A Longitudinal Study of Inflammatory Pathways in Depression

Suicide is a leading cause of death in the US, and its rate continues to increase. Most individuals who die by suicide are in contact with health care, but clinical risk assessment is challenging. Inflammatory biomarkers have tentatively been linked to suicide. However, longitudinal studies establishing their accuracy in tracking suicidal behavior and critical symptoms are lacking. This study is a longitudinal study, with 1,280 total assessments planned, measuring suicidal ideation and behavior, associated clinical symptoms and blood biomarkers of inflammation.

Our overriding aim is to identify a set of biomarkers that distinguish patients with suicidal behavior from depressive patients without suicidal behavior. Further, the investigators intend to define biomarkers that are elevated during active suicidal behavior (at- risk periods) within the same patients (longitudinally).

Our working model is that inflammation (via pro-inflammatory cytokines) induces the kynurenine pathway, leading to an increased production of neurotoxic kynurenine metabolites (i.e., the NMDA-receptor agonist quinolinic acid, or others), which trigger suicidal behavior. The Investigators predict that immunomodulatory cells and molecules, including cytokines and kynurenine metabolites in plasma, may constitute biomarkers of suicidal behavior. The Investigators also predict that elevated inflammatory markers in suicidal individuals will be associated with epigenetic changes, regulating the expression of kynurenine enzymes in blood cells.

Aims:

• Establish biomarkers that indicate risk for active suicidal behavior;
• Determine epigenetic markers in the blood of patients with suicidal behavior.

In Aim 1, the investigators will enroll patients with Major Depressive Disorder (MDD) and active suicidal behavior (planning or attempts), and MDD patients without current or past suicidal behavior. Each subject will be assessed at eight time-points over one year. The Investigators will measure interleukins and acute phase reactants as well as tryptophan, serotonin and metabolites of the kynurenine pathway in peripheral blood.

For aim 2, the investigators will perform whole-genome methylation analysis using Illumina EPIC arrays, followed by gene pathway analyses, in blood of the enrolled patients.

Our project will aid the implementation of biomarkers in clinical care for patients with suicide risk, in order to enable intensified intervention during critical time-points. The biological insight obtained here can guide therapeutic development specifically targeting suicidality, with the ultimate goal of reducing suicide numbers.

Inclusion criteria

• Men and women ages 18 years and older will be included in the study.
• 80 who are diagnosed with MDD by SCID but do not endorse current or past suicidal behaviors.
• 80 who are diagnosed with MDD by SCID and endorse current suicidal behavior as defined by C-SSRS (preparatory acts, aborted or interrupted attempts, as well as completed attempts).
• English speaking.
• Willing and able to take part of the different steps in the study, including follow-up interviews and blood draws.

Exclusion criteria

• Vulnerable populations (e.g. incarcerated individuals).
• Subjects with dementia or otherwise cognitively impaired subjects with difficulty understanding the study procedures.
• Patients with a primary psychiatric diagnosis other than MDD.
• Patients with an active somatic disorder primarily involving the immune system (autoimmune diseases such as Crohns disease, multiple sclerosis, or rheumatoid arthritis; or hematological diseases such as lymphoma or leukemia).
• Patients on chronic and systemic immunomodulatory treatment. Examples are patients with a liver- or kidney transplant or medications used for disorders involving the immune system, as mentioned above. Examples of immunomodulatory treatments are cyclosporin, azathioprine, infliximab, corticosteroid treatment.
• Patients undergoing active treatment for any form of cancer (chemotherapy or immunomodulatory treatments).