Infection requiring hospitalization has been linked to a 43% increased risk of dying by suicide. The finding raises questions about the role of biological mechanisms of infection, particularly neuroinflammation, on suicidal behaviors.

"Our findings indicate that infections may have a relevant role in the pathophysiological mechanisms of suicidal behavior," the investigators, with first author Helene Lund-Sørensen, BM, Copenhagen University Hospital, Denmark, write.

"To our knowledge, this investigation is the largest study to date to examine infections as a predictor of death by suicide," they report.

The researchers also note that although "psychiatric disorders and previous suicide attempts might constitute stronger predictors of suicide, we found that hospitalization with infection accounted for a population-attributable risk of 10.1%.

"The implication is that 1 in 10 suicides could be prevented if infections were to be eliminated entirely, provided that the association was causal," they write.

The study was published online August 10 in JAMA Psychiatry.

Focus on Biological Predictors

The authors note that although psychological predictors of suicide have been studied extensively, less attention has been paid to the effect of biological factors, such as infection.

To estimate the association between hospitalization with infection and the risk for death by suicide, the investigators used Danish nationwide registers, which included a total of 7.22 million Danish citizens aged 15 years or older living in Denmark between January 1, 1980, and December 31, 2011. The patients were observed during a 32-year follow-up period.

The overall rate of hospitalization with infection in the study population was 11.2%, and the rate of infection among individuals who died by suicide (n = 32,683) was 24.1% (n = 7892).

After adjusting for factors that included sex, age, calendar period, cohabitation status, socioeconomic status, and scores on the Charlson Comorbidity Index, the incidence rate ratio (IRR) of suicide was 1.42 among those with infection compared to those without.

In addition, the risk was increased in a dose-dependent manner, with the highest incidence of suicide (IRR, 2.90) among those with seven or more infections. Among those with just one infection, the IRR was 1.34 compared to those with no infections.

The duration of hospitalization for infection treatment was also associated with suicide risk, ranging from an IRR of 2.38 after 94 days of hospitalization to 1.46 for 1 to 4 days of hospitalization. The amount of time since hospitalization was also significant, with the strongest effect 1 and 2 years after hospitalization (P < .001) compared to those without infection.

The increased risk included most types of infection with the exceptions of otitis media and pregnancy-related infections.

The highest suicide risk was associated with hepatitis (IRR, 2.12) and HIV or AIDS (IRR, 2.32) ― a finding that is consistent with previous research showing higher rates of suicidal behavior in those populations. Risk was also notably high in association with infections of the respiratory tract (IRR, 1.54) and sepsis (IRR, 1.51).

Bacterial infections were associated with only a slightly higher risk for suicide compared to viral infections (IRR, 1.37 and 1.26, respectively), a finding that likely rules out antibiotic treatment and its effect on the microbiome in influencing the risk, the authors note.

Surprising Finding

Notably, the increased suicide risk associated with infection was still 1.31-fold higher even among individuals with no history of a psychiatric diagnosis, including those with no history of schizophrenia or affective disorder (IRR, 1.40) and no history of substance use (IRR, 1.35).

"This was one of the most surprising findings," Dr Lund-Sørensen told Medscape Medical News.

"After accounting for individuals diagnosed with any psychiatric disorder, we still found a significant increased risk of dying by suicide after infections, implying that psychiatric disorders may only partly explain the association."

She pointed out the risk was not higher among those who did have a history of a psychiatric diagnosis (IRR, 0.93).

Potential mechanisms linking infection to suicidal behavior are numerous, possibly involving a number of different pathways to the brain, the authors note.

"Although certain infectious agents infect the brain directly, others reach the brain from the periphery, and yet others generate molecular mediators of inflammation that cross from the periphery into the brain and thereby increase the risk of suicide," they write.

In particular, influenza B virus and the parasite Toxoplasma gondii have been linked to suicidal behavior. The latter has been shown to be associated with impulsivity and aggression in psychiatric patients and healthy adults alike.

Inflammatory Evidence

Patients with recent suicide attempts have been shown to have elevated levels of interleukin 6 (IL-6) and the inflammatory metabolite quinolinic acid, and a recent meta-analysis found a robust link between increased IL-6 and IL-1β levels and increased suicidality.

Furthermore, postmortem brain samples of patients who died from suicide have shown increases in quinolinic acid as well as increases in the level of messenger RNA of inflammatory cytokines.

The authors speculate that immune system alterations that can either lead to or result from infection could play a role in suicidal behaviors.

Then again, the psychological effect of simply being hospitalized with a severe infection could itself increase the risk, they speculate.

"However, after adjusting for the effect of long-term and physical diseases using the Charlson Comorbidity Index, the association between infection and suicide was still significant," the authors write.

Dr Lund-Sørensen underscored the fact that the new findings, though compelling, do not show a causal relationship between infection and suicidal behavior.

"Our study can show an association, but not prove that serious infections directly contribute to suicide risk," she said.

"However, our findings do indicate that environmental factors, such as infections, may be relevant and play an important role in the pathophysiological mechanisms of suicidal behavior."

What About Low-Grade Infection?

Commenting on the findings for Medscape Medical News, Lena C. Brundin, MD, PhD, of the Van Andel Research Institute's Laboratory of Psychiatry and Behavioral Medicine, in Grand Rapids, Michigan, said that with inflammation already a heightened area of focus in suicidality and depression, the findings offer highly important new insights.

"It is known that inflammation is present in patients with depression, in particular, in patients with suicidal ideation and behavior. We also know that inflammation can affect the brain and cause depressive symptoms. But few studies have asked the question of where this enigmatic inflammation originates from," said Dr Brundin.

"This is the first large epidemiological study highlighting the role of infections, estimating that over 10% of suicides may be attributable to severe infections."

Dr Brundin, who coauthored an accompanying editorial, also noted that one of the most worrisome aspects of a possible link between infection and suicidality is that infections can be of low grade and long term.

"Chronic, low-grade infections are sometimes not treated and might remain latent in the body for years," she writes.

"It is possible that the link between infections and suicidality might become even stronger when such infections are taken into account ― not only the ones requiring hospitalization."

Dr Brundin believes the study should pave the way for novel treatment studies that probe the effects of the treatment of infection in depressed or suicidal patients. "Trials could attempt to eradicate chronic infections with antibiotics [and] in cases of remaining inflammation without any pathogen, anti-inflammatory treatments" could be considered.

"The perspective of utilizing anti-inflammatory and antibiotic medications in psychiatric patients is revolutionary," she noted.

"Importantly, patients prone to suicidal ideation and behavior need to be enrolled in clinical trials rather than being excluded, which is often the case currently. The risk for depression and suicides in patients with severe infections should also be carefully considered by clinicians caring for these patients," Dr Brundin urged.

The study was funded with an unrestricted scholarship grant from the Lundbeck Foundation. The authors have disclosed no relevant financial relationships. Dr Brundin is the principal investigator of a study on inflammation as a cause of perinatal depression and suicidality that is funded by a grant from the National Institute of Mental Health.

JAMA Psychiatry. Published online August 10, 2016. Full text, Editorial