An Open-Label,Randomized Trial of Methylphenidate and Atomoxetine Treatment in Adults With ADHD

Abstract

Objective: To directly compare the efficacy of methylphenidate and atomoxetine in improving symptoms, social functions, and quality of life among adults with ADHD. Method: This was an 8-to-10-week, open-label, head-to-head, randomized clinical trial with two treatment arms: immediate-release methylphenidate (IR-methylphenidate; n = 31) and atomoxetine once daily (n = 32). The outcome measures included ADHD symptom severity, quality of life, and functional impairments. Results: We found a significant reduction in overall ADHD symptoms and improvement in social functions and quality of life for both groups at Weeks 4 to 5 and Weeks 8 to 10. There was no significant difference in the slope of improvements over time except that atomoxetine was superior to IR-methylphenidate in reducing hyperactive/impulsive symptoms at Weeks 4 to 5. There was no significant group difference in the rates of adverse effects. Conclusion: Both IR-methylphenidate and atomoxetine are well tolerated and efficacious in ethnic Chinese adults with ADHD.

Keywords

adult ADHD methylphenidate atomoxetine life quality social function

Introduction

ADHD, a common lifelong neuropsychiatric disorder, is associated with a wide range of functional impairments (Biederman & Faraone, 2005) from childhood (Biederman et al., 2004) to adulthood (Barkley, Murphy, Dupaul, & Bush, 2002; Biederman et al., 2006; Danckaerts et al., 2010; Friedman et al., 2003). Adults with ADHD were reported to have more job changes (Biederman et al., 2006), higher divorce rates (Biederman et al., 2006), lower social competence (Friedman et al., 2003), a higher risk of adverse driving outcomes (Barkley et al., 2002), and poorer life quality (Danckaerts et al., 2010) than those without.

For decades, psychostimulants, as the first medication approved by the Food and Drug Administration (FDA) for the treatment of ADHD, have been the most widely used agents in treating adults with ADHD (Faraone & Glatt, 2010). Among the psychostimulants, methylphenidate is prescribed most commonly and studied widely (Faraone, Spencer, Aleardi, Pagano, & Biederman, 2004). Both immediate-release methylphenidate (IR-methylphenidate) and osmotic-release oral system methylphenidate (OROS-methylphenidate) are effective in treating adults with ADHD (Adler, Zimmerman, et al., 2009; Kessler et al., 2005) without significant difference between these two regimens (Faraone & Glatt, 2010). In addition to reducing the core symptoms of ADHD, methylphenidate is also effective in reducing driving risk (Cox et al., 2008), and improving academic performance (Hechtman et al., 2004), social function (Greenhill et al., 2001), and quality of life (Coghill, 2010) in adults with ADHD.

Atomoxetine, as a potent inhibitor of the presynaptic norepinephrine transporter, was approved by FDA as the first nonstimulant agent for the treatment of ADHD in 2002 (Gau, Huang, et al., 2007). Atomoxetine is efficacious in reducing ADHD symptoms (Gau, Huang, et al., 2007) and in improving social and family function, and quality of life (Adler, Spencer, et al., 2009; Wehmeier, Schacht, Escobar, Savill, & Harpin, 2010) not only in children (Shang & Gau, 2012) but also in adults with ADHD (Adler, Spencer, et al., 2009; Michelson et al., 2003; T. S. Spencer et al., 1998). Atomoxetine, safe and well tolerated in adults with ADHD (Adler, Zimmerman, et al., 2009), does not have abuse potential (Jasinski, Faries, Moore, Schuh, & Allen, 2008) and is an alternative for those who cannot tolerate or do not improve under psychostimulant treatment (Newcorn et al., 2008).

Although previous meta-analysis (Faraone & Glatt, 2010) revealed the superiority of stimulants over nonstimulants in adults with ADHD, there has been no head-to-head clinical trial of methylphenidate and atomoxetine in adults with ADHD so far in the world. Besides, there are limited treatment data for these two drugs in Asian adult populations (Takahashi et al., 2014). Despite the effectiveness of both medications in adults with ADHD, without direct comparison, we should interpret indirect comparisons of effect sizes of stimulants and nonstimulants with caution (Faraone & Glatt, 2010). To fill the gap of our knowledge about the efficacy and adverse effects of these two drugs in adults with ADHD, the present study aimed to directly compare the treatment response in terms of ADHD symptoms, social function, and quality of life, and the adverse effects of IR-methylphenidate thrice daily and atomoxetine once daily in drug-naïve adults with ADHD in a head-to-head, open-label, 8-to- 10-week randomized clinical trial.

Method

Participants

Adults aged 18 to 50 years who had been identified as probable cases of ADHD through a telephone interview by a board-certified child psychiatrist (H-C.N) for around 30 to 40 min, which included the six questions of the screener of the Chinese Adult ADHD Self-Report Scale–Version 1.1 (Kessler et al., 2005; Yeh, Gau, Kessler, & Wu, 2008), were invited to have a clinical assessment. The clinical assessment was conducted at the Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan. The clinical diagnosis of ADHD was made based on clinical assessments and was further confirmed by the psychiatric interview by the four child psychiatrists (coauthors) using the modified adult version of the ADHD supplement (Chang, Chiu, Wu, & Gau, 2013) of the Chinese version of the Schedule for Affective Disorder and Schizophrenia–Epidemiological Version (K-SADS-E; Gau, Chong, Chen, & Cheng, 2005; Gau & Soong, 1999) for childhood and current diagnosis of ADHD and other psychiatric disorders. The adults who met the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) for ADHD were enrolled to this study.

Participants were excluded if they had any systemic medical illness, such as cardiovascular disease, a history of bipolar disorder, psychosis, major depression, substance-use disorder, learning disability, pervasive developmental disorder, or mental retardation. Participants who currently had depressive or anxiety symptoms, or suicidal ideation, or who had been treated with any psychotropic agents, including medications for ADHD, were also excluded.

A total of 71 screen-positive participants were clinically and psychiatrically assessed by the authors in the hospital. In all, 2 of the 71 participants without currently meeting the full criteria of ADHD were excluded, and 6 of the remaining 69 eligible participants were excluded due to personal reasons (n = 3), being a psychologist (n = 1), and cases of pervasive developmental disorder, not otherwise specified (n = 2). In the end, 63 participants (M age ± SD, 31.3 ± 7.8 years old; male, 58.7%) entered our study and were randomly assigned to the IR-methylphenidate (n = 31; M age ± SD, 31.4 ± 7.2; 18 males, 58.1%) and atomoxetine groups (n = 32; M age ± SD, 31.2 ± 8.4; 19 males, 59.4%). The two groups demonstrated equal distribution in demographics as shown in Table 1.

Table 1.

Demographics, Baseline ADHD symptoms, Quality of Life, and Functional Impairment.

	Methylphenidate (n = 31)	Atomoxetine (n = 32)	F(1,53)/χ²	p value
Male, n (%)	18 (58.1)	19 (59.4)	χ²(1) = 0.01	.916
Age, M (SD)	31.4 (7.2)	31.2 (8.4)	F = 0.01	.904
Educational level, n (%)			χ²(2) = 0.002	.999
College or higher	27 (87.1)	28 (87.5)
Senior high school	3 (9.7)	3 (9.4)
Junior high school or lower	1 (3.2)	1 (3.1)
Employment status, n (%)			χ²(2) = 1.36	.508
Professional	6 (19.4)	3 (9.4)
Technical personnel	12 (38.7)	15 (46.9)
Non-technical personnel	13 (41.9)	14 (43.8)
SNAP-IV, M (SD)
Inattentive	17.6 (6.5)	16.3 (5.8)	F = 0.65	.423
Hyperactive-impulsive	11.5 (7.2)	11.7 (7.1)	F = 0.01	.907
Oppositional	11.9 (6.4)	10.6 (6.4)	F = 0.80	.376
Adult Self-Report Scale, M (SD)
Inattention	26.6 (5.2)	25.7 (5.9)	F = 0.40	.532
Hyperactivity-impulsivity	20.3 (7.4)	20.3 (7.7)	F = 0.00	.999
CGI-ADHD-S, M (SD)	3.7 (0.8)	4.2 (1.2)	F = 3.01	.089
The Adult ADHD Quality of Life Scale
Life productivity	27.15 (7.31)	31.62 (10.37)	F = 3.33	.074
Psychological Health	14.23 (6.07)	16.52 (6.66)	F = 1.76	.191
Relationships	15.23 (4.07)	16.10 (5.09)	F = 0.49	.489
Life outlook	17.77 (3.77)	19.10 (4.15)	F = 1.54	.219
Weiss Functional Impairment Rating Scale–Self-Report
Family	9.92 (4.24)	9.24 (4.90)	F = 0.30	.586
Work	14.20 (7.63)	12.15 (6.13)	F = 1.15	.288
School	15.67 (6.61)	13.67 (6.69)	F = 1.07	.307
Life skills	18.58 (6.05)	14.66 (7.12)	F = 4.78	.033
Self-concept	10.19 (3.10)	9.00 (4.33)	F = 1.35	.250
Social	11.15 (6.49)	8.83 (6.11)	F = 1.87	.177
Risk	10.19 (5.28)	7.31 (5.18)	F = 4.16	.046
Vital signs, M (SD)
Systolic pressure	111.9 (15.8)	112.2 (16.3)	F = 0.00	.949
Diastolic pressure	74.7 (12.2)	71.2 (12.9)	F = 1.14	.290
Heart rate	67.9 (10.7)	68.3 (10.3)	F = 0.02	.903
Height (cm), M (SD)	168.6 (8.5)	168.2 (8.9)	F = 0.03	.873
Weight (kg), M (SD)	67.9 (14.1)	65.6 (14.5)	F = 0.40	.531
Intelligence quotient (IQ)
Full-scale IQ	112.1 (9.3)	112.3 (12.8)	F = 0.00	.955
Performance IQ	110.2 (8.9)	109.9 (13.3)	F = 0.01	.933
Verbal IQ	112.3 (11.7)	112.6(13.5)	F = 0.01	.923

Note. SD = standard deviation; SNAP-IV = Swanson, Nolan, and Pelman–IV; CGI-ADHD-S = Clinical Global Impression–ADHD Severity Rating; IQ = intelligence quotient.

Study Design and Procedures

The Research Ethics Committee of National Taiwan University Hospital, Taiwan (IRB ID, 200705065R; ClinicalTrials.gov number, NCT00550667), approved this study prior to implementation. The potential participants who met the recruitment criteria received a comprehensive explanation of the purpose and procedure of this study, as well as reassurance of confidentiality. Written informed consent was obtained from all the participants.

This was an 8-to 10- week open-label, head-to-head randomized clinical trial. Participants were assigned to either the IR-methylphenidate or the atomoxetine group at a 1:1 ratio, which was determined by a computer-generated random sequence. They would receive three assessments and medication administration at baseline (Visit 1), Weeks 4 to 5 (Visit 2), and Weeks 8 to 10 (Visit 3) after the initial clinical assessment. Participants started to take medication at Visit 1 with IR-methylphenidate (an initial daily dosage of 30 mg, 10 mg three times a day) or atomoxetine (an initial dosage of 0.5 mg/kg in the 1st week and 1.2 mg/kg from the 2nd week). Drug dosage would be titrated at Visit 2 depending on clinical response and adverse effects (maximum daily dosage of IR-methylphenidate = 60 mg, 20 mg thrice daily; maximum daily dosage of atomoxetine = 1.2 mg/kg). The side effects of medications were investigated at Weeks 4 to 5 and Weeks 8 to 10. Body weight, body height, blood pressure, heart rate, and the Clinical Global Impression–ADHD Severity Rating (CGI-ADHD-S) were assessed by the investigators, and several self-reported questionnaires, including the Adult Self-Report Scales (ASRS) and the Chinese Version of the Swanson, Nolan, and Pelman–IV (SNAP-IV) scale for ADHD symptoms, as well as the Adult ADHD Quality-of-Life Scale (AAQoL) and the Weiss Functional Impairment Rating Scale–Self-Report (WFIRS-S) for quality of life and current social impairments were gathered at Visit 1 (baseline), Visit 2 (Weeks 4 to 5), and Visit 3 (Weeks 8 to 10).

Diagnosis of ADHD in adult participants

To obtain the information on ADHD symptoms and diagnoses in adulthood according to the DSM-IV diagnostic criteria, the corresponding author modified the ADHD supplement of the Chinese K-SADS-E (Chang et al., 2013) to assess ADHD symptoms in childhood and adulthood of the participants. The Chinese K-SADS-E has been proved to be a reliable and valid instrument to assess child and adolescent psychiatric disorders (Gau et al., 2005; Gau & Soong, 1999) and has been extensively used in a variety of clinical (Gau & Chiang, 2009; Gau et al., 2010; Gau, Huang, et al., 2007; Gau & Shang, 2010; Gau, Shen, Soong, & Gau, 2006) and epidemiological (Gau, Chong, et al., 2007; Gau et al., 2005) studies in Taiwan.

Five child psychiatrists (four participated in this study) and two research interviewers who majored in psychology had received a 2-year full-time intensive clinical and research training, including the Chinese K-SADS-E interview in child and adolescent psychiatry specifically and psychiatric clinical research in general before this adult ADHD interview training using the adult ADHD supplement of the Chinese K-SADS-E interview training by the corresponding author. They received a 2-month intensive research training including mastery of both the Chinese K-SADS-E and SADS interviews including the modified adult ADHD supplement, being familiar with DSM-IV criteria, watching training DVDs, observing interviews performed by the corresponding author, rating several subjects under the supervision, and completing practice interviews. All of them need to practice interview and interview ratings continuously until their interview ratings reached more than 90% agreement on all 18 ADHD behavioral items and four area-of-functional impairments against the rating by the corresponding author for at least two participants; they then can participate in the interrater reliability study. Using 14 interview assessments, the seven interviewers demonstrated high agreement assessed by the modified adult ADHD supplement (ranging from 84.1% to 97.7% with mean agreement of 91.6% ± 4.59%) against the rating of each item in the K-SADS-E by S.S.G. before study implementation. All the four child psychiatrists participating in this study reach above 90% of all the interview assessments. The kappa statistics among the eight interviewers, including the corresponding author for all the symptom and impairment items, showed moderate to very good agreement ranging from .60 (95% confidence intervals = [0.31, 0.83]) to 1.00. There is 100% agreement in the diagnosis of ADHD at childhood and adulthood among the assessors. In a clinical sample of 38 adult patients suspected of having ADHD, the corresponding author conducted semistructured interviews using both the modified adult ADHD supplement and Conners’ Adult ADHD Diagnostic Interview for DSM-IV (Takahashi et al., 2014). The results showed that in terms of the ADHD diagnosis in childhood and current adulthood, the two instruments were in 100% agreement.

Efficacy Measures

ASRS

The ASRS, an 18-question scale, was developed in conjunction with the revision of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI). The ASRS consists of two subscales, Inattention (nine items) and Hyperactivity-Impulsivity (nine items), according to the 18 DSM-IV ADHD symptom criteria. Each item asks how often a symptom occurred during the last 6 months on a 5-point Likert-type scale: 0 = never, 1 = rarely, 2 = sometimes, 3 = often, and 4 = very often. The psychometric properties of the Chinese ASRS have been established in a sample of 4,329 Taiwanese young adults (Yeh et al., 2008). The intraclass correlations (ICCs) for test–retest reliability ranged from .80 for the Inattention subscale, .82 for the Hyperactivity-Impulsivity subscale, and .85 for the total score. The internal consistency (Cronbach’s α) was high for the Inattention subscale (.87), the Hyperactivity-Impulsivity subscale (.85), and the total score (.91). It has been used in studies on adult ADHD and sleep problems, anxiety/depression symptoms, and life quality in Taiwan (Chao et al., 2008; Gau, Kessler, et al., 2007).

CGI-ADHD-S

The CGI-ADHD-S is a single-item rating scale for the global severity of ADHD symptoms based on the clinician’s overall experience with ADHD patients (National Institute of Mental Health, 1985). Severity is rated on a 7-point scale (with 1 and 7 representing the symptom extremes of normal/not at all ill and among the most extreme cases) with good test–retest reliability (ICC = .82; T. J. Spencer et al., 2010). The Chinese-language CGI-ADHD-S has been extensively used in clinical practice and several clinical trials (Chou et al., 2009; Gau et al., 2008; Gau, Huang, et al., 2007; Gau & Shang, 2010; Gau, Shen, Chou, et al., 2006; Gau, Shen, Soong, et al., 2006; Shang & Gau, 2012; Takahashi et al., 2014) in Taiwan.

AAQoL

The AAQoL is a 29-item scale, rated by the patient on a 5-point Likert-type scale ranging from 1 = not at all/never to 5 = extremely/very often. The AAQoL had four subscales, including Life Productivity (11 items), Psychological Health (6 items), Relationships (5 items), and Life Outlook (7 items). The AAQoL was developed to assess health-related quality of life during the last 2 weeks among adults with ADHD (Brod, Johnston, Able, & Swindle, 2006). Higher scores (maximum 145) indicate better life quality, and lower scores represent greater functional impairments (Matza, Van Brunt, Cates, & Murray, 2011). The Chinese AAQoL was used in a clinical trial of atomoxetine in adults with ADHD in China, Japan, Korea, and Taiwan (Takahashi et al., 2014). Using a sample of 70 young Taiwanese adults for a 4-week test–retest reliability study and a sample of 1,522 young adults for internal consistency of the Chinese AAQoL, the correlations (Pearson correlation [r]; ICC) were low to moderate, and Cronbach’s alpha was high for the total score (r = .59, ICC = .527, α = .88) and for the four subscales: Life Productivity (r = .39, ICC = .378, α = .89), Psychological Health (r = .68, ICC = .661, α = .89), Relationships (r = .52, ICC = .502, α = .81), and Life Outlook (r = .53, ICC = .523, α = .82).

WFIRS-S

The WFIRS-S is a 70-item scale, ranging from 0 = never/not at all to 3 = very often/very much. The WFIRS-S has been used to assess seven domains of functional impairment, including family (8 items), work (11 items), school (11 items), life skills (12 items), self-concept (5 items), social (9 items), and risk (14 items) in clinical trials on ADHD (Hantson et al., 2011; Stein et al., 2011). With the permission by original authors (Margaret D. Weiss and colleagues), the Chinese WFIRS-S was prepared with culture-relevant colloquial expressions and two-way translation by the corresponding author without further modification. Using a sample of 70 Taiwanese young adults for a 4-week test–retest reliability study and a sample of 1,511 young adults for internal consistency of the Chinese WFIRS-S, the correlations (r, ICC) were moderate to high, and Cronbach’s alphas were high for the seven domains of social impairment, including family (r = .57, ICC = .555, α = .84), work (r = .75, ICC = .739, α = .87), school (r = .83, ICC = .824, α = .88), life skills (r = .72, ICC = .704, α = .84), self-concept (r = .62, ICC = .571, α = .92), social (r = .62, ICC = .610, α = .88), and risk (r = .79, ICC = .784, α = .84).

Safety Measures

Safety measures, including decreased appetite, vomiting, insomnia, somnolence, dizziness, stomachaches, headaches, palpitation, and dry mouth, were assessed by open-ended questions during a clinical interview first, followed by a structured interview based on a standard questionnaire listing all the potential adverse effects by the investigators.

Adherence

Subjective and objective assessments were used to determine whether the participants were adherent to IR-methylphenidate and atomoxetine. The subjective assessment was based on retrospective feedback from the participants themselves. The objective assessment of the daily occurrence and frequency of missed doses was based on pill count by research assistants and a standard interview conducted by the investigators. If the data based on the two methods were not consistent with each other, the investigators would interview the participants again and discuss the difference between self-reports and pill count, and then determine the days of taking medication. We compared adherence between the two treatment groups based on average days of taking medication per week.

Data Analysis

SAS Version 9.2 was used to conduct data analysis. The alpha value was pre-selected at the level of p < .05. The intent-to-treat principle was used in the statistical analysis. Mean scores and standard deviation were presented for continuous variables, and number and percentage were presented for categorical variables in the demographic and baseline assessments. One-way repeated-measures ANOVA using the mixed procedure was used to determine differences in behavioral symptoms, psychosocial impairment, and quality of life. Hierarchical linear mixed-effect models were used to address the lack of statistical independence of repeated measurements of the same participants over time (Singer, 1998). In particular, both intercepts and slope (time) effects in the linear mixed model with time-dependent variables were treated as random effects to account for variations among participants in baseline values, and slopes for individual trajectories of symptom changes over three assessments, in addition to the main treatment and fixed-time effect of the two treatment groups. In addition, Cohen’s d was used to compute the effect size for the comparisons between Weeks 4 to 5 and baseline, and between Weeks 8 to 10 and baseline with small, medium, and large effect sizes, Cohen’s d = 0.2 to 0.5, 0.5 to 0.8, and ≥0.8, respectively.

A sample size of 24 in each treatment group has 90% power to detect a difference in the means of 3.4, in which the common standard deviation is 4 under a two-group t-test scenario, with a significance level of 5% (two-sided; Retz et al., 2012). Since a dropout rate of 20% was expected, a total of 30 participants were recruited for each of the two treatment groups.

Results

Sample Description and Medication

At baseline, 31 ADHD adults treated with IR-methylphenidate and 32 ADHD adults treated with atomoxetine did not differ in demographics, vital signs, intelligence, symptom severity, life quality, and social function except that the methylphenidate group had poorer social function in the life skill (p = .033) and risk (p = .046) domains than the atomoxetine group (Table 1). In the IR-methylphenidate group, 26 (83.9%) and 20 (64.5%) completed Visit 2 and Visit 3 assessments, respectively. Participants dropped out of the study due to personal reasons (n = 7), loss of contact (n = 3), and medication change (n = 1). In the atomoxetine group, 29 (90.6%) and 25 (78.1%) completed Visit 2 and Visit 3, respectively. They dropped out due to personal reasons (n = 4), traffic problems (n = 1), and loss of contact (n = 2; Figure 1). There was no obvious significant difference in follow-up compliance between the two groups at Visit 2 (Fisher’s exact p value = .474) and Visit 3 (Fisher’s exact p value = .274). In general, there was no significant baseline difference between ADHD participants who dropped out and those who completed the trials with regard to clinical severity, functional level, and quality of life for the atomoxetine and methylphenidate groups and for the whole sample as well.

Figure 1.

Flow diagram of the randomization procedure and outcome of all recruited participants.

The mean daily dosages were 28.8 mg and 34.8 mg for the IR-methylphenidate group, and 82.0 mg and 83.0 mg for the atomoxetine group at Visit 2 and Visit 3, respectively. There was no significant difference in drug adherence as presented by days of taking medication in a week between the two treatment groups, regardless at Visit 2 (IR-methylphenidate, 6.10 days/week; atomoxetine, 6.63 days/week, p = .26) or at Visit 3 (IR-methylphenidate, 5.60 days/week; atomoxetine, 6.46 days/week, p = .10).

Symptom severity

Both groups had significant decrease in inattention and hyperactivity-impulsivity symptoms assessed by the ASRS and overall symptom severity by the CGI-ADHD-S from baseline to Visit 2 and Visit 3 with large effect size (Table 2). Moreover, the magnitude of reduction in hyperactivity-impulsivity symptoms and overall symptom severity was significantly greater for the atomoxetine group than the IR-methylphenidate group at Weeks 4 to 5 (p < .05, Table 2). However, analysis of slope differences revealed no significant group difference in the slope of mean score reduction for the ASRS and CGI-ADHD-S (Table 2).

Table 2.

Symptom Changes From Baseline to Weeks 4 to 5 and to Weeks 8 to 10 in the IR-Methylphenidate and Atomoxetine Groups.

	Weeks 4 to 5 to baseline					Weeks 8 to 10 to baseline					Slope (β)		Slope difference
	IR-MPH	d	Atomoxetine	d		IR-MPH	d	Atomoxetine	d		IR-MPH	Atomoxetine	F(1,121)
	M (SD)^a	d	M (SD)^a	d	F(1,53)	M (SD)^a	d	M (SD)^a	d	F(1,43)	β (SE)	β (SE)	F(1,121)
Adult Self-Report Scales
Inattention	−5.77 (7.07)***	−1.04	−8.93 (6.74)***	−1.65	2.78	−9.25 (4.33)***	−2.08	−10.20 (6.30)***	−1.66	0.33	−4.70 (0.61)***	−5.14 (0.64)***	0.09
Hyperactivity-Impulsivity	−3.69 (5.92)**	−0.52	−8.11 (8.26)***	−1.25	4.91*	−6.21 (5.83)***	−0.90	−7.80 (7.66)***	−1.05	0.59	−3.18 (0.60)***	−3.86 (0.77)***	0.21
CGI-ADHD-S	−0.75 (0.79)***	−0.81	−1.39 (1.29)***	−1.21	4.51*	−1.20 (0.70)***	−1.60	−1.68 (1.35)***	−1.23	2.09	−0.61 (0.08)***	−0.80 (0.14)***	0.84

Note. IR-MPH = immediate-release methylphenidate; d = Cohen’s d for effect size; β = parameter estimate of slope of changes over time; SD = standard deviation; SE = standard error; CGI-ADHD-S = Clinical Global Impression–ADHD Severity Rating.

Mean differences between baseline and Weeks 4 to 5, Weeks 8 to 10.

p < .05. **p < .01. ***p < .001.

Quality of life

The mean scores for life productivity, psychological health, and relationships domains as assessed by the AAQoL significantly increased from baseline to Weeks 4 to 5 or Weeks 8 to 10 for both groups with medium to large effect sizes assessed by Cohen’s d ranging from 0.59 to 1.63 (p < .01, Table 3). Significant improvement of life outlook from baseline to Weeks 4 to 5 (Cohen’s d = 0.70) or Weeks 8 to 10 (Cohen’s d = 0.81) was only noted in the IR-methylphenidate group (Table 3). There was no significant group difference in the slope of improvement over four domains of quality of life as assessed by using the AAQoL (Table 3).

Table 3.

Changes in Quality of Life and Social Impairments From Baseline to Weeks 4 to 5 and to Weeks 8 to 10 in the IR-Methylphenidate and Atomoxetine Groups.

	Weeks 4 to 5 to baseline					Weeks 8 to 10 to baseline					Slope (β)		Slope difference
	IR-MPH, M (SD)^a	d	Atomoxetine, M (SD)^a	d	F(1,53)	IR-MPH, M (SD)^a	d	Atomoxetine, M (SD)^a	d	F _(1,43)	IR-MPH, β (SE)	Atomoxetine, β (SE)	F(1,121)
The Adult ADHD Quality of Life Scale
Life productivity	8.28 (7.03)***	1.07	8.04 (7.55)***	1.00	0.01	11.05 (6.88)***	1.63	7.43 (9.28)***	0.76	2.11	5.52 (0.75)***	3.91 (0.88)***	1.32
Psychological health	3.64 (6.70)*	0.63	4.28 (6.22)***	0.89	0.13	5.75 (5.09)***	1.11	4.24 (6.51)*	0.59	0.72	2.90 (0.60)***	1.86 (0.66)**	1.50
Relationships	2.96 (3.38)***	0.68	3.57 (4.57)***	0.89	0.30	3.70 (3.47)***	0.97	3.56 (5.27)**	0.68	0.01	1.97 (0.36)***	1.69 (0.49)**	0.22
Life outlook	2.77 (4.26)**	0.70	1.37 (4.05)	0.34	1.50	2.90 (3.16)***	0.81	0.36 (5.31)	0.06	3.56	1.52 (0.42)***	0.13 (0.47)	2.87
Weiss Functional Impairment Rating Scale–Self-Report
Family	−2.20 (4.14)*	−0.49	−2.71 (5.48)*	−0.59	0.15	−4.42 (3.83)***	−1.11	−3.40 (4.99)**	−0.63	0.55	−2.12 (0.40)***	−1.47 (0.51)**	0.67
Work	−4.65 (6.49)**	−0.60	−3.13 (4.80)**	−0.61	0.85	−7.41 (6.77)***	−1.13	−4.19 (6.10)**	−0.84	2.38	−3.59 (0.72)***	−2.21 (0.54)***	1.17
School	−5.13 (5.82)**	−1.02	−6.71 (7.62)**	−1.11	0.40	−8.73 (6.15)***	−1.42	−7.15 (7.06)**	−0.92	0.33	−4.40 (0.71)***	−3.21 (0.88)**	0.73
Life skills	−4.40 (6.61)**	−0.76	−4.43 (6.39)***	−0.71	0.00	−6.65 (5.10)***	−1.19	−4.08 (5.87)*	−0.42	2.39	−3.27 (0.58)***	−1.80 (0.64)**	2.48
Self-concept	−3.16 (2.95)***	−0.83	−2.50 (4.32)***	−0.76	0.41	−5.15 (3.73)***	−1.70	−3.16 (4.37)**	−0.70	2.62	−2.57 (0.37)***	−1.49 (0.47)**	3.09
Social	−3.96 (3.85)***	−0.65	−3.21 (4.93)**	−0.62	0.37	−4.85 (3.18)***	−0.96	−3.40 (4.69)**	−0.45	1.39	−2.65 (0.38)***	−1.48 (0.49)**	2.50
Risk	−4.80 (4.56)***	−1.04	−2.75 (4.09)**	−0.70	2.98	−6.45 (3.47)***	−1.43	−4.08 (4.66)**	−0.88	3.57	−3.19 (0.43)***	−1.87 (0.42)***	3.12

Note. β = parameter estimate of slope of changes over time; IR-MPH = immediate-released methylphenidate; SD = standard deviation; d = Cohen’s d for effect size; SE = standard error.

Mean differences between baseline and Weeks 4 to 5, Weeks 8 to 10.

p < .05. **p < .01. ***p < .001.

Functional impairment

We found that both groups had significant decrease in severity of the seven domains of functional impairment as assessed by the WFIRS-S from baseline to Weeks 4 to 5 or Weeks 8 to 10, indicating a better functional level after treatment with medium to large effect sizes, in general (Cohen’s d ranging from 0.49 to 1.70 for the methylphenidate group and from 0.42 to 1.11 for the atomoxetine group, Table 3). There was no significant group difference in the degree of improvement between the two groups either at Weeks 4 to 5 or at Weeks 8 to 10 and in the slope of decreasing functional impairments as assessed by using the WFIRS-S (Table 3).

Safety

Table 4 revealed the investigator-rated treatment-emergent adverse events in both groups. In general, decreased appetite, vomiting, and palpitation were frequently reported adverse effects for the two groups at Weeks 4 to 5 and Weeks 8 to 10. In addition, the atomoxetine group also reported somnolence, dizziness, and dry mouth at Weeks 4 to 5, and only dry month at Weeks 8 to 10 (>10%). The IR-methylphenidate group also reported insomnia at both visits and headache at Weeks 4 to 5 (>10%). There was no significant group difference in the occurrence of adverse events, and there was no drug-related severe adverse event noted during our study period (Table 4). Moreover, there was no significant change in body weight, blood pressure, or heart rate during the study period (all p values > .05).

Table 4.

Treatment-Emergent Adverse Events Reported in the IR-Methylphenidate and Atomoxetine Groups.

	Weeks 4 to 5			Weeks 8 to 10
	IR-MPH (n = 26)	Atomoxetine (n = 29)	p value	IR-MPH (n = 20)	Atomoxetine (n = 25)	p value
	n (%)	n (%)	p value	n (%)	n (%)	p value
Decreased appetite	12 (46.2)	12 (41.4)	.722	7 (35.0)	8 (32.0)	.832
Vomiting	4 (15.4)	9 (31.0)	.173	4 (20.0)	7 (28.0)	.535
Insomnia	3 (11.5)	4 (13.8)	.802	2 (10.0)	2 (8.0)	.815
Somnolence	2 (7.7)	7 (24.1)	.100	0 (0.0)	1 (4.0)	.366
Dizziness	2 (7.7)	5 (17.2)	.289	2 (10.0)	2 (8.0)	.815
Stomachaches	1 (3.9)	1 (3.5)	.937	1 (5.0)	0 (0.0)	.258
Headaches	4 (15.4)	2 (6.9)	.313	0 (0.0)	0 (0.0)	—
Palpitation	5 (19.2)	5 (17.9)	.897	3 (15.0)	2 (8.0)	.458
Dry mouth	2 (7.7)	4 (14.3)	.441	0 (0.0)	3 (12.0)	.109

Note. IR-MPH = immediate-released methylphenidate.

Discussion

As the first head-to-head randomized clinical trial of adults with ADHD, this 8-to-10-week, open-label, randomized trial lent evidence to support the efficacy of both IR-methylphenidate and atomoxetine in reducing ADHD core symptoms and overall symptom severity, as well as improving wide-ranging social functions and quality of life, corresponding to previous findings regarding the treatment effect of atomoxetine in Asian adults with ADHD (Takahashi et al., 2014), and providing the first data on the effectiveness of methylphenidate in this population. We found that these improvements were not only noted at Weeks 4 to 5 but also maintained throughout the study period for both medications. Furthermore, after comparing the two drugs directly, we found that atomoxetine was noninferior to IR-methylphenidate in the improvement of ADHD core symptoms, social function, and quality of life. Moreover, atomoxetine was superior to IR-methylphenidate in the reduction of hyperactive/impulsive symptoms and overall ADHD severity at Weeks 4 to 5. Finally, we found that both medications were well tolerated without severe adverse events.

Core Symptoms and Severity

Consistent with previous head-to-head comparison studies (Kratochvil et al., 2002; Wang et al., 2007) and a recent direct comparison meta-analysis (Hazell et al., 2011) study in children and adolescents with ADHD, we found that IR-methylphenidate and atomoxetine showed similar efficacy in reducing ADHD core symptoms and overall severity in adults with ADHD. Surprisingly, we found that atomoxetine was significantly superior to IR-methylphenidate in reducing hyperactive/impulsive symptoms and ADHD severity at Weeks 4 to 5 in adults with ADHD, which is inconsistent to the indirect comparison meta-analysis study (Faraone & Glatt, 2010). After reviewing 19 trials of treatment for adult ADHD, Faraone indirectly compared the efficacy of several medications and reported better efficacy for the psychostimulants (effect size = 0.86) than the nonstimulants (effect size = 0.39). There are several possible explanations for the inconsistent findings.

First, in contrast to only two medications, IR-methylphenidate and atomoxetine, in our study, psychostimulants in Faraone’s review included IR-methylphenidate, OROS-methylphenidate, dextroamphetamine, mixed amphetamine salts, and lisdexamfetamine, and nonpsychostimulants included atomoxetine, modafinil, bupropion, and paroxetine. Second, the duration of follow-up in our study was 8 to 10 weeks, while that of the trials included in the meta-analysis ranged from 2 to 20 weeks (Faraone & Glatt, 2010). Third, indirect comparison was reported in the meta-analysis (Faraone & Glatt, 2010), while we compared IR-methylphenidate and atomoxetine directly. Fourth, the average dosage of IR-methylphenidate was around 65 mg/day in Faraone’s review and was lower in ours (28.8 mg/kg at Weeks 4 to 5 and 34.8 mg/kg at Weeks 8 to 10). When mean dosage of methylphenidate increased at Weeks 8 to 10 (34.8 mg/day, 0.5 mg/kg/day), the superiority of atomoxetine disappeared. Although the dosage in our methylphenidate group is still lower than previous Western studies (0.6~1.1 mg/kg/day; Kessler et al., 2005; Mattes, Boswell, & Oliver, 1984; Wender, Reimherr, Wood, & Ward, 1985), most participants in our study were satisfied with the efficacy of 30 mg of IR-methylphenidate per day and decided to maintain the same dosage. The prescription strategy of methylphenidate here is similar to our clinical practice in Taiwan, even higher. The suggested initial dosage of IR-methylphenidate for adult ADHD is 30 mg per day, and the maximum dosage is 60 mg per day in Taiwan. Based on a data analysis of Taiwan’s National Health Insurance Dataset by the corresponding author, the average daily doses for adults aged 18 to 30 years were 17.08 ± 7.49 mg and 17.81 ± 8.95 mg for those who took IR-methylphenidate only and 21.88 ± 12.67 mg and 25.32 ± 12.03 mg for those who took IR-methylphenidate and/or OROS-methylphenidate in 2008 and 2009, respectively.

Last, the participants might have forgotten to take thrice-daily IR-methylphenidate more often than once-daily atomoxetine, which might be more obvious in the initial treatment like the 1st month and is supposed to improve over the 2nd month of treatment, and subsequently might have contributed to the difference in efficacy in ADHD symptom reduction at Weeks 4 to 5. Based on our results shown on Table 2, the effect sizes of symptom reduction were consistent for the atomoxetine group at Weeks 4 to 5 and Weeks 8 to 10, but those apparently increased from Weeks 4 to 5 to Weeks 8 to 10 as compared with baseline for the IR-methylphenidate group. Hence, forgetting to take the full dose of thrice-daily IR-methylphenidate in the 1st month but improving adherence in the 2nd month after reminding may partially explain our findings.

There is possible better drug adherence within a day in the atomoxetine group than in the IR-methylphenidate group (Gau et al., 2008; Gau, Shen, Chou, et al., 2006). Although it is considered that patients have better adherence to the extended-release form of methylphenidate, that is, the OROS-methylphenidate that is available in Taiwan, than to IR-methylphenidate (Chou et al., 2009; Gau et al., 2008), OROS-methylphenidate is not approved by Taiwan’s FDA for treating adults with ADHD, aged 18 years and older, which limits our study design.

Social Function and Quality of Life

In addition to evaluations of core symptoms of ADHD, we also examined treatment efficacy in a wide range of social functions and quality of life, using the WFIRS-S and AAQoL, respectively. Our finding of improving multidomains of social functioning and life quality by either treatment with methylphenidate or atomoxetine corresponds to previous reports of stimulants (Fallu, Richard, Prinzo, & Binder, 2006; Gau, Shen, Soong, et al., 2006; T. J. Spencer, Adler, Weisler, & Youcha, 2008; Weiss et al., 2010) and atomoxetine (Adler, Spencer, Williams, Moore, & Michelson, 2008; Adler, Zimmerman, et al., 2009; Gau, Huang, et al., 2007; Shang & Gau, 2012) in children and adults (Maziade et al., 2009).

Although studies showed that OROS-methylphenidate improved social functions (Fallu et al., 2006) and triple-bead mixed amphetamine salts improved global quality of life (T. J. Spencer et al., 2008), no published paper has discussed the effect of IR-methylphenidate on social function and quality of life. Our study is the first to demonstrate that IR-methylphenidate, similar to other psychostimulants, was effective in improving social functioning and quality of life over 8 to 10 weeks of treatment in adults with ADHD.

To the best of our knowledge, only one study directly compared the effectiveness of IR-methylphenidate and atomoxetine on social functioning and quality of life (Bastiaens, 2008). An 8-month nonrandomized prospective study demonstrated a similar efficacy for stimulants and atomoxetine in improving the quality of life in children with ADHD (Bastiaens, 2008). No such study has been conducted in adults with ADHD. The current study is the first in the world to compare the efficacy of IR-methylphenidate and atomoxetine in the social functioning and quality of life of adults with ADHD, and found the noninferiority of atomoxetine over IR-methylphenidate, which corresponds to Bastiaens’s results in children with ADHD (Bastiaens, 2008).

Adverse Effects

Previous head-to-head studies discussing the adverse effects of stimulants and atomoxetine on children and adolescents with ADHD revealed inconsistent results. In a randomized double-blind comparison trial conducted in China, Korea, and Mexico, children and adolescents treated with atomoxetine had significantly more adverse effects, including anorexia, nausea, somnolence, dizziness, and vomiting, with mild to moderate severity, than those taking twice-daily IR-methylphenidate (Wang et al., 2007), whereas others could not find a difference in adverse effects between stimulants and atomoxetine in children and adolescents with ADHD (Kratochvil et al., 2002; Newcorn et al., 2008). In our study, decreased appetite, vomiting, insomnia, somnolence, dizziness, stomachaches, headache, palpitation and dry mouth were noted after taking IR-methylphenidate or atomoxetine, without any group difference. Of these adverse effects, decreased appetite and vomiting were the most common for both IR-methylphenidate (Gau et al., 2008) and atomoxetine (Gau, Huang, et al., 2007).

Strengths and Limitations

Several limitations of this study should be considered when interpreting the findings. First, IR-methylphenidate is a controlled drug in Taiwan, which prevents us from conducting a double-blind randomized clinical trial as an investigator-initiated clinical trial. The evaluators may have a possible observation bias despite blindness to the treatment. Second, the sample size was smaller in this study than previous head-to-head studies in child populations (Kratochvil et al., 2002; Wang et al., 2007). However, the sample size was estimated to have enough power to prove the noninferiority of atomoxetine over IR-methylphenidate. Third, the generalization of this study is limited due to enrollments from only one medical center in Taipei and the exclusion of some psychiatric comorbidities. Fourth, the short study period limits our understanding of the long-term difference in treatment efficacy and adverse effects of IR-methylphenidate and atomoxetine. Finally, the relatively lower dosage than Western studies (Kessler et al., 2005; Mattes et al., 1984; Wender et al., 1985) but higher than Taiwan’s clinical practice should be taken into account while interpreting our findings.

Several features of our study constitute its strengths. First, this is the first head-to-head study in the world comparing IR-methylphenidate and atomoxetine directly in adults with ADHD. Second, the outcomes were assessed comprehensively by reliable and valid Chinese-language versions of standardized instruments for core symptoms of ADHD, ADHD severity, social functional impairment, and quality of life.

Clinical Implications

Our findings strongly indicate that, similar to Western findings, both IR-methylphenidate and atomoxetine are well tolerated and effective in reducing ADHD core symptoms and improving a wide range of social functioning and quality of life in adults with ADHD. Hence, the two medications are effective and safe for use in treating not only children and adolescents with ADHD in Western and Asian countries but also adults with ADHD. Our findings imply that in addition to nonpharmacological treatment for adults with ADHD, pharmacological treatment with either methylphenidate or atomoxetine is promisingly effective in ethnic Chinese adult populations in Taiwan.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from National Taiwan University Hospital, Taiwan (NTUH97-925), and the preparation of this manuscript was supported by grants from the National Science Council (NSC100-2627-B-002-014) and the National Health Research Institute (NHRI-EX101-10008PI), Taiwan.

Author Biographies

Hsing-Chang Ni got his MD from National Taiwan University (NTU) School of Medicine and received general and child psychiatry training at National Taiwan University Hospital (NTUH). He currently is a doctoral student at Graduate Institute of Clinical Medicine, NTU, and a visiting staff child psychiatrist and lecturer in Chang Gung Memorial Hospital at Linkou, Taiwan.

Yu-Ju Lin got her MD from National Taiwan University School of Medicine, received general and child psychiatry training at NTUH, and got her master’s degree in epidemiology in NTU. She is a visiting staff psychiatrist in Far Eastern Memorial Hospital, Taipei, Taiwan.

Susan Shur-Fen Gau got her MD at Chun-Shan Medical University and PhD in Yale University, and received psychiatry training at NTUH. She is a professor and chairperson, Department of Psychiatry, National Taiwan University and College of Medicine, Taipei, Taiwan, and a professor, Graduate Institute of Clinical Medicine, Graduate Institute of Brain and Mind Sciences, Department of Psychology, School of Occupational Therapy, and Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.

Hui-Chun Huang got her MD from National Cheng Kung University, received psychiatry training at National Cheng Kung University Hospital, and received child psychiatry training at NTUH, Taiwan. She has moved to Taoyuan Mental Hospital, Department of Health, Taiwan, since July 2012.

Li-Kuang Yang got his MD from National Defense Medical University, received general psychiatry training at Beitou Armed Forces Hospital, and received child psychiatry training at NTUH, Taiwan. He is currently studying at the Graduate Institute of Brain and Mind Sciences, NTU, and is a visiting staff psychiatrist and child psychiatrist in Beitou Armed Forces Hospital, Taipei, Taiwan.

References

Adler

L. A.

Spencer

Brown

T. E.

Holdnack

Saylor

Schuh

Kelsey

(2009). Once-daily atomoxetine for adult attention-deficit/hyperactivity disorder: A 6-month, double-blind trial. Journal of Clinical Psychopharmacology, 29, 44-50.

Adler

L. A.

Spencer

T. J.

Williams

D. W.

Moore

R. J.

Michelson

(2008). Long-term, open-label safety and efficacy of atomoxetine in adults with ADHD: Final report of a 4-year study. Journal of Attention Disorders, 12, 248-253.

Adler

L. A.

Zimmerman

Starr

H. L.

Silber

Palumbo

Orman

Spencer

(2009). Efficacy and safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: A randomized, placebo-controlled, double-blind, parallel group, dose-escalation study. Journal of Clinical Psychopharmacology, 29, 239-247.

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author.

Barkley

R. A.

Murphy

K. R.

Dupaul

G. I.

Bush

(2002). Driving in young adults with attention deficit hyperactivity disorder: Knowledge, performance, adverse outcomes, and the role of executive functioning. Journal of the International Neuropsychological Society, 8, 655-672.

Bastiaens

(2008). Both atomoxetine and stimulants improve quality of life in an ADHD population treated in a community clinic. Psychiatric Quarterly, 79, 133-137.

Biederman

Faraone

S. V.

(2005). Attention-deficit hyperactivity disorder. Lancet, 366(9481), 237-248.

Biederman

Faraone

S. V.

Spencer

T. J.

Mick

Monuteaux

M. C.

Aleardi

(2006). Functional impairments in adults with self-reports of diagnosed ADHD: A controlled study of 1001 adults in the community. Journal of Clinical Psychiatry, 67, 524-540.

Biederman

Monuteaux

M. C.

Doyle

A. E.

Seidman

L. J.

Wilens

T. E.

Ferrero

Faraone

S. V.

(2004). Impact of executive function deficits and attention-deficit/hyperactivity disorder (ADHD) on academic outcomes in children. Journal of Consulting and Clinical Psychology, 72, 757-766.

10.

Brod

Johnston

Able

Swindle

(2006). Validation of the adult attention-deficit/hyperactivity disorder quality-of-life scale (AAQoL): A disease-specific quality-of-life measure. Quality of Life Research, 15, 117-129.

11.

Chang

L. R.

Chiu

Y. N.

Y. Y.

Gau

S. S.

(2013). Father’s parenting and father-child relationship among children and adolescents with attention-deficit/hyperactivity disorder. Comprehensive Psychiatry, 54, 128-140. doi:10.1016/j.comppsych.2012.07.008

12.

Chao

C. Y.

Gau

S. S.

Mao

W. C.

Shyu

J. F.

Chen

Y. C.

Yeh

C. B.

(2008). Relationship of attention-deficit-hyperactivity disorder symptoms, depressive/anxiety symptoms, and life quality in young men. Psychiatry & Clinical Neurosciences, 62, 421-426.

13.

Chou

W. J.

Chou

M. C.

Tzang

R. F.

Hsu

Y. C.

Gau

S. S.

Chen

S. J.

Cheng

(2009). Better efficacy for the osmotic release oral system methylphenidate among poor adherents to immediate-release methylphenidate in the three ADHD subtypes. Psychiatry & Clinical Neurosciences, 63, 167-175.

14.

Coghill

(2010). The impact of medications on quality of life in attention-deficit hyperactivity disorder: A systematic review. CNS Drugs, 24, 843-866.

15.

Cox

D. J.

Mikami

A. Y.

Cox

B. S.

Coleman

M. T.

Mahmood

Sood

Merkel

R. L.

(2008). Effect of long-acting OROS methylphenidate on routine driving in young adults with attention-deficit/hyperactivity disorder. Archives of Pediatrics & Adolescent Medicine, 162, 793-794.

16.

Danckaerts

Sonuga-Barke

E. J.

Banaschewski

Buitelaar

Dopfner

Hollis

Steinhausen

(2010). The quality of life of children with attention deficit/hyperactivity disorder: A systematic review. European Child & Adolescent Psychiatry, 19, 83-105.

17.

Fallu

Richard

Prinzo

Binder

(2006). Does OROS-methylphenidate improve core symptoms and deficits in executive function? Results of an open-label trial in adults with attention deficit hyperactivity disorder. Current Medical Research & Opinion, 22, 2557-2566.

18.

Faraone

S. V.

Glatt

S. J.

(2010). A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. Journal of Clinical Psychiatry, 71, 754-763.

19.

Faraone

S. V.

Spencer

Aleardi

Pagano

Biederman

(2004). Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. Journal of Clinical Psychopharmacology, 24, 24-29.

20.

Friedman

S. R.

Rapport

L. J.

Lumley

Tzelepis

VanVoorhis

Stettner

Kakaati

(2003). Aspects of social and emotional competence in adult attention-deficit/hyperactivity disorder. Neuropsychology, 17, 50-58.

21.

Gau

S. S.

Chen

S. J.

Chou

W. J.

Cheng

Tang

C. S.

Chang

H. L.

Huang

(2008). National survey of adherence, efficacy, and side effects of methylphenidate in children with attention-deficit/hyperactivity disorder in Taiwan. Journal of Clinical Psychiatry, 69, 131-140.

22.

Gau

S. S.

Chiang

H. L.

(2009). Sleep problems and disorders among adolescents with persistent and subthreshold attention-deficit/hyperactivity disorders. Sleep, 32, 671-679.

23.

Gau

S. S.

Chong

M. Y.

Chen

T. H.

Cheng

A. T.

(2005). A 3-year panel study of mental disorders among adolescents in Taiwan. American Journal of Psychiatry, 162, 1344-1350.

24.

Gau

S. S.

Chong

M. Y.

Yang

Yen

C. F.

Liang

K. Y.

Cheng

A. T.

(2007). Psychiatric and psychosocial predictors of substance use disorders among adolescents: Longitudinal study. British Journal of Psychiatry, 190, 42-48.

25.

Gau

S. S.

Huang

Y. S.

Soong

W. T.

Chou

M. C.

Chou

W. J.

Shang

C. Y.

. . .Lee

(2007). A randomized, double-blind, placebo-controlled clinical trial on once-daily atomoxetine in Taiwanese children and adolescents with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 17, 447-460.

26.

Gau

S. S.

Kessler

R. C.

Tseng

W. L.

Y. Y.

Chiu

Y. N.

Yeh

C. B.

Hwu

H. G.

(2007). Association between sleep problems and symptoms of attention-deficit/hyperactivity disorder in young adults. Sleep, 30, 195-201.

27.

Gau

S. S.

H. C.

Shang

C. Y.

Soong

W. T.

Y. Y.

Lin

L. Y.

Chiu

. (2010). Psychiatric comorbidity among children and adolescents with and without persistent attention-deficit hyperactivity disorder. Australian and New Zealand Journal of Psychiatry, 44, 135-143.

28.

Gau

S. S.

Shang

C. Y.

(2010). Improvement of executive functions in boys with attention deficit hyperactivity disorder: An open-label follow-up study with once-daily atomoxetine. The International Journal of Neuropsychopharmacology, 13, 243-256.

29.

Gau

S. S.

Shen

H. Y.

Chou

M. C.

Tang

C. S.

Chiu

Y. N.

Gau

C. S.

(2006). Determinants of adherence to methylphenidate and the impact of poor adherence on maternal and family measures. Journal of Child and Adolescent Psychopharmacology, 16, 286-297.

30.

Gau

S. S.

Shen

H. Y.

Soong

W. T.

Gau

C. S.

(2006). An open-label, randomized, active-controlled equivalent trial of osmotic release oral system methylphenidate in children with attention-deficit/hyperactivity disorder in Taiwan. Journal of Child and Adolescent Psychopharmacology, 16, 441-455.

31.

Gau

S. S.

Soong

W. T.

(1999). Psychiatric comorbidity of adolescents with sleep terrors or sleepwalking: A case-control study. Australian and New Zealand Journal of Psychiatry, 33, 734-739.

32.

Greenhill

L. L.

Pliszka

Dulcan

M. K.

Bernet

Arnold

Beitchman

Kroeger

(2001). Summary of the practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 1352-1355.

33.

Hantson

Wang

P. P.

Grizenko-Vida

Ter-Stepanian

Harvey

Joober

Grizenko

(2011). Effectiveness of a therapeutic summer camp for children with ADHD: Phase I clinical intervention trial. Journal of Attention Disorders, 16, 610-617.

34.

Hazell

P. L.

Kohn

M. R.

Dickson

Walton

R. J.

Granger

R. E.

Wyk

G. W.

(2011). Core ADHD symptom improvement with atomoxetine versus methylphenidate: A direct comparison meta-analysis. Journal of Attention Disorders, 15, 674-683.

35.

Hechtman

Abikoff

Klein

R. G.

Weiss

Respitz

Kouri

Pollack

(2004). Academic achievement and emotional status of children with ADHD treated with long-term methylphenidate and multimodal psychosocial treatment. Journal of the American Academy of Child & Adolescent Psychiatry, 43, 812-819.

36.

Jasinski

D. R.

Faries

D. E.

Moore

R. J.

Schuh

L. M.

Allen

A. J.

(2008). Abuse liability assessment of atomoxetine in a drug-abusing population. Drug and Alcohol Dependence, 95, 140-146.

37.

Kessler

R. C.

Adler

Ames

Demler

Faraone

Hiripi

Walters

E. E.

(2005). The World Health Organization adult ADHD Self-Report Scale (ASRS): A short screening scale for use in the general population. Psychological Medicine, 35, 245-256.

38.

Kratochvil

C. J.

Heiligenstein

J. H.

Dittmann

Spencer

T. J.

Biederman

Wernicke

Michelson

(2002). Atomoxetine and methylphenidate treatment in children with ADHD: A prospective, randomized, open-label trial. Journal of the American Academy of Child & Adolescent Psychiatry, 41, 776-784.

39.

Mattes

J. A.

Boswell

Oliver

(1984). Methylphenidate effects on symptoms of attention deficit disorder in adults. Archives of General Psychiatry, 41, 1059-1063.

40.

Matza

L. S.

Van Brunt

D. L.

Cates

Murray

L. T.

(2011). Test—Retest reliability of two patient-report measures for use in adults with ADHD. Journal of Attention Disorders, 15, 557-563.

41.

Maziade

Rouleau

Lee

Rogers

Davis

Dickson

(2009). Atomoxetine and neuropsychological function in children with attention-deficit/hyperactivity disorder: Results of a pilot study. Journal of Child and Adolescent Psychopharmacology, 19, 709-718.

42.

Michelson

Adler

Spencer

Reimherr

F. W.

West

S. A.

Allen

A. J.

Milton

(2003). Atomoxetine in adults with ADHD: Two randomized, placebo-controlled studies. Biological Psychiatry, 53, 112-120.

43.

Newcorn

J. H.

Kratochvil

C. J.

Allen

A. J.

Casat

C. D.

Ruff

D. D.

Moore

R. J.

Atomoxetine/Methylphenidate Comparative Study Group . (2008). Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: Acute comparison and differential response. American Journal of Psychiatry, 165, 721-730.

44.

Retz

Rosler

Ose

Scherag

Alm

Philipsen

Ammer

(2012). Multiscale assessment of treatment efficacy in adults with ADHD: A randomized placebo-controlled, multi-centre study with extended-release methylphenidate. World Journal of Biological Psychiatry, 13, 48-59.

45.

Shang

C. Y.

Gau

S. S.

(2012). Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 22, 353-363.

46.

Singer

. (1998). Using SAS PROC mixed to fit multilevel models, hierarchical models, and individual growth models. Journal of Educational and Behavioral Statistics, 23, 323-355.

47.

Spencer

T. J.

Adler

L. A.

Meihua

Saylor

K. E.

Brown

T. E.

Holdnack

J. A.

Kelsey

D. K.

(2010). Validation of the adult ADHD investigator symptom rating scale (AISRS). Journal of Attention Disorders, 14, 57-68.

48.

Spencer

T. J.

Adler

L. A.

Weisler

R. H.

Youcha

S. H.

(2008). Triple-bead mixed amphetamine salts (SPD465), a novel, enhanced extended-release amphetamine formulation for the treatment of adults with ADHD: A randomized, double-blind, multicenter, placebo-controlled study. Journal of Clinical Psychiatry, 69, 1437-1448.

49.

Spencer

T. S

Biederman

Wilens

Prince

Hatch

Jones

Larry

(1998). Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. American Journal of Psychiatry, 155, 693-695.

50.

Stein

M. A.

Waldman

I. D.

Charney

Aryal

Sable

Gruber

Newcorn

J. H.

(2011). Dose effects and comparative effectiveness of extended release dexmethylphenidate and mixed amphetamine salts. Journal of Child and Adolescent Psychopharmacology, 21, 581-588.

51.

Takahashi

Goto

Takita

Chung

S. K.

Wang

Y. F.

Gau

S. S.

(2014). An open-label, dose-titration tolerability study of atomoxetine hydrochloride in Korean, Chinese and Taiwanese adults with attention-deficit/hyperactivity disorder. Asia-Pacific Psychiatry, 6, 62-70.

52.

Wang

Zheng

Song

D. H.

Shin

Y. J.

Cho

S. C.

Levine

L. R.

(2007). Atomoxetine versus methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: A randomized, double-blind comparison trial. Australian and New Zealand Journal of Psychiatry, 41, 222-230.

53.

Wehmeier

P. M.

Schacht

Escobar

Savill

Harpin

(2010). Differences between children and adolescents in treatment response to atomoxetine and the correlation between health-related quality of life and Attention Deficit/Hyperactivity Disorder core symptoms: Meta-analysis of five atomoxetine trials. Child and Adolescent Psychiatry and Mental Health, 4, 30.

54.

Weiss

M. D.

Gibbins

Goodman

D. W.

Hodgkins

P. S.

Landgraf

J. M.

Faraone

S. V.

(2010). Moderators and mediators of symptoms and quality of life outcomes in an open-label study of adults treated for attention-deficit/hyperactivity disorder. Journal of Clinical Psychiatry, 71, 381-390.

55.

Wender

P. H.

Reimherr

F. W.

Wood

Ward

(1985). A controlled study of methylphenidate in the treatment of attention deficit disorder, residual type, in adults. American Journal of Psychiatry, 142, 547-552.

56.

Yeh

C. B.

Gau

S. S.

Kessler

R. C.

Y. Y.

(2008). Psychometric properties of the Chinese version of the adult ADHD Self-report Scale. International Journal of Methods in Psychiatric Research, 17, 45-54.