Reconsolidation Blockade of Intrusive Trauma- and Cocaine-related Memories

Post-traumatic Stress Disorder Clinical Trial

— Memocycline  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05902819
• Other study ID #: 2022-01177
• Status: Recruiting
• Phase: N/A
• Start date: May 10, 2023
• Est. completion date: December 31, 2024

Study information

• Verified date: December 2023
• Source: Psychiatric University Hospital, Zurich
• Contact: Amelie Zacher, MSc.
• Phone: +41 58 384 35 54
• Email: ameliesophie.zacher[@]bli.uzh.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An investigation of the effect of matrix-metalloproteinase-(MMP)-9 inhibition with minocycline on the reconsolidation of trauma- or cocaine-related memories

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 31, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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 (?GT) 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

Related Conditions & MeSH terms

• Cocaine Use Disorder
• Post-traumatic Stress Disorder
• Stress Disorders, Post-Traumatic
• Stress Disorders, Traumatic

Intervention

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

Drug:
• Minocycline
Single dose of minocycline (200mg) at each of two imagery sessions; Minocycline is given orally in form of a capsule.
• Placebo
Single dose of mannitol (100%) at each of two imagery sessions; Placebo is given orally in form of a capsule.

Locations

Country	Name	City	State
Switzerland	Psychiatric University Hospital Zurich, University of Zurich	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
Psychiatric University Hospital, Zurich	University of Zurich

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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).
Primary	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).
Primary	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	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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.
Secondary	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.
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).
Secondary	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).