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| Name | Class |
|---|---|
| University of Zurich | OTHER |
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An investigation of the effect of matrix-metalloproteinase-(MMP)-9 inhibition with minocycline on the reconsolidation of trauma- or cocaine-related memories
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PTSD intervention group | Experimental | 30 individuals with PTSD will receive imagery with minocycline. |
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| PTSD control group | Placebo Comparator | 30 individuals with PTSD will receive imagery with placebo. |
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| CUD intervention group | Experimental | 30 individuals with CUD will receive imagery with minocycline. |
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| CUD control group | Placebo Comparator | 30 individuals with CUD will receive imagery with placebo. |
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| Healthy control group | No Intervention | 30 healthy individuals who will not receive any intervention. | |
| Clinical control group | No Intervention |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Imagery | Behavioral | Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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) |
| 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. | EMA will be conducted for an average of 12 to 42 days (through study participation from baseline to 3 days after follow-up 1). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Change from baseline MRS-measured glutamate concentrations after 9 to max. 39 days (follow-up 1). |
| Changes in fMRI Blood-Oxygenation-Level Dependent (BOLD) contrasts |
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General Inclusion Criteria:
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:
Inclusion Criteria for the Clinical Controls (PTSD+CUD group):
Exclusion Criteria for the HC, PTSD, CUD, and PTSD+CUD groups:
Exclusion Criteria for Healthy Controls:
Exclusion Criteria for both the PTSD and CUD groups:
Exclusion Criteria for only the PTSD group:
Exclusion Criteria for only the CUD group:
Exclusion Criteria for Clinical Controls (PTSD+CUD group):
- Current diagnosis of severe SUD for alcohol or cannabis, and mild SUD for all other substances (except for nicotine) according to DSM-5
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| Name | Affiliation | Role |
|---|---|---|
| Boris B. Quednow, Prof. Dr. | Psychiatric University Hospital Zurich, University of Zurich | Principal Investigator |
| Birgit Kleim, Prof. Dr. | University Hospital of Psychiatry Zurich, University of Zurich | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital of Psychiatry Zurich, University of Zurich | Zurich | 8032 | Switzerland |
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| ID | Term |
|---|---|
| D013313 | Stress Disorders, Post-Traumatic |
| C562573 | cyclopia sequence |
| ID | Term |
|---|---|
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D008911 | Minocycline |
| ID | Term |
|---|---|
| D013754 | Tetracyclines |
| D009279 | Naphthacenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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Randomized, double-blind, placebo-controlled, parallel group, single center study
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double-blinded
30 individuals with both PTSD and CUD who will not receive any intervention
| Minocycline | Drug | Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule. |
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| Placebo | Drug | Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule. |
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fMRI BOLD contrasts between conditions (neutral/stress/trauma for the PTSD group; neutral/reward/drug for the CUD group) and between groups. |
| Changes from baseline fMRI BOLD contrasts after 9 to max. 39 days (follow-up 1). |
| 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 from baseline HRV after 9 to max. 39 days (follow-up 1). |
| 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 from baseline respiratory rate after 9 to max. 39 days (follow-up 1). |
| 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 from baseline subjective distress after 9 to max. 39 days (follow-up 1). |
| 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 from baseline craving after 9 to max. 39 days (follow-up 1). |
| Change in neurofilament light chain (NfL) levels | NfL levels will be measured in serum samples. | Change from baseline NfL levels after 9 to max. 39 days (follow-up 1). |
| Change in sphingolipid levels | Sphingolipid levels will be measured in plasma samples. | Change from baseline sphingolipid levels after 9 to max. 39 days (follow-up 1). |
| Change in inflammatory biomarker levels | Inflammatory biomarker levels will be measured in serum samples. | Change from baseline inflammatory levels after 9 to max. 39 days (follow-up 1). |
| Change in MMP-9 protein levels | MMP-9 protein levels will be measured in plasma samples. | Change from baseline MMP-9 protein levels after 9 to max. 39 days (follow-up 1). |
| Change in MMP-9 gene expression | MMP-9 gene expression will be measured in blood samples. | Change from baseline MMP-9 gene expression after 9 to max. 39 days (follow-up 1). |
| 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. | Will be measured during 9 to max. 39 days, from baseline until follow-up 1. |
| 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. | Will be measured during 9 to max. 39 days, from baseline until follow-up 1. |
| 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. | Change from baseline OCCUS score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2). |
| 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. | Change from baseline PCL-5 score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2). |
| 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. | Change from baseline BDI-II score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2). |
| 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. | Change from baseline PSQI score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2). |
| 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). | Change from screening GAF score after both 10 to 50 days (follow-up 1) and approx. 4 months (follow-up 2). |
| 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. | Change from screening CAPS-5 score after approx. 4 months (follow-up 2). |
| 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. | Change from screening IPDC after approx. 4 months (follow-up 2). |
| Voice-recorded language features of memories | Voice features and text-based features of reported autobiographical memories recorded during the screening to predict symptoms, with a primary focus on the prediction of intrusion-related features. | Assessed at screening |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |