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Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

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ClinicalTrials.gov Identifier: NCT03223844
Recruitment Status : Recruiting
First Posted : July 21, 2017
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
Ana Weidenauer, Medical University of Vienna

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Schizophrenia Psychosis Sensitisation Drug: Dextroamphetamine Sulfate Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Disentangling Pre- and Postsynaptic Aspects of Amphetamine-induced Sensitization: a Combined [18F]DOPA / [11C]-(+)-PHNO PET Study
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
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 Name: [11C]-(+)-PHNO PET, [18F]FDOPA PET




Primary Outcome Measures :
  1. [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


Secondary Outcome Measures :
  1. [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

  2. 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.

  3. 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.

  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

  5. Impulsiveness [ Time Frame: Baseline, Week 1 ]
    The personality traits impulsiveness will be assessed once during study participation by the questionnaire Barrat Impulsiveness Scale (BIS).

  6. 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).

  7. 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.

  8. 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 ®.

  9. 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.

  10. 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.

  11. 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.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03223844


Contacts
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Contact: Ana Weidenauer, MD +43140400 ext 38370 ana.weidenauer@meduniwien.ac.at
Contact: Matthaeus Willeit, MD +43140400 ext 35690 matthaeus.willeit@meduniwien.ac.at

Locations
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Austria
Medical University of Vienna Recruiting
Vienna, Austria, 1090
Contact: Ana Weidenauer, MD    0043140400 ext 35470    ana.weidenauer@meduniwien.ac.at   
Sponsors and Collaborators
Medical University of Vienna
Investigators
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Principal Investigator: Ana Weidenauer, MD Medical University of Vienna

Publications:
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Responsible Party: Ana Weidenauer, Principal Investigator, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT03223844     History of Changes
Other Study ID Numbers: 16969
First Posted: July 21, 2017    Key Record Dates
Last Update Posted: April 19, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ana Weidenauer, Medical University of Vienna:
Dopamine
Amphetamine
Positron Emission Tomography
Magnetic Resonance Imaging
Schizophrenia
Psychosis
[18F]FDOPA
[11C]-(+)-PHNO

Additional relevant MeSH terms:
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Amphetamine
Dextroamphetamine
Schizophrenia
Psychotic Disorders
Mental Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Dopamine
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents
Central Nervous System Stimulants
Adrenergic Agents
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Uptake Inhibitors