Clinical trial NCT05902819: Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories
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
Overall status: RECRUITING
Phase: NA
Conditions: Post-traumatic Stress Disorder
Cocaine Use Disorder
Keywords: memory reconsolidation blockade
minocycline
MMP-9 inhibition
PTSD
cocaine use disorder
placebo-controlled
Lead sponsor: Psychiatric University Hospital, Zurich
Sponsor class: OTHER
Collaborators: name: University of Zurich
First posted: 2023-06-15
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled, parallel group, single center study
Primary purpose: BASIC_SCIENCE

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.

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

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

Exclusion Criteria for the HC, PTSD, CUD, and PTSD+CUD groups:

* 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 HCN:

* Any self-reported current psychiatric diagnosis except for mild or moderate SUD for nicotine (F17.2)
* Self-reported acute intoxication with alcohol or cannabis
* \>25 intakes of cocaine, amphetamines, methamphetamine, MDMA, ketamine, psychedelics, benzodiazepines, other psychotropic substances such as novel psychoactive substances, non-prescribed opioids or methylphenidate
* Showing signs of acute mental health issues according to the GHQ-12 (Likert scale: cut-off 12 points)
* Self-reported suicidal ideations in the last 12 months

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

Primary outcomes:
measure: Changes in intrusive memories frequency and features
timeFrame: 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)
measure: Change over time in self-reported intrusive memories frequency, arousal and distress
timeFrame: 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: Changes in fMRI Blood-Oxygenation-Level Dependent (BOLD) contrasts
timeFrame: Changes from baseline fMRI BOLD contrasts after 9 to max. 39 days (follow-up 1).
measure: Changes in MRS signal parameters
timeFrame: Change from baseline MRS-measured glutamate concentrations after 9 to max. 39 days (follow-up 1).
Secondary outcomes:
measure: Change in heart rate variability (HRV) during fMRI memory reactivation
timeFrame: Change from baseline HRV after 9 to max. 39 days (follow-up 1).
measure: Change in respiratory rate during fMRI memory reactivation
timeFrame: Change from baseline respiratory rate after 9 to max. 39 days (follow-up 1).
measure: Change in subjective rating of distress before and after memory reactivation
timeFrame: Change from baseline subjective distress after 9 to max. 39 days (follow-up 1).
measure: Change in subjective rating of craving before and after memory reactivation
timeFrame: Change from baseline craving after 9 to max. 39 days (follow-up 1).
measure: Change in neurofilament light chain (NfL) levels
timeFrame: Change from baseline NfL levels after 9 to max. 39 days (follow-up 1).
measure: Change in sphingolipid levels
timeFrame: Change from baseline sphingolipid levels after 9 to max. 39 days (follow-up 1).
measure: Change in inflammatory biomarker levels
timeFrame: Change from baseline inflammatory levels after 9 to max. 39 days (follow-up 1).
measure: Change in MMP-9 protein levels
timeFrame: Change from baseline MMP-9 protein levels after 9 to max. 39 days (follow-up 1).
measure: Change in MMP-9 gene expression
timeFrame: Change from baseline MMP-9 gene expression after 9 to max. 39 days (follow-up 1).
measure: Heartrate variability
timeFrame: Will be measured during 9 to max. 39 days, from baseline until follow-up 1.
measure: Sleep duration
timeFrame: Will be measured during 9 to max. 39 days, from baseline until follow-up 1.
measure: Change in Obsessive Compulsive Cocaine Use Scale (OCCUS)
timeFrame: Change from baseline OCCUS score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
measure: PTSD Checklist for DSM-5 (PCL-5)
timeFrame: Change from baseline PCL-5 score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
measure: Beck Depression Inventory-II (BDI-II)
timeFrame: Change from baseline BDI-II score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
measure: Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Change from baseline PSQI score after both 9 to 39 days (follow-up 1) and approx. 3.5 months (follow-up 2).
measure: Global Assessment of Functioning (GAF)
timeFrame: Change from screening GAF score after both 10 to 50 days (follow-up 1) and approx. 4 months (follow-up 2).
measure: Clinician-Administered PTSD Scale for DSM-5 (CAPS-5)
timeFrame: Change from screening CAPS-5 score after approx. 4 months (follow-up 2).
measure: Changes in the Interview for Psychotropic Drug Consumption (IPDC)
timeFrame: Change from screening IPDC after approx. 4 months (follow-up 2).
measure: Voice-recorded language features of memories
timeFrame: Assessed at screening
Other outcomes:
Locations:
city: Zürich
country: Switzerland
facility: Psychiatric University Hospital Zurich, University of Zurich
Study officials:
affiliation: Psychiatric University Hospital Zurich, University of Zurich
name: Boris B. Quednow, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Psychiatric University Hospital Zurich, University of Zurich
name: Birgit Kleim, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: