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Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories (Memocycline)

Primary Purpose

Post-traumatic Stress Disorder, Cocaine Use Disorder

Status
Recruiting
Phase
Not Applicable
Locations
Switzerland
Study Type
Interventional
Intervention
Imagery
Minocycline
Placebo
Sponsored by
Psychiatric University Hospital, Zurich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Post-traumatic Stress Disorder focused on measuring memory reconsolidation blockade, minocycline, MMP-9 inhibition, PTSD, cocaine use disorder, placebo-controlled

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

General Inclusion Criteria: Ability to read, understand and provide written informed consent Age between 18 and 60 years To be sufficiently fluent in German Inclusion Criteria for the PTSD group: - Current diagnosis of full PTSD according to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), of subthreshold PTSD, as in meeting two to three of the DSM-5 criteria B-E, or of complex PTSD Inclusion Criteria for the CUD group: Current diagnosis of mild, moderate, or severe CUD according to DSM-5 Regular cocaine use in the last 12 months and at least one consumption event in the last 6 months General Exclusion Criteria: Women who are pregnant or breast feeding or intending to become pregnant during the course of the study or within 3 months after Other clinically significant concomitant disease states, e.g., renal failure (i.e., estimated glomerular filtration rate (eGFR; CKD-EPI) lower than 60 ml/min/1.73 m2), hepatic dysfunction (i.e., alanine transaminase (ALT) higher than 90 U/I for women or 110 U/I for men, aspartate aminotransferase (AST) higher than 74 U/I, and/or gamma-glutamyl transferase (γGT) higher than 70 U/I for women or 120 U/I for men), cardiovascular disease, etc. Presence or history of severe neurological disorders, head injuries or systemic/rheumatic disease Diagnosis of schizophrenia, bipolar disorder, or autism spectrum disorder according to DSM-5 Pacemaker, neurostimulator or any other head or heart implants as well as MRI-incompatible metal parts or possibility of metal fragments in the body (MR safety) Claustrophobia (MR safety) Dependence on a hearing aid (MR safety) Inability to follow the procedures of the study, e.g., due to language problems Participation in another study with investigational drugs within the 30 days preceding and during the present study More than three suicide attempts in the past, a suicide attempt within the last 12 months and/or acute suicidality Exclusion Criteria for Healthy Controls: Any current psychiatric diagnosis according to DSM-5 except for mild or moderate substance use disorder (SUD) for nicotine, and mild SUD for alcohol and cannabis Exclusion Criteria for both the PTSD and CUD groups: Allergy to minocycline or to any other ingredient in the named drug Current intake of the following medications interacting with minocycline: acitretin, acetylcystein, aluminiumhydroxid, amitryptiline, any antibiotics, antidiabetic drug such as sulfonylurea, atazanavir, atomoxetine, anticoagulant drugs from the coumarin type, barbiturates, bupropion, carbamazepine, ciclosporin A, isotretinoin, methotrexate, phenytoin, and theophylline Exclusion Criteria for only the PTSD group: Diagnosis of CUD according to DSM-5 (lifetime) Current diagnosis of severe SUD for nicotine, moderate SUD for alcohol and cannabis, and mild SUD for all other substances according to DSM-5 Exclusion Criteria for only the CUD group: Diagnosis of PTSD according to DSM-5 (lifetime) Current diagnosis of severe SUD for alcohol or cannabis, and mild SUD for all other substances (except for nicotine) according to DSM-5

Sites / Locations

  • Psychiatric University Hospital Zurich, University of ZurichRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

No Intervention

Arm Label

PTSD intervention group

PTSD control group

CUD intervention group

CUD control group

Healthy control group

Arm Description

30 individuals with PTSD will receive imagery with minocycline.

30 individuals with PTSD will receive imagery with placebo.

30 individuals with CUD will receive imagery with minocycline.

30 individuals with CUD will receive imagery with placebo.

30 healthy individuals who will not receive any intervention.

Outcomes

Primary Outcome Measures

Changes in intrusive memories frequency and features
Measured with the Intrusion Questionnaire, containing various items on intrusive memories frequency, arousal and distress as well as triggers, and responses.
Change over time in self-reported intrusive memories frequency, arousal and distress
Captured with a short version of the Intrusion Questionnaire implemented as smartphone-based ecological momentary assessment (EMA), containing items on arousal and distress from self-reported intrusive memories.
Changes in fMRI Blood-Oxygenation-Level Dependent (BOLD) contrasts
fMRI BOLD contrasts between conditions (neutral/stress/trauma for the PTSD group; neutral/reward/drug for the CUD group) and between groups.
Changes in MRS signal parameters
Glutamate concentrations are measured using MRS in the amygdala in the PTSD group and in the nucleus accumbens in the CUD group.

Secondary Outcome Measures

Change in heart rate variability (HRV) during fMRI memory reactivation
HRV will be measured during the fMRI cue-reactivity paradigm (listening to trauma- or cocaine-related narratives compared to trauma- and cocaine-unrelated narratives).
Change in respiratory rate during fMRI memory reactivation
Respiratory rate will be measured during the fMRI cue-reactivity paradigm (listening to trauma- or cocaine-related narratives compared to trauma- and cocaine-unrelated narratives).
Change in subjective rating of distress before and after memory reactivation
Current subjective distress will be measured with a visual analogue scale before and after listening to trauma- and cocaine-related narratives compared to trauma- and cocaine-unrelated narratives.
Change in subjective rating of craving before and after memory reactivation
Current subjective craving will be measured with the Cocaine Craving Questionnaire (containing ten questions on current craving scaled from 0 to 10) before and after listening to cocaine-related narratives compared to cocaine-unrelated narratives.
Change in neurofilament light chain (NfL) levels
NfL levels will be measured in serum samples.
Change in sphingolipid levels
Sphingolipid levels will be measured in plasma samples.
Change in inflammatory biomarker levels
Inflammatory biomarker levels will be measured in serum samples.
Change in MMP-9 protein levels
MMP-9 protein levels will be measured in plasma samples.
Change in MMP-9 gene expression
MMP-9 gene expression will be measured in blood samples.
Heartrate variability
Heartrate variability (measured with a wearable (Fitbit)) predicted by the number and quality of intrusive memories experienced. Overall variability per person, in relation to overall health measured at Screening and Baseline as well as pre- and post-intervention variability will be assessed.
Sleep duration
Sleep duration (in minutes), trajectories over the course of the study periods, clusters of variations in duration and sleep quality (as averaged by the algorithm of Fitbit), according to medication/placebo, number of intrusions and overall health measured at Screening and Baseline.
Change in Obsessive Compulsive Cocaine Use Scale (OCCUS)
A 14-item self-report measure that assesses the current inability to control or resist cocaine-related thoughts and behaviors, frequency and impact of thoughts and impulses related to cocaine use, and the degree of interference caused by cocaine related thoughts and behaviors.
PTSD Checklist for DSM-5 (PCL-5)
A 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD in the last 2 weeks prior to the visit.
Beck Depression Inventory-II (BDI-II)
A 21-item self-report measure for assessing the severity of depression in the last 2 weeks prior to the visit.
Pittsburgh Sleep Quality Index (PSQI)
A 19-item self-report measure which assesses sleep quality and disturbances in the last 2 weeks prior to the visit.
Global Assessment of Functioning (GAF)
A numeric scale used by the investigators to rate the current social, occupational, and psychological functioning of a participants. Scores range from 100 (extremely high functioning) to 1 (severely impaired).
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
A 30-item structured interview that is used to assess the 20 DSM-5 PTSD symptoms, subjective distress, impact of symptoms on social and occupational functioning, improvement in symptoms since the previous CAPS administration, and overall PTSD severity, and specifications for the dissociative subtype.
Changes in the Interview for Psychotropic Drug Consumption (IPDC)
A structured interview assessing self-reported patterns of use of common licit and illicit substances during the most representative month of the past year and, in the case of regular cocaine use, also specifically during the past month.

Full Information

First Posted
April 26, 2023
Last Updated
June 5, 2023
Sponsor
Psychiatric University Hospital, Zurich
Collaborators
University of Zurich
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1. Study Identification

Unique Protocol Identification Number
NCT05902819
Brief Title
Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories
Acronym
Memocycline
Official Title
An Investigation of the Effect of MMP-9 Inhibition With Minocycline on the Reconsolidation of Intrusive Trauma- or Cocaine-related Memories
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 10, 2023 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Psychiatric University Hospital, Zurich
Collaborators
University of Zurich

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
An investigation of the effect of matrix-metalloproteinase-(MMP)-9 inhibition with minocycline on the reconsolidation of trauma- or cocaine-related memories
Detailed Description
Intrusive memories are involuntary recollections of past emotional events that can become pathological and persist over time, particularly in post-traumatic stress disorder (PTSD) and cocaine use disorders (CUD). Both PTSD and CUD are characterised by a hypersensitivity and -reactivity to cue-elicited memory reactivation and exhibit common neurological alterations, suggesting shared underlying mechanisms. As intrusive memories significantly contribute to maintaining the cycle of relapse in both disorders, it is important to find a way to attenuate them successfully. Research on memory reconsolidation has led to the development of different (pharmacological) approaches to disrupt the process, which have, however, yielded mixed and unspecific effects so far. The present project aims to investigate the effect of MMP-9 inhibition with minocycline on the reconsolidation of intrusive memories in individuals with CUD or PTSD. Participants will be randomly assigned to a minocycline or placebo group. The study comprises a total of 5 visits during 3 weeks and one follow-up online survey (3 months after the intervention). Participants will receive the study medication before two imagery script-guided memory activation sessions. An ecological momentary assessment (EMA) approach will be employed to track intrusive memories, and glutamate concentration and neural activation will be measured with magnetic resonance spectroscopy (MRS) and functional magnetic resonance (fMRI), respectively, before and after the two imagery sessions.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Post-traumatic Stress Disorder, Cocaine Use Disorder
Keywords
memory reconsolidation blockade, minocycline, MMP-9 inhibition, PTSD, cocaine use disorder, placebo-controlled

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Randomized, double-blind, placebo-controlled, parallel group, single center study
Masking
ParticipantInvestigator
Masking Description
double-blinded
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PTSD intervention group
Arm Type
Experimental
Arm Description
30 individuals with PTSD will receive imagery with minocycline.
Arm Title
PTSD control group
Arm Type
Placebo Comparator
Arm Description
30 individuals with PTSD will receive imagery with placebo.
Arm Title
CUD intervention group
Arm Type
Experimental
Arm Description
30 individuals with CUD will receive imagery with minocycline.
Arm Title
CUD control group
Arm Type
Placebo Comparator
Arm Description
30 individuals with CUD will receive imagery with placebo.
Arm Title
Healthy control group
Arm Type
No Intervention
Arm Description
30 healthy individuals who will not receive any intervention.
Intervention Type
Behavioral
Intervention Name(s)
Imagery
Intervention Description
Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.
Intervention Type
Drug
Intervention Name(s)
Minocycline
Intervention Description
Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule.
Primary Outcome Measure Information:
Title
Changes in intrusive memories frequency and features
Description
Measured with the Intrusion Questionnaire, containing various items on intrusive memories frequency, arousal and distress as well as triggers, and responses.
Time Frame
Changes from baseline intrusive memories frequency and features after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2)
Title
Change over time in self-reported intrusive memories frequency, arousal and distress
Description
Captured with a short version of the Intrusion Questionnaire implemented as smartphone-based ecological momentary assessment (EMA), containing items on arousal and distress from self-reported intrusive memories.
Time Frame
EMA will be conducted for an average of 12 to 42 days (through study participation from baseline to 3 days after follow-up 1).
Title
Changes in fMRI Blood-Oxygenation-Level Dependent (BOLD) contrasts
Description
fMRI BOLD contrasts between conditions (neutral/stress/trauma for the PTSD group; neutral/reward/drug for the CUD group) and between groups.
Time Frame
Changes from baseline fMRI BOLD contrasts after 9 to max. 39 days (follow-up 1).
Title
Changes in MRS signal parameters
Description
Glutamate concentrations are measured using MRS in the amygdala in the PTSD group and in the nucleus accumbens in the CUD group.
Time Frame
Change from baseline MRS-measured glutamate concentrations after 9 to max. 39 days (follow-up 1).
Secondary Outcome Measure Information:
Title
Change in heart rate variability (HRV) during fMRI memory reactivation
Description
HRV will be measured during the fMRI cue-reactivity paradigm (listening to trauma- or cocaine-related narratives compared to trauma- and cocaine-unrelated narratives).
Time Frame
Change from baseline HRV after 9 to max. 39 days (follow-up 1).
Title
Change in respiratory rate during fMRI memory reactivation
Description
Respiratory rate will be measured during the fMRI cue-reactivity paradigm (listening to trauma- or cocaine-related narratives compared to trauma- and cocaine-unrelated narratives).
Time Frame
Change from baseline respiratory rate after 9 to max. 39 days (follow-up 1).
Title
Change in subjective rating of distress before and after memory reactivation
Description
Current subjective distress will be measured with a visual analogue scale before and after listening to trauma- and cocaine-related narratives compared to trauma- and cocaine-unrelated narratives.
Time Frame
Change from baseline subjective distress after 9 to max. 39 days (follow-up 1).
Title
Change in subjective rating of craving before and after memory reactivation
Description
Current subjective craving will be measured with the Cocaine Craving Questionnaire (containing ten questions on current craving scaled from 0 to 10) before and after listening to cocaine-related narratives compared to cocaine-unrelated narratives.
Time Frame
Change from baseline craving after 9 to max. 39 days (follow-up 1).
Title
Change in neurofilament light chain (NfL) levels
Description
NfL levels will be measured in serum samples.
Time Frame
Change from baseline NfL levels after 9 to max. 39 days (follow-up 1).
Title
Change in sphingolipid levels
Description
Sphingolipid levels will be measured in plasma samples.
Time Frame
Change from baseline sphingolipid levels after 9 to max. 39 days (follow-up 1).
Title
Change in inflammatory biomarker levels
Description
Inflammatory biomarker levels will be measured in serum samples.
Time Frame
Change from baseline inflammatory levels after 9 to max. 39 days (follow-up 1).
Title
Change in MMP-9 protein levels
Description
MMP-9 protein levels will be measured in plasma samples.
Time Frame
Change from baseline MMP-9 protein levels after 9 to max. 39 days (follow-up 1).
Title
Change in MMP-9 gene expression
Description
MMP-9 gene expression will be measured in blood samples.
Time Frame
Change from baseline MMP-9 gene expression after 9 to max. 39 days (follow-up 1).
Title
Heartrate variability
Description
Heartrate variability (measured with a wearable (Fitbit)) predicted by the number and quality of intrusive memories experienced. Overall variability per person, in relation to overall health measured at Screening and Baseline as well as pre- and post-intervention variability will be assessed.
Time Frame
Will be measured during 9 to max. 39 days, from baseline until follow-up 1.
Title
Sleep duration
Description
Sleep duration (in minutes), trajectories over the course of the study periods, clusters of variations in duration and sleep quality (as averaged by the algorithm of Fitbit), according to medication/placebo, number of intrusions and overall health measured at Screening and Baseline.
Time Frame
Will be measured during 9 to max. 39 days, from baseline until follow-up 1.
Title
Change in Obsessive Compulsive Cocaine Use Scale (OCCUS)
Description
A 14-item self-report measure that assesses the current inability to control or resist cocaine-related thoughts and behaviors, frequency and impact of thoughts and impulses related to cocaine use, and the degree of interference caused by cocaine related thoughts and behaviors.
Time Frame
Change from baseline OCCUS score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
Title
PTSD Checklist for DSM-5 (PCL-5)
Description
A 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD in the last 2 weeks prior to the visit.
Time Frame
Change from baseline PCL-5 score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
Title
Beck Depression Inventory-II (BDI-II)
Description
A 21-item self-report measure for assessing the severity of depression in the last 2 weeks prior to the visit.
Time Frame
Change from baseline BDI-II score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
Title
Pittsburgh Sleep Quality Index (PSQI)
Description
A 19-item self-report measure which assesses sleep quality and disturbances in the last 2 weeks prior to the visit.
Time Frame
Change from baseline PSQI score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
Title
Global Assessment of Functioning (GAF)
Description
A numeric scale used by the investigators to rate the current social, occupational, and psychological functioning of a participants. Scores range from 100 (extremely high functioning) to 1 (severely impaired).
Time Frame
Change from screening GAF score after both 10 to 50 days (follow-up 1) and approx. 4 months (follow-up 2).
Title
Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
Description
A 30-item structured interview that is used to assess the 20 DSM-5 PTSD symptoms, subjective distress, impact of symptoms on social and occupational functioning, improvement in symptoms since the previous CAPS administration, and overall PTSD severity, and specifications for the dissociative subtype.
Time Frame
Change from screening CAPS-5 score after approx. 4 months (follow-up 2).
Title
Changes in the Interview for Psychotropic Drug Consumption (IPDC)
Description
A structured interview assessing self-reported patterns of use of common licit and illicit substances during the most representative month of the past year and, in the case of regular cocaine use, also specifically during the past month.
Time Frame
Change from screening IPDC after approx. 4 months (follow-up 2).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
General Inclusion Criteria: Ability to read, understand and provide written informed consent Age between 18 and 60 years To be sufficiently fluent in German Inclusion Criteria for the PTSD group: - Current diagnosis of full PTSD according to the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), of subthreshold PTSD, as in meeting two to three of the DSM-5 criteria B-E, or of complex PTSD Inclusion Criteria for the CUD group: Current diagnosis of mild, moderate, or severe CUD according to DSM-5 Regular cocaine use in the last 12 months and at least one consumption event in the last 6 months General Exclusion Criteria: Women who are pregnant or breast feeding or intending to become pregnant during the course of the study or within 3 months after Other clinically significant concomitant disease states, e.g., renal failure (i.e., estimated glomerular filtration rate (eGFR; CKD-EPI) lower than 60 ml/min/1.73 m2), hepatic dysfunction (i.e., alanine transaminase (ALT) higher than 90 U/I for women or 110 U/I for men, aspartate aminotransferase (AST) higher than 74 U/I, and/or gamma-glutamyl transferase (γGT) higher than 70 U/I for women or 120 U/I for men), cardiovascular disease, etc. Presence or history of severe neurological disorders, head injuries or systemic/rheumatic disease Diagnosis of schizophrenia, bipolar disorder, or autism spectrum disorder according to DSM-5 Pacemaker, neurostimulator or any other head or heart implants as well as MRI-incompatible metal parts or possibility of metal fragments in the body (MR safety) Claustrophobia (MR safety) Dependence on a hearing aid (MR safety) Inability to follow the procedures of the study, e.g., due to language problems Participation in another study with investigational drugs within the 30 days preceding and during the present study More than three suicide attempts in the past, a suicide attempt within the last 12 months and/or acute suicidality Exclusion Criteria for Healthy Controls: Any current psychiatric diagnosis according to DSM-5 except for mild or moderate substance use disorder (SUD) for nicotine, and mild SUD for alcohol and cannabis Exclusion Criteria for both the PTSD and CUD groups: Allergy to minocycline or to any other ingredient in the named drug Current intake of the following medications interacting with minocycline: acitretin, acetylcystein, aluminiumhydroxid, amitryptiline, any antibiotics, antidiabetic drug such as sulfonylurea, atazanavir, atomoxetine, anticoagulant drugs from the coumarin type, barbiturates, bupropion, carbamazepine, ciclosporin A, isotretinoin, methotrexate, phenytoin, and theophylline Exclusion Criteria for only the PTSD group: Diagnosis of CUD according to DSM-5 (lifetime) Current diagnosis of severe SUD for nicotine, moderate SUD for alcohol and cannabis, and mild SUD for all other substances according to DSM-5 Exclusion Criteria for only the CUD group: Diagnosis of PTSD according to DSM-5 (lifetime) Current diagnosis of severe SUD for alcohol or cannabis, and mild SUD for all other substances (except for nicotine) according to DSM-5
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Amelie Zacher, MSc.
Phone
+41 58 384 35 54
Email
ameliesophie.zacher@bli.uzh.ch
First Name & Middle Initial & Last Name or Official Title & Degree
Lina Dietiker, MSc.
Email
lina.dietiker@bli.uzh.ch
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boris B. Quednow, Prof. Dr.
Organizational Affiliation
Psychiatric University Hospital Zurich, University of Zurich
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Birgit Kleim, Prof. Dr.
Organizational Affiliation
Psychiatric University Hospital Zurich, University of Zurich
Official's Role
Principal Investigator
Facility Information:
Facility Name
Psychiatric University Hospital Zurich, University of Zurich
City
Zürich
ZIP/Postal Code
8032
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amelie Zacher
Phone
+41 58 384 35 54
Email
ameliesophie.zacher@bli.uzh.ch
First Name & Middle Initial & Last Name & Degree
Lina Dietiker
Phone
+41 58 384 35 54
Email
lina.dietiker@bli.uzh.ch

12. IPD Sharing Statement

Plan to Share IPD
No

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Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories

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