Clinical trial NCT04021823: Neurobiological Analyses Within the FORESEE III Study
Official title: Neurobiological Analyses Within the FORESEE III Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Treatment Resistant Depression
Keywords: Treatment Resistant Depression
Neurobiological correlates of treatment resistant depression
Predictors of treatment response in DBS
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
Collaborators: name: German Center for Neurodegenerative Diseases (DZNE)
name: University Medical Center Freiburg
name: University Hospital, Bonn
name: University of Freiburg
First posted: 2019-07-16
Enrollment: 50
Sex: ALL
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: This study is a sub-project of the FORESEE III study (Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression). The FORESEE III study itself is a randomized, sham-controlled, double blind (patient and observer blinded) clinical trial to assess the antidepressant effect of DBS compared to sham.

The aim of this sub-project is to analyze the time-course of biological correlates of treatment resistant major depression as well as neurobiological markers of treatment response to treatment with DBS in a well-characterized patient population during 12 month of DBS.

Specific neurobiological analyses include testing of

1. epigenetic markers (DNA methylation in candidate genes of depression and epigenome-wide association studies, EWAS)
2. markers of neuroinflammation (cytokines, neuropeptides and other immune factors)
3. micro RNAs and transcriptome signatures
4. markers of neurodegeneration (neurofilament light protein)
5. metabolomic analyses and
6. endocrinological parameters including glucose tolerance.

All markers will be tested in blood samples (and urine samples for metaboloic profiling) before neurosurgery as well as at several time points during DBS and sham condition intervals.

Additionally hemodynamic parameters will be analysed at test stimulation of the slMFB during neurosurgery.

The results will be correlated with clinical and other biological response parameters of the FORESEE III study and are hypothesized to indicate treatment response as well as allowing prediction of response to DBS. All neurobiological analyses will be linked in a tightly integrated and comprehensive translational approach.

Further, a volunteer group of healthy controls will be recruited and tested for blood-markers of neurodegeneration (neurofilament light protein, 4.) as well as metabolomic analyses in blood and urine (5.).

Eligibility criteria: DBS Patients:

Inclusion Criteria:

* 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.

Exclusion Criteria:

* Non-Caucasian (because of requirements for genetic/epigenetic analyses)
* Somatic diseases like diabetes, cancer and severe liver- and kidney-diseases

Healthy Controls:

Inclusion Criteria:

* All healthy volunteers without any clinically significant psychiatric or somatic symptoms are eligible.

Exclusion Criteria:

* Any clinically significant psychiatric symptoms
* Conditions like diabetes, cancer or severe liver- and kidney diseases
* Drug or alcohol abuse

Primary outcomes:
measure: Change from baseline in DNA methylation patterns in plasma at 1 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
measure: Change from baseline in DNA methylation patterns in plasma at 4 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
measure: Change from baseline in DNA methylation patterns in plasma at 12 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
measure: Change from baseline in neuroinflammatory and neuropeptide patterns at 1 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
measure: Change from baseline in neuroinflammatory and neuropeptide patterns at 4 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
measure: Change from baseline in neuroinflammatory and neuropeptide patterns at 12 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
measure: Change from baseline in transcriptome profiles at 1 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
measure: Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 4 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
measure: Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 12 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
measure: Change from baseline in plasma levels of Neurofilament light protein at 2 days before surgical device implantation
timeFrame: At baseline (up to 10 to 7 weeks before surgical device implantation) and at 2 days before surgical device implantation
measure: Change from baseline in plasma levels of Neurofilament light protein at 1 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
measure: Change from baseline in plasma levels of Neurofilament light protein at 4 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
measure: Change from baseline in plasma levels of Neurofilament light protein at 12 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
measure: Change from baseline in metabolite profiles in plasma and urine at 1 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B)
measure: Change from baseline in metabolite profiles in plasma and urine at 4 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B)
measure: Change from baseline in metabolite profiles in plasma and urine at 12 month of deep brain stimulation (DBS)
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups)
measure: Change from baseline in insuline resistance at week 41
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)
measure: Change from baseline in systemic metabolic parameters at week 41
timeFrame: At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups)
measure: Cardiac stroke volume (ml)
timeFrame: At test stimulation of the slMFB during neurosurgery
measure: Non-invasive blood pressure (mmHG)
timeFrame: At test stimulation of the slMFB during neurosurgery
measure: Cardiac stroke volume variation (%)
timeFrame: At teststimulation of the slMFB during neurosurgery
measure: Systemic vascular resistance (mmHg⋅min⋅mL-1)
timeFrame: At test stimulation of the slMFB during neurosurgery
Secondary outcomes:
Other outcomes:
Locations:
city: Freiburg
country: Germany
facility: University Hospital Freiburg
state: Baden Württemberg
Study officials:
affiliation: University of Freiburg
name: Thomas E. Schläpfer, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.