Seeking the Mental Roads that Lead to Suicide

“To be or not to be?” For all too many of us, that is a very real question—and the answer is negative. More than 40,000 people in the US kill themselves each year (probably an underestimate, given the stigma still attaching to suicide), and there may be 20 attempts for each death.

The urgent need for more effective suicide prevention has spurred an increase in research to unravel the biological underpinnings of this complex act, sharpen clinicians’ ability to predict who is at risk and, ultimately, develop strategies to reduce that risk.

An illness in its own right?

In the US, some 90 percent of those who take their own lives have a diagnosable mental illness, typically depression, bipolar disorder, certain personality disorders, schizophrenia, substance abuse, or PTSD (in other countries the proportion is far lower). Interestingly, the lifetime risk of suicide is about the same for people with nearly all of these disorders — 8-10 percent. “There is something consistent across very different diagnoses,” says Maria Oquendo, chair of the department of psychiatry at University of Pennsylvania and immediate past president of the American Psychiatric Association (APA).

Such statistics and other data have led to a fundamental change in thinking: many experts now consider suicidality a psychiatric disorder in its own right. The latest version of the APA’s Diagnostic and Statistical Manual of Mental Disorders (DSM-V)—a kind of consensus document for the field of psychiatry—designates “suicidal behavior disorder” a condition for further study.

As with other psychiatric disorders, a main research objective has become deciphering the neurobiological functions and dysfunctions underlying suicidal thinking and behavior, what Oquendo calls its “biosignature.”

The brain aflame

Much of this work has focused on depression. “In part, this is because it is the most common condition in psychiatry, so it’s easier to find individuals with suicidal behavior for a homogeneous study group,” she says.

The interactions between depression and inflammation were the object of inquiry in a 2017 study at University of Manchester. While the literature linking the two is robust, earlier studies have for the most part looked at inflammation-linked compounds in the body, or post-mortem examination of the brain. Signs of neuroinflammation in the living brain have been elusive.

Replicating an earlier study, the researchers used PET imaging to study 14 depressed individuals and 13 people without depression, measuring translocator protein (TSPO), which is produced when microglia, the resident immune cells of the brain, are activated. The people with depression had significantly higher levels of the compound than those without. The difference was particularly marked in the anterior cingulate cortex (ACC), a mood-regulating brain region.

The increase in TSPO was not uniform, however, says Sophie Holmes, first author of the paper in Biological Psychiatry that reported the research. “We found it in a subset of patients, and we wanted to figure out what was going on in that subset.” What stood out was suicidal ideation. Levels of the protein were significantly raised only in the five patients who reported thinking about suicide.

This was unexpected, says Holmes, who is now at Yale. “We didn’t set out to look at suicidal thoughts.” But it was not entirely a surprise, either, “because a lot of research shows that inflammation is involved in such thinking.”

In future research, Holmes hopes to look at TSPO and suicidality in larger samples of patients that would include those with conditions like PTSD, schizophrenia, and bipolar disorder.

A 2017 review paper reported considerable research linking inflammation to suicidality across a variety of psychiatric diagnoses, and in traumatic brain injury and medical conditions as well.

Citing her own work and that of others, Lena Brundin, of the Center for Neurodegenerative Science and the Van Andel Research Institute, in Grand Rapids, and first author of the review, notes that “pronounced signs of inflammation” appear in about 50 percent of those who attempt suicide. There may be a dose-response effect, she says: the more inflammation, the more severe the suicidal thinking—and the more violent the attempt (i.e. gunshot or hanging, versus overdosing).

The Holmes paper is an important addition to this literature, says Brundin. “It strengthens the hypothesis that the inflammatory changes are specific for suicidality.”

Other systems

But Andrew Miller, director of the behavioral immunology program at Emory University, who did pioneering work in inflammation and depression, has doubts about just what the study shows. TSPO as a marker of inflammation lacks specificity, he says. “We know many activities that microglia can perform, from inflammation, to neuroprotection, to pruning synapses.”

Their role in synaptic remodeling may be particularly relevant here, he suggests. “If you’re suicidal, you’re thinking all the time about what’s going on in your life. The brain is working overtime, and microglia might be quite activated” as a consequence rather than a cause. “It’s a chicken-or-egg sort of thing,” he says.

Increased TSPO in the ACC, part of the brain’s alarm system, in particular, may reflect either a cause (via inflammation) or effect of suicidal ideation.

“I think there’s something here, from the inflammation side,” says Miller. “It’s an intriguing idea. But my position is that we should be more agnostic about what translocator protein binding means.”

Inflammation is not the only neurobiological mechanism linked to suicidal behavior. “Others most implicated are the hypothalamus-pituitary-adrenal (HPA) axis (which responds to stress) and the serotonergic system,” says Brundin. The three can interact: “Inflammation has the potential to drive changes in these systems, or it could be secondary [to them].”

A recent study, reported in JAMA Psychiatry, explored differences in how the brain regulates serotonin, a neurotransmitter that appears central to both mood and anxiety disorders.

The experiment used PET imaging to track the serotonin_1A receptor, which reduces the concentration of the neurotransmitter in synapses. In an earlier study of people who had attempted suicide, senior author Maria Oquendo and her colleagues had found a significant association between the number of these receptors in the dorsal raphe, the brain area whose neurons produces most serotonin, and the lethality (degree of physical damage) of the attempts.

“This paper goes a step further,” Oquendo says. “It’s the first prospective study along these lines: it looks at the ability of this measure to predict what lethality in the future will be.” The researchers did PET scans on 100 patients under treatment for moderate to severe depression. Fifteen of them attempted suicide in the following 2 years, including two who died, “Higher serotonin_1A binding [at the baseline scan] not only predicted higher lethality, but also the degree of suicidal ideation three months and 12 months after the initial evaluation,” she says.

A bigger picture

Such predictive measures could be vitally important. “Suicide is one of the few medical conditions in which the doctor and patient have different goals—the patient may be highly motivated not to reveal what he or she is thinking. We need biological markers so we can identify those at risk,” Oquendo says.

Holmes agrees. “We’re working on the use of inflammatory biomarkers for risk assessment in the hospital or clinic.” If the link is confirmed, “it raises the possibility of preventive measures targeting inflammation.” With a number of anti-inflammatory drugs already approved for clinical use, “I’d like to see these tested in patients with suicidal behavior,” she says. Non-drug approaches like cognitive behavioral therapy, mindfulness, exercise, and diet also appear to modify inflammation and could be part of a preventive strategy.

Beyond direct clinical applications, neurobiological research may give insights into the complex psychological pathways that lead to the desire to take one’s own life.

“We’re looking at subtypes of suicidal behavior,” says Oquendo. “Some attempts seem to be out of the blue, with no perceptible triggering circumstances, and other people seem to be reacting to something in their environment. We’re trying to see if these two types might have ties to different systems—the HPA axis, which mediates the effect of environmental stressors, and the serotonergic system, which mediates more of the ruminative negative thinking, the obsession with suicidal ideas that may occur in the absence of an external trigger.”

Approaching the subject from a different angle, several studies have identified genes associated with suicidality. “We know suicide runs in families, including some children adopted away from their biological parents.” says Oquendo. “There’s evidence that it’s quite heritable.”

Researchers have begun to look beyond genes themselves to the epigenetic changes that influence their activity. In one just-published study, such differences in stress response genes might suggest how environment and heredity combine to determine the seriousness of suicide attempts.

Can genetic and epigenetic profiles be linked to the neurobiological processes that appear to underlie suicidal behavior? This could be the object of future research, as parts of the puzzle fall into place.