Effects of Atomoxetine and Osmotic Release Oral System-Methylphenidate on Executive Functions in Patients with Combined Type Attention-Deficit/Hyperactivity Disorder

Abstract

Objective:

The aim of this study was to evaluate and compare the effects of atomoxetine (ATX) and osmotic release oral system-methylphenidate (OROS-MPH) therapies on executive functions, activities, treatment response time, and adverse effects based on discernible clinical effects in children with combined type attention-deficit/hyperactivity disorder (ADHD).

Methods:

The study sample consisted of 43 children 7–12 years of age, who presented to the outpatient clinic with inattention, hyperactivity, and impulsivity for the first time, and were diagnosed as having combined type ADHD according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria but had not previously used any medication for ADHD. The Wisconsin Card Sorting Test (WCST), Stroop Test TBAG Form (STP), and Visual Auditory Digit Span B (VADS B) were applied to all the patients included. Neuropsychological tests were repeated in 33 patients with good clinical recovery based on the Clinical Global Impressions-Improvement (CGI-I) scale (CGI-I ≤2) at the week in which clinical recovery was observed. The time limit for treatment response was set as 20 weeks.

Results:

It was found that there was significantly increased performance in executive functions with ATX and OROS-MPH in both groups. It was seen that although significantly increased performance was achieved in both perseveration and conceptual learning and reasoning domains by both agents, there was increased performance in more domains by the OROS-MPH group in WSCT. Mean doses were 1.31±0.37 mg/kg/day in the ATX group and 0.90±0.29 mg/kg/day in the OROS-MPH group. Comparable effectiveness (76.19% for ATX vs. 77.27% for OROS-MPH) and adverse effects (57.14% for ATX vs. 54.54% for OROS-MPH) were detected in both groups, whereas there was a significant difference in clinical response times between the groups (13 weeks for ATX vs. 7 weeks for OROS-MPH, p <0.001).

Conclusions:

At the end of the study, it was seen that clinical recovery achieved by ATX and OROS-MPH therapy was associated with improved cognitive processes, and that these agents do not only lead to behavioral changes but also to an improvement in cognitive processes. In addition, improvements in cognitive processes occurred simultaneously with behavioral recovery. Behavior is the result of neurocognitive processes, and further studies on the domains that these drugs affect, or the way in which these agents exert their effects, are needed.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a syndrome characterized by inattention, distractibility, hyperactivity, impulsivity, and impaired executive functions. ADHD, the most common neurobehavioral disorder in school-age children, negatively affects normal development as well as academic and social functionality (Spetie and Arnold 2007). It has been reported that ADHD incidence is 3–5% in school-age children, and that ADHD symptoms persist into adulthood in 30–50% of children with ADHD (Biederman et al. 1996; Polanczyk et al. 2007).

The deficits seen in executive functions are an important part of understanding ADHD (Barkley and Murphy 2006). Neurocognitive studies in patients with ADHD have shown that there are impairments in executive functions, reflecting prefrontal cortex functionality. Therefore, it has been proposed that there may be a variation in the neuroanatomy of the prefrontal cortex in ADHD (Pennington and Ozonoff 1996; Barkley 1997; Seidman et al. 2004). In neuropsychological tests on children with ADHD, it was reported that there was impairment in functions such as alertness, withdrawal of motor response, planning, organization, learning, and recalling verbal information, which are known as executive functions (Seidman et al. 2005). Some studies linked impaired executive functions with attention deficit whereas others linked them to underlying weak inhibitory control (Barkley 1997; Chhabildas et al. 2001).

Stimulants and a nonstimulant agent, atomoxetine (ATX), are preferred in the treatment of ADHD. Although the mechanism of action of osmotic release oral system-methylphenidate (OROS-MPH), a psychostimulant, has not been fully elucidated, it is thought that OROS-MPH exerts its effects by inhibiting dopamine reuptake at the prefrontal cortex and striatum, thus elevating dopamine level in the presynaptic area (Kimko et al. 1999). OROS-MPH is a long-acting, slow-release MPH, which has a pharmacokinetic profile providing controlled MPH release by using osmotic pressure (Swanson et al. 2002). ATX is a selective inhibitor of the presynaptic norepinephrine transporter at the prefrontal cortex. It also has affinity to serotonin and dopamine transporters (Unni 2006). ATX exerts its effects by increasing dopamine and noradrenalin levels through the inhibition of presynaptic norepinephrine transporters, particularly those at the prefrontal cortex (Zhou 2004).

In previous studies, it was seen that drug therapy could eradicate clinical symptoms, but similar effects could not be achieved regarding mental processes. Today, the resolution of clinical symptoms alone is not considered sufficient; it is also considered necessary to enhance the patient's functionality and to optimize quality of life (Karakas 2011). In the literature, there are studies indicating that MPH and ATX have positive effects on executive functions (Riccio et al. 2001; Konrad et al. 2004, 2005; Adler et al. 2014); however, comparative studies are limited (Yildiz et al. 2011; Yang et al. 2012). In addition, the time criterion was taken into account in these studies, in which the tests were repeated after the completion of the planned time period.

In this study, the functional capabilities of the patients who clinically responded well to therapy were assessed simultaneously with clinical responses that may appear at different time periods, and the patients who responded to therapy in the treatment groups were compared by excluding patients with insufficient clinical response.

Methods

Patient selection

This is an open-label, prospective, and randomized study. The study sample consisted of 43 children 7–12 years of age who presented to the outpatient clinic with inattention, hyperactivity, and impulsivity for the first time, and were diagnosed as having combined type ADHD according to Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, but had not previously used any medication for ADHD (American Psychiatric Association 1994).

In all patients, combined type ADHD diagnosis was made by a child psychiatrist according to DSM-IV criteria, through a Kiddie-Schedule for Affective Disorders and Schizophrenia for School Age Children (K-SADS) interview with the patient and mother. In addition, the Clinical Global Impressions-Severity Scale (CGI-S) was applied to determine ADHD severity, and patients with a CGI-S score ≥4 were included in the study. In the patients included, evaluations for secondary factors (anemia, thyroid diseases) that can cause ADHD-like symptoms were performed to exclude the presence of such conditions.

Exclusion criteria were presence of actual psychological, neurological, or psychiatric diseases other than ADHD, ADHD types other than combined type, medication that influences cognitive processes or history of such medication use, and Wechsler Intelligence Scale for Children-Revised (WISC-R) scores <80 or >120.

Protocol

The Wisconsin Card Sorting Test (WCST), Stroop test, and Visual Auditory Digit Span B (VADS B) test were applied to all patients after diagnoses and evaluations. Tests were completed in a total of 30–50 minutes with 20 minute intervals between tests. These tests were applied in a quiet, well-illuminated room by a psychologist blinded to patients and the agents used under standard policies.

After baseline tests, the patients were randomly assigned to two groups to receive ATX (n=21) or OROS-MPH (n=22). In the ATX group, the drug was initiated at a dose of 0.5 mg/kg/day, which was then gradually increased at 2 week intervals, and it was attempted to titrate the dose to 1.2 mg/kg/day. In the OROS-MPH group, the drug was initiated at the lowest commercially available dose, which was then increased at 1 month intervals, and it was attempted to titrate the dose to 1 mg/kg/day using daily doses of 36–54 mg. In general, the time to reach optimum dosage was ∼4–6 weeks.

Throughout the study period, face-to-face interviews with patients and parents were performed every 2 weeks in order to achieve treatment sustainability. A recovery score decreasing to 2 or 1 according to the Clinical Global Impressions-Improvement scale (CGI-I) was set as the time for repetition of tests. The time limit was planned as 20 weeks, and patients who did not respond within this period were considered to be unresponsive patients. The tests were repeated at any time of day in the ATX group, whereas they were repeated within the first 60–180 minutes after ingestion of the drug in the OROS-MPH group.

Several adverse effects (nausea, loss of appetite, abdominal pain, somnolence, headache, fatigue, palpitation, dyspnea) were observed in 12 of 21 patients receiving ATX. The drug was withdrawn in two patients because of adverse effects (headache, abdominal pain, fatigue). Three patients were excluded because they achieved a CGI-I score ≥3 at the end of 20 weeks; therefore, overall, 16 patients completed the posttreatment tests.

Several adverse effects (loss of appetite, abdominal pain, irritability, tingle, headache, nausea, insomnia and tics) were observed in 12 of 22 patients receiving OROS-MPH. The drug was withdrawn in three patients because of adverse effects (irritability, abdominal pain, loss of appetite). Two patients were excluded because they achieved a CGI-I score ≥3 at the end of 20 weeks; therefore, overall, 17 patients completed the posttreatment tests. Therefore, the study was completed with 33 patients.

The patients in both treatment groups were receiving drug therapy for the first time, and they attended without interruption. The dose and duration of drug therapy for each patient were different. Therefore, the time for repetition of tests varied for each patient. The standard value accepted for test repetition was behavioral change. The mean treatment response time was 13 weeks for ATX, whereas it was 7 weeks for OROS-MPH.

All patients and parents gave written informed consent before participation. This study was approved by the Institutional Ethics Committee. The study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice guidelines. The study was registered to clinicaltrials.gov with registration number NCT02352051.

Data collection

Turkish version of the K-SADS Present and Lifetime Version (K-SADS-PL)

This scale was developed by Kaufman (Kaufman et al. 1997). Turkish validation and reliability studies were performed by Gökler (Gökler et al. 2004). It allows the screening of psychiatric diagnoses in a wide spectrum. Patients diagnosed with any psychiatric disorder other than ADHD were excluded. Individual interviews with children and one of their parents were made to complete the scale.

WISC-R

This is a general intelligence test for children and adolescents 6–16 years of age, which was developed by Wechsler (Wechsler 1974). Its validation and reliability for Turkish children have been proven by Savaşır and Şahin (Savaşır and Şahin 1995). In the present study, verbal, performance, and total intelligence quotients were included in the analysis.

WCST

The original test was developed by Berg (Berg 1948). This test was standardized for the Turkish population by Karakaş (Karakaş 2004). It is a test relying on accurately matching response cards to four stimulant cards with different colors, shapes, and numbers of symbols on the card. The subjects attempt to match the cards by themselves, and the rule for matching alters continuously during the test. WCST measures cognitive processes such as administrative control, characterization, perseveration, executive function, conceptualization, abstract thinking, and reasoning, and it is mainly linked to the frontal lobe (dorsolateral prefrontal cortex).

Stroop Test TBAG Form

This was developed by Stroop (Stroop 1935) and standardized for Turkish children by Kılıç et al. (Kılıç et al. 2002). The Stroop test is closely related to the frontal lobe and many other cerebral regions. It provides information about several cognitive processes such as selective attention, response inhibition, interference control, and input processing speed.

VADS B

VADS B is the modified form of the Visual Auditory Span test developed by Koppitz (Koppitz 1977). VADS B is a neuropsychological test that measures short-term memory, sequencing, and sensorimotor integration. The test includes the repetition of a set of numbers with an increasing number of figures; thus, it measures limited capacity in short-term memory. In the subtests of VADS B, the sets are presented visually or in an auditory manner, whereas responses are collected in a written or oral manner. Therefore, the test can assess the ability of sensorimotor integration with varying combinations (auditory-oral, auditory-written, visual-oral, visual-written) in either an inter-sense or in-sense manner.

CGI-S, CGI-I

These two tests (Guy 1976) include a seven point Likert scale, which is commonly and readily used. CGI-S assesses disease severity whereas CGI-I assesses level of recovery.

Statistical analysis

Data were analyzed by using IBM SPSS Statistics 22 software. In numeric values, normal distribution was assessed by using the Shapiro–Wilk test. The χ² exact test was used to compare categorical variables between groups. Our data were highly skewed; therefore, assumptions could not provide for multivariate analysis of variance (MANOVA) and multivariate analysis of covariance (MANCOVA). Then, we analyzed repeated comparisons by using the Wilcoxon test. P <0.05 was considered to be statistically significant.

Results

Ten of 43 patients failed to complete the study for various reasons (adverse effects, unresponsiveness to treatment). Overall, 33 patients (16 patients from the ATX group and 17 patients from the OROS-MPH group) completed the study.

Sociodemographic characteristics

Sociodemographic characteristics such as parental educational level and income were comparable among the patients included. Table 1summarizes patient characteristics including age, gender, hand preference, ADHD severity, and recovery scales.

Table 1.

Clinical Findings in Children with ADHD

	OROS-MPH group n:22	ATX group n:21
Mean age (±SD)	9.59±1.53	9.48±1.47
Gender (female/male)	5/17	6/15
CGI-S (mean±SD)	4.95±0.72	5±0.77
CGI-I (mean±SD)	1.76±0.43	2±00
Hand preference (Left/Right)	2/20	4/17
Response time (mean±SD)	7.35±2.64	13.25±2.35
Dosages mg/kg/day(mean±SD)	0.90±0.29	1.31±0.37

ADHD, attention-deficit/hyperactivity disorder; OROS-MPH, osmotic release oral system-methylphenidate; ATX, atomoxetine; CGI-S,CGI-I; Clinical Global Impressions Severity and Improvement scales.

Effectiveness, time, and adverse effects

Response rate was found to be 76.19% (16/21) in the ATX group, whereas it was 77.27% (17/22) in the OROS-MPH group. According to the CGI-I scale, time to good clinical response (CGI-I ≤2) was 13 weeks for ATX, whereas it was 7 weeks for OROS-MPH (p <0.01) (Table 1). Adverse effects were observed in 57.14% of the patients in the ATX group, whereas they were observed in 54.54% of the patients in the OROS-MPH group. The most common adverse effects were nausea, loss of appetite, and abdominal pain in the ATX group whereas loss of appetite, abdominal pain, and irritability were the most common adverse effects in the OROS-MPH group.

Pretreatment comparison of groups

When the treatment groups were compared regarding pretreatment tests, the only significant difference was detected in the time score of the Stroop test Part 3 (p=0.034). No significant difference was detected in the other scores of the Stroop test, WCST, and VADS B tests between groups (p >0.05).

WCST

Table 2 presents the comparison of the pretreatment and posttreatment WCST scores. It was seen that there was a significant improvement in seven subscores, including number of total errors, number of categories completed, total number of perseverative responses, number of total perseverative errors, percentage of perseverative errors, number of conceptual level responses, and percentage of conceptual level responses in the ATX group. A significant improvement was seen in 10 subscores, including the total number of trials administered, the number of total correct responses, and total number of nonperseverative errors, in the OROS-MPH group, in addition to the abovementioned subscores (Table 2).

Table 2.

WCST Scale Scores at End-Point Versus Baseline for Each Group

	OROS-MPH group n: 17			Atomoxetine group: n: 16
	Baseline	End-point	p value	Baseline	End-point	p value
Total number of responses	128(128-128)	109(94.50-128)	0.013	128(128-128)	127.50(89-128)	0.069
Total number of errors	64(50-77.50)	32(22-46.50)	0.001	63(44.75-75.00)	46(21-59.50)	0.002
Total number of corrects	64(50.50-75.50)	75(72-87)	0.003	65(53.00-71.50)	72.50(65.25-77)	0.112
Number of categories achieved	4(2-4.50)	6(4-6)	0.003	2.50(2-4.75)	5(3.25-6)	0.002
Total perseverative responses	35(27-47)	16(10.50-27)	0.001	34.50(23.50-48.50)	22.50(10.25-33)	0.008
Total perseverative errors	32(22.50-45.50)	15(10-25)	0.001	32(22-40.25)	21.50(10-30.50)	0.007
Total nonperseverative errors	29(20.50-33)	15(10-20)	<0.001	22(16-37.75)	17.50(8.50-28)	0.056
Percentage of perseverative errors	25(17.73-35.54)	13.28(9.67-19.53)	0.001	25(17.18-31.44)	18.33(10.79-23.82)	0.010
Number of responses to complete first category	11(11-18.50)	11(10-19)	0.972	12(11-18)	12(11-19)	0.917
Conceptual level responses	49(36-64.50)	70(64.50-78.50)	0.002	45(32.75-62.50)	62(54-68.75)	0.021
Percentage of conceptual level responses	38.28(28.12-51.55)	68.42(53.90-74.09)	0.001	35.15(25.57-53.51)	54.13(43.18-72.56)	0.002
Failure to maintain set	1(0-2)	1(0-2.50)	0.114	1(0-2.75)	0.5(0-1)	0.085

Wilcoxon signed ranks test; all values are median 25–75th percentiles.

Significant between-group difference p <0.05; statistically significant results are boldface.

WCST, Wisconsin Card Sorting Test; OROS-MPH, osmotic release oral system-methylphenidate.

Stroop

Table 3 presents the comparison of the Stroop scores. A significant improvement was noted in interference control (Part 5) in both groups. In addition, the ATX group had shortened time scores in all parts of the test. In the OROS-MPH group, there was decrease in correction scores in two parts other than part 5, whereas there was a decrease in the time score in one part (Table 3).

Table 3.

Stroop Test Scale Scores at End-Point Versus Baseline for Each Group

	OROS-MPH group n: 17			Atomoxetine group n: 16
	Baseline	End-point	p value	Baseline	End-point	p value
Time (sec)
Section 1	10(9-12.50)	10(9-11)	0.148	11(9.25-13.75)	10(8-11.75)	0.003
Section 2	10(9-12.50)	11(9-14.50)	0.657	12(9.25-15)	11(9-12)	0.017
Section 3	17(14-20.50)	17(14-20)	0.161	20.50(19-27)	17.50(14.25-20.75)	0.001
Section 4	29(24-37)	23(17-29)	0.001	36(29.75-41.25)	24.50(21.25-33.25)	0.001
Error
Section 1	0(0-0)	0(0-0)	0.180	0(0-0)	0(0-0)	0.317
Section 2	0(0-0)	0(0-0)	0.109	0(0-0)	0(0-0)	0.655
Section 3	0(0-0)	0(0-0)	0.705	0(0-0)	0(0-0)	0.480
Section 4	0(0-0)	0(0-0)	0.317	0(0-0)	0(0-0)	0.705
Correction
Section 1	0(0-0)	0(0-0)	0.655	0(0-0)	0(0-0)	0.180
Section 2	0(0-0)	0(0-0)	0.705	0(0-0.75)	0(0-0)	0.059
Section 3	1(0-2)	0(0-1)	0.007	0(0-2)	0.50(0-1)	0.617
Section 4	2(0.50-4)	1(0-2)	0.006	1(0-4)	0(0-1)	0.047
Section 5 (interference control )
Time	44(35-60)	34(23.50-50)	0.001	48.50(35-69.50)	42(30.25-49.75)	0.026
Error	1(0-4.50)	0(0-0.50)	0.058	0.50(0-2.75)	0(0-1)	0.016
Correction	5(3-7.50)	1(0-3)	0.002	3(1.25-6)	1.50(0.25-3)	0.038

Wilcoxon signed ranks test; all values are median 25–75th percentiles.

Significant between-group difference p<0.05; statistically significant results are boldface.

OROS-MPH, osmotic release oral system-methylphenidate.

VADS B

In the VADS B test, there was an improvement in seven score types, including total score, basic scores of visual-oral and auditory-written, as well as composite scores such as auditory stimulation, visual stimulation, verbal expression, and sensory-motor integration in the OROS-MPH group. In the ATX group, there was an improvement in nine score types including the total score, basic scores of auditory-oral and visual-oral, and all composite scores (Table 4).

Table 4.

VADS-B Scale Scores at End-Point Versus Baseline for Each Group

	OROS-MPH group n: 17			Atomoxetine group n: 16
	Baseline	End-point	p value	Baseline	End-point	p value
Basis scores
Auditory oral	5(4-6)	5(4.50-6)	0.107	4(4-5)	6(5-6)	0.003
Visual oral	5(5-6)	6(6-6.50)	0.002	5(5-6)	6(5-6)	0.012
Auditory written	5(4-5)	5(4-5)	0.046	5(4-5)	5(4.25-5)	0.157
Visual written	6(5-6)	6(5-6)	0.782	5.50(4-6.75)	6(5-6)	0.088
Compound scores
Auditory stimulation	9(8-11)	10(9-11)	0.020	9(8-10.75)	10.50(9.25-11)	0.002
Visual stimulation	11(10-12)	12(11-13)	0.035	10.50(9-12)	11.50(11-12.75)	0.015
Oral expression	11(9-11.50)	12(10.50-12)	0.006	9(9-10.75)	11.50(10.25-12)	0.001
Written expression	10(9-12)	11(9-12)	0.249	10(8.25-12)	10(10-11)	0.034
Intrasensory integration	10(9-12)	11(10-12)	0.307	10(9-11)	11.50(11-12)	0.002
Intersensory integration	10(8.50-11.50)	11(10-12)	0.002	10(9-10.75)	10.50(10-11)	0.003
Total score	21(18-23)	21(20-24)	0.014	19.50(17.25-22.50)	22(21-23)	0.001

Wilcoxon signed ranks test; all values are median 25–75th percentiles.

Significant between-group difference p<0.05; statistically significant results are boldface.

VADS-B, Visual Auditory Digit Span B; OROS-MPH, osmotic release oral system-methylphenidate.

Discussion

Although there are comparative studies regarding the treatment effectiveness of ATX and psychostimulant agents, comparative data are limited regarding executive functions. In the present study, we aimed to evaluate and compare the effects on executive functions, activity, treatment response time, and adverse effects of ATX and OROS-MPH therapy, the most commonly used agents in ADHD, based on discernible clinical effects.

In this study, although no selection was made regarding gender in the study sample, a relatively well-defined, uniform study sample, including children with a comparable symptom profile, could be achieved by selecting patients with combined type ADHD and those with CGI-S score <4. In addition, the lack of a significant difference in all three tests other than a subscore (Stroop Part 3 time score) when the test results of the two groups were compared before treatment, showed that the groups were homogenous and comparable.

Although treatment response time was different for each patient, it was 13 weeks for ATX and 7 weeks for methylphenidate. In the present study, optimum dose titration time was ∼4–6 weeks. When effectiveness of therapy was considered, 16 (76.19%) of 21 patients in the ATX group and 17 (77.27%) of 22 patients in the OROS-MPH group responded to therapy, and no significant difference was detected between the two groups regarding efficiency. In a double-blinded, placebo-controlled study by Newcorn et al. (2008), it was found that the response rates to OROS-MPH (56%) and ATX (45%) were significantly higher than those to a placebo, whereas the response rate of OROS-MPH was also higher than that of ATX (Newcorn et al. 2008). As in our study, in a comparative study in 228 children and adolescents by Kratochvil et al., it was found that the mean baseline ADHD Rating Score (ADHD-RS)-IV scores were 39.3 in the ATX group and 37.6 in the MPH group, whereas they were 20.0 and 19.8 at the end of week 10, respectively. However, no significant difference was detected in ADHD RS-IV scores among the groups (Kratochvil et al. 2002). In our study, it is thought that the higher response rate and similar levels of effectiveness could be attributed to prolonged follow-up period (20 weeks), exclusion of patients with comorbid diseases, inclusion of patients with combined type ADHD alone and patients with high clinical severity of ADHD (CGI S ≥4).

When clinical response time was considered, it was found that OROS-MPH had a shorter response time compared with ATX (p <0.001). It was seen that OROS-MPH had apparent superiority regarding response time; however, there was sustainability throughout the day in terms of recovery in executive functions with ATX, whereas it is difficult to suggest such sustainability with OROS-MPH.

Both agents were well-tolerated by patients without withdrawal symptoms, although adverse effects were observed in 57.14% of the patients in the ATX group and in 54.54% of the patients in the OROS-MPH group. The drug withdrawal rates were found to be similar between groups (9.52% for ATX vs. 13.63% for OROS-MPH). These rates were in agreement with the drug withdrawal rates reported in a comparative study by Kratochvil et al. (2002). The most common adverse effects were found to be nausea and loss of appetite in the ATX group, whereas loss of appetite was the most common adverse effect in the OROS-MPH group. These results are in agreement with those reported in studies on ATX and MPH (Michelson et al. 2002; Weiss et al. 2005).

Executive function, described as maintaining an appropriate problem solving set, is among the measurable neurocognitive abilities. Measurement of executive functions can be performed in various domains including set shifting and maintenance, planning, contextual memory, inhibition, integration across place and time, fluency, and working memory (Pennington and Ozonoff 1996). WCST is considered to be the gold standard for measurement of executive functions (Royall et al. 2002). The test measures conceptualization and abstract reasoning, working memory, set shifting, attention, and perseverative tendency. Perseveration measured by the WCST is associated with continually giving the same answer, despite knowing that it is wrong (Karakaş and Dinçer 2011). Perseverative error is one of the most important markers of neuropsychological deficits in ADHD (Nigg 2005). In a review of studies using the WCST in children with ADHD, it was reported that ADHD groups achieved lower scores than controls in 17 of 26 studies (Sergeant et al. 2002). In general, the first 8 WCST scores measure preservative tendency, whereas scores 3, 10, and 12 measure conceptual learning and abstract reasoning (Karakaş and Dinçer 2011). In a study comparing the effects of OROS-MPH and ATX by using the WCST, it was reported that there was recovery in two domains in the ATX group and in three domains in the OROS-MPH group in the tests 12 subscores, and that OROS-MPH therapy was superior in perseverative errors (Yildiz et al. 2011). In our study, significantly increased performance was detected in 10 subscores in the OROS-MPH group, whereas it was detected in only 7 subscores in the ATX group. This indicates that OROS-MPH is superior for both perseveration and conceptual learning and abstract reasoning. In our study, increased performance in more domains could be because only patients with clinical response were included in the study.

The Stroop test measures selective attention, focused attention, and attention control/response to interference by various subtests (MacLeod 1991). In addition, it has been reported that the Stroop test is the gold standard for measuring attention (Karakaş and Dinçer 2011). In many studies using the Stroop test, it was found that it is a sensitive test for ADHD, and those children with ADHD exhibit low performance on this test (Barkley 1997). The interference score in this test has been used in ADHD studies (Van Mourik et al. 2005). In one of two studies comparing OROS-MPH and ATX in children with ADHD by using the Stroop test, it was suggested that OROS-MPH was superior in interference control, whereas it was suggested that both agents had similar effects on interference control in the other study (Yildiz et al. 2011; Yang et al. 2012). In our study, significant improvement was recorded in interference control in both groups. This finding showed that the attention control performances of the patients in both groups were significantly increased against distractors. Another interesting issue was that no error was encountered in any domain other than interference in patients with ADHD. Therefore, one could not suggest a disorder in the error domain in patients with ADHD. The difference in this test should be interpreted as shortening of test completion times without error. From this perspective, it was seen that the ATX group had markedly shorter test completion times and has achieved better results than the OROS-MPH group.

In children with ADHD, difficulties in selective attention and maintaining attention result in short-term memory disorder. VADS B is a neuropsychological tool used in measuring short-term memory, sequencing, sensorimotor integration, attention and concentration. In ADHD, inattention during recognition and perception of peripheral stimulants also impairs the transfer of stimulant into short-term memory.

In this study, a significant performance increase was achieved with treatment in short-term memory, attention, and concentration as measured by VADS B in both treatment groups; however, ATX was associated with performance increase in more domains. No improvement was observed in in-sense integration, or in the auditory, oral, and written domains with OROS-MPH therapy, whereas performance increase was observed in the ATX group.

Limitations

In our study, limitations include small sample size, inability to estimate effects on duration of learning because of lack of control or placebo groups, lack of blinding procedure for clinicians, and use of CGI scale alone as clinical indicator. In addition, having a study sample consisting of patients with combined type ADHD, and exclusion of comorbid conditions, also limited generalization of our study.

Conclusions

In conclusion, our study showed that functionality is recovered simultaneously with behavior in both treatment groups. Because behavior is result of the neurocognitive processes, there is a need for double-blinded, placebo-controlled studies with a larger sample size to investigate the relationship between behavior and functionality.

Clinical Significance

This study is important because it investigates OROS-MPH and ATX treatments regarding the association between clinical response and functional capability of the brain in ADHD. The distinctive feature of this study is the fact that it addresses the association between behavioral change and functionality, and allows comparison of these two agents in many aspects.

Footnotes

Acknowledgment

We thank Ferhan Elmali for help with the statistical analysis.

Disclosures

No competing financial interests exist.

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