Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

April 18, 2018 updated by: Ana Weidenauer, Medical University of Vienna

Disentangling Pre- and Postsynaptic Aspects of Amphetamine-induced Sensitization: a Combined [18F]DOPA / [11C]-(+)-PHNO PET Study

Patients with schizophrenia show enhanced dopamine synthesis capacity and release, an effect that can be evoked in healthy subjects by repeated amphetamine administration. Therefore for the first time the relationship between dopamine synthesis and release will be studied in healthy subjects before and after amphetamine sensitization in order to better understand adaptive mechanisms of the dopamine system.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Positron emission tomography (PET) studies have consistently shown increased brain dopamine (DA) synthesis and enhanced d-amphetamine-induced DA release in patients with schizophrenia. Repeated administration of d-amphetamine leads to an increased subjective and behavioral drug-response. This effect, termed "sensitization", is paralleled by an increase in dopamine release to levels akin to those observed in schizophrenia. Schizophrenia thus goes along with a state of 'natural sensitization' towards amphetamines. However, while it is known that DA synthesis and release are both enhanced in schizophrenia, it is unknown whether sensitization changes indices of presynaptic DA synthesis in the striatum of healthy subjects. Thus, for the first time, this project will study the effects of repeated d-amphetamine on uptake of the DA precursor [18F]FDOPA and on d-amphetamine-induced changes in binding of the D2/3 receptor agonist radioligand [11C]-(+)PHNO in a within-subject design. Before and after amphetamine sensitization by repeated intermittent administration subjects will receive an [18F]FDOPA and and a [11C]-(+)PHNO PET scan. For the investigation of the influence of functional and structural cortical properties on dopamine synthesis and release, functional and structural magnet resonance imaging will be performed before and after sensitization.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
22

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 61 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Males and females aged 18-65, in good general health based on history and physical examination
  • Psychiatrically healthy as determined by the Mini-International Neuropsychiatric Interview (M.I.N.I.PLUS) (94))
  • No relevant abnormalities in laboratory screening including thyroid function tests, blood cell count, serum electrolytes, liver and kidney function, and urinalysis
  • No clinically relevant findings in electrocardiography (ECG)
  • No clinically relevant findings in vital signs (blood pressure and pulse)
  • No regular use of illegal drugs or alcohol abuse based on declared history and confirmed by urine drug screening
  • No history of repeated AMPH (AMPH), cocaine or other stimulant drug use

Exclusion Criteria:

  • Evidence of present psychiatric or neurological illness according to M.I.N.I.-Plus (any personal or first-degree relative history of: schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, and substance dependence)
  • Recreational use of psychostimulant drugs in the past two years; lifetime use of psychostimulants exceeding five exposures
  • Medically significant biochemical or hematological abnormality on screening laboratory studies
  • Women of childbearing potential: Current pregnancy or breast-feeding
  • Clinically relevant abnormalities in the electro-cardiogram (ECG)
  • History of myocardial infarction or angina pectoris
  • Positive urine drug screen within one week prior to PET study day
  • Presence of ferromagnetic metal in the body or heart pacemaker
  • Claustrophobia
  • Any history of arterial hypertension or paroxysmal hypertensive states
  • Established diagnosis of advanced arteriosclerosis
  • Established diagnosis of hyperthyroidism
  • History of hypersensitivity to sympathomimetics
  • History of head trauma resulting in loss of consciousness that required medical intervention
  • Lifetime history of substance dependence (except nicotine)
  • If participation in this study would exceed the annual radiation dose limits (30 mSv) for human subjects
  • Subjects currently participating in research studies
  • Suicidal ideation or likelihood of a suicide or homicide attempt

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Healthy subjects
Measurement of Dextroamphetamine Sulfate-induced dopamine release and synthesis before and after amphetamine sensitization.
Drug: Dextroamphetamine Sulfate
Repeated oral administration of dexamphetamine 0.4mg/KG bodyweight four times.
Other Names:
  • [11C]-(+)-PHNO PET, [18F]FDOPA PET

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
[18F]FDOPA Ki values
Time Frame: Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4
Relative change in regional [18F]FDOPA Ki values after AMPH sensitization
Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
[11C]-(+)-PHNO BPND values
Time Frame: Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4
Relative change in regional [11C]-(+)-PHNO BPND values after AMPH administration before and after sensitization
Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4
Subjective ratings of amphetamine effects (Drug Effects Questionnaire)
Time Frame: Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Subjective ratings will be assessed via questionnaire (Drug Effects Questionnaire) four times throughout the study.
Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Subjective ratings of amphetamine effects (Subjective States Questionnaire)
Time Frame: Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Subjective ratings will be assessed via questionnaire (Subjective States Questionnaire) four times throughout the study.
Baseline, after i.v. amphetamine during PHNO PET, on each of the two sensitization visits and 2 weeks after amphetamine sensitization during PHNO PET scanning over the course of 4 weeks. Time points: Week 1 Week 2 Week 4
Cognitive measures
Time Frame: At baseline, on each of the two sensitization visits after amphetamine administration and 2 weeks after amphetamine sensitization before FDOPA scanning, total timeframe 4 weeks, Time points: Week 1 Week 2 Week 4
Working memory, reward processing and impulsivity will be assessed via a computerized test battery four times throughout the study
At baseline, on each of the two sensitization visits after amphetamine administration and 2 weeks after amphetamine sensitization before FDOPA scanning, total timeframe 4 weeks, Time points: Week 1 Week 2 Week 4
Impulsiveness
Time Frame: Baseline, Week 1
The personality traits impulsiveness will be assessed once during study participation by the questionnaire Barrat Impulsiveness Scale (BIS).
Baseline, Week 1
Personality-related markers
Time Frame: Baseline, Week 1
Personality traits like novelty seeking will be assessed once during study participation using the Temperament and Character Inventory (TCI).
Baseline, Week 1
Peripheral markers of sensitization
Time Frame: Baseline FDOPA scan, baseline PHNO + amphetamine scan, post-sensitization PHNO+ amphetamine scan, post-sensitization FDOPA scan, Time points: Week 1 Week 2 Week 4
Plasma concentration of the dopamine metabolite HVA, glucose and insulin metabolism related parameters (glucose, glucagon, insulin, c-peptide, somatostatin), plasma cocaine and AMPH-regulated transcript (CART) levels will be measured at each PET study day.
Baseline FDOPA scan, baseline PHNO + amphetamine scan, post-sensitization PHNO+ amphetamine scan, post-sensitization FDOPA scan, Time points: Week 1 Week 2 Week 4
Salivary cortisol
Time Frame: Salivary cortisol will be assessed each time amphetamine is administered: At baseline and 30, 60, 90, 145 and 210 minutes after i.v. or oral amphetamine administration.
Salivary cortisol will be assessed using Salivettes ®.
Salivary cortisol will be assessed each time amphetamine is administered: At baseline and 30, 60, 90, 145 and 210 minutes after i.v. or oral amphetamine administration.
Fractional anisotropy (diffusion-weighted tensor imaging) of white matter
Time Frame: Before and after amphetamine sensitization, Week 1, Week 5
Fractional anisotropy of white matter will be measured by means of magnet resonance imaging.
Before and after amphetamine sensitization, Week 1, Week 5
Gray matter volume
Time Frame: Before and after amphetamine sensitization, Week 1, Week 5
Gray matter volume will be measured by means of magnet resonance imaging. T1 and PD sequences will be recorded.
Before and after amphetamine sensitization, Week 1, Week 5
Functional connectivity
Time Frame: Before and after amphetamine sensitization, Week 1, Week 5
Functional connectivity between brain regions will be measured by means of magnet resonance imaging during a resting state of the subject.
Before and after amphetamine sensitization, Week 1, Week 5

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Medical University of Vienna

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ana Weidenauer, MD, Medical University of Vienna

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2018

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2021

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 8, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 14, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 21, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 19, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 18, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 16969

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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