Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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An Investigation of the Effect of MMP-9 Inhibition With Minocycline on the Reconsolidation of Intrusive Trauma- or Cocaine-related Memories

Conditions
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Post-traumatic Stress Disorder, Cocaine Use Disorder

Intervention / Treatment
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* Behavioral: Imagery
* Drug: Minocycline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 Inclusion Criteria for the Clinical Controls (PTSD+CUD 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 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 Diagnosis of CUD according to DSM-5 (lifetime) Diagnosis of PTSD according to DSM-5 (lifetime) 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blind, placebo-controlled, parallel group, single center study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTSD intervention group<br>30 individuals with PTSD will receive imagery with minocycline. | Behavioral: Imagery<br>* Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.<br>Drug: Minocycline<br>* Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule.<br>|
| Placebo Comparator: PTSD control group<br>30 individuals with PTSD will receive imagery with placebo. | Behavioral: Imagery<br>* Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.<br>Drug: Placebo<br>* Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule.<br>|
| Experimental: CUD intervention group<br>30 individuals with CUD will receive imagery with minocycline. | Behavioral: Imagery<br>* Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.<br>Drug: Minocycline<br>* Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule.<br>|
| Placebo Comparator: CUD control group<br>30 individuals with CUD will receive imagery with placebo. | Behavioral: Imagery<br>* Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.<br>Drug: Placebo<br>* Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule.<br>|
| No Intervention: Healthy control group<br>30 healthy individuals who will not receive any intervention. | |
| No Intervention: Clinical control group<br>30 individuals with both PTSD and CUD who will not receive any intervention | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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). | 
| 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 from baseline fMRI BOLD contrasts after 9 to max. 39 days (follow-up 1). | 
| 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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memory reconsolidation blockade, minocycline, MMP-9 inhibition, PTSD, cocaine use disorder, placebo-controlled