To report on the long-term effect modification by age of MPH treatment on brain structure and function, and clinical outcome, as measured by MRI scans, neuropsychological assessment, actigraphy and questionnaires, and to compare these results with…
ID
Source
Brief title
Condition
- Structural brain disorders
- Cognitive and attention disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- phMRI: % change in ASL signal from baseline in response to acute oral MPH
challenge.
- Medication history (obtained from pharmacies of participants with ADHD that
provided written consent).
- Clinical outcome: change in ADHD symptom severity and global clinical
impression.
Secondary outcome
- Structural MRI: % change for several grey and white matter variables,
including cortical thickness, and white matter microstructure (DTI).
- Functional MRI: % change in task-related and resting-state BOLD signal.
- Neuropsychological functioning: change in outcome of several well-validated
neuropsychological (computer) tasks addressing attention, memory, simple
reaction time and executive function.
- Clinical outcome parameters: emotional dysregulation, anxiety and depressive
symptomatology
- Sleep log and actigraphy: % change from baseline.
Background summary
Methylphenidate (MPH) is primarily used as treatment for attention deficit
hyperactivity disorder (ADHD), effectively reducing symptoms of inattention,
hyperactivity, and impulsivity in up to 70% of children. MPH blocks the
dopamine (DA) and norepinephrine (NE) transporters (DAT/NET), thus increasing
extracellular DA and NE in the brain. Its efficacy and safety have been
documented in many studies. However, there is still a gap of knowledge
concerning the influence of 4-month MPH treatment on brain development and its
effect on brain structure and function. Indeed, evidence is accumulating that
the long term effects of psychotropic drugs are age-dependent and differ
markedly between young and adult animals, due to neurochemical imprinting
effects in the developing brain. To investigate the effects of MPH on the
developing human brain and dopamine system, we initiated a unique randomized
controlled trial (RCT) with MPH (ePOD; NTR3103) in 2011. We found at short-term
(trial end), among other things, that in children, but not adults nor placebo
condition, MPH increased DA-reactivity, cortical thickness and white matter
integrity, as well as sleep efficiency. The aim of the proposed study is to
investigate the longitudinal changes in brain structure and function in ADHD
patients compared to controls, in order to assess long-term brain development
and the influence of medication on the course of this development.
Study objective
To report on the long-term effect modification by age of MPH treatment on brain
structure and function, and clinical outcome, as measured by MRI scans,
neuropsychological assessment, actigraphy and questionnaires, and to compare
these results with healthy controls in light of potential normalization of
brain development.
Study design
Naturalistic 8-9 year follow-up study of the ePOD-MPH RCT (NL34509.000.10).
Study burden and risks
Subjects will spend 6 hours during the study visit, during which MRI scans will
be obtained and a neuropsychological assessment will be conducted. Moreover,
participants will be asked to wear and actiwatch and fill in a sleep log for
five days prior to the study visit.
On the day before the study visit all participants will have to adhere to some
simple restrictions regarding medication, alcohol and drug intake, as this may
affect the outcome parameters. On the day of the study visit participants will
have to refrain from smoking and stimulant containing drinks. ADHD patients
currently using medication will have to stop for at least 1 week, in order to
prevent confounding with our study parameters. There are no risks associated
with a medication free period 1 week before the assessment for the ADHD
patients.
In the week before the MRI scan, subjects will be asked to wear an actigraph
for five days and fill in a sleep-diary. During the study visit, subjects will
undergo neuropsychological assessment and will be asked to fill in
questionnaires addressing sleep, substance (ab)use including smoking and
drinking coffee and other possible confounding parameters. Subsequently, they
will undergo the first MRI scan of a maximum of 50 minutes and then will
receive an oral challenge with MPH, which is needed for the phMRI and
resting-state fMRI measurements. Ninety minutes after receiving the oral
challenge, subjects undergo a second MRI scan lasting a maximum of 50 minutes.
MRI is a safe method with no long-term side effects. The dose of the MPH
challenge may cause an increase in heart rate and systolic blood pressure, but
has no significant side effects.
Though the participants of this study will have no direct benefits from
participating, the results contribute to the understanding of the long-term
safety of MPH in young children and adolescents, as more information about the
effects of MPH on the maturing brain will be available. The overall nature and
extent of the added risk associated with participation in the current study is
to be classified as negligible and the burden can be considered minimal.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
ADHD patients:
- patients who participated in the ePOD-MPH RCT 8-9 years prior
(NL34509.000.10), OR
- Male outpatients diagnosed with ADHD (all subtypes) as defined in the
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV,
American Psychiatric Association 1994) and as determined by a structured
interview.
Control subjects:
- aged 19-20 years or 30-50 years
- male
Exclusion criteria
All participants:
-Contra-indications to MRI (metal implants, pacemakers, claustrophobia, etc.).
-Contraindications to MPH challenge: cardiovascular diseases such as
hypertension, arrhythmia, hyperthyroidism, glaucoma, suicidality, psychosis,
Tourette disorder.
Newly included ADHD participants and control subjects:
-IQ < 80 National Adult Reading Test (NART; Nelson 1991, Dutch translation
Schmand et al. 1991)
-(History of) major neurological or medical illness (including epilepsy,
traumatic brain injury and chronic severe tics or Tourette syndrome).
-(History of) treatment with medications that influence the DA system (for ADHD
participants: not including psychostimulants for ADHD treatment ) such as:
neuroleptics, antipsychotics, D2/D3 agonists (pramipexole and ropinirole)
-(History of ) neuropsychiatric disorder other than ADHD (including ADHD for
controls) requiring pharmacological treatment
-(History of) dependency of alcohol or drugs that influence the DA such as:
MDMA, amphetamine, methamphetamine, cocaine, heroin and LSD
-First-degree relative with (history of) schizophrenia or major depression
-Prenatal use of MPH by mother of the patients.
Control subjects only:
-A score >4 on the ADHD Rating Scale (ADHD-RS)(Kooij et al. 2008).
-Prior treatment with MPH or other stimulants for ADHD
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL76068.018.20 |