Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI

NCT02148783 | Terminated Phase 2

• 2 other identifiers: 402693-1HJF grant
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate (Ritalin®). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure tonic DA release provides valuable insight into the molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well as practical information regarding likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off methylphenidate.

Conditions

Traumatic Brain Injury

Keywords

Traumatic brain injury; Attention deficit and memory problems; Methylphenidate; Dopamine receptor imaging; Motivation and reward; Positron emission tomography; Transcranial magnetic stimulation

Outcome Measures

Primary Outcomes (1)

• Relationship between tonic dopamine release (measured by displacement of [11C]-raclopride by oral methylphenidate) and change in processing speed between baseline and after methylphenidate treatment.

  Processing speed will be assessed as a composite score of the following measures: 1. Conners Continuous Performance Test (3rd Edition) 2. SeaShore Rhythm Test 3. Flanker Inhibitory Control and Attention Test 4. Pattern Comparison Processing Speed Test

  Four weeks of treatment with methylphenidate.

Secondary Outcomes (5)

• Relationship between D2/D3 receptor availability in ventral striatum and prefrontal cortex and neuropsychologic deficits.

  Baseline visit

• Relationship between tonic dopamine release in the ventral striatum and prefrontal cortex with neuropsychologic deficits after TBI.

  Baseline visit

• Relationship between D2/D3 receptor availability and functional connectivity of the prefrontal cortex with nodes of the default mode network.

  Baseline visit

• Relationship between TMS-induced short-interval cortical inhibition of M1 and tonic dopamine release.

  Baseline visit

• Test motivation and reward on and off methylphenidate in TBI patients.

  Four weeks of treatment with methylphenidate.

Other Outcomes (1)

• Explore relationship between structural connectivity (measured by Diffusion Tensor Imaging) between the ventral striatum, prefrontal cortex, and ventral tegmental area, and tonic dopamine release in patients with TBI.

  Baseline visit.

Study Arms (1)

methylphenidate administration

EXPERIMENTAL

All participants will receive oral methylphenidate 60 mg before the second TMS study. The participants will receive oral methylphenidate 60 mg before the second PET scan. Subjects will then be treated with oral methylphenidate, using a forced titration. Dose titration will be incremental within 6 days (dose-escalation phase) , starting at 5 mg orally twice daily for 3 days, and 10 mg twice daily for the next 3 days. Then the dose will be increased to 30 mg twice daily starting from day 7 given twice daily for additional 3 weeks.

Drug: methylphenidate; Drug: Placebo

Interventions

methylphenidate DRUG

This is an open-labeled 4 week methylphenidate administration, 30 mg twice daily by mouth. Placebo and methylphenidate will also be administered as a single dose before one of the two PET and TMS sessions, in a single blinded manner (the participant will not know whether active drug or placebo was administered). PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand will be performed after administration of placebo or oral methylphenidate to measure endogenous DA release in TBI patients. Structural MRI will be performed before methylphenidate administration. TMS after placebo or methylphenidate will be performed to measure intracortical inhibition and dopaminergic activity.

Also known as: Ritalin

methylphenidate administration

Placebo DRUG

methylphenidate administration

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18 - 55 years, inclusive
• A history of having sustained a moderate or severe TBI \> 6 months prior to enrollment. Evidence will be any one of the following 3 criteria:
• GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
• Post-traumatic amnesia \> 24 hours
• TBI-related abnormality on neuroimaging (either CT or MRI).
• Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:
• Difficulty in attention or memory.
• One or more of the following symptoms, which started shortly after the trauma and persist for at least three months:
• Fatigability
• Disordered sleep
• Changes in personality
• Apathy or lack of spontaneity
• Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a significant worsening of pre-existing symptoms after trauma.
• Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning.
• Ability to read, write, and speak English

You may not qualify if:

• Evidence of penetrating brain injury.
• Contraindication to methylphenidate therapy:
• Known glaucoma (consistently raised intraocular pressure with or without associated optic nerve damage)
• Motor tics or a family history of Tourette's syndrome (diagnosed by presence of both multiple motor and one or more vocal tics over the period of a year, with no more than three consecutive tic-free months)
• Known hypersensitivity to methylphenidate (hives, difficulty breathing, and swelling of face, lips, tongue, or throat).
• Known severe anxiety or restlessness which prevents from doing day to day activities.
• Known preexisting hypertension, heart failure, myocardial infarction, or ventricular arrhythmia.
• Known preexisting psychosis, bipolar illness.
• History of seizures, or interictal epileptiform discharges (IEDs) on EEG in absence of seizures.
• Known peripheral vasculopathy, including Raynaud's phenomenon.
• History of drug dependence or alcoholism.
• Concomitant treatment with coumadin anticoagulants, anticonvulsants (e.g., phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, clomipramine, desipramine).
• Concomitant therapy with monoamine oxidase inhibitors (such as Marplan (isocarboxazid), Nardil (phenelzine), Emsam (selegiline), and Parnate (tranylcypromine))
• Concomitant treatment with blood pressure medication (both for high and low blood pressure).
• Pregnancy

Sponsors & Collaborators

• Uniformed Services University of the Health Sciences: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

National Institutes of Health, Clinical Center.

Bethesda, Maryland, 20814, United States

Location

Related Publications (2)

• Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, Telang FW, Fowler JS, Logan J, Wong CT, Swanson JM. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J Neurosci. 2012 Jan 18;32(3):841-9. doi: 10.1523/JNEUROSCI.4461-11.2012.

  PMID: 22262882 BACKGROUND

• Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, Coslett HB. Effects of methylphenidate on attention deficits after traumatic brain injury: a multidimensional, randomized, controlled trial. Am J Phys Med Rehabil. 2004 Jun;83(6):401-20. doi: 10.1097/01.phm.0000128789.75375.d3.

  PMID: 15166683 BACKGROUND

MeSH Terms

Conditions

Brain Injuries, Traumatic; Attention Deficit Disorder with Hyperactivity; Memory Disorders

Interventions

Methylphenidate

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Ramon R Diaz-Arrastia, MD, PhD

  Uniformed Services University / NINDS

  STUDY DIRECTOR

• Eric Wassermann, MD

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: May 20, 2014
• First Posted: May 28, 2014
• Study Start: September 1, 2014
• Primary Completion: August 1, 2018
• Study Completion: August 1, 2018
• Last Updated: October 4, 2018

Record last verified: 2018-10

Locations

US (1)