OROS MPH was effective in the long-term treatment of adult ADHD, with a side effect profile similar to that of immediate-release methylphenidate. It was an effective treatment for the DSM-IV symptoms of attention/ disorganization and hyperactivity/impulsivity, plus the additional ADHD symptoms of emotional dysregulation. Patients with symptoms of oppositional impairment benefited from treatment at a level similar to that of patients with only ADHD symptoms. Only 2 (11%) patients experienced a loss of efficacy during the long-term trial, whereas 9 (60%) double-blind nonresponders became responders during this open-label follow-up phase, suggesting that some patients required more than 4 weeks to respond to treatment. Patients with 2 or more PDs did poorly in this trial compared with patients with 1 or no PDs. Patients responded at a wide range of doses, which strongly documents the need for individualized dosing. Confidence in these findings is limited by the small number of participants, particularly within the subgroup analyses.

DISCLOSURES: Mr. Marchant receives grant/research support from Ortho-McNeil Pharmaceuticals, Eli Lilly and Company, and Shire. Dr. Reimherr receives grant/ research support from Ortho-McNeil Pharmaceuticals, Eli Lilly and Company, and Shire. Ms. Halls, Ms. Williams, and Dr. Strong report no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

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CORRESPONDENCE: Fred W. Reimherr, MD, Mood Disorders Clinic, Department of Psychiatry, University of Utah Health Sciences Center, Salt Lake City, UT 84132 USA E-MAIL: fred.reimherr@hsc.utah.edu