There is new evidence in the continuing effort by researchers to probe how depression, stress, and inflammation affect the risk of suicide and suicidal behavior. Results of the new research, published in JAMA Psychiatry, “align with a growing body of literature supporting an association between suicide risk and various manifestations of cerebral neuroinflammation.”

The researchers, co-led led by BBRF Scientific Council member J. John Mann, M.D., and first author Sarah Herzog, Ph.D., both of Columbia University, note that decades of study have made clear that suicide risk is “multifactorial,” reflecting complex interactions between predisposing vulnerabilities such as genetics or family history and more immediate stressors such as major depressive episodes, acute or chronic stress, or other environmental conditions.

Dr. Mann, a renowned expert in the study of suicide, is the 2022 BBRF Colvin Prize winner and a 2008 BBRF Distinguished Investigator. The team also included Nadine Melhem, Ph.D., a 2013 and 2004 BBRF Young Investigator, and M. Elizabeth Sublette, M.D., Ph.D., a 2007 BBRF Young Investigator.

There is already considerable evidence of a relation between inflammation and suicide risk. Elevated inflammation levels in both the brain and the body’s periphery have been linked with risk. Postmortem examination has revealed structural alterations in brain cells called microglia in individuals who have died by suicide. Microglia are immune cells unique to the brain and central nervous system, and elevation in their numbers is usually taken to indicate immune system activation. Other postmortem studies have shown elevated expression of cytokines (specifically IL-4 and IL-13) in a part of the cortex in such individuals. Cytokines are chemical messengers whose numbers also increase when the immune system is active. Postmortem results have also shown that in other parts of the body—outside the central nervous system and brain—inflammatory markers including IL-6, TNA-alpha, and C-reactive protein are elevated in people who have died by suicide.

Despite this important evidence, it remains unclear precisely how inflammation, in the brain or in the body’s periphery, might affect suicide risk or a propensity for suicidal behavior. It has been proposed that neuroinflammation “may reflect a stress-sensitized brain state that confers risk for suicide by heightening an individual’s negative reactions to stress.” This stress reaction might take the form, for instance, of suicidal ideation and/or negative mood.

It is understood that life stressors are the most common intermediate event appearing to precipitate suicidal behavior, the team notes. Their study sought to determine whether pro-inflammatory processes in the central nervous system (including the brain) are associated with the acute emergence of suicidal ideation and negative mood specifically when stressors are present.

Hoping to shed light on the question, the team recruited 53 individuals (70% female; average age 30) with a diagnosis of current major depressive disorder. Nearly half had a co-morbid personality disorder, and 37% had a past history of substance use disorder. Importantly, 38 of the 53 had no past history of suicide attempt, while 15 did have such a history. Also important: of those who had a history, an average of 5 years had elapsed since the last suicide attempt.

Participants’ diagnoses were confirmed at the start of the study and suicide attempt history was taken. Participants also completed self-report measures of current suicidal ideation and depression severity. These assessments took place within about 3 weeks of a PET scan made of each participant’s brain.

Just before the scan, each was given an intravenous injection containing an imaging-sensitive radiotracer that enabled the team to detect a protein called TSPO over a 90-minute scan period. This protein is found throughout the body and performs various functions; in the brain, TSPO is found in the outer membrane of microglia cells, and evidence of its binding (which the PET scan detects) is regarded an excellent indicator of immune system activation. Participants also gave arterial blood samples to detect levels of TSPO binding in the body’s periphery during the PET scan.

A subgroup of 21 study participants completed 7 days of ecological momentary assessment (EMA), delivered via a smartphone or other electronic device. In most cases, this occurred within about 2 weeks of the PET scan. Each of the 21 was asked to report 6 times daily on levels of suicidal ideation, negative affect, and stressors. EMA allows for measurement of the emergence of suicidal ideation and related mood symptoms in response to real-world events which in turn could then be compared with levels of possible biomarkers such as TSPO.

Results in the subgroup that provided EMA assessments indicated that elevated TSPO binding in the brain was associated with greater suicidal ideation and negative affect during EMA sessions in which a stressor was reported (compared with sessions in which no stress was reported). Various methods were used by the team to conclude that this link between TSPO binding (i.e., elevated immune activity) and suicidal ideation was not accounted for either by the intensity of a participant’s depression before the PET scan, or by the intensity of negative feelings that were experienced and reported.

The team interpreted this as meaning that while TSPO might still be associated with both depression and negative affect, its association with suicidal ideation in the specific context of stress “is independent of mood symptoms.” The same conclusion was supported by looking at data from participants in the current study who did and did not have suicidal ideation. They found “significantly higher TSPO binding” in those with depression who reported suicidal ideation compared with those who reported no suicidal ideation.

In sum, the study suggests to the team that elevated TSPO binding in the brain “is associated with the propensity to experience more severe depressive symptoms” when stress is present. Put another way: elevated TSPO binding in people with depression may be an indicator of vulnerability to acute stress-related increases in suicidal ideation, and thus, risk of suicide.

In this study there was no evidence linking suicide attempt history and TSPO binding in the brain. This may reflect the fact that for the average study participant about 5 years had elapsed between the most recent suicide attempt and the PET scan. Future studies with larger samples might conduct the same testing in individuals with a recent suicide attempt in order to further clarify the link between TSPO binding and suicide risk.

As for the biology that might explain their observations, the team noted that elevations in TSPO binding in the brain may reflect a range of pro-inflammatory alterations not only in microglia, but also astrocytes and other cell types expressing the TSPO protein. Overall, the team said the study results support the broad concept of an association between suicide risk and manifestations of neuroinflammation in the brain and central nervous system.