Genetic Modulation of Working Memory in Attention Deficit Hyperactivity Disorder (ADHD)

Study Overview
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Brief Summary
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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.

Official Title
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Genetic Modulation of Functional Brain Activity of Attention-deficit/Hyperactivity Disorder-related Working Memory Processes

Conditions
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ADHD

Intervention / Treatment
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* Drug: Methylphenidate, non-retard


Participation Criteria
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Eligibility Criteria
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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, vasoligature 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, hyperthyreoidism, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: methylphenidate, non-retard<br> | Drug: Methylphenidate, non-retard<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain activation | Functional brain activity during the working memory task as measured by fMRI. For each participant and conditions the estimated parameters are metric, and can be further analysed with ANOVAs or t-tests. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychology | Correct answers and reaction time for the working memory paradigm Stroop task | 6 weeks | 
| ADHD core symptoms: measured by ADHS Self Rating Scale (ASRS) score |  | 6 weeks | 
| ADHD core symptoms: measured by Conners Adult ADHD Rating Scales (CAARS) |  | 6 weeks | 
| ADHD core symptoms: measured by Clinical Global Impressions (CGI) Scale of ADHD Severity |  | 6 weeks | 
| ADHD criteria measured by the Wender-Reimherr Interview (WRI) |  | 6 weeks |