Dopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol)

ID: NCT00634556
Status: Completed
Phase: Phase 1
Start Date: February 01, 2006
First Submitted: March 05, 2008
Last Updated: February 08, 2018
Results: N/A
Sponsors & Collaborators: Washington University School of Medicine, National Institute of Mental Health (NIMH)
Location: United States
Conditions: Tourette Syndrome
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Study Description

Brief Summary

Dr. Kevin J. Black at Washington University is conducting a study to learn whether we can use MRI scans to test dopamine function in the brain and to determine whether the brain performs memory tasks differently in Tourette Syndrome (TS). TS is a movement disorder characterized by vocal tics (sounds) and motor tics (movements). We will measure how and where brain activity changes using magnetic resonance imaging (MRI) scans during memory tasks and after taking levodopa. Levodopa is a drug commonly used for the treatment of Parkinson's disease (PD), a very different movement disorder.

Detailed Description

Clinical observations suggest that in TS there is abnormal function in the brain's motor system that can be modified by manipulating dopamine. My colleagues and I have hypothesized that nonmotor brain systems may also show dopamine-sensitive functional abnormalities. Recently we tested this hypothesis using functional magnetic resonance imaging (fMRI). A cognitive task involving working memory (WM) produced excessive activation of several brain regions in TS subjects compared to controls, but this excessive activation normalized after administering the dopamine precursor levodopa (Hershey et al, 2004).

We can state the following focused hypotheses and corresponding specific aims:

(1) In TS, normal performance during a working memory (WM) task requires greater activation of specific brain regions (parietal cortex, medial frontal cortex and thalamus) than in control subjects, and this excess fMRI response is reduced (improved) by exogenous levodopa. (2) These fMRI results in TS relate specifically to WM, to TS, and to dopamine receptor activation, rather than to non-WM components of the cognitive task, comorbidity, placebo effects, or other confounds.

Specific Aim 1. Test whether the preliminary fMRI results generalize to a larger and more representative sample of adults with TS.

Specific Aim 2. Clarify the variables that interact to produce the differential fMRI responses to a WM task and levodopa observed in TS subjects vs controls.

2a. Task components. Control for non-WM components of the task and delineate a "dose-response" curve for effects of WM load on fMRI responses.

2b. Clinical variables. Test whether the fMRI results in our preliminary data are associated with TS itself rather than with comorbid conditions, treatment history, demographic variables, or state variables such as current tic severity / tic suppression.

2c. Pharmacology. Test whether the post-levodopa changes in WM-related fMRI signal relate specifically to levodopa plasma concentration (rather than practice effects, placebo effects, or passage of time) and are replicated by a nonselective dopamine receptor agonist or by a dopamine D2/D3/D4 agonist.
Condition or disease Intervention/treatment Phase

Tourette Syndrome

Drug: levodopa solution 2mg/ml for i.v. use
Other Names
L-DOPA L-3,4-dihydroxyphenylalanine
Drug: placebo
Other Names
NaCl 0.9% in water
Phase 1

Tracking Information

First Submitted DateMarch 05, 2008
Last Update Posted DateFebruary 08, 2018
Start DateFebruary 01, 2006
Actual Completion DateOctober 01, 2010
Primary Completion DateOctober 01, 2010
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • BOLD (blood oxygen-level dependent) fMRI (functional magnetic resonance imaging) response to a working memory task [Time Frame: From about 30 to 120 minutes after infusion begins]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • serum prolactin concentration [Time Frame: approximately 2 hours after infusion begins]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleDopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol)
Official TitleDopaminergic Effects on Cortical Function in Tourette's (Levodopa Protocol)
Brief Summary

Dr. Kevin J. Black at Washington University is conducting a study to learn whether we can use MRI scans to test dopamine function in the brain and to determine whether the brain performs memory tasks differently in Tourette Syndrome (TS). TS is a movement disorder characterized by vocal tics (sounds) and motor tics (movements). We will measure how and where brain activity changes using magnetic resonance imaging (MRI) scans during memory tasks and after taking levodopa. Levodopa is a drug commonly used for the treatment of Parkinson's disease (PD), a very different movement disorder.

Detailed Description

Clinical observations suggest that in TS there is abnormal function in the brain's motor system that can be modified by manipulating dopamine. My colleagues and I have hypothesized that nonmotor brain systems may also show dopamine-sensitive functional abnormalities. Recently we tested this hypothesis using functional magnetic resonance imaging (fMRI). A cognitive task involving working memory (WM) produced excessive activation of several brain regions in TS subjects compared to controls, but this excessive activation normalized after administering the dopamine precursor levodopa (Hershey et al, 2004).

We can state the following focused hypotheses and corresponding specific aims:

(1) In TS, normal performance during a working memory (WM) task requires greater activation of specific brain regions (parietal cortex, medial frontal cortex and thalamus) than in control subjects, and this excess fMRI response is reduced (improved) by exogenous levodopa. (2) These fMRI results in TS relate specifically to WM, to TS, and to dopamine receptor activation, rather than to non-WM components of the cognitive task, comorbidity, placebo effects, or other confounds.

Specific Aim 1. Test whether the preliminary fMRI results generalize to a larger and more representative sample of adults with TS.

Specific Aim 2. Clarify the variables that interact to produce the differential fMRI responses to a WM task and levodopa observed in TS subjects vs controls.

2a. Task components. Control for non-WM components of the task and delineate a "dose-response" curve for effects of WM load on fMRI responses.

2b. Clinical variables. Test whether the fMRI results in our preliminary data are associated with TS itself rather than with comorbid conditions, treatment history, demographic variables, or state variables such as current tic severity / tic suppression.

2c. Pharmacology. Test whether the post-levodopa changes in WM-related fMRI signal relate specifically to levodopa plasma concentration (rather than practice effects, placebo effects, or passage of time) and are replicated by a nonselective dopamine receptor agonist or by a dopamine D2/D3/D4 agonist.

Study TypeInterventional
Study PhasePhase 1
Estimated Enrollment
49
Allocation
Randomized
Interventional Model
Factorial Assignment
Masking
Quadruple
Primary Purpose
Other
Conditions
Tourette Syndrome
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: levodopa solution 2mg/ml for i.v. use

2mg/mL in normal saline

Other Names
L-DOPA
L-3,4-dihydroxyphenylalanine
Drug: placebo

normal saline

Other Names
NaCl 0.9% in water
Study Groups/Cohorts
levodopa solution 2mg/ml for i.v. use
levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.

Placebo
normal saline i.v.

Study Arms
Experimental levodopa solution 2mg/ml for i.v. use
levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.
Drug : levodopa solution 2mg/ml for i.v. use
2mg/mL in normal saline

Placebo Comparator Placebo
normal saline i.v.
Drug : placebo
normal saline

Arm Intervention/Treatment
Experimental levodopa solution 2mg/ml for i.v. use
levodopa solution in saline, given intravenously, dosed as per "final protocol" in Black et al 2003.
Drug : levodopa solution 2mg/ml for i.v. use
Placebo Comparator Placebo
normal saline i.v.
Drug : placebo

Recruitment Information

Recruitment Status:Completed
Enrollment49
Completion DateOctober 01, 2010
Eligibility Criteria: Inclusion Criteria:
- Age 18-55.
- Tic subjects must meet DSM-IV-TR criteria for a chronic tic disorder.
- Controls are matched for age (within 4 years), sex, handedness (right-handed, non-right-handed), and education (within 2 years), and if possible for race and ethnicity

Exclusion Criteria:
- Inability to give competent informed consent.
- Lactation, pregnancy or possibility of pregnancy.
- Contraindication to MRI (pacemaker; nontrivial metallic foreign bodies; significant claustrophobia).
- Contraindication to levodopa or carbidopa (known allergy).
- Significant neurological disease (not counting the tic disorder).
- Current renal, cardiac or hepatic disease that would make study participation less safe.
- Head injury with loss of consciousness for more than 5 minutes or with neurological sequelae.
- Lifetime history of serious lifetime psychopathology or substance abuse. (Specific exclusions are: lifetime diagnosis of mental retardation, autism, psychosis, mania, somatization disorder, panic disorder, social phobia [excludes symptoms present only when treated with a neuroleptic], anorexia nervosa or bulimia, drug or alcohol dependence, antisocial personality disorder, or dementia, or current major depression.)
- Depot neuroleptics in the past 6 months.
- Other antipsychotics within the past 2 weeks.
- Behavioral therapy for Tics of OCD sx in the past 2 weeks.
- For one half of the subjects in each diagnostic group: any brain-active medications within the past 2 weeks. For the remaining subjects: neuroactive medications in the past 2 weeks other than SSRIs, alpha-2 agonists, norepinephrine reuptake inhibitors, or clonazepam.
- Additional exclusions for controls: No history of tic disorder, OCD or ADHD. If under age 25, no first-degree relative with a tic disorder. No exposure to neuroleptics in the past year and none ever for a period exceeding a week.
GenderAll
Age18 Years to 55 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
Contacts
Not Available
Listed Location Countries
United States

Administrative Information

NCT Number:NCT00634556
Other Study ID Numbers
05-0832
R01MH073856-01A1
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible PartyKevin J. Black, MD, Washington University
Study Sponsor
Washington University School of Medicine
Collaborators
National Institute of Mental Health (NIMH)
Investigators
Principal Investigator
Kevin J Black, MD
Washington Universisty School of Medicine