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Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

Primary Purpose

Schizophrenia, Psychosis, Sensitisation

Status

Unknown status

Phase

Not Applicable

Locations

Austria

Study Type

Interventional

Intervention

Dextroamphetamine Sulfate

About this trial

This is an interventional basic science trial for Schizophrenia focused on measuring Dopamine, Amphetamine, Positron Emission Tomography, Magnetic Resonance Imaging, Schizophrenia, Psychosis, [18F]FDOPA, [11C]-(+)-PHNO

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Medical University of ViennaRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Healthy subjects

Arm Description

Measurement of Dextroamphetamine Sulfate-induced dopamine release and synthesis before and after amphetamine sensitization.

Outcomes

Primary Outcome Measures

[18F]FDOPA Ki values

Relative change in regional [18F]FDOPA Ki values after AMPH sensitization

Secondary Outcome Measures

[11C]-(+)-PHNO BPND values

Relative change in regional [11C]-(+)-PHNO BPND values after AMPH administration before and after sensitization

Subjective ratings of amphetamine effects (Drug Effects Questionnaire)

Subjective ratings will be assessed via questionnaire (Drug Effects Questionnaire) four times throughout the study.

Subjective ratings of amphetamine effects (Subjective States Questionnaire)

Subjective ratings will be assessed via questionnaire (Subjective States Questionnaire) four times throughout the study.

Cognitive measures

Working memory, reward processing and impulsivity will be assessed via a computerized test battery four times throughout the study

Impulsiveness

The personality traits impulsiveness will be assessed once during study participation by the questionnaire Barrat Impulsiveness Scale (BIS).

Personality-related markers

Personality traits like novelty seeking will be assessed once during study participation using the Temperament and Character Inventory (TCI).

Peripheral markers of sensitization

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.

Salivary cortisol

Salivary cortisol will be assessed using Salivettes ®.

Fractional anisotropy (diffusion-weighted tensor imaging) of white matter

Fractional anisotropy of white matter will be measured by means of magnet resonance imaging.

Gray matter volume

Gray matter volume will be measured by means of magnet resonance imaging. T1 and PD sequences will be recorded.

Functional connectivity

Functional connectivity between brain regions will be measured by means of magnet resonance imaging during a resting state of the subject.

Full Information

NCT ID

NCT03223844

First Posted

July 8, 2017

Last Updated

April 18, 2018

Sponsor

Medical University of Vienna

1. Study Identification

Unique Protocol Identification Number

NCT03223844

Brief Title

Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2018

Overall Recruitment Status

Unknown status

Study Start Date

January 1, 2018 (Actual)

Primary Completion Date

August 2021 (Anticipated)

Study Completion Date

December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical University of Vienna

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Schizophrenia, Psychosis, Sensitisation

Keywords

Dopamine, Amphetamine, Positron Emission Tomography, Magnetic Resonance Imaging, Schizophrenia, Psychosis, [18F]FDOPA, [11C]-(+)-PHNO

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

22 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Healthy subjects

Arm Type

Experimental

Arm Description

Measurement of Dextroamphetamine Sulfate-induced dopamine release and synthesis before and after amphetamine sensitization.

Intervention Type

Drug

Intervention Name(s)

Dextroamphetamine Sulfate

Other Intervention Name(s)

[11C]-(+)-PHNO PET, [18F]FDOPA PET

Intervention Description

Repeated oral administration of dexamphetamine 0.4mg/KG bodyweight four times.

Primary Outcome Measure Information:

Title

[18F]FDOPA Ki values

Description

Relative change in regional [18F]FDOPA Ki values after AMPH sensitization

Time Frame

Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4

Secondary Outcome Measure Information:

Title

[11C]-(+)-PHNO BPND values

Description

Relative change in regional [11C]-(+)-PHNO BPND values after AMPH administration before and after sensitization

Time Frame

Baseline and 2 weeks after amphetamine sensitization, Week 1 and Week 4

Title

Subjective ratings of amphetamine effects (Drug Effects Questionnaire)

Description

Subjective ratings will be assessed via questionnaire (Drug Effects Questionnaire) four times throughout the study.

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

Title

Subjective ratings of amphetamine effects (Subjective States Questionnaire)

Description

Subjective ratings will be assessed via questionnaire (Subjective States Questionnaire) four times throughout the study.

Time Frame

Title

Cognitive measures

Description

Working memory, reward processing and impulsivity will be assessed via a computerized test battery four times throughout the study

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

Title

Impulsiveness

Description

The personality traits impulsiveness will be assessed once during study participation by the questionnaire Barrat Impulsiveness Scale (BIS).

Time Frame

Baseline, Week 1

Title

Personality-related markers

Description

Personality traits like novelty seeking will be assessed once during study participation using the Temperament and Character Inventory (TCI).

Time Frame

Baseline, Week 1

Title

Peripheral markers of sensitization

Description

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

Title

Salivary cortisol

Description

Salivary cortisol will be assessed using Salivettes ®.

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.

Title

Fractional anisotropy (diffusion-weighted tensor imaging) of white matter

Description

Fractional anisotropy of white matter will be measured by means of magnet resonance imaging.

Time Frame

Before and after amphetamine sensitization, Week 1, Week 5

Title

Gray matter volume

Description

Gray matter volume will be measured by means of magnet resonance imaging. T1 and PD sequences will be recorded.

Time Frame

Before and after amphetamine sensitization, Week 1, Week 5

Title

Functional connectivity

Description

Functional connectivity between brain regions will be measured by means of magnet resonance imaging during a resting state of the subject.

Time Frame

Before and after amphetamine sensitization, Week 1, Week 5

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility 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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ana Weidenauer, MD

Phone

+43140400

Ext

38370

ana.weidenauer@meduniwien.ac.at

First Name & Middle Initial & Last Name or Official Title & Degree

Matthaeus Willeit, MD

Phone

+43140400

Ext

35690

matthaeus.willeit@meduniwien.ac.at

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ana Weidenauer, MD

Organizational Affiliation

Medical University of Vienna

Official's Role

Principal Investigator

Facility Information:

Facility Name

Medical University of Vienna

City

Vienna

ZIP/Postal Code

1090

Country

Austria

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ana Weidenauer, MD

Phone

0043140400

Ext

35470

ana.weidenauer@meduniwien.ac.at

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

27613293

Citation

Weidenauer A, Bauer M, Sauerzopf U, Bartova L, Praschak-Rieder N, Sitte HH, Kasper S, Willeit M. Making Sense of: Sensitization in Schizophrenia. Int J Neuropsychopharmacol. 2016 Dec 31;20(1):1-10. doi: 10.1093/ijnp/pyw081. Print 2017 Jan.

Results Reference

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PubMed Identifier

27690184

Citation

Sauerzopf U, Sacco R, Novarino G, Niello M, Weidenauer A, Praschak-Rieder N, Sitte H, Willeit M. Are reprogrammed cells a useful tool for studying dopamine dysfunction in psychotic disorders? A review of the current evidence. Eur J Neurosci. 2017 Jan;45(1):45-57. doi: 10.1111/ejn.13418. Epub 2016 Oct 19.

Results Reference

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Influence of Amphetamine-induced Sensitization on Dopamine Synthesis and Release

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