Role of Inflammation in Suicide: From Mechanisms to Treatment

“It is known that peripheral cytokines can be trafficked into the CNS either through regions with limited blood – brain barrier (BBB) permeability, such as the circumventricular organs and the choroid plexus, or through a compromised BBB (Dantzer et al , 2008), which has been reported to be leaky in suicidal individual…”

“Aberrations in inflammatory cytokines have been reported in several neuropsychiatric conditions, including MDD, schizophrenia, and bipolar disorders (Dowlati et al , 2010; Miller et al , 2011; Munkholm et al , 2013).”

“…in several downstream factors, including epigenetic changes, hypothalamic – pituitary – adrenal (HPA) axis activation and neuronal plasticity, informed to a large extent by animal studies and post-mortem studies (Labonte et al , 2013; Labonte et al , 2012; McGowan et al , 2009; Roth et al , 2011).”

“Indeed, a multitude of papers have shown that patients with depression display inflammation (Dowlati et al , 2010; Howren et al , 2009; Liu et al , 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of…”

“Aberrations in inflammatory cytokines have been reported in several neuropsychiatric conditions, including MDD, schizophrenia, and bipolar disorders (Dowlati et al , 2010; Miller et al , 2011; Munkholm et al , 2013).”

“In addition, ketamine can be metabolized in vivo via P450 enzymes to produce various metabolites, some of which are biologically active, such as (2R, 6R)-hydroxynorketamine (HNK), and mediate anti-depressant effects by activation of AMPA receptors (Zanos et al , 2016).”

“1,25-dihydroxyvitamin D3 attenuates immune response by suppressing the effects of IL-2 and IFN-γ , produced by Th1 cells, subsequently preventing the activation and proliferation of T-cell populations (Cippitelli and Santoni, 1998).”

“In addition, it should be noted that certain metabolites do not freely cross the BBB, and it might, therefore, be of importance to study the CSF levels of metabolites when determining their correlation to neuropsychiatric symptoms (Schwarcz et al , 2012).”

“Familial transmission and early life adversity (ELA) are distal events associated with suicide risk (Mann, 2003; Moscicki, 1994) .”

“Men are also likely to employ more violent methods of suicide than women (Canetto and Sakinofsky, 1998).”

“Inflammatory cytokines such as IFN-γ , IL-6, IL-1 β , and TNF-α are potent activators of IDO and/or TDO (Kim et al , 2012; Mandi and Vecsei, 2012; Schwieler et al , 2015; Taylor and Feng, 1991; Urata et al , 2014).”

“Indeed, a multitude of papers have shown that patients with depression display inflammation (Dowlati et al, 2010; Howren et al, 2009; Liu et al, 2012; Valkanova et al, 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of depression (particularly o…”

“KYNA, on the other hand, blocks the cholinergic α 7 nicotinic receptor and antagonizes the glycine site of the NMDA receptor (Hilmas et al , 2001; Stone, 1993).”

“Indeed, a multitude of papers have shown that patients with depression display inflammation (Dowlati et al , 2010; Howren et al , 2009; Liu et al , 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of…”

“Several clinical trials have found that ketamine robustly decreases depressive and suicidal symptoms in as little as 40 min with effects lasting for several weeks (DiazGranados et al , 2010; Larkin and Beautrais, 2011; Price and Mathew, 2015; Price et al , 2009; Zarate et al , 2012).”

“Subsequently, Steiner et al (2008) demonstrated increased microgliosis, indicative of an enhanced inflammation, in suicide victims with a diagnosis of depression and schizophrenia.”

“KYNA, on the other hand, blocks the cholinergic α7 nicotinic receptor and antagonizes the glycine site of the NMDA receptor (Hilmas et al, 2001; Stone, 1993) .”

“…of GSK3, has been found effective in decreasing depressive-like and aggressive behavior in animal models (Beurel and Jope, 2014) and reducing suicidal attempts and suicide completion in patients with bipolar as well as unipolar depression (Baldessarini et al , 2006; Guzzetta et al , 2007).”

“The risk for suicide is much higher in individuals with substance abuse disorder compared with general population (Wilcox et al , 2004).”

“…, 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of depression (particularly of inflammation-induced depression) (Dantzer and Walker, 2014; Maes et al , 2011; Myint et al , 2012; Reus et al , 2015).”

“…have found that tocilizumab is able to effectively treat several inflammatory and autoimmune diseases (Choy et al , 2002; Fonseka et al , 2015; Ito et al , 2004) and a recently initiated RCT will access the ability of tocilizumab to decrease depressive symptomology in treatment-resistant…”

“The serotonin system is one of the most widely studied neurotransmitter systems in depressive disorders (Vaswani et al , 2003) and its dysregulation by inflammatory cytokines could be one of the mechanisms underlying suicidal ideation and behavior (Oquendo et al , 2014).”

“Several clinical trials have found that ketamine robustly decreases depressive and suicidal symptoms in as little as 40 min with effects lasting for several weeks (DiazGranados et al , 2010; Larkin and Beautrais, 2011; Price and Mathew, 2015; Price et al , 2009; Zarate et al , 2012).”

“In a subset of MS patients with no history of psychiatric illness, treatment with IFN-γ worsens depressive symptoms and induces suicidal ideation or attempts (Benros et al , 2011; Chwastiak et al , 2002; Fragoso et al , 2010).”

“The host immune response CD4 + and CD8 + T cells are responsible for keeping the parasite under control and relatively quiescent in the central nervous system (Gazzinelli et al , 1992).”

“Interestingly, a post-mortem study found increased QUIN immunoreactivity in suicidal depressed patients seemingly in agreement with our findings (Steiner et al , 2011).”

“In line with these findings, Wohleb et al demonstrated increased peripheral myeloid cell trafficking into perivascular spaces and specific brain regions using a repeated social defeat stress model.”

“Patients with MS report high rates of depression reaching ~ 40% in these patients (Chwastiak et al , 2002).”

“IL-1 β and TNF-α have been shown to enhance the expression and activation of serotonin transporters in cell lines via a p38 mitogen-activated protein kinase pathway (Mossner et al , 1998; Ramamoorthy et al , 1995; Zhu et al , 2006; Zhu et al , 2005).”

“In an interesting study, Torres-Platas et al (2014) showed that depressed individuals who committed suicide have a greater proportion of activated microglia in the anterior cingulate cortex white matter compared with subjects without psychiatric disorders who died from other causes.”

“On the other hand, plasma KYNA has been previously shown to be reduced in depressed patients, although neither QUIN nor cytokine levels were profiled in these patients (Myint et al , 2007).”

“Previous studies have found that tocilizumab is able to effectively treat several inflammatory and autoimmune diseases (Choy et al , 2002; Fonseka et al , 2015; Ito et al , 2004) and a recently initiated RCT will access the ability of tocilizumab to decrease depressive symptomology in…”

“In addition, we observed that IL-6 levels in these patients correlated with the severity of depression as assessed by Montgomery – Asberg Depression Rating Scale (Lindqvist et al , 2009).”

“They observed that the rates of suicide attempts were higher in relatives of adolescent suicide victims even after controlling for familial rates of psycho-pathology, suggesting that familial transmission of suicide is discrete from psychopathology (Brent et al , 1996).”

“They are widely expressed in different cell types of the CNS and are identified to have diverse functions, from cognition to memory (Okun et al , 2010; Okun et al , 2011).”

“TLRs have a critical role in regulating innate immune response and facilitating immune function in the event of infection (Hanke and Kielian, 2011).”

“…in several downstream factors, including epigenetic changes, hypothalamic – pituitary – adrenal (HPA) axis activation and neuronal plasticity, informed to a large extent by animal studies and post-mortem studies (Labonte et al , 2013; Labonte et al , 2012; McGowan et al , 2009; Roth et al , 2011).”

“They also observed increased dopamine release in response to T. gondii infection (Prandovszky et al, 2011) .”

“Animal studies also showed that ketamine is capable of reducing depressive effects in LPS-injected mice, which exhibit activation of the kynurenine pathway in the brain through IDO induction (O ’ Connor et al , 2009; Walker et al , 2013).”

“…can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy (Buter et al , 1993; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Renault et al , 1987).”

“Aberrations in inflammatory cytokines have been reported in several neuropsychiatric conditions, including MDD, schizophrenia, and bipolar disorders (Dowlati et al , 2010; Miller et al , 2011; Munkholm et al , 2013).”

“Death by suicide may account for at least 15% of mortality in MS populations (Sadovnick et al , 1991).”

“Inflammatory cytokines such as IFN-γ , IL-6, IL-1 β , and TNF-α are potent activators of IDO and/or TDO (Kim et al , 2012; Mandi and Vecsei, 2012; Schwieler et al , 2015; Taylor and Feng, 1991; Urata et al , 2014).”

“Pandey et al (2012) reported that post-mortem brain tissue from teenage suicide victims had increased mRNA and protein levels of IL-1 β , IL-6, and tumor necrosis factor alpha (TNF-α ) in certain cortical regions (Brodmann area 10).”

“They also found increased IL-1β and IL-6 in post-mortem brain tissue from suicide completers and reported that reduced CSF levels of IL-8 were associated with suicidal behavior (Black and Miller, 2015) .”

“Cytokine administration in both animals and humans is known to activate the HPA axis (Dunn, 2000).”

“The increase in QUIN was also correlated with the suicidal intent in this cohort of patients (Erhardt et al , 2013).”

“These traits are often co-morbid with different psychiatric disorders such as bipolar disorders and substance abuse disorders (Brent et al , 1994; Cuomo et al , 2008; McGirr et al , 2008).”

“…in several downstream factors, including epigenetic changes, hypothalamic – pituitary – adrenal (HPA) axis activation and neuronal plasticity, informed to a large extent by animal studies and post-mortem studies (Labonte et al , 2013; Labonte et al , 2012; McGowan et al , 2009; Roth et al , 2011).”

“In addition to NMDA receptor activation, QUIN also inhibits astrocytic uptake of glutamate by inhibiting glutamine synthetase and increases neuronal glutamate release (Tavares et al , 2002).”

“Inflammatory cytokines such as IFN-γ , IL-6, IL-1 β , and TNF-α are potent activators of IDO and/or TDO (Kim et al , 2012; Mandi and Vecsei, 2012; Schwieler et al , 2015; Taylor and Feng, 1991; Urata et al , 2014).”

“HPA axis activation also correlates with the onset of depressive symptoms in patients who undergo interferon therapy compared with those who do not (Capuron et al , 2003).”

“These traits are often co-morbid with different psychiatric disorders such as bipolar disorders and substance abuse disorders (Brent et al , 1994; Cuomo et al , 2008; McGirr et al , 2008).”

“Not only did we find QUIN to be elevated over 2 years, we also observed that high levels of IL-6 and lower KYNA in the same patient group correlated with the severity of suicidal ideation and depressive symptoms (Bay-Richter et al , 2015).”

“Moreover, the T. gondii genome encodes for tyrosine hydroxylase, a rate-limiting enzyme in the synthesis of dopamine, wherein it catalyzes the conversion of tyrosine into L-DOPA (Gaskell et al , 2009).”

“The serotonin system is one of the most widely studied neurotransmitter systems in depressive disorders (Vaswani et al , 2003) and its dysregulation by inflammatory cytokines could be one of the mechanisms underlying suicidal ideation and behavior (Oquendo et al , 2014).”

“Evidence at this point is scarce, but indicates that the inflammatory changes and generation of kynurenine neurotoxic metabolites are, at least, more pronounced in suicidal individuals (Janelidze et al , 2011; O ’ Donovan et al , 2013; Sublette et al , 2011).”

“A RCT conducted by Nery et al (2008) has found that adjunctive treatment with celecoxib is able to produce a rapid antidepressant effect in bipolar disorder patients during depressive or mixed phases.”

“…of inflammation contributing to depression and suicidal behavior are highlighted by studies showing increased incidence following IFN-based treatment in cancer and hepatitis patients (Capuron et al , 2000; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Miyaoka et al , 1999).”

“Familial transmission and early life adversity (ELA) are distal events associated with suicide risk (Mann, 2003; Moscicki, 1994).”

“As mentioned above, NR1 is a subunit of the ionotropic glutamate NMDA receptor (Perez-Otano et al , 2001).”

“Interestingly, the presence of anti-NR1 antibodies has been consistently reported in the CSF of SLE patients and correlates positively with their neuropsychiatric symptoms (Arinuma et al , 2008; Fragoso-Loyo et al , 2008; Gono et al , 2011; Lapteva et al , 2006; Yoshio et al , 2006).”

“First, Tonelli et al (2008) reported elevated mRNA transcripts of IL-4 and IL-13 in the orbitofrontal cortex of suicide victims.”

“Interestingly, the presence of anti-NR1 antibodies has been consistently reported in the CSF of SLE patients and correlates positively with their neuropsychiatric symptoms (Arinuma et al , 2008; Fragoso-Loyo et al , 2008; Gono et al , 2011; Lapteva et al , 2006; Yoshio et al , 2006).”

“Evidence at this point is scarce, but indicates that the inflammatory changes and generation of kynurenine neurotoxic metabolites are, at least, more pronounced in suicidal individuals (Janelidze et al , 2011; O ’ Donovan et al , 2013; Sublette et al , 2011).”

“In rodents, for example, infection with T. gondii elicits release of IFN-γ , IL-12, IL-8, and TNF-α primarily by cells of the innate immune system (Miller et al , 2009).”

“…can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy (Buter et al , 1993; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Renault et al , 1987).”

“…can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy (Buter et al , 1993; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Renault et al , 1987).”

“Physical or sexual abuse and parental neglect are significantly associated with suicidal risk (Brezo et al , 2008).”

“IL-1 β and TNF-α have been shown to enhance the expression and activation of serotonin transporters in cell lines via a p38 mitogen-activated protein kinase pathway (Mossner et al , 1998; Ramamoorthy et al , 1995; Zhu et al , 2006; Zhu et al , 2005).”

“Inflammatory cytokines such as IFN-γ , IL-6, IL-1 β , and TNF-α are potent activators of IDO and/or TDO (Kim et al , 2012; Mandi and Vecsei, 2012; Schwieler et al , 2015; Taylor and Feng, 1991; Urata et al , 2014).”

“…, 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of depression (particularly of inflammation-induced depression) (Dantzer and Walker, 2014; Maes et al , 2011; Myint et al , 2012; Reus et al , 2015).”

“Interestingly, latent T. gondii infection has been identified as a risk factor for suicide and suicide attempts (Arling et al , 2009; Ling et al , 2011).”

“Preliminary data from an open-label study of patients with MDD suggest that adjunctive minocycline treatment is able to reduce the severity of depressive and psychotic symptoms (Miyaoka et al , 2012).”

“…in several downstream factors, including epigenetic changes, hypothalamic – pituitary – adrenal (HPA) axis activation and neuronal plasticity, informed to a large extent by animal studies and post-mortem studies (Labonte et al , 2013; Labonte et al , 2012; McGowan et al , 2009; Roth et al , 2011).”

“Interestingly, O'Donovan et al (2013) demonstrated that increased inflammation correlated with the degree of suicidal ideation in patients with depression, even after controlling for active suicide attempts and degree of depressive symptoms.”

“…of GSK3, has been found effective in decreasing depressive-like and aggressive behavior in animal models (Beurel and Jope, 2014) and reducing suicidal attempts and suicide completion in patients with bipolar as well as unipolar depression (Baldessarini et al , 2006; Guzzetta et al , 2007).”

“It is well established that ~ 30 – 45% of patients receiving IFN treatment develop depressive-like symptoms during the course of therapy, with a proportion of them experiencing these symptoms long after therapy has ceased (Meyers et al , 1991; Miyaoka et al , 1999).”

“Toxoplasma gondii is a common protozoan parasite that establishes latency in the muscle and brain (Henriquez et al , 2009).”

“They are widely expressed in different cell types of the CNS and are identified to have diverse functions, from cognition to memory (Okun et al , 2010; Okun et al , 2011).”

“Schnieder et al (2014) reported similar findings, where they observed increased density of perivascular cells in prefrontal cortex white matter of suicide victims.”

“In a registry-based study, Tidemalm et al (2011) assessed suicides in probands of individuals who died by suicide, and determined that the risk does run in families and is influenced by both genetic and shared environmental factors.”

“Prevalence of depression is estimated to be fourfold higher in SLE patients compared with non-SLE patients with at least 75% of SLE patients being diagnosed with depression during their lifetime (Palagini et al , 2013).”

“These long-lasting effects of the TBI could be, in part, responsible for the increased risk of suicidality observed in veterans (Brenner et al , 2011).”

“Several recent meta-analyses of randomized controlled trials (RCTs) have found a COX-2 inhibitor celecoxib to be an effective add-on treatment for unipolar depression as celecoxib decreases depression severity and increases remission rates (Faridhosseini et al , 2014; Na et al , 2014).”

“Interestingly, the presence of anti-NR1 antibodies has been consistently reported in the CSF of SLE patients and correlates positively with their neuropsychiatric symptoms (Arinuma et al , 2008; Fragoso-Loyo et al , 2008; Gono et al , 2011; Lapteva et al , 2006; Yoshio et al , 2006).”

“These traits are often co-morbid with different psychiatric disorders such as bipolar disorders and substance abuse disorders (Brent et al , 1994; Cuomo et al , 2008; McGirr et al , 2008).”

“In the only study to date on suicidal subjects, Pandey et al (2014), concluded that, irrespective of psychiatric diagnoses, mRNA and protein levels of TLR3 and TLR4 were consistently dysregulated in suicide victims (depressed and non-depressed).”

“A study by Okusaga et al (2011) found higher seropositivity for influenza B virus in patients with a history of suicide attempt, whereas seropositivity for all three types of viruses (influenza A, B, and coronaviruses) was associated with the history of mood disorders.”

“In a study involving the largest cohort of TBI patients (two million controls and 200 000 Swedish TBI patients), it was determined that those with TBI are three times more likely to die of suicide than controls (Fazel et al , 2014).”

“IL-1 β and TNF-α have been shown to enhance the expression and activation of serotonin transporters in cell lines via a p38 mitogen-activated protein kinase pathway (Mossner et al , 1998; Ramamoorthy et al , 1995; Zhu et al , 2006; Zhu et al , 2005).”

“In previous studies, sirukumab was able to decrease inflammatory symptoms in patients with rheumatoid arthritis (Smolen et al , 2014; Tanaka and Martin Mola, 2014).”

“A similar study in a smaller cohort of Danish MS patients identified a twofold increase in risk of death by suicide compared with the general population, with the greatest risk in the first year following diagnosis (Bronnum-Hansen et al, 2005) .”

“Clinical studies also indicate a relationship between inflammation and traits of aggression and impulsivity (Coccaro et al , 2014; Isung et al , 2014; Mommersteeg et al , 2008; Suarez et al , 2002).”

“Death by suicide followed soon after the last emergency department visit in the group of frequent attempters compared with other attenders (Da Cruz et al, 2011) .”

“Interestingly, latent T. gondii infection has been identified as a risk factor for suicide and suicide attempts (Arling et al , 2009; Ling et al , 2011).”

“Clinical studies also indicate a relationship between inflammation and traits of aggression and impulsivity (Coccaro et al, 2014; Isung et al, 2014; Mommersteeg et al, 2008; Suarez et al, 2002) .”

“QUIN is a selective N-methyl-Daspartic acid (NMDA) receptor agonist and acts via activation of the NR1+NR2A and NR1+NR2B NMDA receptor subunits (de Carvalho et al, 1996) .”

“…target could be regulation of the balance between Th1 and Th2-type T-cell populations, as several studies have found an imbalance of these cell types and their corresponding cytokines in the blood of MDD patients with suicidality (Huang and Lee, 2007; Kim et al , 2008; Mendlovic et al , 1999).”

“However, there are studies that also report a decrease in cytokine levels in suicidal individuals (Clark et al , 2016; Gabbay et al , 2009).”

“…, 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of depression (particularly of inflammation-induced depression) (Dantzer and Walker, 2014; Maes et al , 2011; Myint et al , 2012; Reus et al , 2015).”

“It is well established that ~ 30 – 45% of patients receiving IFN treatment develop depressive-like symptoms during the course of therapy, with a proportion of them experiencing these symptoms long after therapy has ceased (Meyers et al , 1991; Miyaoka et al , 1999).”

“An early study found that patients with a history of suicide attempts have increased blood levels of the soluble IL-2 receptors compared with healthy controls (Nassberger and Traskman-Bendz, 1993). This was followed by two post-mortem studies, which independently provided evidence of increased inflammation in the brai…”

“IL-1 β and TNF-α have been shown to enhance the expression and activation of serotonin transporters in cell lines via a p38 mitogen-activated protein kinase pathway (Mossner et al , 1998; Ramamoorthy et al , 1995; Zhu et al , 2006; Zhu et al , 2005).”

“…studies have shown that infliximab and etanercept, another TNF-α blocker, are capable of improving symptoms of depression in patients with various inflammatory conditions (Ersozlu-Bozkirli et al , 2015; Ertenli et al , 2012; Gelfand et al , 2008; Minderhoud et al , 2007; Tookman et al , 2008).”

“A study by Mackay et al (2006) found an increase in activation of the kynurenine pathway, which was sustained for at least 1 year (and possibly longer) following TBI.”

“Meanwhile, another study determined that during the first year after mild-to-severe TBI, suicidal ideation was present in 25% of patients (Mackelprang et al , 2014).”

“Reactivation of infection has also been associated with traits such as aggression and impulsivity, two behavioral endophenotypes associated with suicidal behavior (Cook et al , 2015).”

“Twenty or more suicide attempts occur for every one death by suicide, suggesting that suicide attempts are more frequent than suicide itself (Bertolote et al , 2010).”

“Interestingly, the presence of anti-NR1 antibodies has been consistently reported in the CSF of SLE patients and correlates positively with their neuropsychiatric symptoms (Arinuma et al , 2008; Fragoso-Loyo et al , 2008; Gono et al , 2011; Lapteva et al , 2006; Yoshio et al , 2006).”

“In a subset of MS patients with no history of psychiatric illness, treatment with IFN-γ worsens depressive symptoms and induces suicidal ideation or attempts (Benros et al , 2011; Chwastiak et al , 2002; Fragoso et al , 2010).”

“About 17 – 71% of SLE patients present with psychiatric symptoms (Wekking, 1993).”

“Lower vitamin D levels also correlated with elevated levels of inflammatory cytokines in the suicidal and depressive patients (Grudet et al , 2014).”

“4-Cl-KYN exerts similar antidepressant effects of ketamine, but not side effects in animal models (Zanos et al , 2015).”

“Roy (2003) assessed the association between childhood trauma and suicide attempts in individuals with substance abuse and determined that in these individuals, suicide attempts were associated with childhood trauma.”

“Another study determined an increased risk for suicide completion in a Swedish cohort of MS patients (Fredrikson et al , 2003).”

“…can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy (Buter et al , 1993; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Renault et al , 1987).”

“…, 2012; Valkanova et al , 2013) and the exact same mechanisms (inflammation and activation of the kynurenine pathway) are proposed as the mechanism of depression (particularly of inflammation-induced depression) (Dantzer and Walker, 2014; Maes et al , 2011; Myint et al , 2012; Reus et al , 2015).”

“…studies have shown that infliximab and etanercept, another TNF-α blocker, are capable of improving symptoms of depression in patients with various inflammatory conditions (Ersozlu-Bozkirli et al , 2015; Ertenli et al , 2012; Gelfand et al , 2008; Minderhoud et al , 2007; Tookman et al , 2008).”

“A previous study had found lower CSF levels of neuroprotective IL-8 levels in suicide attempters compared with healthy controls, confirming dysregulation of the immune system in suicidal patients (Isung et al , 2012).”

“…target could be regulation of the balance between Th1 and Th2-type T-cell populations, as several studies have found an imbalance of these cell types and their corresponding cytokines in the blood of MDD patients with suicidality (Huang and Lee, 2007; Kim et al , 2008; Mendlovic et al , 1999).”

“Thus, they found an alternative rational for the etiology of TBI, involving immune activation and increase in cognitive deficits associated with impulse control and suicidal behavior (Juengst et al , 2014).”

“However, there are studies that also report a decrease in cytokine levels in suicidal individuals (Clark et al , 2016; Gabbay et al , 2009).”

“…promising pharmacological target is glycogen synthase kinase-3 (GSK3), which raises the levels of pro-inflammatory cytokines and, thus, is thought to promote the development of aggression and depressive symptoms, which are closely linked to development of suicidality (Beurel and Jope, 2014).”

“KYNA also antagonizes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, which has been implicated in the pathophysiology of depression and in the mechanism of action of several antidepressant drugs (Freudenberg et al, 2015; Schwarcz et al, 2012) .”

“In previous studies, sirukumab was able to decrease inflammatory symptoms in patients with rheumatoid arthritis (Smolen et al , 2014; Tanaka and Martin Mola, 2014).”

“Recently, using a rodent model of T. gondii infection, Notarangelo et al (2014) showed that brain kynurenine and QUIN levels are persistently elevated in infected animals.”

“Several recent meta-analyses of randomized controlled trials (RCTs) have found a COX-2 inhibitor celecoxib to be an effective add-on treatment for unipolar depression as celecoxib decreases depression severity and increases remission rates (Faridhosseini et al , 2014; Na et al , 2014).”

“…limited blood – brain barrier (BBB) permeability, such as the circumventricular organs and the choroid plexus, or through a compromised BBB (Dantzer et al , 2008), which has been reported to be leaky in suicidal individuals (Bayard-Burfield et al , 1996; Falcone et al , 2010; Ventorp et al , 2016).”

“Umhau et al (2013) investigated vitamin D status in a cohort of active duty military service professional and found that low levels of vitamin D correlate with increased suicide risk.”

“Since then, we found that decreased IL-8 levels were specific to patients with anxiety and identified the presence of a single-nucleotide polymorphism in the promoter region of the IL-8 gene, which predicted more severe anxiety in the suicide attempters (Janelidze et al , 2015).”

“Clinical studies also indicate a relationship between inflammation and traits of aggression and impulsivity (Coccaro et al , 2014; Isung et al , 2014; Mommersteeg et al , 2008; Suarez et al , 2002).”

“Examining a Chinese population of SLE patients, Pan et al reported a 34% prevalence of suicidal ideation, with lower estimates ranging from 8 to 12% reported in other SLE populations across the world (Ishikura et al , 2001; Xie et al , 2012; Zakeri et al , 2012).”

“Low levels of vitamin D have been linked with MDD and other psychiatric illnesses (Kjaergaard et al, 2011) , and recent studies have begun to explore its role in suicidal behavior.”

“Pentoxifylline is a phosphodiesterase inhibitor, which, among other effects, decreases the expression of pro-inflammatory cytokines such as TNF-α , IL-1, and IL-6 in blood cells (Ferrari et al , 2010; Gonzalez-Espinoza et al , 2012; Neuner et al , 1994; Pollice et al , 2001).”

“More studies are clearly needed to support the relationship between inflammation and suicidality in youth, as suggested by a recent meta-analysis (Kim et al , 2014).”

“Examining a Chinese population of SLE patients, Pan et al reported a 34% prevalence of suicidal ideation, with lower estimates ranging from 8 to 12% reported in other SLE populations across the world (Ishikura et al , 2001; Xie et al , 2012; Zakeri et al , 2012).”

“Furthermore, Price et al (2004) found that drug dependence was associated with PTSD and suicidal behavior in a cohort of Vietnam veterans assessed over a period of 25 years.”

“However, a follow-up study found a decrease in the number of QUIN reactive microglia in the hippocampi from the same suicide victims (Busse et al , 2015).”

“Currently, ongoing RCTs are investigating the effect of minocycline add-on treatment for the management of depressive symptoms in patients with treatment-resistant depression (Husain et al , 2015), MDD (Dean et al , 2014), and bipolar depression (Savitz et al , 2012).”

“…target could be regulation of the balance between Th1 and Th2-type T-cell populations, as several studies have found an imbalance of these cell types and their corresponding cytokines in the blood of MDD patients with suicidality (Huang and Lee, 2007; Kim et al , 2008; Mendlovic et al , 1999).”

“For example, in individuals with personality disorders, elevated TNF-α and C-reactive protein (CRP) are associated with aggressive traits (Coccaro, 2006).”

“Acute IL-6 administration is also known to increase serotonin release in rat striatum (Zhang et al , 2001).”

“Interestingly, the presence of anti-NR1 antibodies has been consistently reported in the CSF of SLE patients and correlates positively with their neuropsychiatric symptoms (Arinuma et al , 2008; Fragoso-Loyo et al , 2008; Gono et al , 2011; Lapteva et al , 2006; Yoshio et al , 2006).”

“…studies have shown that infliximab and etanercept, another TNF-α blocker, are capable of improving symptoms of depression in patients with various inflammatory conditions (Ersozlu-Bozkirli et al , 2015; Ertenli et al , 2012; Gelfand et al , 2008; Minderhoud et al , 2007; Tookman et al , 2008).”

“Inflammatory cytokines such as IFN-γ , IL-6, IL-1 β , and TNF-α are potent activators of IDO and/or TDO (Kim et al , 2012; Mandi and Vecsei, 2012; Schwieler et al , 2015; Taylor and Feng, 1991; Urata et al , 2014).”

“Pentoxifylline is a phosphodiesterase inhibitor, which, among other effects, decreases the expression of pro-inflammatory cytokines such as TNF-α , IL-1, and IL-6 in blood cells (Ferrari et al , 2010; Gonzalez-Espinoza et al , 2012; Neuner et al , 1994; Pollice et al , 2001).”

“Recently, the onset of de novo depression has been associated with the higher levels of cytomegalovirus IgG antibodies with the odds of incident depression being three times greater in individuals with antibody levels in the highest quartile (Simanek et al , 2014).”

“Interestingly, Dahl et al (2015) also reported that depressive episodes in MDD patients are not associated with an increase in plasma kynurenine metabolite levels, despite the presence of elevated cytokine levels in these individuals.”

“…condition that does not involve inflammation, have previously attempted suicide compared with 7% of adolescents with thalassemia major, a condition that is often characterized by the presence of chronic vascular inflammatory state (Ghanizadeh and Baligh-Jahromi, 2009; Ghanizadeh et al , 2006).”

“Although it has also been shown to decrease depressive-like behavior in animal models (Bah et al , 2011; Elgarf et al , 2014), whether it can be replicated in humans has not yet been determined.”

“Previous studies have found that tocilizumab is able to effectively treat several inflammatory and autoimmune diseases (Choy et al , 2002; Fonseka et al , 2015; Ito et al , 2004) and a recently initiated RCT will access the ability of tocilizumab to decrease depressive symptomology in…”

“Such targets could include TLRs, activation of which regulates the production of pro-inflammatory cytokines, as some studies have found some abnormalities in brain and blood TLRs ’ levels in depressed and suicidal patients (Pandey et al , 2014; Wu et al , 2015).”

“Interestingly, Dahl et al (2015) also reported that depressive episodes in MDD patients are not associated with an increase in plasma kynurenine metabolite levels, despite the presence of elevated cytokine levels in these individuals.”

“Clinical studies also indicate a relationship between inflammation and traits of aggression and impulsivity (Coccaro et al , 2014; Isung et al , 2014; Mommersteeg et al , 2008; Suarez et al , 2002).”

“Examining a Chinese population of SLE patients, Pan et al reported a 34% prevalence of suicidal ideation, with lower estimates ranging from 8 to 12% reported in other SLE populations across the world (Ishikura et al , 2001; Xie et al , 2012; Zakeri et al , 2012).”

“Several clinical trials have found that ketamine robustly decreases depressive and suicidal symptoms in as little as 40 min with effects lasting for several weeks (DiazGranados et al , 2010; Larkin and Beautrais, 2011; Price and Mathew, 2015; Price et al , 2009; Zarate et al , 2012).”

“We have previously shown that suicide attempters have an increased BBB permeability, which is associated with increased CSF levels of glycosaminoglycan hyaluronic acid, which is a ligand for CD44 and is indicative of increased neuroinflammation (Ventorp et al , 2016).”

“Alavi et al (2012) found that, before treatment, 36% of chronic hepatitis C patients suffer from major depression and 18% endure a moderate-to-severe suicide risk.”

“Although it has also been shown to decrease depressive-like behavior in animal models (Bah et al , 2011; Elgarf et al , 2014), whether it can be replicated in humans has not yet been determined.”

“For example,~1% of adolescents with hemophilia, a genetic condition that does not involve inflammation, have previously attempted suicide compared with 7% of adolescents with thalassemia major, a condition that is often characterized by the presence of chronic vascular inflammatory state (Ghanizadeh and Baligh-Jahromi…”

“…studies have shown that infliximab and etanercept, another TNF-α blocker, are capable of improving symptoms of depression in patients with various inflammatory conditions (Ersozlu-Bozkirli et al , 2015; Ertenli et al , 2012; Gelfand et al , 2008; Minderhoud et al , 2007; Tookman et al , 2008).”

“It is known that peripheral cytokines can be trafficked into the CNS either through regions with limited blood-brain barrier (BBB) permeability, such as the circumventricular organs and the choroid plexus, or through a compromised BBB (Dantzer et al, 2008) , which has been reported to be leaky in suicidal individuals…”

“Currently, ongoing RCTs are investigating the effect of minocycline add-on treatment for the management of depressive symptoms in patients with treatment-resistant depression (Husain et al , 2015), MDD (Dean et al , 2014), and bipolar depression (Savitz et al , 2012).”

“Pentoxifylline is a phosphodiesterase inhibitor, which, among other effects, decreases the expression of pro-inflammatory cytokines such as TNF-α , IL-1, and IL-6 in blood cells (Ferrari et al , 2010; Gonzalez-Espinoza et al , 2012; Neuner et al , 1994; Pollice et al , 2001).”

“The prevalence of MDD, suicidal ideation, and attempted suicides in HIV patients is reported to be up to 27.2%, 31%, and 32.7%, respectively (Serafini et al , 2015).”

“…can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy (Buter et al , 1993; Capuron et al , 2004; Dieperink et al , 2004; Janssen et al , 1994; Renault et al , 1987).”

“Mounting evidence also suggests that neuroinflammation may be particularly pronounced in suicidality (43).”

“and an increasing body of research is indicative of a strong link between suicidality and inflammation [56].”

“48,49 Potential roles for the gut microbiome and microbial dysbiosis in both sources of premature mortality are also increasingly the focus of investigation.”

“Elevated immune‐inflammatory signaling may also contribute to both the pathophysiology of suicide [45] and sleep disturbances [46, 47].”

“It is also noteworthy that increased NMDA agonist levels seem to be affected by inflammatory processes [10].”

“160 Although many are already United States FDA approved for other indications, these medications should first undergo a battery of testing in animals establishing their potential for improving depressive-like symptoms, aggression, impulsivity, and decision-making, to select the most suitable drugs for subsequent clin…”

“Immune response is often accompanied by inflammation [26,27], and inflammation is usually regulated by cytokines and chemokines [28,29].”

“In the future, inflammatory levels may become essential in the way we assess and manage patients with MDD (Tonelli et al., 2008; Lindqvist et al., 2009; Steiner et al., 2011; Pandey et al., 2012; Brundin et al., 2017).”

“(2011) who reported changes in cytokine and kynurenine concentrations only in suicidally depressed patients, a finding consistent with other evidence (Brundin et al., 2017).”

“This is especially important considering that biological mechanisms proposed for suicidality and depression largely overlap (Brundin et al., 2017).”

“The SARS‐CoV‐2‐induced cytokine ‘storm’ has been shown to play a major role in the propagation of neuropsychiatric symptoms associated with COVID‐19, while aberrations in inflammatory cytokines have been proposed as pathophysiological correlates of suicidality (22,63,65,66).”

“Aussi, chez les sujets âgés, la solitude est associée à des modifications biologiques participant à la vulnérabilité suicidaire [49] : élévation des marqueurs inflammatoires périphériques et expansion des cellules sanguines mononuclées [50] .”

“Pro-inflammatory conditions may play an upstream role in suicide-related behavior, including neurotropic pathogens, traumatic brain injury and autoimmune disorders (Brundin et al., 2017).”

“Inflammatory cytokines may contribute to activation of the kynurenine pathway of tryptophan catabolism, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and alterations in monoamine metabolism (6).”

“Some of the strongest evidence for an association between ky - nurenines and illness have been noted for schizophrenia (Erhardt et al., 2017 ; Stone & Darlington, 2013 ; Wonodi et al., 2011 ) and sui - cidality (Brundin et al., 2016 , 2017 ).”

“Studies have reported associations between higher levels of circulating inflammatory markers (systemic inflammation) and self-harm, suicide and suicide attempt (Serafini et al., 2020; Black and Miller, 2015; Brundin et al., 2017; Osimo et al., 2018; Ganança et al., 2016).”

“These post-mortem studies found increased inflammation in the brain and cerebrospinal fluid, as well as increased levels of inflammatory cytokines [7].”

“…markers, including cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α), have been consistently observed in individuals with major depressive disorder, particularly those exhibiting suicidal thoughts or behaviors [9].”

“been demonstrated to be continuously elevated in the patients who had suicide attempts, and the levels were highest in close proximity to the attempt.(94) Quinolinic acid is an NMDA receptor agonist which leads to an excess of calcium influx into neurons.”

“Beyond serotonin reduction, the shift from TRY to QUIN is also posited to detrimentally affect the metabolism of kynurenic acid (KYNA), an N-methyl-D-aspartic acid (NMDA) receptor antagonist that is considered neuroprotective due to its inhibitory effect on glutamate neurotransmission (91, 92).”

“Experiencing adverse life events, namely physical abuse and displaying aggressive behaviour both during childhood and adulthood can dysregulate the immune system as a response to a stressful traumatic stimulus resulting in higher levels of inflammatory parameters (Brundin et al. 2017; Lippard and Nemeroff 2020) as we…”

“Inflammation has been linked with a potential critical role in suicidal behavior (Brundin et al., 2017; Brundin et al., 2015; Janelidze and Brundin, 2013; Lund-Sorensen et al., 2016).”

“Reports indicate a pro-inflammatory state associated with suicidal behavior (Brundin et al., 2017).”

“Furthermore, given the significant reduction in the risk factors that are known to predispose to suicidal behaviour and death by suicide (Brundin et al., 2017; Chen et al., 2023; Lengvenyte et al., 2021), GLP1 agonists used chronically can even turn out to be protective in this regard and join the…”

“Particularly, inflammation can trigger depressive symptoms and is associated with suicidal behavior in patients treated with IFN-based or IL-2 immuno-therapy [52].”

“This path could also be a reason for suicidality among adolescents in consideration of the positive effect of being overweight, inflammation, and depression on suicidality [67,68].”

“For example, increased blood levels of TNF-α and interleukin 6 (IL-6) are associated with suicidal ideation and attempt (Brundin et al. 2017).”

“For example, IL-6 and TNF-α affect suicide risk in depressed patients by affecting the serotonergic system (Brundin, Bryleva, & Thirtamara Rajamani, 2017; Pandey et al., 2012).”

“Previousstudiesfoundincreasedin fl ammatory cytokines and microgliosis in those who attempted suicide or committed suicide, suggesting that neuroin fl ammation is associated with suicide 54 .”

“The immune system may also play a key role in suicide vulnerability (Brundin et al., 2017) (see Table 1).”

“This finding was not surprising as suicidality has previously been associated with inflammation [95, 96].”

“Apart from these conditions, peripheral infections with neuroinflammatory components such as the HIV-AIDS and neuroborreliosis are known to increase neuropsychiatric symptoms (Brundin et al., 2017).”

“This has been implicated in the pathophysiology of suicidal behavior (4).”