Peripheral Immunomarker Validation in Treatment-resistant Depression

Depressive Disorder, Major Clinical Trial

— BIODEP  

Official title:

A Clinical Biomarker Study of Immunological Phenotypes Associated With Monoaminergic Anti-depressant Response, and the Brain and Cognitive Phenotypes Associated With Variation in Peripheral C-reactive Protein (CRP) Levels, in Patients With Major Depressive Disorder (MDD).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02752178
• Other study ID #: 15/EE/0092
• Status: Completed
• Start date: June 2015
• Est. completion date: September 2018

Study information

• Verified date: September 2018
• Source: University of Cambridge
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is a study to characterise the role of inflammatory processes in depression. There is compelling evidence that inflammation is often associated with, and can cause, depression. It is currently less clear that antiinflammatory drugs have meaningful antidepressant effect. One of the goals is to identify the subset of depressed patients that is most likely to respond better to an antiinflammatory drug than to a conventional antidepressant. The investigators will therefore undertake a study of patients with a diagnosis of major depressive disorder including four groups: i) incompletely responsive patients who have demonstrated failure to respond consistently or completely to standard treatment, ii) those who have responded well to treatment and are not currently depressed, iii) untreated patients who are currently depressed, iv) healthy volunteers with no history of depression. Participants will undergo a clinical assessment, an interview with a trained member of the research team and will complete self-rated questionnaires. Investigators will collect blood and saliva samples to measure certain immune markers. They will also perform magnetic resonance imaging (MRI) scans to look for MRI markers in the brain and investigate brain inflammation in a subsample of these patients using positron emission topography (PET) and cerebrospinal fluid (CSF) sampling (also called lumbar puncture).

Description:

The hypotheses are (i) that therapeutic resistance to monoaminergic (MA) antidepressant drugs is associated with peripheral biomarkers indicating abnormal activation of the innate immune system; and (ii) that peripheral inflammation, defined by blood levels of C-reactive protein (CRP), is associated with central nervous system inflammation and abnormal brain structure and function.

The objectives are to test these two hypotheses by collecting clinical, immunological and neuroimaging data on patients with depression (DEP+) recruited from a network of clinical research sites in the United Kingdom.

Primary objective:

To measure peripheral immunophenotypes in healthy volunteers (at least N=50) and 3 groups of depressed patients, categorised by their exposure and therapeutic response to monoaminergic antidepressants (up to N=200):

• Incompletely responsive patients (approximately N ~100) who are currently depressed after greater than 6 weeks of treatment with one or more monoaminergic antidepressants (DEP+MA+);

• Responsive patients (approximately N~50) who are not currently depressed after greater than 6 weeks of treatment with a monoaminergic antidepressant (DEP-MA+);

• Untreated patients (approximately N~50) who are currently depressed but have not been treated with monoaminergic antidepressants in the previous 6 weeks (DEP+MA-);

• Healthy volunteers (approximately N~50) who have no personal history of depression requiring treatment with either monoaminergic antidepressants or other clinical interventions including psychotherapy (DEP-MA-).

Secondary objective:

To measure brain and cognitive phenotypes in a subsample of up to N=100 depressed patients recruited, preferably from the primary cohort, on the basis of their CRP levels:

• Low CRP patients (N~45) will have CRP <= 3 mg/L

• High CRP patients (N~45) will have CRP > 3 mg/L

• Healthy volunteers (at least N=45).

All subjects in this sample will be assessed using structural and functional magnetic resonance imaging (MRI) and subjects providing additional specific consents will also be assessed using positron emission tomography (PET-MR), and/or lumbar puncture (LP) for cerebrospinal fluid (CSF) sampling.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 393
• Est. completion date: September 2018
• Est. primary completion date: September 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 25 Years to 50 Years

Eligibility

Inclusion Criteria:

• Major depressive disorder diagnosed by structured clinical interview in accordance with Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria

• Aged 25-50 years inclusive

• HAM-D score at baseline

1. DEP+MA+ subgroup > 13

2. DEP+MA- subgroup > 17

3. DEP-MA+ subgroup < 7

• Able and willing to give informed consent, including consent to sharing of clinical information with the participant's general practitioner

• Willing to abstain from strenuous exercise for 72 hours prior to assessment

• Able to write, speak and understand English

Exclusion Criteria:

• Life time history of bipolar disorder or nonaffective psychosis

• Concurrent medication likely to compromise the interpretation of immunological data (including, but not limited to corticosteroids, or any other substance to be determined by the Principal Investigator or delegate)

• Pregnancy or breast feeding

• Active alcohol or drug abuse or dependence in the last 6 months

• Participation in clinical trial of an investigational drug within the last 12 months

• Lifetime history of any serious medical disorder likely to compromise the interpretation of immunological data (including, but not limited to, immunological disorders, cardiovascular disorders, malignancies or infection, or any other condition to be determined by the Principal Investigator or delegate)

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Depressive Disorder, Treatment-Resistant

Intervention

Other:
• MA
Monoaminergic antidepressant use
• DEP
Depression measured using the Hamilton Depression (HAM-D) questionnaire

Locations

Country	Name	City	State
United Kingdom	University of Sussex	Brighton
United Kingdom	University of Cambridge	Cambridge
United Kingdom	University of Glasgow	Glasgow
United Kingdom	King's College London	London
United Kingdom	University of Oxford	Oxford

Sponsors (8)

Lead Sponsor	Collaborator
University of Cambridge	GlaxoSmithKline, H. Lundbeck A/S, Janssen, LP, King's College London, University of Glasgow, University of Oxford, University of Sussex

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	C-reactive protein (CRP) levels (mg/l)		One year after last participant visit
Primary	Flow cytometric immunophenotype	The exact antibody panel will be developed during the research study	One year after last participant visit
Secondary	Structural parameters of the brain	Measured using MRI. Specifically: larger grey matter volume loss, quantitative parameters (T1, T2), magnetization transfer, and the microstructure of grey and white matter	One year after last participant visit
Secondary	Response to stimulus	Specifically: functional MRI (fMRI) signatures obtained in an emotional face recognition and a reward processing task, respectively.	One year after last participant visit
Secondary	Microglial activation in the brain	Measured using Positron Emission Tomography (PET)	One year after last participant visit
Secondary	Pro-inflammatory (M1-like) phenotype-producing cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a circulating in cerebrospinal fluid		One year after last participant visit