Peripheral Immunomarker Validation in Treatment-resistant Depression

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).

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.

Eligibility Criteria:
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)