Neurobiological Analyses Within the FORESEE III Study

NCT04021823 | Unknown

• 1 other identifier: 40418
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

In this observational, non-invasive clinical study different neurobiological analyses will be performed in a group of patients with severe treatment resistant major depression participating in an efficacy study of deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB) - FORESEE III.

Conditions

Treatment Resistant Depression

Keywords

Treatment Resistant Depression; Neurobiological correlates of treatment resistant depression; Predictors of treatment response in DBS

Outcome Measures

Primary Outcomes (22)

• Change from baseline in DNA methylation patterns in plasma at 1 month of deep brain stimulation (DBS)

  Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.

  At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)

• Change from baseline in DNA methylation patterns in plasma at 4 month of deep brain stimulation (DBS)

  Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.

  At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)

• Change from baseline in DNA methylation patterns in plasma at 12 month of deep brain stimulation (DBS)

  Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression.

  At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)

• Change from baseline in neuroinflammatory and neuropeptide patterns at 1 month of deep brain stimulation (DBS)

  A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.

  At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)

• Change from baseline in neuroinflammatory and neuropeptide patterns at 4 month of deep brain stimulation (DBS)

  A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.

  At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)

• Change from baseline in neuroinflammatory and neuropeptide patterns at 12 month of deep brain stimulation (DBS)

  A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors.

  At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)

• Change from baseline in transcriptome profiles at 1 month of deep brain stimulation (DBS)

  A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.

  At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)

• Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 4 month of deep brain stimulation (DBS)

  A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.

  At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)

• Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 12 month of deep brain stimulation (DBS)

  A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles.

  At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)

• Change from baseline in plasma levels of Neurofilament light protein at 2 days before surgical device implantation

  Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.

  At baseline (up to 10 to 7 weeks before surgical device implantation) and at 2 days before surgical device implantation

• Change from baseline in plasma levels of Neurofilament light protein at 1 month of deep brain stimulation (DBS)

  Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.

  At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)

• Change from baseline in plasma levels of Neurofilament light protein at 4 month of deep brain stimulation (DBS)

  Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.

  At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)

• Change from baseline in plasma levels of Neurofilament light protein at 12 month of deep brain stimulation (DBS)

  Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays.

  At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)

• Change from baseline in metabolite profiles in plasma and urine at 1 month of deep brain stimulation (DBS)

  Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.

  At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)

• Change from baseline in metabolite profiles in plasma and urine at 4 month of deep brain stimulation (DBS)

  Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.

  At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)

• Change from baseline in metabolite profiles in plasma and urine at 12 month of deep brain stimulation (DBS)

  Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis.

  At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)

• Change from baseline in insuline resistance at week 41

  An oral glucose tolerance test with blood measures of glucose, insulin and c-peptide at several time points during a period of 3 hours after oral intake of 75g glucose will be performed.

  At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)

• Change from baseline in systemic metabolic parameters at week 41

  Different systemic metabolic parameters will be measured in blood.

  At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)

• Cardiac stroke volume (ml)

  Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).

  At test stimulation of the slMFB during neurosurgery

• Non-invasive blood pressure (mmHG)

  Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).

  At test stimulation of the slMFB during neurosurgery

• Cardiac stroke volume variation (%)

  Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring)

  At teststimulation of the slMFB during neurosurgery

• Systemic vascular resistance (mmHg⋅min⋅mL-1)

  Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring).

  At test stimulation of the slMFB during neurosurgery

Study Arms (2)

DBS patients

Patients with treatment resistant major depression participating in the FORESEE III study.

Healthy controls

Age- and sex-matched healthy controls undergoing analyses of neurodegenerative markers (neurofilament light protein) in blood and metabolomic analyses in blood and urine.

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Eligible participants are patients who participate in the FORESEE III study (NCT03653858) and have provided written informed consent to take part in this additional observational study. All patients suffering from severe, treatment-resistant depression, i.e. patients who have not sufficiently improved under established antidepressant therapies (such as psychotherapy, antidepressant drug therapy, and electroconvulsive therapy). As well as age- and sex-matched healthy controls.

You may qualify if:

• All enrolled subjects of the Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression (FORESEE III) may participate in this study.

You may not qualify if:

• Non-Caucasian (because of requirements for genetic/epigenetic analyses)
• Somatic diseases like diabetes, cancer and severe liver- and kidney-diseases
• Healthy Controls:
• All healthy volunteers without any clinically significant psychiatric or somatic symptoms are eligible.
• Any clinically significant psychiatric symptoms
• Conditions like diabetes, cancer or severe liver- and kidney diseases
• Drug or alcohol abuse

Sponsors & Collaborators

• University Hospital Freiburg: lead
• German Center for Neurodegenerative Diseases (DZNE): collaborator
• University Medical Center Freiburg: collaborator
• University Hospital, Bonn: collaborator
• University of Freiburg: collaborator

Study Sites (1)

University Hospital Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

RECRUITING

Related Publications (1)

• Spanier S, Kilian HM, Meyer DM, Schlaepfer TE. Treatment resistance in major depression is correlated with increased plasma levels of neurofilament light protein reflecting axonal damage. Med Hypotheses. 2019 Jun;127:159-161. doi: 10.1016/j.mehy.2019.03.022. Epub 2019 Mar 23.

  PMID: 31088642 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Treatment-Resistant

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Thomas E. Schläpfer, Prof. Dr.

  University of Freiburg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Susanne Spanier

CONTACT

‭+49 761 270 69800‬; susanne.spanier@uniklinik-freiburg.de

Thomas E. Schläpfer, Prof. Dr.

CONTACT

0049 761 270 68820; thomas.schlaepfer@uniklinik-freiburg.de

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Dr. Thomas E. Schläpfer

Study Record Dates

• First Submitted: June 24, 2019
• First Posted: July 16, 2019
• Study Start: August 1, 2019
• Primary Completion: June 1, 2022
• Study Completion: June 1, 2023
• Last Updated: November 10, 2020

Record last verified: 2020-11

Locations

DE (1)