Introduction
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome with onset during childhood and often persists into adulthood [
1‐
3]. The core ADHD symptoms include a frequent and persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning in daily living [
4]. In adults, some studies have reported that inattention and executive dysfunction becomes more prominent while impulsivity remains problematic and hyperactivity decreases [
5,
6]. The prevalence of ADHD in adults is in the range 2%-5% worldwide [
7‐
9]. In Sweden, the number of clinical adult patients diagnosed with ADHD increased from 0.58 per 1,000 persons in 2006 to 3.54 per 1,000 persons in 2011 [
10]. In a Swedish study of outpatients in general psychiatric care, 22% were diagnosed with ADHD in adulthood [
11]. Parallelly, the number of patients in need of support and treatment increases.
The treatment of adults with ADHD should follow a multimodal and multidisciplinary approach (e.g., psychoeducation, cognitive behavior therapy, coaching for ADHD and pharmacotherapy [
5]). However, many adults request pharmacological treatment. One of the most common pharmacological treatments of ADHD in adults involves primary methylphenidate (MPH) [
12]. MPH is a psychostimulant that blocks the reuptake of norepinephrine and dopamine and improves the symptoms and impairing behaviours associated with ADHD. MPH is provided in different formulations e.g., immediate release (IR-MPH) and extended release (ER-MPH). Numerous randomized, double blind, placebo-controlled treatment studies have explored positive effects of MPH in adults with ADHD [
13‐
17]. In most of the studies, the patients were given osmotic-release oral system methylphenidate (OROS-MPH) or (ER-MPH) in doses up to 1.3 mg/kg/day [
13,
14]. However, placebo responders have been reported in the range of 39%-46%, depending on the primary outcome measures chosen and differences in duration of follow-up [
13,
15,
18].
The placebo effect is well known and a clinically important phenomenon in the patient’s treatment. Extensive research has been conducted to elucidate this [
19,
20].
Most placebo-controlled studies have reported subjective outcomes (i.e., clinical assessments and self-report scales). Although Biederman et al., [
21] have found strong correlations between clinician-assessed ADHD symptoms and patients self-reports, many patients have difficulties judging if their medical treatment has any effect [
21,
22]. Self-assessment instruments are often too non-specific, and thereby too inclusive, because many patients without ADHD may rate themselves highly on these scales [
23,
24].
One approach to improve assessment in ADHD is to supplement clinical judgement with computerized continuous performance tests (CPTs). The CPT is a neuropsychological assessment tool that provides an objective and standardized method for assessing attention and impulsivity. It eliminates subjective biases that can occur in self-report measures and provides quantifiable data. The CPT may be useful for monitoring the effects of ADHD treatment interventions.
It is often a challenge to meet the patients’ requests for drug treatment. The medical staff needs support in their assessments to evaluate the effect of the drug for each patient. In contrast to patients’ subjective self-reports, it would be useful to have an objective tool to assess the patients’ level of response in different core signs. MPH is available as immediate release (IR-MPH), which could be suitable for medical evaluation. By offering the patient IR-MPH together with a CPT, a relatively quick response is made possible. The assessment and the results from the objective measurement can make it easier to offer adequate long-term treatment for each patient. One of several CPTs is the QbTest which is developed to measure the core symptoms of ADHD and can be used when to start a pharmacological treatment with a new patient [
25]. Bijlenga et al., concluded that the QbTest is more sensitive to medication effects than the ADHD Rating Scale (ADHD-RS) [
26].
Placebo responses in earlier studies were found to increase toward the end of the treatment periods [
27,
28]. However, little is known about the immediate effects of placebo on the core symptoms of ADHD in adults. Do they already occur during the first drug trial with CPTs? Increased knowledge of the impact of the placebo response on the core symptoms may improve decisions about which treatment is most advantageous. It is therefore relevant to analyse the effects of placebo on performance in the ADHD core symptoms, hyperactivity, inattention and impulsivity.
The aim of the present study was to examine the effects of one single-dose IR-MPH compared to one single-dose placebo on performance in ADHD core symptoms during clinical assessments in adults with untreated ADHD. We assumed that IR-MPH would improve participants´ performance in the cardinal parameters QbActivity and QbInattention. Regarding placebo, we hypothesized that the placebo response would be lower compared to IR-MPH but effective in all three core symptoms. The placebo response would be higher at the beginning of the task, then decrease towards the end because adults with ADHD often have difficulty focusing for a longer period. Throughout this paper, we will use the term “placebo response” as to the outcome of a clinical trial.
Results
Demographic characteristics of the sample are shown in Table
1. Forty adults, 29 females (mean age = 33.5 years) and 11 males (mean age = 34.7 years), were included in the study. None of the participants had earlier been diagnosed or treated for any neuropsychiatric diagnoses. The participants had an average IQ score (mean = 96.8) on the WAIS and no history of substance dependence. Most adults met the criteria for combined presentation of ADHD. There were no statistically significant differences in demographics between the two groups. The adults were given one single-dose 20 mg IR-MPH (i.e., the mean IR-MPH dose was 0.26 [0.17–0.34] mg/kg) and one single-dose placebo on different trial days. There were no differences between groups or gender.
Table 1
Clinical and demographic characteristics of the participants when included in the study (n = 40)
Gender
| | | ns |
Female (n) | 15 | 14 | |
Male (n) | 5 | 6 | |
Age; [mean years (SD)] | 33.45 (8.27) | 34.20 (11.63) | ns |
Height cm; [mean (SD] | 168,1 (7.6) | 171.6 (9.7) | ns |
Weight kg; [mean (SD)] | 76.6 (13.7) | 82.2 (13.2) | ns |
Smoking cigarettes (n) | 8 | 5 | ns |
Snuff (n) | 5 | 9 | ns |
GAFa; [mean (SD)] | 66.55 (6.93) | 67.15 (7.04) | ns |
ADHD presentation | | | ns |
Hyperactive/impulsive (n) | 5 | 5 | |
Inattentive (n) | 2 | 2 | |
Combined (n) | 13 | 13 | |
ASRSb Hyperactivity; [mean (SD)] | 21.70 (7.16) | 20.40 (5.54) | ns |
ASRS Inattention; [mean (SD)] | 24.45 (6.39) | 24.25 (5.29) | ns |
ASRS Total; [mean (SD)] | 46.15 (12.49) | 44.15 (10.63) | ns |
QbTest
c [Z-mean (SD)]
|
QbHyperactivity; [mean (SD)] | 2.04 (1.27) | 1.95 (1.33) | ns |
QbInattention; [mean (SD)] | 1.77 (0.83) | 1.66 (0.81) | ns |
QbImpulsivity; [mean (SD)] | 0.96 (1.46) | 1.35 (1.73) | ns |
Efficacy measures
Efficacy results are summarized in Table
2. Our primary outcome measures were changes in the cardinal parameters QbActivity, QbInattention and QbImpulsivity on the QbTest. Compared to baseline, the participants´ performance were statistically significant improved in the cardinal parameter QbInattention, F (3, 117) = 38.25,
p < 0.001, after given IR-MPH (mean diff = 1.14, [95% CI 0.90—1.37], and after placebo (mean diff = 0.60, [95% CI 0.38—0.82)], with the effect sizes (ES) 1.17 and 0.63 respectively. A medication order effect was found. Adults in the placebo/MPH group performed statistically significant better in the cardinal parameter QbInattention on the first trial day compared to the second trial day after given placebo (mean diff = 0.49, [95% CI 0.08—0.91], F (1, 39) = 5.89,
p < 0.02). IR-MPH improved performance in the cardinal parameters QbActivity (mean diff = 0.81, [95% CI 0.49—1.13], F (2.42, 94.30) = 14.98,
p < 0.001), and QbImpulsivity (mean diff = 0.46, [95% CI 0.13—0.79], F (3, 117) = 2.79,
p < 0.04). No statistically significant differences were found between baseline and placebo in the cardinal parameters QbActivity and QbImpulsivity. There were no significant differences between females and males.
Table 2
Comparisons of delta scores on the QbTest between baseline, placebo and IR-MPH (n = 40)
Cardinal Parameters |
QbActivityc | 0.15 | 0.60 | .710 | 0.12 | 0.81 | 0.99 | .001 | 0.60 | 0.66 | 1.21 | .001 | 0.83 |
QbInattentionc | 0.60 | 0.68 | .001 | 0.63 | 1.14 | 0.73 | .001 | 1.17 | 0.54 | 0.86 | .001 | 0.77 |
QbImpulsivityc | 0.18 | 1.13 | 1.000 | 0.13 | 0.46 | 1.04 | .047 | 0.35 | 0.28 | 1.52 | .259 | 0.26 |
Activity Measures |
Time Active (%) | 3.80 | 10.67 | .182 | 0.15 | 10.05 | 17.46 | .005 | 0.38 | 6.25 | 21.29 | .071 | 0.44 |
Distance (meter) | 1.34 | 4.48 | .396 | 0.09 | 4.28 | 6.43 | .001 | 0.37 | 2.94 | 8.13 | .028 | 0.54 |
Area (cm) | 7.51 | 17.36 | .066 | 0.19 | 19.42 | 29.12 | .001 | 0.53 | 11.91 | 35.27 | .039 | 0.51 |
Attention & Impulsive measures |
Reaction Time (ms) | 50.17 | 6.87 | .001 | 0.44 | 71.10 | 55.26 | .001 | 0.72 | 20.92 | 78.19 | .098 | 0.67 |
Reaction Time Variation (ms) | 22.82 | 32.22 | .001 | 0.50 | 40.12 | 39.89 | .001 | 0.91 | 17.30 | 43.37 | .016 | 0.48 |
Normalised Variation (%) | 2.10 | 5.78 | .162 | 0.38 | 3.52 | 5.23 | .001 | 0.72 | 1.43 | 6.86 | .197 | 0.26 |
Omission Error (%) | 5.47 | 11.71 | .032 | 0.38 | 16.65 | 15.53 | .001 | 1.32 | 11.18 | 18.18 | .001 | 0.82 |
Commission Error (%) | 0.42 | 1.24 | .229 | 0.14 | 0.74 | 1.73 | .058 | 0.18 | 0.32 | 1.98 | .249 | 0.21 |
Error Rate (%) | 4.87 | 4.35 | .001 | 0.37 | 1.72 | 3.24 | .011 | 1.00 | 3.15 | 5.14 | .001 | 0.83 |
Clinically significant improvements
An improvement in performance after IR-MPH compared to baseline, and after placebo compared to baseline was considered significant if the Qb-score was decreased ≥ 0.5. A deterioration in performance was considered if the Qb-score was increased ≥ 0.5. The distribution of changes in the cardinal parameters are shown in Table
3. Adults who changed from a slightly divergent score (Qb-score ≥ 1.3) to a normal score (Qb-score ≤ 1.0), of those with a ≥ 0.5 Qb-score reduction, were considered clinically improved. The proportion of adults who were considered clinically improved in the parameters QbInattention, QbActivity and QbImpulsivity after given IR-MPH were 21/36, 20/24 and 12/21, respectively. Corresponding proportions after given placebo were 15/24, 11/12 and 7/14, respectively.
Table 3
Distribution of changes in Qb-scores for the cardinal parameters (n = 40)
Improvementb
| 36 (90.0) | 24 (60.0) | 24 (60.0) | 12 (30.0) | 21 (52.5) | 14 (35.0) |
No change | 3 (7.5) | 12 (30.0) | 13 (32.5) | 21 (52.5) | 10 (25.0) | 13 (32.5) |
Deteriorationc
| 1 (2.5) | 4 (10.0) | 3 (7.5) | 7 (17.5) | 9 (22.5) | 13 (32.5) |
The adults’ performance in the three five-minute Quartiles Q2, Q3 and Q4 during the QbTest are shown in Table
4. Both in baseline and after the adults were given placebo, the activity measures (Time Active, Distance, Area and Microevents) statistically significant increased from Q2 to Q4. After the adults were given IR-MPH, only the activity measure Area statistically significant increased between Q2 to Q4. No statistically significant differences were found between Q2, Q3 and Q4 during baseline, IR-MPH and placebo conditions for the inattention and impulsivity measures.
Table 4
Means in the five-minute Quartiles Q2, Q3 and Q4 during the QbTest (n = 40)
Activity measures
|
Time active (%) | 28.30 | 29.30 | 34.15 | Q4 > Q2,Q3 | 19.82 | 21.42 | 21.30 | ns | 22.27 | 25.07 | 27.15 | Q4 > Q2;Q3 > Q2 |
Distance (m) | 3.95 | 4.21 | 4.85 | Q4 > Q2;Q3 > Q2 | 2.85 | 3.04 | 3.19 | ns | 3.50 | 3.92 | 3.90 | Q4 > Q2;Q3 > Q2 |
Area (cm2) | 18.70 | 21.02 | 25.17 | Q4 > Q2,Q3;Q3 > Q2 | 12.22 | 13.70 | 14.82 | Q4 > Q2 | 15.70 | 17.95 | 18.80 | Q4 > Q2;Q3 > Q2 |
Microevents (mm) | 2.31 | 2.46 | 2.82 | Q4 > Q2,Q3 | 1.72 | 1.86 | 1.93 | ns | 1.96 | 2.22 | 2.27 | Q4 > Q2;Q3 > Q2 |
Attention & Impulsive measures
|
Reaction Time (ms) | 624.75 | 640.12 | 631.80 | ns | 558.07 | 547.30 | 555.37 | ns | 584.07 | 574.72 | 574.40 | ns |
Reaction Time Var (ms) | 185.60 | 191.32 | 182.67 | ns | 135.22 | 132.70 | 132.85 | ns | 147.77 | 146.65 | 147.70 | ns |
Normalized Var (%) | 29.37 | 29.60 | 28.55 | ns | 27.90 | 23.97 | 23.65 | ns | 24.90 | 25.25 | 25.57 | ns |
Omission Error (%) | 21.81 | 25.34 | 25.65 | ns | 7.34 | 8.56 | 8.47 | ns | 17.04 | 17.12 | 16.28 | ns |
Commission Error (%) | 2.74 | 2.17 | 2.36 | ns | 1.46 | 1.59 | 1.59 | ns | 1.60 | 1.37 | 1.33 | ns |
Test–retest reliability
Intra-class correlations (ICC) between the two baselines on the first and second trial day for the cardinal parameters QbActivity, QbInattention and QbImpulsivity were 0.92, 0.86 and 0.89, respectively. ICC for the activity parameters Time Active, Distance, Area and Microevents were 0.93, 0.97, 0.95 and 0.96, respectively. ICC for the attention and impulse control measures Reaction Time, Reaction Time Variation, Omission Error and Commission Error were 0.85, 0.79, 0.90 and 0.83, respectively. All correlations were statistically significant at the 0.001 level.
Discussion
The aim of the present study was to examine the effects of one single-dose IR-MPH compared to one single-dose placebo on performance in ADHD core symptoms during clinical assessment with continuous performance test. In a double-blinded crossover procedure, adults were administered IR-MPH in one session and placebo in the other in randomized order. To our knowledge this is the first study that has examined one single-dose IR-MPH compared to one single-dose placebo in clinical trials with the QbTest in adult patients.
The results of our study show significant improvements in all three core symptoms, and all included parameters except commission error, after intake of one single-dose IR-MPH. Our data are in accordance with results from an earlier study in children [
40].
We also noted significant improvements in the cardinal parameter QbInattention and the parameters Reaction Time, Reaction Time Variation and Omission Error after intake of placebo. When we analysed the two groups separately, adults in the placebo/MPH group performed significantly better in the cardinal parameter QbInattention on the first trial day, compared to the second trial day. Adults in the MPH/placebo group also improved their performance in the cardinal parameter QbInattention when given placebo, despite they were verbally informed about the presence of a placebo in one of the trial days. The difference in performance between baseline and placebo may be due to high treatment expectations. According to expectancy theory, placebo effects are mediated by explicit expectancies [
41]. These participants had as adults requested a neuropsychiatric assessment for their problems and expected pharmacological treatment. The adults may have expected relief in their symptoms, and this may have made them better to concentrate on the task. Contrary to our hypothesis, placebo showed no effect on neither QbActivity nor QbImpulsivity.
Commission error showed a low effect size in the study probably because this measure has lower sensitivity for adults with ADHD compared to children. In earlier studies, higher rates of Commission Error were found in children compared to adolescents and adults [
36,
40,
42]. Pettersson et al., found that only the cardinal parameters QbActivity and QbInattention were significant predictors of clinical diagnosis in adult ADHD [
43].
Further, we hypothesized the placebo response would be higher in the beginning and decrease at the end of the test, since adults with ADHD often have difficulties in focusing during a longer period. When we analysed changes in the adults´ performance in the five-minute Quartiles Q2, Q3 and Q4, we noted significantly increases in the activity measures during baseline from Q2 to Q4. Similar results have been reported by Lis et al. [
36]. These significantly differences between Q2 and Q4 were also found after the adults were given placebo. As expected, there were no differences found during the IR-MPH condition, due to it was an active substance. Regarding inattention and impulsivity parameters, we noted no differences between Q2 and Q4 in baseline, IR-MPH and placebo conditions during the QbTest. This may indicate that when a person has problems with inattention these are stable over time, compared to problems with activity, which are increasing over time. When we analysed the placebo responders, we found 60% of the adults improved in the cardinal parameter QbInattention (i.e., a decrease by Qb-score ≥ 0.5). However, we must consider that the test situation only lasted for twenty minutes. Further studies with a longer observation period are needed to confirm this.
Limitations and strengths
One limitation of our study is the unequal distribution of female (72.5%) and male (27.5%) participants. More than half of the patients referred for the neuropsychiatric examination were females. However, there were no differences in gender distribution between adults receiving placebo first or receiving placebo at the second session. In addition, our results showed no differences in performance between females and males during the trial days. Similar proportion in gender (78% females) was reported in a Swedish study [
44]. Findings from earlier studies indicate that ADHD is identified more frequently in boys than girls in childhood and more females are identified and become diagnosed in adulthood. However, the differences in prevalence according to gender become far less skewed with age, as well as gender differences in symptoms are limited in adults [
8,
45,
46]. Considering the size of the female distribution, hormonal mood changes in females that could have affected the patient’s performance, should have been analysed.
Despite these limitations, strengths of this study are the use of data from a clinical setting. All participants had gone through careful diagnostic procedures, based on validated clinical instruments, including cognitive testing, assigned by trained clinical professionals. Retrospective reports of childhood symptoms were also obtained from the participants´ parents or other relatives. The participants had no history of previous pharmacological treatment regarding their ADHD diagnosis. During the neuropsychiatric assessment period and when the adults were in the research project, they were monitored for alcohol and drug use and females were screened for pregnancy. Before every QbTest, nicotine, snuff and caffeine use were controlled for.
A crossover design was used, where participants were exposed to both test conditions similarly. We used two baselines, one for each day of the trial, to ensure current baseline values and accurately measure the difference between baselines and pills. The two baselines were also used to control for any learning effects, since earlier studies have reported better performance during the second administered CPT [
17,
47]. The order of stimulus in the QbTest is randomized in order to prevent practice effects [
25]. In addition, we used the baselines to control for carry over effects, although carry over effects are generally less likely in cross-over trials on IR-MPH because of its short pharmacokinetic half-life. Moreover, the test–retest reliability between the two baselines on each trial day was high and in accordance with a previous study [
48,
49].
Two studies have found better improvements in participants with most severe baseline symptoms, compared to participants with less severe symptoms [
26,
27]. We therefore used a lower cut-off (Qb = 1.3) than the recommended (i.e., Qb-score ≥ 1.5, to indicate a divergent score [
25]). The lower cut-off was chosen to avoid regression to the mean effects.
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