Clinical trial NCT04647500: Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome
Official title: Effects of Modulation of the Dopaminergic System Using Methylphenidate on Memory and Executive Processes in Individuals With 22q11.2 Deletion Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: 22q11.2 Deletion Syndrome
Lead sponsor: University of Geneva, Switzerland
Sponsor class: OTHER
First posted: 2020-12-01
Enrollment: 45
Sex: ALL
Minimum age (years): 8
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Depending on medication history and current psychostimulant medication, participants are included either in the consumer group (composed of participants with ongoing methylphenidate treatment) or in the naïve group (composed of participants naïve to the molecule)
Primary purpose: OTHER

Brief summary: Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition associated with a high risk of psychiatric disorders, including schizophrenia spectrum disorders. This population is characterized by a specific neurocognitive profile and atypical brain development. Methylphenidate is a psychostimulant used in the treatment of attention deficit with/without hyperactivity (ADHD). Although ADHD is one of the most important co-morbidities in 22q11DS, affecting 35-45% of patients, to date only two studies have focused on quantifying the efficacy of this treatment in this population. The objective of this study is to quantify the improvement in cognitive performance as well as the differences in brain connectivity associated with the methylphenidate molecule in a population at risk of cognitive impairment and the development of schizophrenia.

Detailed description: This study aimed to investigate the effects of methylphenidate (Concerta ®) in patients with 22q11DS. Outcome is evaluated based on changes in clinical and cognitive measures as well as brain connectivity (with magnetic resonance imaging and electroencephalography). Treatment benefits are evaluated in an intra-subject design, i.e. performance with/without treatment are compared for each patient. Depending on medication history and current psychostimulant medication, participants are included either in the consumer group (composed of participants with ongoing methylphenidate treatment) or in the naïve group (composed of participants naïve to the molecule). To the naive participants the investigators prescribe a 13-day treatment of Concerta ® at a weight-adjusted dose of 0.7 mg/kg). The treatment phase begins with a lower introductory dose for the first 5 days before moving on to the weight-adjusted dose. The effect of treatment on cognitive measures is assessed on day 6, with memory monitoring on days 7 and 13. The treatment effect evaluated using clinical measures and questionnaires was conducted at the end of the treatment phase to ensure multiple opportunities for observation by the participant and caregivers. For consumer participants, the procedure was similar. For visits with methylphenidate, participants will be asked to take their usual prescription. In order to best follow the procedure of the naïve group, for the visits without methylphenidate, the consumer participants were asked to interrupt their usual prescription for 13 days. Since many participants usually interrupt their treatment during vacations or sometimes on weekends, compliance is not a barrier. For methylphenidate-free visits, a 5-day break prior to assessment with cognitive measures will be requested from each participant. Again, in order to ensure several opportunities for observation for the participant and caregivers, assessments with clinical measures and questionnaires will be conducted at the end of the break, on day 13.

The research hypothesis of this study is that methylphenidate treatment has a beneficial effect on clinical and cognitive performance. Scores in the tests evaluating these areas are expected to be significantly better than when the tests were administered in the absence of the substance. A change in brain connectivity is also expected when the drug is taken, tending towards a "normalization" of brain connectivity. Finally, to find the link between changes in cognitive measures and changes in brain connectivity is investigated.

Eligibility criteria: Inclusion Criteria:

* Male or female with confirmed 22q11DS diagnosis.
* Minimum age of 8 years or maximum age of 25 years and 11 months.
* Attention difficulties pointed out by parents and/or the participant.
* Sufficient verbal expression and comprehension skills to understand and follow instructions based on initial interview.

Exclusion Criteria:

* Participants younger than 8 years and older that 25 years and 11 months.
* Previous adverse experience with MPH
* Cardio-vascular diseases including rhythm disorders, severe hypertension, cardiac insufficiency, obliterating cardiac and peripheral arterial disease, preexisting cerebrovascular affections, hemodynamically significant congenital heart defect, channelopathies.
* For the naïve group only: corrected QT (QTc) distance at baseline electrocardiogram above 460 milliseconds or elongation at control electrocardiogram (Day 6 of treatment) superior to 30 milliseconds with functional complaint.
* Psychiatric affections including anxiety attack, psychic tension or restlessness, manic episode, marked psychotic symptoms, schizophrenia, borderline personality disorder, clinical depression (present or past), suicidal episode, diagnosis or family history of Tourette syndrome, alcohol or drug abuse.
* Other somatic affections including hyperthyroid, glaucoma, pheochromocytoma.
* Concurrent treatment with monoamine oxidase inhibitors or interruption less than 14 days before beginning of treatment.
* Pregnancy or breastfeeding.

Primary outcomes:
measure: Conners' Continuous performance test, third edition (CPT-3)
timeFrame: CPT-3 pre-treatment
measure: Conners' Continuous performance test, third edition (CPT-3)
timeFrame: CPT-3 6 days of treatment
measure: Conners' Continuous performance test, third edition (CPT-3)
timeFrame: CPT-3 one month after the end of treatment
measure: Stroop task
timeFrame: Stroop inhibition ratio pre-treatment
measure: Stroop task
timeFrame: Stroop inhibition ratio 6 days of treatment
measure: Stroop task
timeFrame: Stroop inhibition ratio one month after the end of treatment
measure: Letter-number sequencing
timeFrame: Letter-number Sequencing pre-treatment
measure: Letter-number sequencing
timeFrame: Letter-number Sequencing 6 days of treatment
measure: Letter-number sequencing
timeFrame: Letter-number Sequencing one month after the end of treatment
measure: Color Trails test (CTT)
timeFrame: CTT flexibility ratio pre-treatment
measure: Color Trails test (CTT)
timeFrame: CTT flexibility ratio 6 days of treatment
measure: Color Trails test (CTT)
timeFrame: CTT flexibility ratio one month after the end of treatment
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB)
timeFrame: CANTAB pre-treatment
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB)
timeFrame: CANTAB 6 days of treatment
measure: Cambridge Neuropsychological Test Automated Battery (CANTAB)
timeFrame: CANTAB one month after the end of treatment
measure: 15 signes & 15 words
timeFrame: 15 signes & 15 words pre-treatment
measure: 15 signes & 15 words
timeFrame: 15 signes & 15 words 6 days of treatment
measure: 15 signes & 15 words
timeFrame: 15 signes & 15 words one month after the end of treatment
measure: ADHD symptoms
timeFrame: ADHD symptoms pre-treatment
measure: ADHD symptoms
timeFrame: ADHD symptoms 13 days of treatment
measure: ADHD symptoms
timeFrame: ADHD symptoms one month after the end of treatment
Secondary outcomes:
measure: Magnetic Resonance Imaging (MRI) T1-weighted
timeFrame: MRI T1-weighted pre-treatment
measure: Magnetic Resonance Imaging (MRI) T1-weighted
timeFrame: MRI T1-weighted 6 days of treatment
measure: Magnetic Resonance Imaging (MRI) T1-weighted
timeFrame: MRI T1-weighted one month after the end of treatment
measure: MRI Spectroscopy
timeFrame: MRI Spectroscopy pre-treatment
measure: MRI Spectroscopy
timeFrame: MRI Spectroscopy 6 days of treatment
measure: MRI Spectroscopy
timeFrame: MRI Spectroscopy one month after the end of treatment
measure: MRI Resting State
timeFrame: MRI resting state pre-treatment
measure: MRI Resting State
timeFrame: MRI resting state 6 days of treatment
measure: MRI Resting State
timeFrame: MRI resting state one month after the end of treatment
measure: MRI Diffusion weighted images
timeFrame: MRI DSI pre-treatment
measure: MRI Diffusion weighted images
timeFrame: MRI DSI 6 days of treatment
measure: MRI Diffusion weighted images
timeFrame: MRI DSI one month after the end of treatment
measure: Electroencephalography (EEG) resting state
timeFrame: EEG resting state pre-treatment
measure: Electroencephalography (EEG) resting state
timeFrame: EEG resting state 6 days of treatment
measure: Electroencephalography (EEG) resting state
timeFrame: EEG resting state one month after the end of treatment
measure: EEG auditory
timeFrame: EEG Auditory pre-treatment
measure: EEG auditory
timeFrame: EEG Auditory 6 days of treatment
measure: EEG auditory
timeFrame: EEG Auditory one month after the end of treatment
measure: EEG visual
timeFrame: EEG Visual pre-treatment
measure: EEG visual
timeFrame: EEG Visual 6 days of treatment
measure: EEG visual
timeFrame: EEG Visual one month after the end of treatment
measure: Behavior Rating Inventory of Executive Function (BRIEF) questionnaire
timeFrame: BRIEF pre-treatment
measure: Behavior Rating Inventory of Executive Function (BRIEF) questionnaire
timeFrame: BRIEF 13 days of treatment
measure: Behavior Rating Inventory of Executive Function (BRIEF) questionnaire
timeFrame: BRIEF one month after the end of treatment
Other outcomes:
measure: Sensory-motor conflict 1
timeFrame: Synchrony condition pre-treatment
measure: Sensory-motor conflict 1
timeFrame: Synchrony condition 6 days of treatment
measure: Sensory-motor conflict 1
timeFrame: Synchrony condition one month after the end of treatment
measure: Sensory-motor conflict 2
timeFrame: Asynchrony condition pre-treatment
measure: Sensory-motor conflict 2
timeFrame: Asynchrony condition 6 days of treatment
measure: Sensory-motor conflict 2
timeFrame: Asynchrony condition one month after the end of treatment
Locations:
city: Geneva
country: Switzerland
facility: Developmental imaging and psychopathology lab
Study officials:
affiliation: University of Geneva, faculty of medicine
name: Stephan Eliez, Professor
role: PRINCIPAL_INVESTIGATOR
References: