Study I consisted of 63 participants, 31 men and 32 women, with a mean age of 35.16 years (SD = 11.90). Participants had a diagnosis of ADHD at mean age 34.31 (SD = 11.58) according to the Diagnostic and Statistical Manual of Mental Disorders IV [3]. Behavior ratings of Study I are presented in Table 1. There were no significant differences (ps < 0.05) between men and women with regard to age or any of the behavior rating scales for ADHD.

Table 7.

Flow Chart of Study II

Laboratory assessments of ADHD symptoms before and after clinical treatment with single doses of either short-acting or modified-release formulations of MPH was conducted. Levels of sensitivity and specificity for Prediction of ADHD (PADHD) were investigated using frequency distributions before (no, yes) and after (no, yes) treatment. Fisher´s exact test was employed to analyze treatment (baseline, follow-up) and PADHD (no, yes). A mixed design with analyses of variances was used with dependent variables of Hyperactivity, Inattention, Impulsivity and the Weighed Core Symptom scale (WCS). The independent variables were Treatment (before, after) and Gender (men, women).

Qb-Test-Plus. This instrument [19-21] combines an XX-type Continuous Performance Test (CPT) installed as a software program on a PC and an activity test during 20 minutes. While performing the CPT on the computer, movements of the participants are recorded using an infrared Motion Tracking System (MTS) following a reflective marker attached to a head-band. The CPT involves rapid presentation of stimuli involving color (blue, red) and shape (circle, square) on the screen and participants are instructed to press a hand-held button when stimuli repeats itself (a target) and not to press the button when stimuli varies relative to the previous one (a non-target). The stimuli are presented at a pace of one per two seconds, each one visible for 200 milliseconds, and the total number of stimuli is 600, presented with a 25 % target probability. The purpose of Qb-Test-Plus is to provide objective information regarding cardinal symptoms of ADHD; hyperactivity on basis of motor-activity measured with the camera, and inattention and impulsivity on basis of the CPT-test [19]. Operationalization of variables was done according to a previous study [17]. Hyperactivity was operationalized with the parameter called "distance", i.e., the length (meter) of the path travelled by the headband reflector during the test. Inattention was operationalized as omission errors and impulsivity was operationalized as commission errors.

Weighed Core Symptoms scale (WCS). This scale summarizes the total level of ADHD core symptoms in adults on a scale with ten cut-points ranging from 0 to 100 [17] where 0 indicate maximal amount of and 100 indicate complete absence of ADHD symptoms. The scale is based upon raw scores from the summed and operationalized measures from the Qb-Test-Plus in which the results of hyperactivity have been multiplied with three, inattention with two and impulsivity with one. The ten cut-points of WCS were developed through a procedure previously described [17]. In the present study, WCS correlated (Pearsons’ r) with baseline measures of hyperactivity (r = 0.80, p < 0.001), inattention (r = 0.62, p < 0.001), but not with impulsivity (p > 0.05).

Prediction of ADHD (PADHD). This categorical predictor variable [17] regarding ADHD (No/Yes) is based on ADHD behavioral measures from the Qb-Test-Plus (Q-scores), i.e., hyperactivity measured in distance, inattention measured with omission errors and impulsivity measured with commission errors. PADHD was developed using qualitative analyses and assessment trials in which the level of sensitivity and specificity was evaluated. The variable generates 86 % sensitivity and 83 % specificity when predicting ADHD versus normative participants from the adult general population, and the probability of PADHD making a correct classification regarding ADHD was 83 and 85 % respectively [17, 18].

The Adult Self Report Scale for Adult ADHD v1.1 (ASRS). This screening instrument [22] is derived from the criterions of ADHD in DSM-IV. Part A is the screener and includes the 6 most predictive items while part B holds an additional 12 items, all rated on a five-point scale. The maximum total score for the scale is 72 and 24 for the screener. A value of nine or more on the screener indicates ADHD with high probability [22].

Wender Utah Rating Scale (WURS). This scale [23, 24] retrospectively measures the severance of ADHD symptoms in childhood on a 5 point scale (0= not at all/only a little, 1= to some extent, 2= a lot, 3= severely, 4= completely). Adult subjects rate 61 items related to relevant areas, and 25 of the questions are especially sensitive to ADHD [23]. A cut- off of 46 on the 25-item screener (maximum score of 100) is indicative of ADHD.

Wender Reimherr ADHD Symptoms Scale for Patients (WRASS 1). WRASS [23] estimates symptoms of ADHD from the adult patients point of view on a 5-point scale (0= not at all/only a little, 1= to some extent, 2= a lot, 3= severely, 4= completely). The scale covers areas of attention, hyperactivity, instability of mood, organizational difficulties, sensitivity to stress and impulsivity and is commonly used in Swedish psychiatry with a clinical cut-off of 69, maximum score is 140.

Conners Adult ADHD Rating Scale- Short version (CAARSS). This official self-report short-version scale [25] measures 26 items related to four areas of adult ADHD: Inattention, Hyperactivity/restlessness, Impulsivity/emotional lability and problems with self-concept on a four-point scale (0 = never, 1 = sometimes, 2 = often, 3 = very often) and the maximum score is 78.

The current study belongs to a series of investigations performed by the present authors and approved in 2008 by the Regional Ethical Review Board in Uppsala, Sweden (Dnr: 2008/110/2). ADHD-assessments had previously been carried out at the Clinic of neuropsychiatry and CBT, Cereb (n = 51), the psychiatric clinic of the County Council in Varmland (n = 11) or the NU-health-care psychiatric clinic, all Swedish (n = 1). Neuropsychiatric assessments were carried out with similar neuropsychological procedures and included for example retrospective and current medical anamnesis, first- and second part behavior ratings and structured interviews, and psychological tests of memory and attention. In most cases (n = 51), assessments included also the unstandardized report of Qb-Test-Plus. Inclusion criterions were 18 to 65 years of age, diagnosis of ADHD according to DSM-IV [3], described chronic course of ADHD symptoms in childhood with some symptoms present before age seven and continue to meet DSM-IV criteria at the time of assessment.

Testing was standardized and performed individually. Participants became seated in front of the PC using a chair without armrests in order to ensure a non-reclining body-position. Instructions were given both verbally and with a standardized video [19]. Participants performed a one minutes pre-test to ensure the instructions had been understood correctly. Participants performed the Qb-Test-Plus for 20 minutes in a room with minimal sensory stimuli. Measures were performed at the same day at 103.16 minutes (SD = 55.36) from oral intake of MPH (n = 51), or some days (M = 13.75, SD = 21.55, range = 1 to 60 days) after baseline at 193.43 minutes (SD = 122.51) from oral intake of MPH (n = 12). Participants were ordinated a short-acting formulation of 10 mg (n = 35) or 20 mg (n = 18) of MPH, or a modified-release formulation of 18 mg of MPH (n = 9) from doctors. One participant was ordinated 54 mg of a modified-release formulation and hence the mean average dosage for the entire sample (N = 63) was 13.69 mg (SD = 6.97, range = 10 to 54). Subjects were informed that enrollment was voluntary and that dropping-out would not interfere with medical treatment or other health-care. The informed consent was signed before any study-related procedures. Participation was associated with travel reimbursement.

Sensitivity and specificity for Prediction of ADHD was investigated using frequency tables for baseline and treatment conditions. Results are presented in Table 2. Fisher´s Exact Test (5 % level) indicated most participants in the yes-ADHD condition before treatment and in the no-ADHD condition after treatment (p < 0.001).

A mixed Pillai’s MANOVA (2 x 2 factorial design) was conducted with Treatment (before, after) and Gender (men, women) as independent variables, and Hyperactivity, Inattention and Impulsivity as dependent variables. The analysis revealed significant effects for Treatment (p < 0.001, Eta² = 0.74, power > 0.99), and Gender (p = 0.038, Eta² = 0.132, power = 0.68), but not for the interaction Group x Gender (p = 0.357, Eta² = 0.053, power = 0.28).

Core Symptoms. Univariate F-tests revealed significant effects with regard to Treatment for Hyperactivity [F (1, 61) = 115.44, p < 0.001], Inattention [F (1, 61) = 97.19, p < 0.001], and Impulsivity [F (1, 61) = 25.82, p < 0.001] where the before treatment condition generated lower scores on all variables (indicating higher symptom levels) as compared to the after treatment condition. With regard to Gender, univariate F-tests revealed a significant effect only for Inattention, [F (1, 61) = 8.00, p = 0.006] but not for Hyperactivity or Impulsivity (ps > 0.05). Further analyses showed that women had lower scores on Inattention, indicating higher symptom levels, as compared to men. Means and standard deviations are presented in Table 3.

WCS. Since the Weighed Core Symptom scale is a composite measure it was analyzed separately with a mixed ANOVA. The analyses showed significant effects for Treatment [F (1, 61) = 101.782, p < 0.001], Gender [F (1, 61) = 13.16, p < 0.001] and for the interaction Treatment x Gender [F (1, 61) = 5.80, p < 0.05]. Descriptive analyses showed that the baseline condition was associated with lower scores (indicating higher symptom levels) than the treatment condition, and that men in the treatment condition had higher scores (indicating lower symptom levels) than women in the treatment condition. Regarding the interaction effect, descriptive analyses showed that men gained more improvement from treatment than women. Means and standard deviations are presented in Table 3.

A total of 30 participants were assessed for eligibility but 20 of them dropped-out, see Table 7. Thus, Study II consisted of 10 participants, 4 men and 6 women, with an ADHD diagnosis according to DSM-IV [3] and whose first MPH- dose was to be initiated and titrated. Behavioral data are presented in Table 6. Participants were outpatients previously diagnosed with ADHD at the psychiatric clinic in the county council of Varmland (n = 8) or in the NU-health care psychiatric clinic (n = 2). Neuropsychiatric assessments included psychiatric and medical anamnesis, first- and second part behavior ratings and structured interviews, and psychological tests of memory and attention. In four cases, additional tests of cognitive functioning, intelligence, memory and attention were also included. Inclusion criterias were 18 to 65 years of age, diagnosis of ADHD according to DSM-IV, described chronic course of ADHD symptoms in childhood with some symptoms present before age seven and continue to meet DSM-IV criteria at the time of assessment.

Pre- and post titration analyses with PADHD (no/yes ADHD) included levels of sensitivity and specificity. Dependent variables were objective measures of Hyperactivity, Inattention, Impulsivity and WCS. Measures were collected at baseline, for each dose level (18/27, 36, 54, 72) and for the optimal dose level follow-up at three months. Wilcoxon signed rank test (5 % level) was used to analyze titration effect upon dependent variables and behavior ratings.

All instruments are presented in the instruments section of Study I.

General study procedures are described in Paper I. Titration time total was individual with one to four weeks interval between each increment of the dose level. Modified-release MPH were ordinated starting at 18 and 27 mg respectively. Study measures were obtained at minimum one to maximum seven days from each increment of the dose level and the psychometric testing generally occurred at 103.16 minutes (SD = 55.36) from oral intake. The treatment follow-up was standardized to twelve weeks after the initiation of each patients optimal dose level. Titration was entirely governed by doctors and patients, both blinded from the study measures. Subjects were informed that enrollment was voluntary and that dropping out of the study would not interfere with medical treatment or other health-care. Drop-outs (N = 20) are not analyzed in this pilot study, see Table 7.

Sensitivity and specificity for ADHD at pre- and post titration are in Table 4.

The Wilcoxon signed rank test (5 % level) was employed to assess pre- and post titration conditions with regard to WCS and core symptom measures. WCS was significantly different between the two conditions (Z = 2.82, p = 0.005). Hyperactivity was not significantly different (p = 0.059). However the result could be regarded as a non-significant trend since a Paired-Samples t-test (5 % level) yielded a significant effect t (9) = -2.34, p = 0.044. Inattention was significantly different (Z = 2.70, p = 0.007) and finally, Impulsivity differed between the two conditions (Z = 2.20, p = 0.028). For means and standard deviations see Table 5.

The Wilcoxon signed rank test (5 % level) was employed to assess WCS and core symptom measures during titration. Baseline versus the 18/27 mg condition yielded significant differences for WCS (Z = 2.25, p = 0.024) but not for Hyperactivity, Inattention or Impulsivity (ps > 0.05). The 18/27 versus 36 mg comparison yielded significant differences for WCS (Z = 2.06, p = 0.039) but not for Hyperactivity, Inattention or Impulsivity (ps > 0.05). Comparing the 36 vs. 54 mg and the 54 vs. 72 mg yielded no significant differences for any of the measures (ps > 0.05). For means and standard deviations see Table 5.

A Wilcoxon signed rank test (5 % level) was employed to assess baseline and follow-up conditions with regard to Wender Adult ADHD Rating Scale (WRASS), the ASRS self-rating scale (ASRSS) and the Conner’s Adult ADHD Self Rating Scale Short Version (CARSS). Means and standard deviations are presented in Table 6. WRASS was significantly different between the two conditions (Z = -2.31, p = 0.021) and descriptive statistics showed that the baseline condition had a significantly higher mean score than the follow-up condition. The ASRS self-ratings were significantly different (Z = -2.67, p = 0.008) and higher at baseline than during follow-up. CAARSS also differed between the two conditions (Z = -2.67, p = 0.008) and were higher during baseline than follow-up. It should be noted that higher scores indicates higher levels of ADHD symptoms for all measures whereas higher values of WCS indicates lower levels of ADHD symptoms.