ADHD
Conditions
Brief summary
In this study the investigators will measure the functional brain activity of adult Attention Deficit Hyperactivity Disorder (ADHD) patients, genotyped according to the COMT genotype, during a Working Memory Paradigm, before and after a placebo controlled treatment with MPH for 6 WEEKS. Within this design, the investigators will be able to evaluate the therapeutic effect of MPH treatment on cognitive functions.
Interventions
DRUGMethylphenidate, non-retard
Medication (methylphenidate, non-retard) will be titrated to optimal response within 6 weeks, with a maximum of 10 mg/day in week 1, 20 mg/day in week 2, 30 mg/day in week 3, 40 mg/day in week 4, 50 mg/day in week 5, and 60 mg/day in week 6, unless adverse effects emerged. After successful adjustment, medication will be maintained until week 6. Dosing will be based on at least two-weekly evaluations by a psychiatrist, including an interview with a review of symptoms and side effects, completion of the Clinical Global Impression (CGI) scale and completion of a standardised Side Effects Rating Scale for psychostimulants (SERS). The maximal daily dosage of MPH is 60 mg. Within this double blind study the same procedure is applied for the placebo condition.
DRUGPlacebo
Sponsors
German Research Foundation
Wuerzburg University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Only participants will be included who (1) fulfil the diagnostic criteria defined in guidelines for the diagnosis of ADHD in childhood and adulthood and who (2) would be treated with MPH also for clinical indications outside the study. * Provision of written informed consent * A diagnosis of a ADHD (314.xx) by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV) * Females and males aged 18-50 years * Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at enrolment * Able to understand and comply with the requirements of the study * Right-handed according Edinburgh Handedness Inventory (Oldfield, 1971) * German as first language * Caucasian ethnicity
Exclusion criteria
* Pregnancy or lactation; women capable of childbearing are required to use a reliable method (Pearl-index \< 1%) of contraception (e.g. hormonal treatment, intrauterine device, vasoligation in the partner, sexual abstinent) * Any current DSM-IV Axis I disorder not defined in the inclusion criteria requiring current additional treatment * Motoric tics, siblings with tics or positive family history or diagnosis of a Tourette syndrome * Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others * Known intolerance or lack of response to methylphenidate, as judged by the investigator * Present pre-treatment with methylphenidate (within the last three month prior to study treatment) * Intake of MAO-inhibitors within the last 14 days prior to study treatment * Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment * Unstable or inadequately treated medical illness (e.g. Congestive Heart Failure / CHF, angina pectoris, hypertension, narrow angle glaucoma, hyperthyroidism, thyreotoxicosis, cardiac arrhythmia, cardiac infarction) as judged by the investigator. * Epilepsy * An absolute neutrophil count (ANC) of minor 1.5 x 10 exp 9 per litre * Involvement in the planning and conduct of the study * Previous enrolment or randomisation of treatment in the present study * Participation in another drug trial within 4 weeks prior to enrolment into this study * Moderate, severe, or profound mental retardation * Heart pacemakers, cochlea implants, other metal parts in the head outside the mouth
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Activation | 6 weeks | Functional brain activity in right Superior Frontal Gyrus (SFG) during the working memory task post treatment as measured by fMRI. For each participant and conditions the estimated parameters are metric, and can be further analysed with ANOVAs or t-tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychology | 6 weeks | Accuracy for the working memory paradigm at post. Accuracy was defined as the ratio of correct responses (correctly pressed and correctly not pressed) to total number of stimuli. Higher values indicate better perfromance.The theoretical range goes from 0 to 1. |
| ADHD Core Symptoms: Measured by Conners Adult ADHD Rating Scales (CAARS), Inattention Scale | 6 weeks | Changes in CAARS scale ( T-values, 50 indicates the population mean with a standard deviation of 10) from pre to post. Higher T values indicate higher symptoms. T-score over 60 indicates clinically relevant ADHS symptoms More negative values of the difference indicate higher symptom reduction, therefore a better outcome. Range of T-values for pre and post measurements between 35 and 90, potential range for differences -55 to +55 |
Countries
Germany
Participant flow
Recruitment details
Study Start: May 2011 Primary Completion: December 2012 Study Completion: March 2013 Wuerzburg University Hospital
Participants by arm
| Arm | Count |
|---|---|
| Methylphenidate, Non-retard Methylphenidate, non-retard: Medication (methylphenidate, non-retard) will be titrated to optimal response within 6 weeks, with a maximum of 10 mg/day in week 1, 20 mg/day in week 2, 30 mg/day in week 3, 40 mg/day in week 4, 50 mg/day in week 5, and 60 mg/day in week 6, unless adverse effects emerged. After successful adjustment, medication will be maintained until week 6. Dosing will be based on at least two-weekly evaluations by a psychiatrist, including an interview with a review of symptoms and side effects, completion of the Clinical Global Impression (CGI) scale and completion of a standardised Side Effects Rating Scale for psychostimulants (SERS). The maximal daily dosage of MPH is 60 mg. Within this double blind study the same procedure is applied for the placebo condition. | 19 |
| Control: Placebo For placebo treatment the same procedure was applied like in the verum condition | 16 |
| Total | 35 |
Baseline characteristics
| Characteristic | Control: Placebo | Total | Methylphenidate, Non-retard |
|---|---|---|---|
| Age, Continuous | 35.3 years STANDARD_DEVIATION 10.2 | 36.3 years STANDARD_DEVIATION 9.9 | 37.2 years STANDARD_DEVIATION 9.7 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Germany | 16 participants | 35 participants | 19 participants |
| Sex: Female, Male Female | 7 Participants | 16 Participants | 9 Participants |
| Sex: Female, Male Male | 9 Participants | 19 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 16 |
| other Total, other adverse events | 18 / 19 | 10 / 16 |
| serious Total, serious adverse events | 1 / 19 | 0 / 16 |
Outcome results
Primary
Brain Activation
Functional brain activity in right Superior Frontal Gyrus (SFG) during the working memory task post treatment as measured by fMRI. For each participant and conditions the estimated parameters are metric, and can be further analysed with ANOVAs or t-tests.
Time frame: 6 weeks
Population: lost of data due to fmri specific issues
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate, Non-retard | Brain Activation | 0.19 Beta weights of contrast | Standard Error 0.09 |
| Control: Placebo | Brain Activation | -0.08 Beta weights of contrast | Standard Error 0.08 |
p-value: =0.09SPM two-sample t-test
Secondary
ADHD Core Symptoms: Measured by Conners Adult ADHD Rating Scales (CAARS), Inattention Scale
Changes in CAARS scale ( T-values, 50 indicates the population mean with a standard deviation of 10) from pre to post. Higher T values indicate higher symptoms. T-score over 60 indicates clinically relevant ADHS symptoms More negative values of the difference indicate higher symptom reduction, therefore a better outcome. Range of T-values for pre and post measurements between 35 and 90, potential range for differences -55 to +55
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate, Non-retard | ADHD Core Symptoms: Measured by Conners Adult ADHD Rating Scales (CAARS), Inattention Scale | -18.9 T-score | Standard Error 3.76 |
| Control: Placebo | ADHD Core Symptoms: Measured by Conners Adult ADHD Rating Scales (CAARS), Inattention Scale | -12 T-score | Standard Error 4.44 |
p-value: =0.09t-test, 1 sided
Secondary
Neuropsychology
Accuracy for the working memory paradigm at post. Accuracy was defined as the ratio of correct responses (correctly pressed and correctly not pressed) to total number of stimuli. Higher values indicate better perfromance.The theoretical range goes from 0 to 1.
Time frame: 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylphenidate, Non-retard | Neuropsychology | 0.97 accuracy index | Standard Deviation 0.03 |
| Control: Placebo | Neuropsychology | 0.98 accuracy index | Standard Deviation 0.01 |
p-value: =0.16t-test, 1 sided