Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories

N/AActive Not RecruitingNCT05902819

Psychiatric University Hospital, Zurich210 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

210

Conditions

Post-traumatic Stress Disorder Cocaine Use Disorder

Interventions

ImageryBEHAVIORAL

Guided imagery of personal trauma- or cocaine-related memory approximately 120min after study medication was given.

MinocyclineDRUG

Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule.

PlaceboDRUG

Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Psychiatric University Hospital Zurich, University of Zurich

Zurich, Switzerland

Outcomes

Primary Outcomes

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.

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)

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.

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).

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.

Time frame: 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.

Time frame: Change from baseline MRS-measured glutamate concentrations after 9 to max. 39 days (follow-up 1).

Secondary Outcomes

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).

Time frame: Change from baseline HRV after 9 to max. 39 days (follow-up 1).

Data from ClinicalTrials.gov

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