Tracking Peripheral Immune Response in Patients with Recent Suicide Attempts: A Longitudinal Approach

Suicide attempts are a major public health concern and occur far more frequently than suicide deaths. Yet despite their impact, we still lack reliable biological indicators that can help identify who is at highest risk or explain why some individuals experience a suicide attempt during an episode of depression while others do not. Growing research suggests that the immune system may play a role in suicidal behavior, but most studies have used single blood measurements and have not followed patients over time. As a result, it remains unclear whether immune changes are temporary reactions to acute stress, specific to suicidal behavior, or long-standing traits that persist even after recovery.

This study aims to address these questions by following individuals who have recently made a suicide attempt and comparing them with individuals who have depression but have never attempted suicide. We focus on a specific part of the immune system: T cells, which help regulate inflammation. Under certain conditions, such as chronic stress or continuous activation, T cells can become exhausted, meaning they lose their ability to function effectively. Two proteins found on the surface of these cells Programmed Death-1 (PD-1) and Lymphocyte Activation Gene-3 (LAG-3) are well-known indicators of this exhaustion. Our preliminary findings suggest that these markers may be elevated in people with suicidal behavior, but no study has examined how they change over time.

We will recruit 100 adults aged 18-60 who are currently experiencing a major depressive episode. Half will have made a suicide attempt within the previous 96 hours, and half will be individuals with depression but no lifetime history of attempts or suicidal thoughts. All participants will be evaluated using standardized psychiatric interviews, depression severity scales, and measures of life stress and childhood adversity. Blood samples will be collected at the first visit and again six months later.

Using these samples, we will measure several indicators of immune function. These include:

1. the presence of exhaustion markers (PD-1 and LAG-3) on T cells;

2. the ability of T cells to produce key signaling molecules after stimulation; and

3. levels of inflammatory molecules circulating in the blood.

Aim 1 will examine whether immune exhaustion is a temporary, state-dependent change related to the suicide attempt. We expect that PD-1 and LAG-3 levels will be high shortly after the attempt but decrease six months later in those who recover.

Aim 2 will test whether these changes are specific to suicide attempts and not just a result of depression. We hypothesize that individuals with a recent attempt will show higher immune exhaustion at baseline than depressed individuals without any history of attempts.

Aim 3 will determine whether some immune changes persist beyond recovery, suggesting a trait-like biological vulnerability.

This project could advance the field by identifying stable immune markers associated with suicide attempts, improving our ability to detect risk, and informing the development of future interventions.