Role of Inflammation in Suicide: From Mechanisms to Treatment

Neuropsychopharmacology (5 July 2016) | doi:10.1038/npp.2016.116

Role of Inflammation in Suicide: From Mechanisms to Treatment

Lena Brundin, Elena Y Bryleva and Keerthi Thirtamara Rajamani

Abstract

Suicidal behavior is complex and manifests because of a confluence of diverse factors. One such factor involves dysregulation of the immune system, which has been linked to the pathophysiology of suicidal behavior. This review will provide a brief description of suicidality and discuss the contribution of upstream and downstream factors in the etiology of suicidal behavior, within the contextual framework of inflammation. The contribution of inflammatory conditions such as traumatic brain injury, autoimmune disorders, and infections to neuropsychiatric symptoms and suicidality is only beginning to be explored. We will summarize studies of inflammation in the etiology of suicide, and provide a neurobiological basis for different mechanisms by which inflammation might contribute to the pathophysiology. Finally, we will review treatments that affect upstream and downstream pathways related to inflammation in suicidality.

Evidence of kynurenine pathway alterations in suicidality

In 2011, Sublette et al. 71 reported that the blood level of kynurenine, the first metabolite produced along the kynurenine pathway, is significantly elevated in suicide attempters with depression compared to non‐suicidal patients with depression, t(58) = 2.1, P = 0.04. This suggests that the activation of the kynurenine pathway in the periphery may serve as a marker, potentially distinguishing suicidal from non‐suicidal depressed patients. Kynurenine can freely pass through the BBB, and while in the brain, it can initiate inflammation and lead to further production of the secondary kynurenine metabolites 58. It has not been firmly established whether peripheral QUIN, KYNA and several other metabolites cross the BBB, and therefore, central measures of these markers in psychiatric patients are currently highly relevant to increase our understanding of their contribution to psychiatric illness. In a study where we measured KYNA and QUIN in the CSF of suicide attempters, QUIN levels were found to be more than twice as high as those in healthy controls, while KYNA levels were unaltered 72. This gave rise to an increased QUIN/KYNA quotient, indicative of a potential net positive effect on NMDA receptor transmission in suicidality. Moreover, CSF QUIN correlated with CSF IL‐6 levels, suggesting that the kynurenine pathway and the generation of QUIN had been induced by an active inflammatory process 72. A further example suggesting a role for QUIN in suicidality was the finding of a positive association between high CSF QUIN levels and high suicidal intent (Spearman ρ = 0.3, P = 0.03). In a follow‐up study, we measured CSF levels of the metabolites repeatedly over the first years following a suicide attempt 73. We found that the QUIN levels were continuously elevated in the patients who had performed a suicide attempt, while the levels were highest in close proximity to the attempt. The magnitude of their depressive and suicidal symptoms fluctuated with increasing cytokine levels and decreasing KYNA levels. In line with this, decreased plasma KYNA levels in depressed patients have previously been observed 74, although recent studies indicate that patients with depression without suicidality may not have any significant changes in the peripheral kynurenine pathway 75.

Interestingly, this accumulating evidence suggests that subsets of patients, prone to suicidal behaviour, could be sensitive to inflammatory changes and may develop symptoms upon such challenges, possibly as a result of an enzymatic imbalance of the kynurenine pathway in the CNS. The increased levels of QUIN could also contribute to the cell loss and structural changes in cortical and subcortical regions that have been reported in patients with suicidal behaviour, due to the neurotoxic effects of the metabolite 76. Recent postmortem data from suicide completers support the data gathered in attempters, by showing increased counts of QUIN‐reactive microglia cells in the subgenual anterior cingulate cortex (sACC) and anterior midcingulate cortex (aMCC) of those with depression who completed suicide 77. The findings that an NMDA receptor agonist (QUIN) is increased and an NMDA receptor antagonist (KYNA) is found to be decreased in patients support a role for a glutamatergic mechanism in the generation of suicidality. Noteworthy, the findings of exceptionally high levels of the NMDA receptor agonist QUIN in the CNS of suicidal patients could provide a neurobiological rationale for the rapid remedial effects of ketamine, an NMDA receptor antagonist, on suicidal ideation 78, 79. It remains to be described how enzymes in the kynurenine pathway are regulated. It is currently not known whether specific cytokines activate some of the enzymes in the kynurenine pathway in preference over others, or why some metabolites would accumulate in favor of another. In this respect, it has been suggested that genetic variants could pay a role 80.

Suicidal ideation and behaviour in somatic conditions with increased inflammation

The studies described above shows that inflammation is present in some cohorts of suicidal patients and that inflammation also is specifically associated with clinically important symptoms of suicidal behaviour. In addition, studies in both animals and human subjects confirm the causal relation between cytokines and symptoms of hopelessness, aggression and hostility, intermediate phenotypes for suicidal behaviour 14, 15, 16. Therefore, it is possible that inflammation observed in patients with so‐called ‘primary psychiatric conditions’ is actually part of a pathogenic mechanism that contributes to suicidal symptoms. Many somatic conditions are associated with increased peripheral and central inflammation. If our hypothesis is true, then, suicidal ideation and behaviour should also be increased in some of these somatic conditions.

Suicide, asthma and allergies

Asthma and allergies consist of an array of innate and adaptive immune responses, locally as well as systemically in the peripheral blood 81. To our knowledge, it is currently not known if there are any CNS inflammatory changes in these conditions. This topic is of interest, as several epidemiological studies have shown a link between suicide, allergies and asthma. There is an increased risk for both suicidal ideation, completed suicides and suicide attempts in patients with asthma 82. A large epidemiological study from Taiwan investigated suicide rates in more than 160 000 high school students, with and without asthma, over 12 years 83. The suicide rate in students with asthma was more than double that of the control group, with no difference in the number of natural deaths. In another epidemiological study from the Unites States (US), both suicidal ideation and suicide attempts were found to be associated with a current diagnosis of asthma 84. The risk increase for suicidal ideation and attempts seems to be approximately two‐ to three‐fold, with numbers varying between different studies.

A spring peak of suicides is observed each year around the world, but there is no current explanation for this phenomenon 85. Hypothetically, the increased amount of seasonal aeroallergens known to peak in spring, such as airborne pollen, could lead to increased upper airway inflammation and an increased risk of suicidal behaviour, in particular in sensitized individuals. A study from the United States over 4 years did indeed report an increased rate of suicides during the peaks in tree pollen in females 86. While a subsequent study in the United States failed to replicate the original finding 87, this was later replicated by a large population study in Denmark 88. It is important to note that the seasonal variation may be related to several factors, such as the exposure to visible and UV light, and seasonal variations of vitamin D levels, as discussed below. In addition, intranasal corticosteroids, first‐line treatment for allergic rhinitis, are known to reduce cytokine production in the nasal airways and have been pharmaco‐ecologically shown to be negatively associated with suicide rates. 89.

Vitamin D, inflammation and suicidality

Vitamin D is the common term for a group of related substances, particularly cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). The effects of vitamin D on the immune system include a shift in the T helper (Th)‐balance toward a Th2 phenotype, which in simplified terms can be said to lead to a less pro‐inflammatory state. As there is an over‐representation of vitamin D deficiency in patients with psychiatric illness 90, the lack of vitamin D has been proposed to contribute to the underlying disease mechanisms 91. Two studies to date have addressed the association between vitamin D and suicidality 92, 93. Umhau et al. investigated the vitamin D levels in blood samples from around 1000 active duty US military service members, of which half completed suicide over the year following the blood sample. They found that low vitamin D status was common in active military members, and the lowest levels were associated with an increased risk for suicide 92. In the study by Grudet et al., it was found that as many as 90% of patients with a recent suicide attempt had suboptimal levels of vitamin D, and 60% had a clear clinical deficiency. As expected, vitamin D in the blood correlated inversely with the levels of pro‐inflammatory cytokines 93.

Autoimmunity and suicidality

Increased rates of suicidality are also observed in autoimmune disorders such as systemic lupus erythematosus (SLE), MS and celiac disease. Approximately 40% of patients with SLE and MS develop depression at some point during their illness 94, 95. The neurobiological changes in SLE frequently include antibodies against the NMDA receptor, as well as microglial activation and BBB dysfunction 96. The prevalence of suicidal ideation was as high as 34% in a sample of around 300 Chinese patients with SLE 97. In a cohort of over 12 000 hospitalized patients with MS, Fredrikson et al. 98 found an increased suicide risk (odds risk ratio = 2.3) when compared to the general population. A smaller scale study of around 100 patients with MS in Denmark confirmed the two‐fold increased risk of dying by suicide 99. A large epidemiological study on a total of over 29 000 individuals with celiac disease in Sweden established that the patients with inflammatory disease also have a two‐fold increased risk for suicide 100.

Traumatic brain injury and suicidality

Traumatic brain injury (TBI) is a well‐known cause of neuroinflammation and glial activation 101. The effects on the brain parenchyma can be long lasting and has been proposed to underlie the increased suicidal behaviour observed in veterans as well as to constitute a risk factor in sports associated with frequent head trauma 102. Interestingly, in a recent large epidemiological study, the death records were compared between around 200 000 individuals who had been hospitalized due to TBI in Sweden over a 40‐year period and over 2 million controls, never hospitalized for TBI, as well as 150 000 unaffected siblings of the TBI victims 103. It was found that the TBI victims were more than 3 times as likely than the general population and unaffected siblings to die from suicide. Juengst et al. 104 measured serum and CSF levels of TNF‐α in patients with moderate and severe TBI as well as in controls. They found that the TBI patients had significantly higher TNF‐α levels than healthy controls and that the levels were associated both with disinhibition and suicidal ideation up to 12 months after the injury. Among 559 patients with mild‐to‐severe TBI, 25% reported suicidal ideation at one or more time points over the first year after the injury 105.

Infections and suicidality

Infectious agents in the CNS are likely to greatly increase the CSF levels of cytokines and kynurenine metabolites 106. Therefore, such infections can give important insights into the role of neuroinflammation in the development of suicidal symptoms. It is known that neuroborreliosis and neurosyphilis, as well as late‐stage HIV and AIDS, all frequently lead to neuropsychiatric symptoms. However, the prevalence and incidence rates of suicidality in these conditions still remain to be established. Suicide rates in patients that suffered from bacterial and viral meningitis are also unknown, but would be of relevance as such patients may be at heightened risk and could benefit from increased surveillance. There are also neurotrophic pathogens of low virulence, known to reside relatively quietly within the CNS of immuno‐competent hosts after infection. Such pathogens include the parasite Toxoplasma gondii (T. gondii). Interestingly, accumulating research now shows that such chronic, low‐grade infections may exert effects on the host brain to a much larger extent than previously thought. Repeated studies now confirm that there is a significantly increased risk for suicidal behaviour in individuals that are positive for T. gondii infection 107, 108, 109, 110. About 30% of the world's population is infected with the parasite in developing, as well as industrial, parts of the world. The initial peripheral infection is associated with none or very limited flulike symptoms in immunocompetent hosts, where after the parasite enters the brain, to form intracellular cysts in neurons and glial cells. A chronic infection with T. gondii can lead to increased neuroinflammation and increased production of kynurenine metabolites within the brain, potentially at the localized sites of the parasitic cysts 111. Moreover, it is possible that the parasite and the surrounding inflammatory changes could show varying degrees of activity, depending on the immunocompetence of the host. Finally, it has been shown that the T. gondii parasite contains two genes encoding tyrosine hydroxylase, the enzyme responsible for producing l‐dopa 112. Changes in impulsivity and the regulation of fear might increase the risk for suicidal behaviour, perhaps particularly in combination with inflammatory changes in the CNS. We analyzed the antibody titers to T. gondii in a small study of recent suicide attempters and controls and found that seropositivity was associated with a greatly increased odds risk ratio for suicide attempt (adjusted odds risk ratio = 7.1; P = 0.01) 109 . In a large epidemiological study of 45 000 Danish mothers, seropositive subjects had an increased relative risk of 1.8 for violent suicide attempts and 2.1 for suicides compared to non‐infected mothers 110. These results are consistent with previously reported small samples of patients with mood disorders and younger patients with schizophrenia, both studies eliminating the potential confound of mental illness by including both healthy controls and also psychiatric controls as comparison 107, 108. Recently, T. gondii infection has been linked, independent of mental illness, with intermediate phenotypes of suicidal behaviour such as trait aggression (in women) and impulsivity (in younger men) 113.

Discussion

 In summary, there is a growing body of evidence that inflammation, as manifested by increased levels of pro‐inflammatory cytokines and inflammatory metabolites, is present in patients with suicidal behaviour and ideation. The inflammatory changes can be detected in the periphery, CSF and brain parenchyma of affected patients. Inflammation activates the kynurenine pathway, with a down‐stream production of metabolites with effects on glutamate neurotransmission, which could be an important biological mechanism responsible for symptom generation. The rapid antisuicidal effect of the NMDA receptor antagonist, ketamine, may be due to its effect on the same biological pathway. In addition, cytokines induce site‐specific effects on behaviour and emotion in different brain areas. Our knowledge in this field is just beginning to evolve. In order to find the optimal treatment regimen for suicidal symptoms, it is of critical importance to identify both the upstream triggers of inflammation, the downstream neurobiological effectors, as well as moderators that convey vulnerability or resilience. Importantly, there are several anti‐inflammatory treatments that are clinically approved for other indications. The effects of these common anti‐inflammatory agents could be tested in patients with suicidal behaviour and ideation in randomized controlled trials (RCTs), after it has been concluded which one of them have the optimal effects in reducing CNS inflammation. Future clinical trials should also, for example, evaluate the effects of antiparasitic treatment on T. gondii infection in patients with suicidal behaviour. Other novel therapeutic strategies could include inhibition of the first enzyme of the kynurenine pathway, IDO‐1, or target microglial activation by means of drugs such as minocycline. As knowledge increases about the role of specific cytokines for symptom generation, specific cytokine blockers, potentially with access to the CNS, could also be developed and tested. Finally, it makes sense to screen patients prior to clinical trials to identify subgroups of patients with increased inflammation, or vulnerability to inflammation, in order to minimize heterogeneity of treatment response 114. Identification of such subgroups of patients with an inflammatory profile is expected to increase the precision of anti‐inflammatory treatments in reducing suicide risk, at the same time preventing unnecessary exposure to anti‐inflammatory treatments in those unlikely to benefit.