Baseline Severity of Parent-Perceived Inattentiveness Is Predictive of the Difference Between Subjective and Objective Methylphenidate Responses in Children with Attention-Deficit/Hyperactivity Disorder

Abstract

Objective:

The purpose of this study was to find potential variables associated with the difference between subjective and object treatment responses in children with attention-deficit/hyperactivity disorder (ADHD) treated with OROS-methylphenidate (MPH).

Methods:

We conducted a post-hoc analysis of data from a multicenter, open-label, 12 week trial of OROS-MPH in Korean children with ADHD. The subjective outcome measurement was the parent version of the ADHD Rating Scale-IV (ARS-P), and the objective outcome measurement was the Continuous Performance Test (CPT). We compared the children's demographic and disease-related variables among four groups, classified according to whether they showed subjective or objective improvement after MPH treatment.

Results:

Higher baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective treatment response among objective nonresponders (p=0.033). Lower baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective nonresponse among objective responders (p=0.045). Lower baseline omission errors (p=0.006) and response time variability scores (p=0.011) on the CPT were associated with a significantly higher probability of both objective and subjective responses, compared with both types of nonresponse to treatment.

Conclusions:

The baseline severity of parent-perceived inattentive symptoms was predictive of differences in subjective and objective treatment responses, and the baseline severity of neuropsychological deficit (inattention and inconsistency of attention) was predictive of responses, using both subjective and objective measurements.

Introduction

A ttention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in selective attention, sustained attention, and inhibitory control (Biederman and Faraone 2005). Psychostimulants, particularly methylphenidate (MPH), constitute the first-line pharmacotherapy for ADHD patients. The response rate to MPH is ∼85% (Biederman and Faraone 2005; Nutt et al. 2007). In other words, 15% of children receiving this treatment will not experience improvement. The reasons behind the variability in treatment response in ADHD are not fully understood. Female sex, higher intelligence quotient (IQ), considerable inattentiveness, younger age, and associated comorbidities might account for the variability of treatment response in children and adolescents with ADHD (Buitelaar et al. 1995, 1999; The MTA cooperative group 1999; Ghuman et al. 2007; van der Oord et al. 2008; Tamm et al. 2013). It has, however, been consistently observed that higher dosages of stimulants and higher baseline severity of ADHD symptoms result in a higher percentage of responders (Medori et al. 2008; Newcorn et al. 2010; Buitelaar et al. 2011).

A widely used assessment of treatment efficacy relies on reports by parents and teachers (Shah et al. 2005). However, according to Brewis's literature review (Brewis 2002), parents' and teachers' reports tend to be subjective. Parent and teacher ratings appear to be influenced by the identity of the person reporting the behavior, rather than by the reported behavior itself. The accuracy of subjective assessments is often questioned because they are prone to the placebo effect (Sumner et al. 2010). Another difficulty lies in differentiating between the behavioral response (decreases in the hyperactive-impulsive symptoms) and improvement in attention.

Although there are no laboratory tests for assessing ADHD, there has been increasing recognition of the potential clinical utility of more objective measurements for the diagnosis and the assessment of drug efficacy. The most commonly used group of measurements is the Continuous Performance Test (CPT) (Greenberg and Waldman 1993). The CPT involves the rapid presentation of stimuli on a computer screen for an extended period of time. Children with ADHD are typically measured based on the number of omission errors (failing to press for a target), commission errors (pressing for a nontarget), response time, and response time variability. According to the literature, the sensitivity and specificity of the CPT are 70–80%, and its reliability is ∼0.8 (Greenberg 1987; Forbes 1998; Llorente et al. 2001). Although CPT scores lack sufficient sensitivity and specificity, the CPT's efficacy in measuring drug response is 95% and is, therefore, quite satisfactory (Greenberg and Waldman 1993).

In previous studies comparing subjective ADHD symptom rating scales, with scores obtained using an objective neuropsychological test for the assessment of hyperactivity, inattention, and impulsivity, it was found that agreement between these two measurements was not as strong as anticipated (Manor et al. 2008; Sumner et al. 2010). These results prompted us to find potential predictors associated with differences between subjective perceptions and objective measurements in children with ADHD treated with MPH. Therefore, we conducted a post-hoc analysis of a multicenter, open-label, 12 week trial of OROS-MPH to investigate the influence of baseline characteristics on differences between subjective and objective outcome measurements in children with ADHD.

Methods

Study design and subjects

This study has been previously described in detail (Kim et al. 2013). In brief, this was a multicenter, open-label, 12 week trial of OROS-MPH in drug-naive children (6–12 years of age) with diagnoses of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), criteria (American Psychiatric Association 1994). Other requirements for inclusion were the absence of a current depressive or anxiety disorder requiring drug therapy and no history of bipolar disorder, psychotic disorders, substance use disorders, Tourette's syndrome, pervasive developmental disorders, mental retardation, organic brain disease, or seizure disorders. To diagnose ADHD and any comorbid disorders, we used the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) (Kim et al. 2004).

Following screening, the eligible patients were enrolled in the study, and they completed baseline assessments prior to starting treatment. We initiated participants with 18 mg of OROS-MPH per day in children with body weights <30 kg and with 27 mg/day in children with body weights >30 kg. The doses could be adjusted upward in 9 mg or 18 mg increments per week and downward in 9 mg decrements over 8 weeks, depending upon each patient's symptom severity and drug tolerability. The maximum OROS-MPH dose was 54 mg/day. The study was approved by the institutional review board (IRB) for human subjects at the Seoul National University Hospital and other participating hospitals. Parents/guardians provided written informed consent, and the children provided oral assent to participate in this study.

Treatment response and its correlates

The employed subjective outcome measurement was the parental version of the ADHD Rating Scale-IV (ARS-P) (DuPaul 1991; So et al. 2002), and the objective outcome measurement was the CPT. The four variables we recorded on the CPT were omission errors, commission errors, response times, and response time variability, and the composite score (mean scores of the four variables) was calculated. Subjective treatment response was defined as a ≥50% decrease in ARS-P total score from baseline. Objective treatment response was defined as a ≥15% (1.5 SD) increase in the mean composite score on the CPT from baseline. Both the parents and investigators were blinded to the results of the CPT, and the children were blinded to the results of the ARS. The subjects were classified into four groups according to whether they showed subjective or objective responses after MPH treatment: 1) Nonresponders on both the ARS-P and CPT; 2) ARS-P responders without CPT response; 3) CPT responders without ARS-P response; and 4) responders on both the ARS-P and CPT.

The following 10 parameters, which were assessed at screening or baseline, were used in the analysis as possible correlates of treatment response: 1) Age (years); 2) sex (male/female); 3) subtype of ADHD (combined/inattentive/hyperactive-impulsive/not otherwise specified); 4) comorbidity; 5) mean dose of MPH (mg/kg); 6) baseline score on the Clinical Global Impressions-Severity (CGI-S) scale; 7) baseline score on the ARS-P; 8) baseline score on the CPT; 9) baseline score on the maternal Beck Depression Inventory (BDI); and 10) baseline score on the Parenting Stress Index (PSI).

The ARS-P is a symptom severity scale consisting of 18 items, including 9 inattentive items and 9 hyperactive-impulsive items, according to the DSM-IV criteria (So et al. 2002). The BDI consists of 21 items for measuring the subjective severity of depression (Han et al. 1986). The Korean version of the Parenting Stress Index-Short Form (PSI-SF) is composed of 20 items, comprising 8 child characteristic-related stress items, 9 parent–child interaction-related stress items, and 3 achievement expectation-related stress items (Shin and Chung 1998). For all cited scales, the higher the score was, the greater the severity or parent's perceived stress was.

Statistical analyses

We compared demographic and disease-related variables among the four groups using ANOVA for continuous variables and the χ² test for categorical variables. Multivariate logistic regression analysis was used to analyze possible predictors of subjective and objective treatment responses. Variables that showed group differences by ANOVA or the χ² test at an α level <0.05 were included in the multivariate regression analysis. All of the statistical analyses were performed with SPSS (version 12.0; SPSS Inc., Chicago, IL), and an α-level <0.05 was considered significant.

Results

Among the 132 subjects initially recruited, 119 completed the ARS-P and the CPT at the last visit (12 weeks after treatment) and were included in the post-hoc analysis. Forty-three subjects (36.1%) were nonresponders according to both subjective and objective measurements, 29 (24.4%) were subjective responders without objective responses, 18 (15.1%) were objective responders without subjective responses, and 29 (24.4%) were responders according to both subjective and objective measurements.

There were differences in age, dose of MPH (mg/kg), baseline inattentive scores on the ARS-P, and baseline omission errors and response time variability scores on the CPT among the four groups (Table 1). Post-hoc comparison revealed that nonresponders on both subjective and objective measurements were older than objective responders with or without subjective responses (p=0.049 or 0.012, respectively); the dose of MPH (mg/kg) was higher in objective responders without subjective responses compared with nonresponders, according to both subjective and objective measurements (p=0.047), and baseline omission errors and response time variability scores on the CPT were lower in objective responders than in objective nonresponders, regardless of subjective response to treatment (p<0.001).

Table 1.

Responders and Nonresponders According to the Parent-Rated ARS and the CAT

	Nonresponders on both ARS-P and CPT^a (n=43)	ARS-P responders without CPT response^b (n=29)	CPT responders without ARS-P response^c (n=18)	Responders in both ARS-P and CPT^d (n=29)
	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	χ ² or F	p	Contrast
Age	9.35 (1.41)	9.07 (1.28)	8.11 (1.49)	8.45 (1.40)	4.57	0.005	a>c, d
Male, n (%)	34 (79.1)	21 (72.4)	17 (94.4)	26 (89.7)	5.17	0.160
Type, n (%)					9.95	0.355
Combined	24 (55.8)	16 (55.2)	13 (72.2)	20 (69.0)
Inattentive	11 (25.6)	10 (34.5)	4 (22.2)	8 (27.6)
Hyperactive-Impulsive	2 (4.7)	2 (6.9)	1 (5.6)	1 (3.4)
NOS	6 (14.0)	1 (3.4)	0	0
Comorbidity, n(%)
ODD	5 (11.6)	3 (10.3)	2 (11.1)	1 (3.4)
Tic	5 (11.6)	2 (6.9)	2 (11.1)	3 (10.3)
Anxiety disorder	1 (2.3)	5 (17.2)	3 (16.7)	2 (6.9)
Enuresis	3 (7.0)	0	3 (16.7)	2 (6.9)
Methylphenidate dose, mg/kg	0.95 (0.27)	0.99 (0.26)	1.16 (0.31)	1.06 (0.29)	2.80	0.043	a<c
Baseline CGI-S	4.98 (0.80)	5.10 (0.86)	5.39 (0.92)	5.35 (0.97)	1.50	0.217
Baseline ARS-P
Total	23.72 (9.12)	26.03 (10.25)	21.39 (6.61)	27.79 (9.58)	2.21	0.091
Inattentive	12.98 (4.61)	15.52 (5. 48)	12.06 (4.08)	15.07 (5.50)	2.85	0.041
Hyperactive-Impulsive	10.74 (5.11)	10.52 (6.14)	9.33 (3.41)	12.72 (5.73)	1.81	0.150
Baseline CPT
Omission errors	102.30 (10.05)	102.10 (17.13)	65.06 (28.11)	78.72 (26.38)	21.58	<0.001	a, b>c, d
Commission errors	86.51 (23.22)	91.97 (25.19)	80.72 (29.86)	79.07 (30.27)	1.35	0.263
Response time	93.12 (17.03)	88.45 (17.20)	87.00 (35.61)	85.79 (22.13)	0.76	0.521
RTSD	84.26 (21.87)	88.69 (16.70)	58.28 (27.90)	60.34 (29.04)	12.04	<0.001	a, b>c, d
Baseline BDI	11.19 (7.38)	13.03 (6.18)	13.44 (11.21)	9.76 (7.39)	1.24	0.300
Baseline PSI
Difficult child	24.56 (5.34)	23.79 (5.64)	24.28 (5.77)	24.03 (4.75)	0.13	0.942
Parent-child interaction	23.72 (4.20)	24.72 (4.58)	24.61 (5.11)	22.66 (5.56)	1.09	0.358
Learning problem	10.28 (2.76)	10.17 (2.47)	10.39 (2.33)	10.00 (2.30)	0.11	0.954

ARS, Attention-Deficit-Hyperactivity Disorder Rating Scale; ARS-P, Attention-Deficit-Hyperactivity Disorder Rating Scale, parent version; CPT, Continuous Performance Test; NOS, not otherwise specified; ODD, oppositional defiant disorder; CGI-S, Clinical Global Impressions – Severity; RTSD, response time variability; BDI, Beck Depression Inventory; PSI, Parenting Stress Index.

Table 2 shows the results of multivariate analyses using the stepwise backward logistic regression model. Higher baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective response among objective nonresponders (p=0.033). Lower baseline inattentive scores on the ARS-P were associated with a significantly higher probability of subjective nonresponse among objective responders (p=0.045). Lower baseline omission errors (p=0.006) and response time variability scores (p=0.011) on the CPT were associated with a significantly higher probability of both objective and subjective responses compared with both types of nonresponse to treatment.

Table 2.

Multivariate Logistic Regression Analyses

	CPT nonresponder with ARS-P response vs. both nonresponders^a		CPT responders without ARS-P response vs. both responders^a		Both responders vs. both nonresponders^a
	OR (95% CI)^b	p	OR (95% CI)^b	p	OR (95% CI)^b	p
Age	0.83 (0.56–1.24)	0.366	0.99 (0.61–1.60)	0.956	0.68 (0.40–1.16)	0.155
Methylphenidate dose, mg/kg	1.60 (0.23–11.07)	0.634	1.81 (0.18–18.44)	0.616	5.23 (0.54–50.67)	0.153
Baseline ARS-P inattentive score	1.13 (1.01–1.26)	0.033	0.86 (0.75–0.99)	0.045	1.10 (0.96–1.26)	0.171
Baseline omission errors	1.00 (0.95–1.04)	0.851	0.98 (0.95–1.00)	0.082	0.95 (0.91–0.99)	0.006
Baseline RTSD	1.02 (0.99–1.05)	0.251	1.00 (0.97–1.02)	0.653	0.97 (0.94–0.99)	0.011

Multivariate logistic regression analyses, including all variables in Table 2 (variables that showed group differences in ANOVA at an α level <0.05); the latter is the reference group.

Odds ratio adjusted for all variables in Table 2 except for itself.

ARS, Attention-Deficit-Hyperactivity Disorder Rating Scale; ARS-P, Attention-Deficit-Hyperactivity Disorder Rating Scale, parent version; CAT, CPT, Continuous Performance Test; RTSD, response time variability.

Discussion

To the best of our knowledge, this was the first study to find potential variables associated with differences between subjective and objective responses to MPH in children with ADHD. The major findings of this study were that the baseline severity of parent-perceived inattentive symptoms was predictive of differences in subjective and objective treatment responses and that the baseline severity of neuropsychological deficits (inattention and inconsistency) was predictive of responses according to both subjective and objective measurements.

Parents who perceived their children's inattentive symptoms as severe were more likely to report subjective improvement after treatment, although objective improvement did not occur. Over the long term, parents who perceived their children's inattentive symptoms as mild were more likely to deny subjective improvement, although objective improvement occurred. Subjects with higher inattentive scores at baseline can experience greater improvements over time simply because they have the greatest room for improvement (Buitelaar et al. 2011, 2012). However, it is an interesting finding that parent-perceived inattentiveness, rather than hyperactive-impulsive symptoms or CPT results, was most strongly associated with differences between subjective perception and objective measurements, which suggests a specific role of parent-perceived inattentive symptoms on the placebo effect.

Comparisons between nonresponders according to both objective and subjective measurements and responders according to both measurements revealed that greater omission errors and response time variability were most strongly associated with genuine treatment response. Previous studies have reported strong associations between higher baseline symptom severity and superior treatment outcomes (Newcorn et al. 2010; Buitelaar et al. 2011). Neuropsychological deficits, rather than parent-rated symptoms, can reflect baseline disease severity better; therefore, these deficits are more likely to be predictive of genuine treatment response (superior outcomes on both subjective and objective measurements). Again, inattention measured by omission errors was associated with treatment response, but impulsivity measured by commission errors was not. Response time variability, which is interpreted as a measurement of variability or consistency of attention, has been proposed as a leading endophenotype for ADHD (Castellanos and Tannock 2002), and its utility for assessing stimulant response has been previously reported (Lee et al. 2009).

Consistent with previous studies that reported associations of younger age and higher MPH doses with treatment response (mostly measured by investigators) (Buitelaar et al. 1995; Spencer et al. 1995; Faraone et al. 2004; Biederman et al. 2006; Medori et al. 2008), we found younger ages and higher MPH doses in objective responders compared with objective nonresponders, but we did not find these differences between subjective responders and subjective nonresponders. In addition, age and dosage of MPH were not predictive of treatment response when subjective and objective disease severity was taken into account.

We must interpret the present study's results in the context of the following limitations. First, because of the post-hoc nature of the analysis, some important predictive variables might have been missed, as they were not evaluated in the present study (such as motivational measurements of children and the personality traits of their parents). Second, because this study was a non-comparative, open-label trial, a genuine placebo effect could not be evaluated, although the differences between subjective perceptions and objective measurements might have been related to the placebo effect. Third, we did not use the investigator- or teacher-rated ARS to measure treatment response. Finally, the sample size of this study was small, which might have prevented us from obtaining sufficient statistical power to detect significant group differences; therefore, the results should be interpreted carefully.

Conclusions

The baseline severity of parent-perceived inattentive symptoms was predictive of differences in subjective and objective treatment responses, and the baseline severity of neuropsychological deficits (inattention and inconsistency of attention) was predictive of response according to both subjective and objective measurements.

Clinical Significance

The results of this study suggest that children with ADHD with severe inattentive symptoms are more likely to achieve parental-perceived benefits and that those with greater omission errors and response time variability are more likely to achieve both parental-perceived benefits and neuropsychological improvement after MPH treatment.

Disclosures

Drs. Bung-Nyun Kim, Jae-Won Kim, Min-Sup Shin, Soo-Churl Cho, and Doug-Hyun Han were investigators in this clinical study. All authors have no conflicts of interests or financial ties to disclosure. However, data have been analyzed and the article was written by the primary authors, and funding did not limit the authors' abilities.

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