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Keywords:

  • attention-deficit–hyperactivity disorder;
  • functionality;
  • OROS-MPH;
  • recovery rate;
  • remission rate

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Aim:  To determine the differences in the remission rate, recovery rate, functional improvement, and treatment adherence related to treatment with short-acting immediate-release methylphenidate (IR-MPH) and long-acting osmotic-release oral system-methylphenidate (OROS-MPH) in a naturalistic setting among Taiwanese children with attention-deficit–hyperactivity disorder (ADHD).

Methods:  A total of 757 children with ADHD, aged 6–18 years, was evaluated using the following in order determine functional improvement and treatment adherence: the Chinese version of the Swanson, Nolan, and Pelham, version IV scale (SNAP-IV-C), Clinical Global Impression-ADHD-Severity (CGI-S) to measure remission and recovery rates, the Chinese version of the Social Adjustment Inventory for Children and Adolescents (CSAICA), and caregiver's satisfaction rate, treatment adherence, and frequency of adverse effects.

Results:  According to the SNAP-IV-C scores, the remission rate was 30.72%, and the recovery rate was 16.38%. Compared to short-acting IR-MPH, OROS-MPH was associated with greater functional improvement and treatment adherence among children with ADHD.

Conclusion:  OROS-MPH treatment at the adequate dosage can achieve higher remission and recovery rates, produce greater functional improvement, and result in better treatment adherence than IR-MPH treatment.

ATTENTION-DEFICIT–HYPERACTIVITY DISORDER (ADHD) is a common pediatric mental disorder that often manifests as chronic learning difficulty and emotional disturbance during childhood.1 Although ADHD is common, the causes of ADHD remain unclear; most authors agree, however, that around 80% of cases are due to hereditary factors.2 Many child mental health-care experts are in agreement that children with ADHD receive delayed or ineffective treatment due to a variety of biopsychosocial obstacles.3,4 Therefore, ADHD may be allowed to progress unchecked, and recovery from ADHD via longitudinal follow up or through general developmental strategies may be difficult.5,6

Although immediate-release methylphenidate (IR-MPH; short-acting treatment) was introduced in 1953, ADHD was considered to be a treatable disease only after the publication of DSM-III-R in 1987.7 Moreover, after the Multimodal Treatment Study on ADHD (MTA study) in the USA, main effective ADHD treatment was considered to be a combination therapy including pharmacotherapy and behavior modification.8 Many researchers had already compared treatment response rate for IR-MPH with that of the osmotic-release oral system (OROS-MPH; long-acting treatment), introduced in 1983.9,10 Among them, the newly introduced OROS-MPH treatment was more effective11,12 and had better patient adherence than IR-MPH treatment.13,14

Effective treatment for children with ADHD should result in functional improvement in addition to symptomatic improvement. In other words, the most effective ADHD treatment should minimize or even completely eliminate ADHD symptoms and optimize functioning in various areas such as academic performance,15 social interaction,16,17 and family functioning.18 Moreover, some authors, following the concept of remission originally established by studying depressed patients treated with antidepressants,19,20 indicated that remission can be achievable under specific OROS-MPH.19,21

Most of these studies on the remission rate and response rate of ADHD patients, comparing two frequently used types of MPH preparation (OROS-MPH vs IR-MPH), had been conducted in Canada by Steel et al.21 Little information regarding the aforementioned parameters is available for ADHD patients in Asian countries.22 Using the hypothesis that OROS-MPH is superior in effectiveness to its IR form, as per Western research, the aim of the present study was to determine the remission rate, recovery rate, and functional improvement for two types of MPH treatment, namely, OROS-MPH and IR-MPH, among the Taiwanese population using a naturalistic observation design.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Participants

A total of 757 children with ADHD, aged 6–18 years, underwent a 48-week-long prospective observational study conducted in nine centers (Mackay Memorial Hospital; Dr Enherya Hospital; Tri-Service General Hospital; Taiwan Adventist Hospital; Chang Gung Memorial Hospital; National Kaohsiung University Hospital; Taipei Municipal Gan-Dau Hospital; Changhua Christian Hospital; Lin Shin Hospital). The inclusion criteria were as follows: (i) age 6–18 years old and diagnosis of ADHD according to DSM-IV23 by 18 trained and certified child and adolescent psychiatrists; (ii) no ADHD medication for at least 4 weeks; (iii) living with parents/caregiver(s) who could complete questionnaires during the study; (iv) ability of parent(s) or guardian(s) to provide signed and dated informed consent for the participation of their children/wards in the study; and (v) being still at school. The exclusion criteria were as follows: (i) parent(s)/caregiver(s) with known or suspected psychotic disease, mental retardation, or any mental condition that may affect their ability to complete the questionnaires; (ii) glaucoma or seizures; (iii) parent(s)/caregiver(s) (in the case of patients whose parent(s)/caregiver(s) were to fill the questionnaires) with drug or alcohol abuse/dependence within the prior 6 months; (iv) serious or uncontrolled medical illness; and (v) use of one or both of the study drugs within the past month.

Data collection

Designated investigators and subjects filled out the information required by the protocol into case-report forms. The entered data were systematically checked by data-management staff, using error messages printed from validation programs and database listings. Non-obvious errors or omissions were entered in data-query forms, which were returned to the investigation site for resolution. During the study observation period, standardized measures among naturalistic treatment conditions were obtained in weeks 4, 12, 24, 36, and 48 during usual clinical follow-up examinations. Subjects were allowed to withdraw from the study at any time, and their reasons for withdrawal or loss to follow up were recorded.

Remission and recovery measurements

Swanson, Nolan, and Pelham, version IV scale, Chinese version:  Parents and investigators rated ADHD symptoms using Swanson, Nolan and Pelham, version IV scale, Chinese version (SNAP-IV-C) at every follow-up session in order to measure the remission and recovery rate of treatment. The SNAP-IV-C consists of the following items: inattention, hyperactivity/impulsivity, and oppositional symptoms. These items reflect the core symptoms of ADHD and oppositional defiant disorder as defined in DSM-IV. According to the psychometric properties of SNAP-IV-C in Taiwan, the intraclass correlation coefficients (ICC) for the three subscales of the Chinese SNAP-IV ranged from 0.59 to 0.72 for the parent form and from 0.60 to 0.84 for the teacher form. All subscales of both the parent and teacher forms had excellent internal consistency, with Cronbach's α >0.88.24 The remission rate in SNAP-IV-C was defined as <1 (not at all or just a little in ADHD symptom) on each of 18 ADHD items. The recovery rate in SNAP-IV-C was defined as remission lasting >12 weeks.

Clinical Global Impression-ADHD-Severity scale:  Clinicians used the Clinical Global Impression-ADHD Severity scale (CGI-S) during every follow-up session. The CGI-S is a single-item rating of the global severity of ADHD symptoms based on the clinician's overall impression in relation to other ADHD patients. Severity is rated on a 7-point scale (7 representing the most severe symptoms). The remission rate in CGI-S was defined as <2 points (not ill or minimally ill) on clinical global impression on ADHD severity. The recovery rate in CGI-S was defined as remission lasting >12 weeks.

Functional improvement

Chinese version of the Social Adjustment Inventory for Children and Adolescents:  Parents and investigators rated the social functioning of children with ADHD using the Chinese version of the Social Adjustment Inventory for Children and Adolescents (CSAICA). The test–retest reliability and internal consistency for child reports (Pearson correlation coefficient, 0.36–0.84; ICC, 0.33–0.82; Cronbach's α, 0.69–0.88) and for parental reports (ICC, 0.33–0.78; Cronbach's α, 0.67–0.89) of this scale have been previously confirmed.25

Adherence to treatment

In order to assess medication adherence for children with ADHD, parents/caregivers were asked to report the caregiver's satisfaction rate, the frequency of adverse effects, and mean dose of MPH to understand the non-compliance risk. The parents/caregivers' satisfaction with the current ADHD treatment was measured on a 5-point Likert scale as follows: 1, completely dissatisfied; 2, somewhat dissatisfied; 3, neutral; 4, somewhat satisfied; and 5, completely satisfied. The frequency of adverse effects was determined using a symptom checklist that included the following items: decreased appetite, nausea, somnolence, insomnia, headache, dizziness, abdominal pain, and stomach ache.

Statistical analysis

Data were summarized with respect to demographic and baseline characteristics. Descriptive analysis was conducted, including the percentage of categorical parameters, and the mean and standard deviation of continuous parameters. Due to the expected heterogeneity, subgroups of subjects were formed on the basis of actual MPH-utilization patterns, and analyses were conducted within the subgroups. The following subgroups were created according to naturally occurring drug-use patterns: no treatment; IR-MPH only; OROS-MPH only; and IR-MPH+OROS-MPH. Data from the IR-MPH only group were used as a reference for comparisons with data from the other groups at the end of the study. Treatment effectiveness was determined by calculating the remission and recovery rates using SNAP-IV-C and CGI-S scores. Remission was defined as a score of <1 (‘not at all’ scored 0 or ‘just a little’ scored 1) on each of the 18 ADHD items on the SNAP-IV-C scale. Recovery was defined as remission lasting for >12 weeks. This was an observational study, not a randomized controlled trial, therefore it is possible that the sampling distribution could reflect real-life clinical situations in Taiwan. Potential confounders resulting from imbalance among the four groups were adjusted as covariates in a generalized estimating equation (GEE) model. Under consideration of clustering measurements, within-subject differences and effect of time sequence, GEE were used to adjust the data for odds ratio (OR) calculations in a cluster randomized trial, and the effectiveness of treatment was calculated for the four groups. Also, there were five follow ups (weeks 4, 12, 24, 36, and 48). We used the GEE model to handle repeat measurement data and missing data. For testing the improvement of CSAICA subscores, we separately generated a GEE model for each subdomain. This method is known to have a multiple comparisons problem, therefore we used Bonferroni corrections to control for experiment-wide false positives (α = 0.05/25 = 0.002). Statistical results are therefore given with unadjusted (P < 0.05), and adjusted levels of significance (P < 0.001, and P < 0.0001).

Analysis of variance (ANOVA) was used to test for differences among demographic and baseline scores for the total and among the four subgroups (no treatment, IR-MPH, OROS-MPH, and IR-MPH+OROS-MPH), . Categorical data are presented as n (%) and were compared with the chi-squared test, and continuous data are presented as mean ± SD and were compared with ANOVA. The CSAICA scores were also compared among the four groups using GEE. The analyses consisted of summary statistics and 95% confidence intervals (CI). The drug dosage at the end of the study was compared using Student's t-test. Caregiver satisfaction rate was assessed using the Mantel–Haenszel trend and the chi-squared trend test. Treatment adherence was evaluated using chi-squared test. The frequency of adverse effects was also determined. Adverse effects were summarized according to the number and percentage of subjects experiencing any given adverse effect (person-times per 3 person-months).

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Demographic characteristics

We enrolled 757 children with ADHD; 607 (80.18%) of these were boys. The mean (±SD) age of the children was 10.05 ± 2.65 years. A total of 608 children (80.32%) attended elementary school. The mean age at onset of ADHD symptoms was 7.40 ± 2.69 years. The combined, inattention, and hyperactivity-impulsivity subtypes were present in 58.52%, 36.72%, and 4.76% of children, respectively. Further, 21.80% of children with ADHD had concurrent oppositional defiant disorder, and the same proportion had a history of prior treatment for ADHD. A family history of psychiatric disorder was present in 21.40%.

We divided the patients into groups based on naturally occurring treatment patterns (no treatment, IR-MPH, OROS-MPH, and IR-MPH+OROS-MPH; Table 1). At the beginning of the study, we found that, compared to the untreated children, those treated with OROS-MPH were older (10.26 ± 2.55 years vs 9.40 ± 2.16 years; P < 0.001), had worse scores on the parent-rated SNAP-IV-C (45.20 ± 12.71 vs 39.46 ± 14.08; P < 0.001), had a higher prevalence of oppositional defiant disorder (ODD) comorbidity (65.45% vs 2.42%; P < 0.001) or somatization disorder (66.67% vs 0%; P < 0.001), and more often had a family history of psychiatric disorders (31.48% vs 8.64%; P = 0.031) than untreated children. These data indicate that the children in the treatment groups had more severe ADHD symptoms than those in the no treatment group. Although the treatment plan was based on patient need and physician justification, according to Table 1 we found that these ADHD children with older age, comorbid with ODD, conduct disorder, anxiety disorder, and somatization disorder tended to be prescribed with long-acting OROS-MPH before entrance to the presents naturalistic study. Also for those ADHD children with comorbid illnesses, we found that they were more likely to use other concomitant treatment (including other non-stimulant drug or psychosocial intervention; P < 0.001) instead of stimulant medication. There was no significant difference, however, for concomitant psychosocial therapy, including all kinds of skill training and psychotherapy (P = 0.080) for ADHD children with comorbidity.

Table 1.  Demographic data and baseline characteristics (mean ± SD)
CharacteristicOverallIR-MPHNo treatmentOROS-MPHIR+OROS-MPHP
(n = 757)(n = 265)(n = 70)(n = 293)(n = 129)
  1. *P < 0.05, **P < 0.001.

  2. ADHD, attention-deficit–hyperactivity disorder; CGI-S, Clinical Global Impression-ADHD-Severity; CSAICA, Social Adjustment Inventory for Children and Adolescents; IR-MPH, immediate-release methylphenidate; ODD, oppositional defiant disorder; OROS-MPH, osmotic-release oral system-methylphenidate; SNAP-IV-C, Swanson, Nolan, and Pelham, version IV scale, Chinese version.

Sex, n (%)     0.871
 Male607 (80.18)216 (81.51)56 (80.00)235 (80.20)100 (77.52) 
 Female150 (19.82)49 (18.49)14 (20.00)58 (19.80)29 (22.48) 
Age (years)10.05 ± 2.659.55 ± 2.679.40 ± 2.1610.26 ± 2.5510.92 ± 2.80<0.001**
Education status, n (%)     0.024*
 Kindergarten9 (1.19)5 (1.89)2 (2.86)2 (0.68)0 (0.00) 
 Elementary608 (80.32)219 (82.64)59 (84.29)238 (81.23)92 (71.32) 
 Junior high122 (16.12)35 (13.21)9 (12.86)46 (15.70)32 (24.81) 
 Senior high18 (2.38)6 (2.26)0 (0.00)7 (2.39)5 (3.88) 
Onset age (years)7.40 ± 2.696.82 ± 2.616.44 ± 1.777.98 ± 2.657.90 ± 3.00<0.001**
Subtype, n (%)     0.072
 Inattentive278 (36.72)82 (30.94)31 (44.29)118 (40.27)47 (36.43) 
 Hyperactive–impulsive36 (4.76)14 (5.28)6 (8.57)9 (3.07)7 (5.43) 
 Combined443 (58.52)169 (63.77)33 (47.14)166 (56.66)75 (58.14) 
Comorbid illness, n (%)      
 ODD165 (21.80)22 (8.30)4 (5.71)108 (36.86)31 (24.03)<0.001**
 Conduct disorder14 (1.85)2 (0.75)0 (0.00)11 (3.75)1 (0.78)0.015*
 Anxiety disorder23 (3.04)12 (4.53)5 (7.14)2 (0.68)4 (3.10)0.005*
 Depressive disorder3 (0.40)0 (0.00)1 (1.43)2 (0.68)0 (0.00)0.191
 Tic disorder20 (2.64)5 (1.89)5 (7.14)7 (2.39)3 (2.33)0.206
 Tourette's disorder12 (1.59)3 (1.13)1 (1.43)6 (2.05)2 (1.55)0.857
 Somatization39 (5.15)2 (0.75)0 (0.00)26 (8.87)11 (8.53)<0.001**
 Others56 (7.40)20 (7.55)6 (8.57)20 (6.83)10 (7.75)0.958
Prior treatment165 (21.80)54 (20.38)8 (11.43)73 (24.91)30 (23.26)0.087
Concomitant medication for ADHD, n (%)      
 All subjects50 (6.61)14 (5.28)13 (18.57)18 (6.14)5 (3.88)0.003*
 Comorbid illnessn = 272n = 60n = 22n = 144n = 46 
 22 (8.09)5 (8.33)8 (36.36)9 (6.25)0 (0.00)<0.001**
Concomitant therapy for ADHD, n (%)      
 All subjects79 (10.44)15 (5.66)18 (25.71)40 (13.65)6 (4.65)<0.001**
 Comorbid illnessn = 272n = 60n = 22n = 144n = 46 
 27 (9.93)4 (6.67)6 (27.27)14 (9.72)3 (6.52)0.080
Family history, n (%)162 (21.40)58 (21.89)14 (20.00)51 (17.41)39 (30.23)0.031*
SNAP-IV-C score42.88 ± 13.3640.68 ± 13.2239.46 ± 14.0845.20 ± 12.7144.00 ± 13.70<0.001
CGI-S score4.18 ± 0.704.11 ± 0.654.37 ± 0.764.18 ± 0.684.23 ± 0.810.04*
CSAICA-all items1.97 ± 0.351.91 ± 0.341.89 ± 0.342.03 ± 0.361.99 ± 0.38<0.001**
 Academic performance2.17 ± 0.872.19 ± 0.871.92 ± 0.822.18 ± 0.862.28 ± 0.870.045*
 Attitude toward teacher1.82 ± 0.811.74 ± 0.791.67 ± 0.651.90 ± 0.811.75 ± 0.830.034*
 Social behavior in school2.14 ± 0.642.00 ± 0.642.08 ± 0.632.27 ± 0.622.10 ± 0.66<0.001**
 Problems in school2.00 ± 0.511.93 ± 0.511.89 ± 0.432.05 ± 0.522.07 ± 0.540.005*
 Activities in spare time2.61 ± 0.462.60 ± 0.462.55 ± 0.502.63 ± 0.472.63 ± 0.440.551
 Problems in spare time2.03 ± 0.651.95 ± 0.631.88 ± 0.612.11 ± 0.652.13 ± 0.680.002*
 Relationship with peers2.27 ± 0.652.23 ± 0.612.27 ± 0.722.31 ± 0.672.28 ± 0.700.570
 Problems with peers1.59 ± 0.461.53 ± 0.421.51 ± 0.411.66 ± 0.471.62 ± 0.520.002
 Relationship with siblings1.81 ± 0.651.73 ± 0.621.76 ± 0.691.86 ± 0.671.83 ± 0.700.154
 Problems with siblings1.33 ± 0.421.28 ± 0.391.28 ± 0.451.40 ± 0.461.31 ± 0.390.015*
 Interaction with mother1.75 ± 0.651.67 ± 0.651.69 ± 0.591.81 ± 0.671.75 ± 0.650.098
 Interaction with father2.06 ± 0.751.94 ± 0.732.00 ± 0.612.15 ± 0.772.01 ± 0.780.015*
 Problems with family1.57 ± 0.531.51 ± 0.481.53 ± 0.521.66 ± 0.561.53 ± 0.490.005
CSAICA-all interviewers2.04 ± 0.461.96 ± 0.432.02 ± 0.482.12 ± 0.462.07 ± 0.48<0.001**
 Problems in school2.37 ± 0.872.24 ± 0.852.21 ± 0.742.51 ± 0.882.36 ± 0.940.002*
 Activities in spare time2.68 ± 0.682.65 ± 0.672.73 ± 0.742.72 ± 0.702.67 ± 0.640.643
 Problems in spare time2.14 ± 0.872.04 ± 0.811.94 ± 0.882.24 ± 0.872.26 ± 0.830.004*
 Relationship with peers2.32 ± 0.772.23 ± 0.742.36 ± 0.802.35 ± 0.802.41 ± 0.770.130
 Problems with peers1.87 ± 0.851.76 ± 0.821.83 ± 0.802.02 ± 0.871.92 ± 0.880.004*
 Relationship with siblings1.84 ± 0.751.74 ± 0.761.87 ± 0.851.89 ± 0.751.94 ± 0.780.081
 Problems with siblings1.50 ± 0.731.41 ± 0.701.43 ± 0.721.61 ± 0.771.45 ± 0.680.015*
 Interaction with mother1.76 ± 0.771.64 ± 0.731.81 ± 0.751.80 ± 0.781.77 ± 0.820.065
 Interaction with father2.12 ± 0.862.05 ± 0.872.11 ± 0.732.16 ± 0.852.10 ± 0.910.503
 Problems with family1.64 ± 0.741.56 ± 0.711.61 ± 0.791.73 ± 0.741.63 ± 0.730.058
 Problems in school2.37 ± 0.872.24 ± 0.852.21 ± 0.742.51 ± 0.882.36 ± 0.940.002*

Remission and recovery rates

At the end of the study, we compared the no treatment group, IR-MPH only group, and OROS-MPH only group, using data from the IR-MPH only group for baseline comparisons. We found that at 12-month follow up, the remission rate was clearly higher in the OROS-MPH only group than in the IR-MPH only group, as reflected by the SNAP-IV-C scores (30.72% vs 13.72%; OR, 1.61; 95%CI: 1.24–2.08; P = 0.0003) and the CGI-S scores (13.99% vs 5.66%; OR, 1.74; 95%CI: 1.18–2.56; P = 0.0053). OROS-MPH treatment was also significantly superior to IR-MPH treatment when assessed on the basis of the recovery rate, as determined from the SNAP-IV-C scores (16.38% vs 7.17%; OR, 1.96, 95%CI: 1.29–2.98; P = 0.0016) and CGI-S scores (5.80% vs 1.89%; OR, 2.75; 95%CI: 1.21–6.24; P = 0.015; Table 2). The differences in the remission and recovery rates between the OROS-MPH-based treatment groups and the IR-MPH only group are shown in Figure 1.

Table 2.  Remission and recovery rates
  IR-MPHWithout MPHOROS-MPHIR + OROS-MPH
(%, OR)(%, OR, 95%CI)(%, OR, 95%CI)(%, OR, 95%CI)
  1. *P < 0.05, **P < 0.001; compared with IR-MPH treatment group.

  2. ADHD, attention-deficit–hyperactivity disorder; CGI-S, Clinical Global Impression-ADHD-Severity; CI, confidence interval; IR-MPH, immediate-release methylphenidate; OR, odds ratio; OROS-MPH, osmotic-release oral system-methylphenidate; SNAP-IV-C, Swanson, Nolan, and Pelham, version IV scale, Chinese version.

Remission rate**SNAP-IV-C14.72, 1.008.57*, 0.45 (0.21–0.96)30.72**, 1.61 (1.24–2.08)28.68*, 1.65 (1.19–2.30)
CGI-S5.66, 1.008.57, 0.69 (0.30–1.60)13.99*, 1.74 (1.18–2.56)18.60, 2.04 (1.25–3.32)
Recovery rate**SNAP-IV-C7.17, 1.0004.29, 0.48 (0.15–1.51)16.38*, 1.96 (1.29–2.98)19.38*, 2.01 (1.23–3.30)
CGI-S1.89, 1.0001.43, 0.58 (0.12–2.81)5.80*, 2.75 (1.21–6.24)7.75*, 3.33 (1.39–7.93)
image

Figure 1. (a) Swanson, Nolan, and Pelham, version IV scale, Chinese version, remission and (c) recovery rate vs methylphenidate (MPH) type; (b) Clinical Global Impression-ADHD-Severity scale remission and (d) recovery rate vs MPH type. (○) Osmotic-release oral system-methylphenidate only; (□) immediate-release methylphenidate only.

Download figure to PowerPoint

Functional improvement

OROS-MPH was significantly superior to IR-MPH in terms of improvement in social functioning, including social behavior in school, problems in school, problems during spare time, problems with peers, interactions with mother. The all-item CSAICA score (various problems from parent's view) was 1.81 ± 0.01 and 1.73 ± 0.01 for the IR-MPH and OROS-MPH treatments, respectively (P < 0.0001; Table 3).

Table 3.  CSAICA scores
ItemIR-MPHNo treatmentOROS-MPHIR + OROS-MPH
(Mean ± SD)(Mean ± SD)(Mean ± SD)(Mean ± SD)
  • **P < 0.001, ***P < 0.0001.

  • Mean: least square mean calculated using the generalized estimating equation model; compared with IR-MPH treatment group.

  • ADHD, attention-deficit–hyperactivity disorder; CSAICA, Social Adjustment Inventory for Children and Adolescents; IR-MPH, immediate-release methylphenidate; OROS-MPH, osmotic-release oral system-methylphenidate.

Academic performance1.99 ± 0.022.08 ± 0.061.93 ± 0.021.87 ± 0.03
Attitude toward teacher1.63 ± 0.031.77 ± 0.061.53 ± 0.031.59 ± 0.04
Social behavior in school1.91 ± 0.022.05 ± 0.061.78 ± 0.02***1.78 ± 0.03**
Problems in school1.68 ± 0.021.82 ± 0.041.59 ± 0.02***1.58 ± 0.02***
Activities in spare time2.51 ± 0.022.55 ± 0.042.45 ± 0.022.48 ± 0.03
Problems in spare time1.76 ± 0.021.87 ± 0.051.68 ± 0.02**1.66 ± 0.03
Relationship with peers2.16 ± 0.022.25 ± 0.052.13 ± 0.022.13 ± 0.03
Problems with peers1.46 ± 0.011.47 ± 0.041.39 ± 0.01***1.38 ± 0.02
Relationship with siblings1.75 ± 0.021.79 ± 0.061.69 ± 0.021.76 ± 0.03
Problems with siblings1.25 ± 0.011.24 ± 0.041.20 ± 0.011.22 ± 0.02
Interaction with mother1.69 ± 0.021.73 ± 0.051.60 ± 0.02**1.63 ± 0.03
Interaction with father1.95 ± 0.022.00 ± 0.061.87 ± 0.021.91 ± 0.03
Problems with family1.43 ± 0.021.45 ± 0.041.38 ± 0.021.40 ± 0.02
All Items1.81 ± 0.011.87 ± 0.031.73 ± 0.01***1.74 ± 0.02***
Interviewer Global Score    
 Problems in school1.91 ± 0.032.04 ± 0.071.72 ± 0.03***1.73 ± 0.04**
 Activities in spare time2.59 ± 0.032.58 ± 0.072.48 ± 0.03**2.48 ± 0.04
 Problems in spare time1.81 ± 0.031.88 ± 0.071.69 ± 0.03**1.66 ± 0.04**
 Relationship with peers2.25 ± 0.032.34 ± 0.062.19 ± 0.032.19 ± 0.04
 Problems with peers1.58 ± 0.031.68 ± 0.061.53 ± 0.031.52 ± 0.04
 Relationship with siblings1.79 ± 0.031.81 ± 0.071.77 ± 0.031.79 ± 0.04
 Problems with siblings1.36 ± 0.021.41 ± 0.061.30 ± 0.021.35 ± 0.03
 Interaction with mother1.70 ± 0.031.70 ± 0.061.58 ± 0.02***1.63 ± 0.03
 Interaction with father1.99 ± 0.032.02 ± 0.071.95 ± 0.031.94 ± 0.04
 Problems with family1.45 ± 0.021.55 ± 0.061.36 ± 0.021.43 ± 0.03
 All interviewers1.87 ± 0.011.92 ± 0.041.78 ± 0.01***1.79 ± 0.02**
Adherence to treatment

Patient adherence to OROS-MPH treatment was better than that to IR-MPH treatment (67.24% vs 36.23%; P < 0.0001; Table 4). More caregivers were completely satisfied with the OROS-MPH treatment than with the IR-MPH treatment (7.51% vs 3.40%; P = 0.0071). Decreased appetite was more frequently reported as an adverse effect of OROS-MPH treatment than of IR-MPH treatment (35.77% vs 21.39%; Table 5). The mean dose of MPH was higher in the OROS-MPH group than in the IR-MPH group (30.16 ± 10.75 mg/day vs 19.40 ± 11.40 mg/day; P < 0.0001; Table 6).

Table 4.  Adherence to MPH treatment at last visit
 IR-MPHOROS-MPHIR + OROS-MPH
n (%)n (%)n (%)
  • Chi-squared test, excluding ND/NA; compared with IR-MPH treatment group.

  • IR-MPH, immediate-release methylphenidate; NA, not available; ND, not done; OROS-MPH, osmotic-release oral system-methylphenidate.

Good adherence96 (36.23)197 (67.24)82 (63.57)
Poor adherence125 (47.17)82 (27.99)39 (30.23)
ND/NA44 (16.60)14 (4.78)8 (6.20)
P <0.0001<0.0001
Table 5.  Caregiver satisfaction rate and adverse effects (person-times per 3 person-months)
 IR-MPHNo treatmentOROS-MPHIR + OROS-MPH
n (%)n (%)n (%)n (%)
  • Mantel–Haenszel chi-squared trend test.

  • IR-MPH, immediate-release methylphenidate; OROS-MPH, osmotic-release oral system-methylphenidate.

Completely dissatisfied3 (1.13)1 (1.43)2 (0.68)4 (3.10)
Somewhat dissatisfied17 (6.42)10 (14.29)30 (10.24)19 (14.73)
Neutral90 (33.96)41 (58.57)55 (18.77)27 (20.93)
Somewhat satisfied146 (55.09)16 (22.86)184 (62.80)70 (54.26)
Completely satisfied9 (3.40)2 (2.86)22 (7.51)9 (6.98)
PReference<0.00010.00710.9653
Completely dissatisfied3 (1.13)1 (1.43)2 (0.68)4 (3.10)
Somewhat dissatisfied17 (6.42)10 (14.29)30 (10.24)19 (14.73)
Neutral90 (33.96)41 (58.57)55 (18.77)27 (20.93)
Somewhat satisfied146 (55.09)16 (22.86)184 (62.80)70 (54.26)
Completely satisfied9 (3.40)2 (2.86)22 (7.51)9 (6.98)
PReference<0.00010.00710.9653
Adverse effects    
 Decreased appetite21.390.5835.7728.32
 Nausea3.781.165.073.64
 Somnolence1.890.580.991.12
 Insomnia2.910.006.816.17
 Headache3.490.002.231.68
 Dizziness2.620.003.961.40
 Abdominal pain2.330.585.574.77
 Stomach ache0.290.000.370.28
Table 6.  MPH dose at end of study (mean ± SD)
 IR-MPHOROS-MPHIR-MPH + OROS-MPH
  • Student's t-test.

  • IR-MPH, immediate-release methylphenidate; OROS-MPH, osmotic-release oral system-methylphenidate.

Dosage 1 (mg/day)19.40 ± 11.4030.16 ± 10.7541.39 ± 13.35
Dosage 2 (mg/kg per day)0.63 ± 0.290.86 ± 0.271.08 ± 0.44
PReference<0.0001<0.0001

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

The aim of the present study was to confirm whether the superiority of OROS-MPH treatment over IR-MPH treatment, in terms of higher rates of remission and recovery, and greater improvement in social functioning, that has been reported in the Western literature is maintained in the Taiwanese population. We found that once-daily treatment with long-acting OROS-MPH was associated with higher remission and recovery rates, greater improvement in social functioning, better adherence, and higher drug dosage than usual IR-MPH-based treatments (OROS, 30.16 ± 10.75 mg vs IR, 19.40 ± 11.40 mg). Also, because only few concomitant psychosocial interventions were provided by the clinician (not shown), this naturalistic study is important because it focuses only on the drug treatment effect of the two different kinds of MPH. This naturalistic observational study plays a useful role in clarifying general trends in MPH utilization and comparing remission and recovery rates between two differently acting MPH delivery systems in the Asian population.

Analysis of the four study groups showed that treatment effectiveness increased in the following order: no treatment group, IR-MPH only, OROS-MPH only, IR-MPH+OROS-MPH. The remission and recovery rates for the children with ADHD treated with short-acting MPH was 0.15–0.45-fold higher than those untreated. Supporting the MTA study recommendation, this finding demonstrates that pharmacotherapy is not only helpful for children with ADHD but also important for reaching remission or achieving recovery from ADHD.8,26 Regarding the actual remission or recovery rate of pharmacotherapy for children with ADHD, in the present study, 30.72% of children with ADHD attained remission on OROS-MPH; further, this remission rate was 1.61-fold greater than that obtained on short-acting IR-MPH. A total of 16.38% of children with ADHD achieved recovery on OROS-MPH according to SNAP-IV-C scores, and this recovery rate was 1.96-fold greater than that on IR-MPH. Therefore, the present naturalistic observational study of Taiwanese ADHD children highlights higher remission rates compatible with those of recently published western studies,19,21 and shows that higher recovery rates are achievable when using long-acting OROS-MPH compared to short-acting IR-MPH.

Once-daily OROS-MPH improves treatment adherence among patients with ADHD according to a study conducted in Taiwan.27 The present results are compatible with that study; another study also found higher adherence with OROS-MPH (67.24%) than IR-MPH (36.23%).28 With regard to risks that influence treatment adherence, severity of ADHD symptoms, presence of oppositional defiant disorder/conduct disorder, learning difficulties, anxiety, age, family dysfunction, socioeconomic adversity, response to treatment at school and parent satisfaction are usually regarded as factors that exacerbate poor treatment adherence.29–31 Compatible with results of two local studies,4,13 the present results indicate that long-acting OROS-MPH treatment actually reduced poor treatment adherence and raised caregiver satisfaction rate compared to IR-MPH treatment.

Regarding the difference in adverse effects among the three groups, the present results are similar to other studies:4,9 there were no significant differences related to adverse effects between the two different MPH delivery systems or the combination of the two different MPH delivery systems. This finding is against general thinking that children with ADHD experience less adverse effects when using OROS-MPH than IR-MPH. A possible explanation is that the dosage of OROS-MPH during the short study period was higher than that of IR-MPH; therefore, a similar percentage of patients experienced loss of appetite in both the OROS-MPH and IR-MPH groups. But although the frequency of adverse effects was similar between the long- and short-acting MPH, the parents were more satisfied with OROS-MPH than with IR-MPH, and hence, adherence to the former treatment was greater than that to the latter.

Steele et al. have emphasized that an adequate dose of MPH (36 mg/day) is required to attain remission in ADHD.19 In the present study, a mean dose of 30.16 ± 10.75 mg/day OROS-MPH was sufficient to induce remission, which is near that required in the Steele et al. study in Canada. But the mean dose to achieve remission in the Taiwanese IR-MPH group was 19.40 ± 11.40 mg/day, which is 50% lower than that used for the Canadian subjects in the Steele et al. study. A study in Korea also found that children with ADHD experienced more adverse effects, specifically loss of appetite, and usually required a lower mean dose than that reported in Western literature.16 A possible explanation for lower IR-MPH doses is that Asian parents are very anxious about the side-effects of short-acting stimulant drugs. This may explain why Taiwanese or Asian subjects usually use lower doses than Western subjects.

Functional improvement, as determined using the parents' and investigators' global scores, was better in the OROS-MPH-based treatment groups than in the IR-MPH-only group for all the parameters studied, except for relationship with peers. In particular, OROS-MPH was found to significantly improve the parameter ‘problems in interaction with mother’, as determined using the investigators' scores. The possible reason for the absence of significant improvement in relationship with peers may be that investigators and parents find it more difficult to evaluate this parameter than teachers. Or that the stimulant effect produces better results in study performance than interpersonal relationships, because it improves attention. Previous authors, however, have assessed only academic or emotional improvement after OROS-MPH treatment.16,17 Our present study demonstrates effectiveness in social interpersonal functioning improvement among children with ADHD32,33 when using OROS-MPH rather than IR-MPH.

This study had the following limitations. First, although the study involved nine hospitals, four phases of assessment, and 1 year of follow up, the results cannot be generalized to all children with ADHD in Taiwan. Second, the actual MPH-utilization patterns in the present study were divided into four groups according to natural observation. Although we divided the OROS-MPH-based treatment groups into the OROS-MPH only group and the OROS-MPH+IR-MPH group, the significant effectiveness of pure OROS-MPH treatment might not have been fully estimated; also, there are no details on significant group differences in dose change of MPH. Third, in the OROS-MPH+IR-MPH group, we did not specify whether IR-MPH was used as the physician recommended (at 17.00 hours) or as a twice- or thrice-daily treatment to strengthen the effect of OROS-MPH or lower the cost of OROS-MPH therapy (national insurance in Taiwan limits the use of OROS-MPH because of economic reasons). Fourth, the reference for the Chinese version of SNAP-IV is not an international journal easily accessible by international readers. Fifth, teacher ratings were not used to assess symptom severity and social function. And sixth, symptom improvement cannot be explained only by MPH treatment. Other treatment factors should be explored.

In conclusion, remission; recovery, functional improvement, and good adherence can be achieved using an adequate dose of OROS-MPH.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

We thank all the child psychiatrists who participated in this study. This research was supported by Jansesse-Cilag, Taiwan (protocol ID: CCT-TWN-MA5).

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
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