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Biomarkers of Neuroinflammation and Anti-Inflammatory Treatments in Major Depressive Disorder

22. maj 2019 opdateret af: Jeff Meyer, Centre for Addiction and Mental Health
The purpose of this study is to determine if translocator protein total distribution volume (TSPO VT) is elevated in major depressive disorder that is not responding to medication and if adding minocycline can affect TSPO VT. Many remain treatment resistant with common antidepressant treatments and the investigators think it may be due to poor targeting of brain pathologies.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

There will be three Phases in the study. Only MDE subjects will be invited to continue to Phase 2 and 3. Subjects will be invited to continue to the subsequent Phase given they meet entry criteria described below:

Phase 1: The investigators will evaluate whether TSPO is elevated in individuals during a current MDE compared to healthy controls. Eligible participants will receive one [18F]FEPPA PET scan and one MRI scan. Other measures will include urine sample, blood samples for genetic and peripheral biomarker analysis, a neurocognitive battery, mood scales and questionnaires.

Phase 2: Participants who have elevated TSPO VT in Phase 1 and are agreeable to receiving minocycline will be invited to participate in Phase 2. Based on our previous results participants will be considered candidates for Phase 2 if TSPO VT ≥ 10.5 (HAB) or ≥8.5 (MAB) in any of the primary regions of interest (prefrontal cortex, anterior cingulate cortex or insula). Eligible participants will be invited to participate in a randomized, double blind, placebo controlled trial, to receive either minocycline or placebo. After the eight weeks of treatment, participants will receive one [18F]FEPPA PET scan. Other measures will include urine samples, blood samples, mood scales and questionnaires.

Phase 3: If, after the initial eight week treatment period with either minocycline or placebo, any participant continues to have depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 8) they will be invited to participate in an eight week open label trial of celecoxib. Participants not eligible for Phase 2 may also be invited to participate in Phase 3 directly from Phase 1.

Undersøgelsestype

Interventionel

Tilmelding (Forventet)

115

Fase

  • Tidlig fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5T 1R8
        • Centre for Addiction and Mental Health

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år til 65 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ja

Køn, der er berettiget til at studere

Alle

Beskrivelse

Group 1 - Current major depressive episode (MDE) secondary to MDD

Inclusion Criteria:

  • good physical health with no active medical conditions
  • non-cigarette smoking
  • no past or current substance abuse or dependence
  • negative urine pregnancy test at screening and scan days (for women)
  • primary diagnosis of current major depressive episode (MDE) and major depressive disorder (MDD) verified by SCID for DSM IV
  • score greater than 19 on the 17 item HDRS
  • non-response to a clinical trial of at least one antidepressant given at appropriate clinical dose
  • willing to take medication for the duration of the trial and has previously taken antidepressants for the duration of the trial
  • presently taking an antidepressant at a standard clinical dose.

Exclusion Criteria:

  • history of neurological illness or autoimmune disorders
  • never taken a tricyclic antidepressant or an antidepressant that raises norepinephrine
  • received treatment with electroconvulsive therapy or mechanical brain stimulation in the previous 6 months
  • currently taking medication contraindicated or that may possibly interact with either minocycline or celecoxib
  • known intolerance or allergy to minocycline, other tetracyclines, sulfonamides or NSAIDs
  • taken diazepam or other benzodiazepine use within the past month, except for lorazepam and clonazepam
  • use of anti-inflammatory drugs or tetracyclines lasting ≥1 week within the past month
  • history of severe hepatic or renal insufficiency, asthma, allergies, gastrointestinal disease, ischemic heart disease, cerebrovascular disease or congestive heart failure
  • lactose intolerance

Group 2 - Healthy Controls - Phase 1 (baseline scan) only

Inclusion criteria:

  • score below 8 on the 17 item HDRS
  • good physical health
  • non-cigarette smoking
  • negative urine pregnancy test at screening and scan days (for women)
  • negative urine screen for drugs of abuse

Exclusion criteria:

  • past or current diagnosis of axis I or axis II disorder as determined by the SCID I and SCID II for DSM IV
  • history of psychotropic medication use
  • history of neurological illness or autoimmune disorder

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Grundvidenskab
  • Tildeling: Randomiseret
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Firedobbelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Minocycline
The dose of minocycline would be 50mg per day on week 1, 50mg bid on week 2 and 100mg bid weeks 3-8. For tapering, the dose will be reduced to 50mg bid for a week, and then stopped.
Medicin: Minocycline
50 mg and 100 mg capsule, oral administration
Andre navne:
  • Mylan-minocycline
Placebo komparator: Placebo
The number and appearance of the pills would be identical to those in the minocycline arm.
Medicin: Placebo
Lactose monohydrate in identical gel capsules to minocycline, oral administration.
Andre navne:
  • Laktosemonohydrat
Andet: Celecoxib
This will be an open label trial for those with Hamilton Depression Rating Scale score ≥ 8 following the minocycline v. placebo trial or those not eligible for Phase 2. Dose of celecoxib will be 100 mg bid for the first week and 200mg bid for weeks 2-8. For tapering, the dose of celecoxib will be reduced to 100mg bid for one week, and then stopped.
Medicin: Celecoxib
100 mg and 200 mg capsules, oral administration.
Andre navne:
  • Celebrex (Pfizer)

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Translocator total distribution volume (TSPO VT): Treatment Effect of Minocycline in MDE Subjects
Tidsramme: Pre- and post-minocycline or placebo treatment= 8 weeks total between pretreatment and posttreatment scans
TSPO VT will be measured using [18F]FEPPA positron emission tomography brain scans. Eligible MDE participants will be randomized to either minocycline or placebo. Following 8 weeks of either minocycline or placebo treatment, MDE participants will have a second PET scan .
Pre- and post-minocycline or placebo treatment= 8 weeks total between pretreatment and posttreatment scans
Translocator total distribution volume (TSPO VT): Difference between MDE and healthy subjects
Tidsramme: Pre-treatment scan will take place up to 8 weeks from initial assessment
Compare baseline TSPO VT prior to treatment between MDE group and healthy group
Pre-treatment scan will take place up to 8 weeks from initial assessment

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Change in Hamilton Depression Rating Scale Score
Tidsramme: Pre- and post-minocycline treatment (8 weeks total between pre- and post-treatment). Pre- and post-celecoxib treatment (8 weeks total between pre- and post-treatment).
Change in HDRS score following minocycline vs. placebo treatment. Change in HDRS score following celecoxib treatment.
Pre- and post-minocycline treatment (8 weeks total between pre- and post-treatment). Pre- and post-celecoxib treatment (8 weeks total between pre- and post-treatment).

Andre resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Hopkins Verbal Learning Test-Revised
Tidsramme: Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure)
To assess verbal memory we will administer the Hopkins Verbal Learning Test-Revised to MDE participants before and after treatment.
Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure)
Brief Visuospatial Memory Test-Revised
Tidsramme: Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure)
To assess visuospatial memory we will administer the Brief Visuospatial Memory Test-Revised to MDE participants before and after treatment.
Pre- and post-minocycline or placebo treatment (8 weeks between pre- and post-treatment measure)
Comprehensive Trails Making Test
Tidsramme: Pre- and post-minocycline or placebo treatment.
To assess psychomotor speed and attention we will administer the Comprehensive Trails Making Test to MDE participants before and after treatment.
Pre- and post-minocycline or placebo treatment.
Genetic sample
Tidsramme: Phase 1-single sample
The priority of the genetic sample is to analyze the alleles of polymorphism rs6971 which has an association with the affinity of most second generation TSPO ligands including [18F]FEPPA. The genetic sample will also be used to study sequences of genes that are believed to affect TSPO expression, inflammation, mood and conditions that may predispose to mood disorders.
Phase 1-single sample
Blood samples (serum and plasma)
Tidsramme: Pre- and post-minocycline or placebo treatment (8 weeks between measures). Pre- and post-celecoxib treatment (8 weeks between measures).
Analyses will include complete blood cell count (CBC), ESR, hepatic and renal function. Peripheral marker analyses will include proteins related to TSPO expression and inflammation. Plasma minocycline and celecoxib levels will be analyzed.
Pre- and post-minocycline or placebo treatment (8 weeks between measures). Pre- and post-celecoxib treatment (8 weeks between measures).

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Centre for Addiction and Mental Health

Efterforskere

  • Ledende efterforsker: Jeffrey H Meyer, MD, PhD, Centre for Addiction and Mental Health; University of Toronto

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. februar 2015

Primær færdiggørelse (Faktiske)

1. april 2019

Studieafslutning (Faktiske)

1. april 2019

Datoer for studieregistrering

Først indsendt

4. februar 2015

Først indsendt, der opfyldte QC-kriterier

9. februar 2015

Først opslået (Skøn)

13. februar 2015

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

23. maj 2019

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

22. maj 2019

Sidst verificeret

1. maj 2019

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • REB056/2014

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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