Long-term effects of stimulants on neurocognitive performance of Taiwanese children with attention-deficit/hyperactivity disorder

Attention deficit hyperactivity (ADHD), one of the most common behavioral and neurocognitive disorders [1], is characterized by persistent over activity, inattention and impulsivity. The American Psychiatric Association (APA, 1994) diagnostic guideline [Diagnostic and Statistical Manual, version IV (DSM-IV)] classified ADHD into three subtypes: (a) inattentive, (b) hyperactive–impulsive and (c) combined. According to the DSM-IV, text version (DSM-IV-TR) diagnostic guidelines, the prevalence of ADHD is estimated at 3–7% in school-age children [2, 3]. Due to the nature of the populations sampled, diagnostic criteria used, cultural differences, and methodological limitations, the prevalence of ADHD in various cultures varies. The prevalence is estimated to be about 8.4–11.7% in Taiwan [4]; 2.4% in Australia [5]; and 4% in Japan [6]. The negative outcomes of ADHD include peer rejection, low self-esteem, academic underachievement, and learning disabilities [7, 8]. Cognitive function impairment as in executive dysfunction and a lower intellectual coefficient were also found in ADHD children. Although the concept of executive function is broad and variable, overall it is used in reference to the higher brain process involved in planning problem-solving and can be screened using the Wechsler Intelligence Scale (WISC) [9]. From the intellectual coefficient perspective, a meta-analytic review by Frazier et al. reported that the ADHD groups performed at an average of 9.15 points lower than the control group in their Full Scale Intelligence Quotient (FSIQ), assuming a theoretical standard deviation of 15 [10].

Methylphenidate (MPH), a kind of central nervous system (CNS) stimulant, is the most frequently prescribed medication for ADHD, and its clinical efficacy is well established [11]. The effects of MPH on attention result from a combination of noradrenergic and dopaminergic mechanisms [12], which are assumed to ameliorate the two principal problems of attention deficiency and impulsivity/hyperactivity in children with ADHD. Moreover, scholars hypothesized that treating ADHD symptoms via stimulant drugs not only decreased the negative impact of ADHD, but possibly also benefited the neurocognitive performances of children with ADHD [13]. A previous meta-analysis by Kavale et al. found that stimulant treatment for an average period of 18 weeks led to a mean gain of about 6 to 7 points in FSIQ, and 6 points in both the Verbal Intelligence Quotient (VIQ) and Performance Intelligence Quotient (PIQ) [14]. Another meta-analysis by Thurber and Walker [15] also demonstrated that short-term stimulant drug effects could result in a mean increase of 2.25 points in the FSIQ. Recent studies that focus on intellectual outcomes after a long-term treatment period have shown that long-term stimulant treatment for at least one year could increase the Intelligence Quotient (IQ) score in children with ADHD, and that more improvement in IQ scores was found in the group of those who could maintain a longer treatment duration [16, 17]. That is, the intellectual performance of children with ADHD may be improved with long-term CNS stimulant treatment, as well as short-term stimulant treatment, but a bigger gain with long-term treatment is suspected. In addition to the decreased severity of core symptoms, avoidance of negative consequences and improved neurocognitive performances of children with ADHD, MPH has been shown to counteract the detrimental effects of earlier-origin developmental insults [18] and has age-dependent effects on prefrontal neurons [19, 20]. So it is also suspected that starting drug treatment at an earlier age may have more benefits.

In Taiwan, a high prevalence rate of ADHD was noticed about ten years ago [4], but there is still little research comparing neurocognitive function between children with ADHD and healthy children. And even though the positive effect of CNS stimulants in ADHD treatment has been reported in many studies, there are still few studies examining the long-term effect of CNS stimulants on neurocognitive function and in different age groups. Therefore, in this study, we have several objectives as below: 1) to better understand the neurocognitive performance of ADHD children in Taiwan as measured by the WISC-III and to further compare the results with healthy controls; 2) to investigate the changes in rating scale and IQ and the influences on the domains of the WISC subtests after long-term MPH treatment in Taiwanese children with ADHD; 3) to explore if there is more benefit to long-term MPH treatment; and 4) to know if MPH treatment has a diverse effect on neurocognitive profiles in different age groups.

A total of 171 children with ADHD were included in our study.

In this study, children with ADHD had lower VIQ and FIQ than healthy children without ADHD. The findings in this study showed that FIQ was approximately 9 points lower in children with ADHD than in healthy children. This is compatible with the results of a previous meta-analytic review, which reported that ADHD groups performed at an average of 9.15 FIQ points lower than the control group [10]. We also found that children with ADHD performed poorly on several subtests of the WISC-III, including Similarities, Vocabulary, and Coding, compared to healthy children. The finding that children with ADHD perform poorly in Coding is consistent with several studies [27‐30]. However, there continues to be incongruence in the profile of other WISC-III subtests for children with ADHD. A previous study [9] revealed lower scores in Picture Arrangement, Block Design, and Object Assembly in ADHD groups. But their sample size of 26 control participants and 35 children with ADHD was relatively small. Since their study had limited data and various methodological differences from our study, comparing our results would result in inconsistencies.

The benefits to cognitive function after MPH treatment were noted in many studies [31‐34], but there is sparse research and incongruent results in the area of the effect of MPH on subtests of the intelligence test. For example, the ADHD children's improvement on several WISC-III subtests after drug treatment in this study was incompatible with the results of another study that found a positive effect of MPH on the verbal comprehension index [35]. Therefore, the potential influence of MPH on the performance of ADHD children on the WISC-III, except for the IQ scores, needs further research.

There are no recommendations regarding the optimal period for ADHD drug treatment. According to the results of this study, the degree of improvement in ADHD symptom severity was not significantly different relative to the patient's age on receiving MPH treatment. On the other hand, significantly better performance in some subtests and subscales of the WISC-III (such as Similarities, Comprehension, and Object Assembly) was noted in the 6–8 years age group. This suggests that it would be best to start MPH treatment for ADHD at a younger age. However, previous studies have not found that younger age groups obtained more benefits in various aspects than older age groups as a result of MPH treatment. Thus, more research is needed to corroborate this finding and to reach a conclusion.

It has been hypothesized that attention deficit in ADHD children would substantially influence IQ [13], so improving attention would secondarily improve IQ scores. However, this hypothesis was not supported by previous studies, which revealed no significant correlation between the severity of ADHD symptoms and WISC-III IQ scores [36, 37]. In addition, the hypothesis that improving attention would secondarily improve IQ scores has also been refuted. Several studies found that improvements in behavioral symptoms had no correlation with changes in cognitive parameters [35, 38, 39]. This is also consistent with our results that no association was found between improvements in ADHD symptoms and changes in the scores of the WISC-III subtests and subscales (i.e., VCI, POI, FDI, PSI, FIQ, VIQ, and PIQ). It seems that the better performance on intelligence tests after MPH treatment did not result from lessening ADHD symptoms. MPH may possibly produce a different benefit and utilize another mechanism of improving performance on the WISC-III, aside from ameliorating suboptimal test-taking behavior in ADHD children. But MPH may not actually improve construct of IQ as much as it just improves accuracy on the test due to improved attention should be kept in mind.

There are several limitations in this study. First, the sample enrolled in the study did not include all patients with ADHD, so the findings might not be applicable to the entire population of ADHD patients. Second, the sample size in the study was relatively small, particularly for the control group, and some WISC-III subtests (i.e., Symbol Search and Digit Span) were not administered to the control group. Therefore, the statistical power in this study was limited in its ability to detect the changes from pre- to post-treatment and the differences between ADHD and healthy children. Large-scale studies using integrated psychometric measurements are needed. Third, the majority of children with ADHD were male, so the influence of sex could not be ruled out. Fourth, this was not a randomized controlled trial and whether to start MPH treatment or not was based on clinical evaluation and most importantly the opinions of the parents of the ADHD children. Fifth, the interval between the 1^st and 2^nd administration of the WISC-III was not long enough to ignore the practical effect without controversy. Sixth, other treatments (i.e., cognitive behavioral therapy, parental training, attention training) associated with MPH treatment were often performed in clinical practice, but the interactions and their possible effect on the WISC-III was not followed up in this study.

Although many limitations have been noted, a number of strengths can also be found in this study. First, real-world children with ADHD were sampled and given an appropriate dose of MPH in line with clinical guidelines. Second, the 1^st and 2^nd administration of the WISC-III was given at least one year apart, thus reducing the possible practical effect to a limited degree [24, 40]. Although the sample size of ADHD children with/without MPH treatment was small in this study, the practical effect could not totally explain the improvement in the WISC-III after MPH treatment, because there were no significant changes in the ADHD children who did not receive MPH treatment after one year. Third, all participants were free from medication for at least one week before performing the WISC-III, which would reduce the direct influence of medication on improving test-taking behavior. Thus, the present study is valuable because of its strengths.

According to the findings in this study, we suggest that long-term MPH treatment may improve neurocognitive profiles, which were shown in the performance of the ADHD children on several subtests and in IQ scores of the WISC-III. And the improvement had no correlation with the decrement of ADHD symptoms and baseline ADHD severity. Starting stimulant treatment at as young an age as possible is advised due to the greater benefits seen in the 6–8 years age group. But more research using a controlled sample to replicate the findings is needed.