Inflammation and treatment strategies for suicidal behavior.

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Published in final edited form as: World J Biol Psychiatry. 2026 Apr 30;27(5):403–423. doi: 10.1080/15622975.2026.2659772 Inflammation and treatment strategies for suicidal behavior Chittaranjan Behera a , Srishti Gupta a , Richard Shelton b , Yogesh Dwivedi b Author information Article notes Copyright and License information a Department of Forensic Medicine & Toxicology, All India Institute of Medical Sciences, New Delhi, India b Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, USA Author contributions CRediT: Chittaranjan Behera : Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing; Srishti Gupta : Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing; Richard Shelton : Data curation, Writing – original draft, Writing – review & editing; Yogesh Dwivedi : Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. ✉ CONTACT Yogesh Dwivedi, yogeshdwivedi@uabmc.edu , ydwivedi@uab.edu , Distinguished Professor and Elesabeth Ridgely Shook Endowed Chair Co-Director, UAB Depression and Suicide Center Department of Psychiatry and Behavioral Neurobiology University of Alabama at Birmingham SC711 Sparks Center 1720 2nd Avenue South Birmingham, Alabama 35242, USA Issue date 2026 Jun. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. PMC Copyright notice PMCID: PMC13231395  NIHMSID: NIHMS2175221  PMID: 42059933 The publisher's version of this article is available at World J Biol Psychiatry Abstract Objectives: Suicide is a major global health problem. Growing evidence shows that immune dysregulation and inflammation contribute to suicidality. This review summarises inflammatory mechanisms associated with suicidal behaviour and evaluates emerging therapeutic strategies targeting these pathways. Methods: A narrative literature review was conducted using a combination of keywords, including suicide, therapy, pharmacotherapy, and inflammation, with Boolean operators across PubMed and Google Scholar, emphasising risk factors and interventions aimed at reducing inflammatory activity and consequent suicidal behaviour. Results: Individuals with suicidal behaviour exhibit elevated pro-inflammatory cytokines (interleukin-6, interleukin-1β, tumour necrosis factor-α), C-reactive protein (CRP), and chemokines in blood, CSF, and brain tissue. These markers alter the hypothalamic-pituitary-adrenal (HPA) axis, monoamine systems, and glutamatergic signalling. Inflammatory activation of indoleamine 2,3-dioxygenase shifts tryptophan metabolism towards neurotoxic kynurenine metabolites, such as quinolinic acid, reducing serotonin and promoting NMDA-mediated excitotoxicity, potentially increasing impulsivity and acute suicidal ideation. Neuroinflammation also disrupts glutamate signalling through microglial/astrocytic dysfunction and altered Mammalian target of Rapamycin Complex 1 (mTORC1) pathways. Several immunomodulatory treatments – including lithium, ketamine/esketamine, cyclooxygenase-2 (COX-2) inhibitors, cytokine antagonists, and kynurenine-pathway modulators – show promise in reducing inflammation-linked to suicidal risk. Conclusions: Precision-based approaches integrating inflammatory biomarkers, genetics, and clinical profiles may help identify individuals most likely to benefit from immunomodulatory therapies, supporting more personalised, biologically informed suicide-prevention strategies. Keywords: Suicide, inflammation, pharmacotherapy, treatment, antidepressants, anti-inflammatory, lithium, ketamine Introduction Global suicide remains a major public health concern, with the World Health Organisation reporting 727,000 suicide deaths in 2021, the third leading cause of death among individuals aged 15–29 ( WHO 2025 ). In the United States in 2023, suicide accounted for over 49,300 deaths, making it the eleventh leading cause of mortality ( NIMH 2026 ). It was the second leading cause of death for individuals aged 10–34 and the fourth leading cause for those between 35 and 44 years. Attempted suicide is more frequent than completed suicide, with a lifetime prevalence of about 3.5% ( Bostwick et al. 2016 ). Roughly 90% of individuals who die by suicide have a history of a clinical mental disorder ( Mann et al. 2021 ). The most common mental disorders linked to death by suicide are mood disorders (major depressive disorder and bipolar disorder), post-traumatic stress disorder, substance use disorders, and psychotic disorders, including schizophrenia. The prevalence of suicidal ideation is 51–60% in patients diagnosed with major depression ( Gladstone et al. 2001 ). There are relatively few treatments available that reduce suicide risk, either acutely or chronically. To date, pharmacological approaches for treating and preventing suicide depend mostly on treating associated mental disorders and other comorbid diseases as opposed to the underlying suicidality per se. The existing management of patients with an acute risk for suicide typically consists of hospitalisation, crisis stabilisation, plus pharmacotherapy, psychotherapy, electroconvulsive therapy, ketamine, esketamine, or combinations thereof. Some forms of psychotherapy have well-established evidence supporting their use in suicidal patients. As a pharmacotherapy, lithium has been used to reduce suicidal risk in patients with depression or bipolar disorder as a long-term therapy ( Gershon et al. 2009 ; Kovacsics et al. 2009 ; Al Jurdi et al. 2015 ), but not in acute crisis ( Siegel et al. 2021 ). Similarly, clozapine reduces the risk of recurrent suicidal behaviours in patients with schizophrenia or schizoaffective disorder in longer-term treatment ( Meltzer 2003 ; Lee et al. 2023 ). Over the past decade, a growing body of clinical, neurobiological, and translational research has demonstrated that alterations in inflammatory signalling are robustly associated with suicidal behaviour across diagnostic categories ( Brundin et al. 2017 ; Baldini et al. 2025 ; Herzog et al. 2025 ). Multiple studies have shown that individuals with suicidal ideation or a history of suicide attempts exhibit elevated circulating levels of pro-inflammatory cytokines – including interleukin (IL)- 6, IL-1β, Tumour necrosis factor-α (TNF-α) – and acute-phase proteins such as C-reactive protein (CRP), suggesting a state of systemic immune activation ( Lindqvist et al. 2009 ; Serafini et al. 2020 ; Bramness et al. 2023 ; Sun et al. 2023 ; Shah et al. 2025 ). Parallel findings in cerebrospinal fluid and post-mortem brain tissue further support the presence of heightened neuroinflammation in suicide, with increased cytokine expression and microglial activation observed in regions implicated in mood regulation and impulsivity, such as the prefrontal cortex and anterior cingulate cortex ( Pandey et al. 2012 ; 2014 ; 2019 ; Baharikhoob and Kolla 2020 ; Kaushik et al. 2025 ). Converging evidence indicates that these inflammatory changes are not merely correlative but may play a causal role by modulating key neurobiological systems involved in stress responsivity, affect regulation, and behavioural control ( Sălcudean et al. 2025 ). For example, inflammation-driven activation of the kynurenine pathway reduces serotonin bioavailability and increases the production of neuroactive metabolites, such as quinolinic acid, an NMDA receptor agonist that promotes glutamatergic excitotoxicity and synaptic dysfunction, processes strongly implicated in suicidality ( Bryleva and Brundin 2017 ; Muneer 2020 ). In this review, we synthesise current evidence linking immune dysregulation to suicidality by examining multiple interacting biological pathways, including cytokine-mediated effects on monoamine metabolism, (hypothalamic-pituitary-adrenal) HPA axis perturbations, alterations in glutamatergic neurotransmission, and microglial-driven neuroplasticity changes. We highlight how inflammatory signalling interfaces with known suicide-related phenotypes such as impulsivity, aggression, and stress sensitivity, and we consider emerging work on inflammatory endophenotypes that may identify individuals at heightened risk. We also discuss the mechanisms and therapeutic potential of anti-inflammatory, anti-cytokine, and immunomodulatory agents that have been investigated as interventions for reducing suicidality. These include established treatments such as lithium and ketamine, both of which exhibit potent immunomodulatory and antisuicidal effects, as well as COX-2 inhibitors, cytokine-neutralizing monoclonal antibodies, and modulators of the kynurenine pathway that aim to correct inflammation-driven neurochemical abnormalities. Finally, we evaluate the translational opportunities and challenges associated with targeting inflammatory processes in suicide prevention, emphasising the need for biomarker-guided approaches to identify patients most likely to benefit from immunomodulatory therapeutics. Methods This narrative literature review was conducted using PubMed and Google Scholar. A combination of keywords ‘suicide’, ‘therapy’, ‘pharmacotherapy’, ‘inflammation’ was used along with the Boolean operators ‘OR’ and/or ‘AND’, search tailored according to the requirements of the included databases. Studies emphasising inflammation as a suicide risk factor and therapeutic findings aimed at reducing inflammatory activity and consequently suicidal behaviour were included. Inflammatory pathways and suicidal behaviour Pro-inflammatory cytokines As mentioned earlier, suicide is strongly associated with major depressive disorder (MDD). Many people with MDD presented with elevated levels of pro-inflammatory cytokines such as interleukin IL-6 and TNF-α without evidence of underlying inflammatory disease ( Miller and Raison 2016 ); however, high levels of IL-6 and TNF-α were shown to be associated with suicide attempts or suicidal ideation in depressed adults, even after controlling for depression ( Kim et al. 2008 ; Janelidze et al. 2011 ). Increased levels of IL-6 in cerebrospinal fluid (CSF) in suicide attempters have been found compared with normal control subjects ( Lindqvist et al. 2009 ). Recent meta-analyses show that there are more pro-inflammatory cytokines, C-reactive protein, and chemokine levels in the blood, CSF, and post-mortem brain samples from suicidal patients ( Black and Miller 2015 ). Increased mRNA levels of IL-1β, IL-6, and TNF-α have also been reported in the prefrontal cortex of depressed, suicidal subjects ( Pandey et al. 2012 ). Anti-inflammatory cytokines may also contribute to the pathophysiology of suicide; however, the evidence for their involvement is variable ( Maes et al. 2011 ; Chen et al. 2024 ; Tian et al. 2024 ; Zhao et al. 2025 ). On the other hand, genetic studies have identified cytokine variants that are significantly associated with suicidal behaviour ( de Medeiros Alves et al. 2017 ; Noroozi et al. 2018 ; Kaushik et al. 2024 ; García-Gutiérrez et al. 2025 ; Kaushik et al. 2025 ). Collectively, these findings – particularly those involving pro-inflammatory cytokines – indicate that elevated systemic inflammation is linked to suicidality. In addition to suicidal behaviour, associations between non-suicidal self-injury (NSSI) and plasma cytokine levels have also been reported ( Wang et al. 2025 ). Elevated inflammatory markers are also associated with suicidality in paediatric populations. A systematic review of nine cross-sectional and seven longitudinal studies examining the relationship between suicidality and inflammatory markers found that five of the cross-sectional studies and three of the longitudinal studies supported a link between systemic pro-inflammatory markers and suicidal behaviour ( Kim et al. 2008 ). Three additional studies evaluating early life adversity (ELA) reported that ELA was more strongly associated with inflammation than with depression. As ELA is a well-established risk factor for both depression and suicidality ( Afifi et al. 2008 ; Yıldız et al. 2023 ) and is linked to heightened systemic inflammation ( Coelho et al. 2014 ), these findings align with similar patterns observed in adult samples ( Danese et al. 2007 ). Despite these associations, it remains unclear whether inflammation mediates the relationship between ELA and suicidality in paediatric groups or whether ELA independently contributes to both. One study measuring high-sensitivity C-reactive protein (hsCRP) in 174 children with and without a history of ELA found elevated hsCRP only in those with both depression and ELA, but not in the ELA-only or depression-only groups ( Danese et al. 2011 ). Comparable results have been reported in adult cohorts, where depressed individuals with a history of ELA exhibited higher hsCRP levels than those without ELA exposure ( Danese et al. 2008 ). Collectively, these findings suggest that systemic inflammation is not simply a consequence of ELA alone but may instead reflect an interaction among ELA, inflammation, and psychopathology, including depression and suicidality. However, not all studies have reported a significant correlation between suicidal behaviour and inflammatory cytokines ( Serafini et al. 2016 ). A systematic review and meta-analysis of 24 articles found no significant differences in cytokine levels between depressed patients with and without suicidal ideation and controls ( Moshfeghinia et al. 2025 ). In another meta-analysis conducted across 6 and 23 studies for fatal and non-fatal suicide attempts, respectively, no significant association of IL-6 for either type of suicidal behaviour was reported ( Panzenhagen et al. 2023 ). HPA axis and its regulation Glucocorticoids (GC), which are crucial for maintaining homeostasis ( Papadimitriou and Priftis 2009 ), are largely regulated by the major neuro-endocrine system, i.e. HPA axis ( Spiga et al. 2014 ; Packard et al. 2016 ), which primarily includes hypothalamus, pituitary gland, and adrenal gland ( Mosili et al. 2024 ). Their role is pivotal in managing and responding to stress, whether physical or emotional. Briefly, in response to changes in an organism’s internal or external environment, the hypothalamus releases the neurohormones corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the anterior pituitary, triggering the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH then acts on the adrenal cortex to initiate a cascade that results in the synthesis of cortisol, the principal GC in humans ( Papadimitriou and Priftis 2009 ). These GCs also exert negative feedback on the pituitary and hypothalamus, thereby regulating their own production and facilitating organisms’ homeostasis ( Leonard 2005 ). In females, the HPA axis produces higher levels of stress-associated hormones and initiates more rapidly ( Goel et al. 2014 ). Pro-inflammatory cytokines potentially activate the HPA axis ( Turnbull and Rivier 1999 ; Silverman et al. 2003 ; Tu et al. 2007 ) as their receptors have been identified within this pathway ( Turnbull and Rivier 1995 ) resulting in increased levels of circulating GC ( Turnbull and Rivier 1999 ; Goel et al. 2014 ). Release of CRH, directly stimulated in the hypothalamus by IL-1β and TNF-α via signalling pathways, results in increased expression of the CRH gene ( Turnbull and Rivier 1999 ; Goel et al. 2014 ) ( Turnbull and Rivier 1999 ). IL-6 at the pituitary level can lead to the release of ACTH ( Turnbull and Rivier 1995 ; Mahmood et al. 2020 ) along with IL-1β and TNF-α. The direct action of these cytokines on the pituitary involves multiple signalling pathways, including the activation of biomechanism that suppresses cytokine signalling-3 (SOCS-3) ( Bousquet et al. 2001 ). Besides, IL-1 and TNF-α can also directly affect adrenal GC production ( Bornstein 2000 ). Gonadal hormones also mediate the HPA axis, wherein oestrogens decrease, and androgens increase HPA activity respectively ( Goel et al. 2014 ). In addition to this, the serotonergic system has also been widely studied and linked with the HPA axis and systemic inflammation ( Leonard 2005 ). Activation of these receptors inhibits the HPA axis, reducing the release of CRH and ACTH and leading to low GC levels. However, impairment of these receptors can also result in disinhibition in the HPA axis, leading to exaggerated stress responses ( Leonard 2005 ). Although differences in the number of 5-HT 2 receptors were suggested in the pre-frontal cortex region among individuals dying by suicide ( Mann et al. 1989 ), no difference in their binding pattern was observed between depressed suicide attempters and non-attempters ( Mann et al. 2019 ). 5-HT1A receptors have also been reported to be associated with the lethality of suicide attempts ( Melhem et al. 2022 ). Pro-inflammatory cytokines can disrupt serotonin biosynthesis, leading to impaired receptor function and ultimately pointing to HPA axis dysfunction ( Leonard 2005 ). Meta-analysis of 36 studies reported involvement of the HPA axis in suicide risk irrespective of the presence of psychiatric comorbidity among study subjects ( Berardelli et al. 2020 ). Another cumulative evidence from 41 studies reported a significant association between HPA axis stress pathway genes and suicidal behaviour ( Hernández-Díaz et al. 2021 ). However, another study by Mann et al. found no association between serotonin transporter site polymorphism in the prefrontal cortical region and suicide ( Mann et al. 2000 ). Intracellular cytokine signalling effect on Central monoamine synthesis Intracellular cytokine signalling significantly influences central monoamine synthesis, metabolism, and reuptake, particularly in the serotonin system ( Shelton and Miller 2010 ). Tryptophan, an essential amino acid for protein synthesis ( Bipath et al. 2015 ), is absorbed by the gut, depending upon the homeostatic microbiome ( Sales et al. 2023 ). Serotonin is synthesised from tryptophan through the actions of tryptophan hydroxylase (TH) and aromatic amino acid decarboxylase (AAAD). However, more than 90% of unbound tryptophan after protein synthesis is catabolized via the kynurenine pathway (KP) ( Bipath et al. 2015 ; Sales et al. 2023 ), resulting in the formation of neuroactive metabolites, thereby reducing precursor availability for serotonin synthesis. When tryptophan enters the KP, it undergoes enzymatic oxidation by either tryptophan-2, 3-dioxygenase (TDO) or indoleamine-2,3-dioxygenase (IDO), resulting in the formation of neuroprotective kynurenic acid (KYNA) or neurotoxic quinolinic acid (QUIN) ( Haduch et al. 2023 ). The initial downstream product of tryptophan in the KP, N-formylkynurenine, either results in the formation of neuroactive chemicals, wherein it is transaminated by kynurenine amino transferases (KATs) forming KYNA, conferring potent neuroprotective properties via NMDA receptor antagonism, or hydroxylated by kynurenine-3-monooxygenase (KMO), resulting in the formation of QUIN via 3-hydroxykynurenine (3-HK), with potent neurotoxic properties ( Feng et al. 2000 ; Stone 2001 ). Regulation of QUIN:KYNA is vital for maintaining the homeostatic balance of kynurenine metabolites, whose dysregulation has been widely implicated in neurodegenerative and psychiatric disorders ( Campbell et al. 2014 ). Under physiological conditions, vitamins, compartmentalisation of metabolism, and renal excretion govern KP ( Mithaiwala et al. 2021 ). On the other hand, basal tryptophan metabolism is primarily regulated by TDO ( Larkin et al. 2016 ). But, during systemic inflammation, there is increased production of pro-inflammatory cytokines and increased IDO expression, which drive tryptophan catabolism during immune activation ( Larkin et al. 2016 ; Mithaiwala et al. 2021 ). As a consequence of IDO upregulation, kynurenine levels increase disproportionately in the body. Following immune stimulation, KMO activity is also upregulated, metabolising more kynurenine towards QA. However, enzyme KAT is not upregulated or induced in response to inflammation, which affects the QUIN:KYNA balance towards the neurotoxic branch ( Campbell et al. 2014 ; Mithaiwala et al. 2021 ). Because most tryptophan is normally metabolised via IDO and TDO, sustained systemic inflammation can reduce tryptophan availability and diminish serotonin synthesis ( Christmas et al. 2011 ). Animal studies show that IDO activation produces depression-like behaviours ( O’Connor et al. 2009 ). In acute inflammatory states induced by lipopolysaccharide (LPS), serotonin levels do not immediately decline; instead, serotonin turnover increases. Inhibition of IDO – via agents such as minocycline or 1-methyltryptophan – reduces cytokine production and prevents the emergence of these behaviours. Although acute inflammation may not immediately reduce serotonin synthesis, prolonged activation of IDO/TDO likely contributes to long-term deficits ( O’Connor et al. 2009 ). These findings highlight the potential importance of kynurenine and its downstream metabolites, such as QUIN, in mediating inflammation-related behavioural effects. Several inflammatory pathways, including those activated by TNF-α ( Popov and Schultze 2008 ) and interferon γ (IFNγ) ( Wu et al. 2018 ), stimulate IDO via signalling pathways such as signal transducer and activator of transcription 1a (STAT1a), interferon regulatory factor-1 (IRF1), NF-κB, and p38 mitogen-activated protein kinase (p38 MAPK) ( Miller et al. 2009 ). Activation of p38 MAPK by IL-1β and TNF-α enhances serotonin transporter phosphorylation, increasing serotonin reuptake and ultimately reducing synaptic serotonin ( Zhu et al. 2006 ). Clinical studies demonstrate that immune activation also alters tryptophan metabolism: treatment of cancer patients with IL-2 or IFN-α lowers serum tryptophan levels, and the degree of tryptophan reduction correlates with depressive symptoms ( Capuron et al. 2002 ). Additionally, in cancer patients receiving IFN-α, those who developed depression exhibited higher kynurenine and lower tryptophan levels than non-depressed patients ( Capuron et al. 2003 ). Tryptophan depletion, achieved experimentally through an amino acid mixture lacking tryptophan, has shown that many patients – particularly those with partial or full remission on serotonin reuptake inhibitors – experience rapid relapse that reverses with tryptophan supplementation ( Delgado et al. 1999 ; Moore et al. 2000 ). Notably, individuals without a personal history of depression but with a family history also show acute mood deterioration following tryptophan depletion, unlike those without such a history ( Benkelfat 1994 ). These findings suggest that certain individuals may be especially sensitive to reductions in tryptophan and serotonin, predisposing them to worsening depression or relapse. While immune activation can reduce dopamine and norepinephrine, serotonin depletion appears to be relevant to suicide risk based on the reported evidence. Low serotonin levels and increased turnover are associated with impulsivity ( Worbe et al. 2014 ) and aggression ( Stanley et al. 2000 ; Bortolato et al. 2013 ), core suicide-related phenotypes ( Dumais et al. 2005 ; Galtress et al. 2012 ). Not all individuals who engage in suicidal behaviour exhibit reduced serotonin synthesis or increased turnover; however, a subset is particularly vulnerable. In these individuals, decreases in brain serotonin may worsen depressive symptoms and heighten underlying impulsive or aggressive tendencies, precipitating acute suicidal ideation or behaviour. Prior work identifies two broad suicidal phenotypes: a more impulsive, potentially aggressive type and a more planful, less impulsive type ( Turecki 2005 ). It is, therefore, proposed that some individuals with major depression – and possibly some without a depression history – could be especially sensitive to tryptophan and serotonin depletion, increasing their susceptibility to acute suicidality. Activation of IDO shifts tryptophan metabolism towards kynurenine, leading to the production of cytotoxic metabolites such as 3-hydroxykynurenine and quinolinic acid (QUIN). QUIN is generated primarily by macrophages and microglia ( Guillemin et al. 2003 ). The latter are resident macrophages in the central nervous system and serve a critical role in brain immune defense ( Yin et al. 2017 ). A clinical study showed elevated plasma kynurenine in individuals with major depression who recently attempted suicide compared with depressed non-attempters and healthy controls ( Sublette et al. 2011 ). Post-mortem analyses further demonstrate increased QUIN concentrations in the subgenual anterior cingulate cortex and anterior midcingulate cortex of depressed individuals who died by suicide ( Steiner et al. 2011 ). Altered serum concentrations of tryptophan and kynurenine have also been reported in patients with suicide attempts ( Demirci et al. 2025 ) or elevated suicide risk ( Messaoud et al. 2022 ; Nettis et al. 2023 ; Yang et al. 2025 ), and higher salivary tryptophan levels have been observed in schizophrenia patients with a history of suicide attempts ( Yin et al. 2025 ). Taken together, these findings strongly link QUIN activity in the pathophysiology of depression and suicidality. Systematic reviews and meta-analyses have indicated an association of serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) ( Hoertel et al. 2021 ; Sharma et al. 2021 ) and dopamine metabolite homovanillic acid (HVA) ( Hoertel et al. 2021 ) in the CSF of suicide attempters. Polymorphism in serotonin transporter genes has been found to possess a significant association with suicidal behaviour in psychiatric patients, also with violent suicides ( Lin and Tsai 2004 ). Linking glutamatergic dysfunction to neuroinflammation and suicide Research increasingly implicates glutamatergic dysfunction in suicidal behaviour ( Can et al. 2023 ). These glutamatergic abnormalities are tightly intertwined with upstream neuroinflammatory processes ( Serafini et al. 2015 ; Fairless et al. 2021 ). Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α activate the kynurenine pathway, increasing production of quinolinic acid (QUIN), a potent NMDA receptor agonist that promotes excitotoxicity ( Addae and Stone 2022 ). Elevated QUIN has been consistently observed in individuals with suicidal behaviour and in post-mortem brain regions implicated in affect regulation ( Bryleva and Brundin 2017 ). When sustained, QUIN-mediated NMDAR overactivation reduces synaptic density, induces astrocytic apoptosis, and disrupts glutamate recycling – mechanisms directly contributing to the glutamatergic abnormalities noted in suicidal phenotypes. These inflammatory effects converge on key neuroplasticity pathways, including the brain-derived neurotrophic factor-Tropomyosin receptor kinase B-Mammalian target of Rapamycin Complex 1 (BDNF–TrkB–mTORC1) signalling cascade. Reduced AMPAR activation and impaired BDNF-mediated synaptic plasticity, whether from inflammatory cytokine exposure or QUIN-induced NMDAR overactivation, may heighten risk for suicidal ideation by diminishing stress resilience ( Dwivedi 2009 ; De Simone et al. 2022 ). Thus, the intersection of neuroinflammation, kynurenine-pathway activation, and glutamatergic dysfunction provides a unifying mechanistic pathway through which inflammatory states can drive suicidality in susceptible individuals ( Erhardt et al. 2013 ; Can et al. 2023 ). Pharmacotherapy regulating inflammation in suicidality A growing body of evidence suggests that pharmacological agents that modulate inflammatory pathways may exert therapeutic effects on suicidality, either directly or indirectly. Although the mechanistic relationship between inflammation and suicidal behaviour remains complex, converging data indicate that targeting neuroimmune dysregulation could represent a promising strategy for both acute and long-term suicide prevention. Table 1 summarises studies that have been conducted to determine the efficacy of varied pharmacotherapy arms in the treatment of suicidal behaviour across different diagnoses. Table 1. Characteristics of studies investigating the treatment efficacy of various pharmacotherapies in suicidal behaviour. Study design Study period Sample size Pharmaco-treatment Diagnosis Major findings Reference Comparative 8 years N = 51535 Li ( n = 21129) Li or valproate BPD I, II, NOS; schizoaffective disorders Reduction in suicide related events by 14% for periods of Li treatment, in contrast to valproate. Differences in HR for both lines of treatment were found to be statistically significant. ( Song et al. 2017 ) Naturalistic retrospective cohort study 35 years N = 4441 Li, anti-convulsant, anti-depressants, or anti-psychotics BPD I, II; MDD and episodes; Schizophrenia and schizoaffective disorders; OCD, GAD, and others Long-term treatment with anti-convulsant and Li was reported to be associated with lower suicide risk. On the contrary, long-term treatment with antidepressants was found to be associated with elevated suicide risk. ( Sani et al. 2011 ) Retrospective observational Average 6.7 years N = 167 Long-term Li prophylaxis Recurrent affective disorders Both responders and non-responders exhibited a reduction in suicide attempts upon Li treatment. More than 90% percent of excellent responders reported no subsequent attempt for suicide after Li administration. ( Ahrens and Müller-Oerlinghausen 2001 ) Comparative 5 years N = 12,662 Li ( n = 3200) Li, Divalproex, Carbamazepine, Gabapentin, Lamotrigine, Oxcarbazepine, or Combination BPD I and II Li was found to be associated with a lower risk of suicide attempt. ( Collins and McFarland 2008 ) Retrospective-cohort study 8 years N = 20638 Li ( n = 9151) Li, Divalproex, Carbamazepine, or combination BPD Divalproex was found to be significantly less effective than Li for suicidal death (HR 2.7), attempts leading to hospitalisation (HR 1.7), and attempts ascertained in the emergency department (HR 1.8). ( Goodwin et al. 2003 ) Randomised placebo-controlled trial 4 years N = 156 Ketamine ( n = 73) Placebo or ketamine BPD, Depressive disorder, and others Ketamine induced remission of severe suicidal ideation, with the effect persisting for about 6 weeks in almost two-thirds of the patient population. ( Abbar et al. 2022 ) Randomised multi-centre trial 2 years Clozapine N = 980 ( n = 490) Clozapine or Olanzapine Schizophrenia or schizoaffective disorders Compared to olanzapine, patients administered clozapine demonstrated a lower risk of suicidal behaviour. ( Meltzer 2003 ) Randomised placebo-controlled double-blind 3 years N = 18 Li/Valproate + ketamine hypochloride/ placebo Treatment resistant bipolar-depression Depressive symptoms were found to be significantly elevated in subjects who received ketamine as compared to placebo, and were generally well tolerated. (Diazgranados et al. 2010) Double blind randomised controlled trial Not specified N = 57 Ketamine ( n = 36) Ketamine hydrocholride or midazolam Treatment resistant unipolar-depression The most significant reduction in explicit suicidal cognition was ketamine specific. About 53% of the ketamine-treated patients scored zero on all three explicit suicide measures. ( Price et al. 2009 ) Post-hoc analysis of four independent clinical trials Not specified N = 133 Ketamine TRD (MDD or BPD I or II) Upon controlling the effects of ketamine on anxiety and depression, a significant reduction in suicide ideation was reported to be associated with ketamine infusion. ( Ballard et al. 2014 ) Prospective cohort study 9 years N = 175 Li, divalproex, or carbamazepine BPD I A substantial reduction in the risk of suicide attempt was found when pharmacotherapy, particularly Li, and highly structured psychosocial treatment designed for BPD or a general supportive intervention, were combined. ( Rucci et al. 2002 ) Randomised placebo-controlled 1 year N = 167 Li ( n = 84) Li or placebo Affective spectrum disorder Li was found to be associated with a lower risk of suicidal behaviour (in the context of completed suicide) in adults suffering from mood disorders. ( Lauterbach et al. 2008 ) Randomised placebo-controlled double-blind 3.5 years N = 519 Li ( n = 255) Li or placebo BPD or depression Subjects who abruptly stopped receiving the placebo or Li during study treatment demonstrated elevated rates of suicide related behaviour. However, no significant association between Li administration and suicide prevention was found. ( Katz et al. 2022 ) Randomised double-blind 7 years N = 94 Li ( n = 46) Li or valproate BPD + depressed/mixed state Li exhibited significant antisuicidal effects in subjects aged 42 or above, independently of prior sociodemographic or clinical history, in contrast to valproate for a similar age group. ( Dervic et al. 2023 ) Randomised midazolam-controlled double-blind Approx 1 year N = 80 Ketamine ( n = 40) Ketamine or midazolam MDD with suicidal ideation Administration of ketamine orally (3 mg/kg) resulted in a rapid reduction of suicide ideation in the participants. ( Seraj et al. 2025 ) Randomised double-blind parallel-arm controlled 1 year N = 36 Ketamine ( n = 18) Ketamine or placebo TRD Repeated infusion of ketamine can potentially reduce the symptoms of depression and suicidal ideation, independent of comorbid personality or psychiatric disorders. ( Ahmed et al. 2023 ) Randomised active-placebo-controlled 1.5 years N = 54 Esketamine ( n = 27) Esketamine or midazolam MDD Changes in C-SSRS ideation and intensity were significantly greater in the esketamine group than in the midazolam group from baseline to day 6 post-intervention. Thus, three-dose intravenous infusion of esketamine was well-tolerated for the treatment of adolescents with MDD and SI ( Zhou et al. 2024 ) Prospective observational study 2 years N = 23 Sub-cutaneous ketamine Depression Subcutaneous administration of ketamine resulted in a substantial reduction in C-SSRS scores, with the majority achieving remission after a span of eight sessions that sustained over time and were well-tolerated. ( Anzolin et al. 2024 ) Randomised placebo-controlled double-blind POC trial 2 years N = 30 Ketamine ( n = 15) Intra-nasal ketamine or placebo Varied Fixed and single-dose intranasal ketamine was found to have alleviated the symptoms of acute SI about four hours post administration in a highly suicidal cohort. ( Domany and McCullumsmith 2022 ) Randomised controlled trial 5 years N = 37 Ketamine ( n = 20) Ketamine or midazolam Cancer Ketamine supplementation induced rapid antidepressant and antisuicidal effects among newly diagnosed cancer patients with a significant reduction in SI score on day 1 and day 3 in ketamine-treated patients, in contrast to midazolam. ( Fan et al. 2017 ) Prospective observational study 9 years N = 5091 Li ( n = 827) Divalproex ( n = 1953) Carbamazepine ( n = 615) Combination ( n = 323) Li, Divalproex, and/or carbamazepine BPD Short-term exposure to all three mood-stabilisers reduced the risk of suicide, suicidal deaths, and all-cause deaths among subjects. However, there were no statistically significant differences in the treatment efficiency of the three pharmacotherapies in the context of suicide protection. ( Tsai et al. 2016 ) Retrospective chart review analysis 9 years N = 405 Mood stabiliser ( n = 192) Mood stabilisers- Li, divalproex, carbamazepine Antidepressants Anti-psychotics BPD I, II, NOS, schizoaffective disorders No significant differences in the antisuicidal properties were reported among the three classes of mood stabilisers. Additionally, their discontinuation poses an increased risk of suicide attempts and SI. ( Yerevanian et al. 2007 ) Randomised parallel-group controlled trial 1 year N = 56 Li + UC ( n = 29) UC w/o Li ( n = 27) Li Unipolar major depression No significant differences in the survival probability were found between the two treatment points. ( Girlanda et al. 2014 ) Randomised double-blind controlled trial 2.5 years N = 98 Li ( n = 49) Valproate ( n = 49) Li or valproate BPD No significant differences between the two treatment groups were reported with regards to time to suicide attempt or suicide event ( Oquendo et al. 2011 ) Retrospective observational study 1 year N = 5522 Gabapentin ( n = 2421) Li ( n = 3101) Gabapentin or Li BPD Relative to Li, gabapentin was found to be significantly associated with a doubled risk of suicidality ( Leith et al. 2019 ) Randomised double-blind trial N = 80 Ketamine ( n = 40) Ketamine or midazolam MDD Within 24 h, adjunctive ketamine, as compared to midazolam, presented a greater reduction in SI ( Grunebaum et al. 2018 ) Randomised controlled trial Approx 3 years N = 439 Fluoxetine ( n = 109) Fluoxetine + CBT ( n = 107) CBT ( n = 111) Placebo ( n = 112) Fluoxetine and/or CBT or placebo MDD Suicidal thinking significantly improved in all four groups, with the greatest reduction in Fluoxetine + CBT treatment ( March et al. 2004 ) Open in a new tab Li = Lithium; N = number; MDD = Major Depressive Disorder; BPD = Bipolar Disorder; UPD = Unipolar Disorder; TAU = Treatment As Usual; APT = Adjunctive Personalised Treatment; TRD = Treatment Resistant Depression; C-SSRS = Columbia Suicide Severity Rating Scale; SI = Suicidal ideation; POC = Proof of Concept; HR = Hazards Ratio; NOS = Not Otherwise Specified; OCD = Obsessive Compulsive Disorder; GAD = Generalized Anxiety Disorder; UC = Usual Care; w/o = without; CBT = Cognitive Behavioural Therapy. Lithium Glycogen synthase kinase-3 (GSK3), a key target of lithium, is a major regulator of inflammation and cell migration ( Jope et al. 2007 ). Stress increases inflammation, in part, by activating GSK3. The two GSK3 isoforms, GSK3α and GSK3β, share substantial structural homology and are normally inhibited through serine phosphorylation; however, physiological phosphorylation is often insufficient to fully suppress their activity. Increased GSK3 activity elevates pro-inflammatory cytokines – including IL-1β, IL-6, and TNF – following Toll-like receptor (TLR) stimulation in monocytes and peripheral blood mononuclear cells ( Lampson 1987 ). Stress-induced GSK3 activation has been linked to greater cytokine expression and to aggression- and depression-like behaviours in animal studies ( Beurel and Jope 2014 ). Certain GSK3β variants are also associated with impulsivity and heightened suicide risk in bipolar disorder ( Jiménez et al. 2013 , 2014 ), underscoring the enzyme’s role in both risk traits and suicidal behaviour. A post-mortem brain study also indicated a possible role of GSK3β in suicidal behaviour ( Pandey et al. 2009 ). Lithium is a potent GSK3 inhibitor and reduces production of IL-1β, IL-6, and TNF-α in monocytes, microglia, and astrocytes ( Beurel and Jope 2014 ). By competing with magnesium at the GSK3 binding site, lithium markedly decreases impulsive, aggressive, and depression-like behaviours in preclinical models ( Galtress et al. 2012 ; Beurel and Jope 2014 ) and lowers suicidality in patients with bipolar and unipolar depression ( Hollander et al. 2005 ). Intracellularly, lithium suppresses GSK3β-mediated inflammatory and oxidative pathways, while extracellularly it modulates the HPA axis and serotonin signalling ( Malhi et al. 2018 ). It further reduces the expression of inflammatory mediators across downstream pathways, including arachidonic acid metabolism ( Zhou et al. 2025 ). Despite substantial evidence of antisuicidal benefit ( Hafeman et al. 2020 ; Chen et al. 2023 ; Ng et al. 2023 ; Szmulewicz et al. 2023 ), clinical findings remain mixed ( Katz et al. 2022 ), with more consistent effects in older bipolar patients ( Dervic et al. 2023 ) and some adolescents with severe illness ( Desai Boström et al. 2023 ). There is also evidence that lithium can exert direct anti-inflammatory effects by inhibiting COX-2, prostaglandin E2, IL-1, and arachidonic acid turnover, while increasing anti-inflammatory cytokines such as IL-2 and IL-10 ( Nassar and Azab 2014 ). Whether these immunomodulatory actions directly contribute to its antisuicidal effects remains to be clarified. Ketamine Ketamine, originally approved by the U.S. Food and Drug Administration as an anaesthetic, has since demonstrated rapid antidepressant effects in major depressive disorder, including treatment-resistant and ( Zarate et al. 2006 ; Serafini et al. 2014 ; Haikazian et al. 2025 ) bipolar depression ( Price et al. 2009 ; Diazgranados et al. 2010; Zarate et al. 2012 ; Wilkinson et al. 2018 ; Jawad et al. 2023 ). Intravenous ketamine and intranasal esketamine also show well-established antisuicidal properties, some of which appear independent of their antidepressant effects ( Ballard et al. 2014 ; Plöderl et al. 2026 ). A single subanesthetic dose (0.5 mg/kg) can reduce suicidal ideation within hours, with benefits lasting up to two weeks. Repeated administration of IV ketamine ( Singh et al. 2016 ) or intranasal esketamine ( Canuso et al. 2018 ; Popova et al. 2019 ; Canuso et al. 2021 ; Bell 2023 ) can produce sustained antidepressant and antisuicidal responses, with therapeutic effects typically emerging within hours ( Krystal et al. 2013 ; Wilkinson et al. 2018 ; Canuso et al. 2021 ). Mechanistically, ketamine is a phencyclidine derivative and a non-competitive NMDA receptor antagonist. Its antidepressant and antisuicidal actions may involve blockade of quinolinic-acid–mediated NMDA receptor activation. Ketamine also reduces circulating pro-inflammatory cytokines – including TNF-α, IL-6, IL-8 ( Spencer et al. 2022 ), and IL-1β ( Chen et al. 2009 ), while sparing anti-inflammatory cytokines. Notably, ketamine does not alter cytokine production in the absence of an inflammatory trigger. It suppresses proinflammatory cytokines but not anti-inflammatory ones, preventing exaggerated inflammatory reactions ( De Kock et al. 2013 ). It also appears to suppress macrophage and microglial activity ( Chang et al. 2005 ; Spencer et al. 2022 ). Elevated baseline IL-6 levels have also been identified as a potential predictor of ketamine treatment response ( Yang et al. 2015 ). Preclinical studies show that lipopolysaccharide-induced increases in inflammatory cytokines and depression-like behaviours are prevented by NMDA receptor blockade with ketamine ( Walker et al. 2013 ). Ketamine, therefore, may exert its antidepressant and antisuicidal effects by both direct effects, that is, blockade of QUIN binding to NMDAR, and indirect anti-inflammatory effects. Clinical trials further report remission of severe suicidal ideation lasting up to six weeks in a substantial proportion of patients ( Abbar et al. 2022 ). In randomised controlled trials, changes in C-SSRS ideation and intensity were significantly greater in the esketamine-administered group than in the midazolam group ( Zhou et al. 2024 ). However, isolated reports describe cases in which esketamine administration coincided with the emergence of severe suicidal ideation ( Vanicek et al. 2022 ), underscoring the need for careful monitoring. A systematic review and meta-analysis evaluated the anti-inflammatory effects of ketamine ( Dale et al. 2012 ). In this study, 14 reports, comprising 684 participants, were included. The analysis indicated that ketamine reduced IL-6 levels post-operatively compared with baseline. The authors concluded that intraoperative ketamine administration significantly reduced postoperative IL-6 levels, suggesting an anti-inflammatory effect. Another meta-analysis of nine human and 22 animal studies indicated a strong effect of ketamine on pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, along with decreases in IDO ( Kopra et al. 2021 ). Although these findings confirm ketamine’s broad anti-inflammatory effects, the extent to which these mechanisms directly mediate its antidepressant or antisuicidal actions remains unclear. NR2B and other NMDA receptor antagonists The NMDA receptor is a heterotetramer composed of two GluN1 and typically two GluN2 subunits, functioning as a calcium and sodium influx channel and a potassium efflux channel. Ketamine and esketamine act as non-selective channel blockers, while arketamine – the R-enantiomer of ketamine – is under investigation for treatment-resistant depression ( Hashimoto 2019 ). Glycine serves as a co-agonist at a distinct binding site on the GluN2 subunit. Several agents targeting GluN2 subtypes, particularly GluN2B, are in development ( Krystal et al. 2019 ). These antagonists may be especially effective for inflammation-induced depression, consistent with the rationale supporting ketamine and esketamine. Preclinical work shows that LPS exposure increases inflammatory cytokines and causes depression-like behaviours in mice. Interestingly, one study showed that GluN2A knockout mice containing a null mutation of the Grin2A gene were resilient to LPS administration, suggesting that inhibition of GluN2A may be an effective treatment for inflammation-induced depression in humans ( Francija et al. 2019 ). The study also showed that the GluN2A null mice did not show the expected increase in IL-6 in the brain that was demonstrated in wild-type mice. Therefore, channel blockers and GluN2B and GluN2A subunit antagonists may be effective for inflammation-induced depression or suicidality. 4-Chlo-Kynurenine (4-CL-KYN) In the kynurenine pathway, the activity of the NMDA receptor requires the binding of glycine or D-serine to an obligatory co-agonist (‘glycine B’) site, which is located on the GluN1 subunit ( Berger et al. 1998 ; Strong et al. 2014 ). 7-Chlorokynurenic acid (7-Cl-KYNA) is a potent and highly selective competitive glycine B receptor antagonist that has been widely used as a pharmacological probe to study the biology of the NMDA receptor ( Kemp et al. 1988 ). However, the therapeutic use of 7-Cl-KYNA is limited because of its poor penetration of the blood-brain barrier. Its prodrug, 4-chlorokynurenine (4-Cl-KYN), a halogenated derivative of L-kynurenine, can readily cross the blood-brain barrier after systemic administration and is then converted to 7-Cl-KYNA within astrocytes ( Boros and Vécsei 2020 ). A study evaluated the antidepressant efficacy and side effect profile of 4-Cl-KYN compared to ketamine and found no side effects in animal models ( Zanos et al. 2015 ). Interestingly, these beneficial mood-altering effects depend on AMPA receptor activity, suggesting an important relationship between NMDA and AMPA receptors in generating the antidepressant response. 4-CL-KYN, however, did not succeed in antidepressant trials ( Boros and Vécsei 2020 ), and the current research on suicidal behaviour remains obscure. TAK-242-toll-like receptors (TLRs) antagonist Toll-like receptors (TLRs) can be activated by both stress and pathogens, triggering inflammatory responses in the central nervous system. Although the precise mechanisms underlying elevated proinflammatory cytokines in the brains of suicide subjects remain unclear, evidence suggests that abnormalities in innate immune receptors, known as TLRs, may contribute ( Hanke and Kielian 2011 ). Activated TLRs induce cytokine and chemokine production through MyD88-dependent and -independent pathways, ultimately activating NF-κB signalling ( O’Neill 2006 ). Post-mortem studies have shown increased mRNA expression of TLR3 and TLR4 in the dorsolateral prefrontal cortex (dlPFC) of both depressed suicide and depressed non-suicide subjects compared with controls, whereas protein expression of these receptors appears elevated only in suicide subjects ( Pandey et al. 2014 ). TLR4 antagonists have demonstrated the ability to attenuate stress-induced neuroinflammation ( Gárate et al. 2013 ), and compounds such as TAK-242 are emerging as potential therapeutic candidates for mitigating inflammatory responses associated with stress-related neuropsychiatric disorders ( Gárate et al. 2014 ). Antidepressants Selective serotonin reuptake inhibitors (SSRIs) may reduce levels of pro-inflammatory cytokines. For example, sertraline has been shown to decrease IL-1β mRNA expression after a single dose and to reduce TNF-α with repeated dosing ( Sitges et al. 2014 ; Patel et al. 2022 ; Rajkumar 2024 ). Large-scale meta-analytic evidence indicates that SSRIs lower suicide risk and suicidal behaviour in adults with depression, though these benefits typically require sustained treatment. In contrast, SSRIs do not provide rapid antisuicidal effects and may transiently increase suicidal ideation or non-suicidal self-injury in adolescents and young adults up to age 24 ( Miller et al. 2014 ). Several other antidepressant classes, including tricyclics, serotonin–norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, also demonstrate anti-inflammatory properties, such as reducing pro-inflammatory cytokines and enhancing anti-inflammatory signalling ( De Berardis et al. 2010 ). Many of these agents additionally attenuate microglial activation, whereas some drugs, such as bupropion and agomelatine, show minimal or inconsistent effects ( Mariani et al. 2022 ). Notably, most mechanistic data come from in vitro studies using sup- raphysiological drug concentrations, while ex vivo rodent studies have reported decreased microglial activation markers following 8–28 days of antidepressant exposure ( Mariani et al. 2022 ). Overall, multiple antidepressants appear to mitigate systemic and central inflammatory markers; however, the extent to which these anti-inflammatory effects contribute to their long-term antidepressant or antisuicidal efficacy remains uncertain. Clozapine Clozapine remains the only FDA-approved medication with a specific indication for reducing suicidal behaviour, particularly in schizophrenia and schizoaffective disorder ( Lee et al. 2023 ; Chen et al. 2024 ; Waszak et al. 2025 ). Large-scale systematic reviews report that clozapine significantly lowers both suicide attempts and mortality from suicide compared with other antipsychotics ( Masdrakis and Baldwin 2023 ). Although its anti-inflammatory mechanisms are less well defined than those of lithium or ketamine, clozapine is known to reduce microglial activation, decrease pro-inflammatory cytokine production, and modulate oxidative stress, factors implicated in the neurobiology of suicide ( V. Giridharan et al. 2020 ; Waszak et al. 2025 ). Thus, part of its anti-suicidal effect may involve stabilising neuroimmune dysregulation commonly observed in psychotic disorders ( Waszak et al. 2025 ). Cyclooxygenase-2 (COX-2) inhibitors COX-2 plays a key role in inflammatory responses by inducing prostaglandin E 2 (PGE 2 ) and increasing IDO expression ( Cesario et al. 2011 ; Jin et al. 2023 ). Prostaglandins regulate tissue homeostasis but, when dysregulated, can disrupt the blood–brain barrier, allowing peripheral inflammatory mediators to enter the brain ( Ricciotti and FitzGerald 2011 ). NSAIDs such as ibuprofen and celecoxib inhibit COX-2 and reduce inflammation and may assist in treating the symptoms of neuropsychiatric disorders ( Mesripour et al. 2019 ; Sethi et al. 2019 ). Two meta-analyses in depressed patients found NSAIDs to be modestly more effective than placebo ( Köhler et al. 2014 ; Na et al. 2014 ), and one study reported that IL-6 reductions with celecoxib correlated with improvements in depression severity ( Abbasi et al. 2012 ). However, the overall differences between NSAIDs and placebo were small, and many studies were limited by small sample sizes. A pooled analysis of five post-approval osteoarthritis trials (ibuprofen, naproxen, celecoxib) showed slightly greater reductions in PHQ-9 scores with NSAIDs compared to placebo, but these findings were likely confounded by improvements in pain rather than direct antidepressant effects ( Iyengar et al. 2013 ). Another investigation, a Phase IIA, 2 × 2 factorial trial in bipolar depression, evaluated minocycline, aspirin, their combination, and placebo as adjunctive treatments ( Savitz et al. 2012 ). The study found modest improvements in depressive symptoms in some treatment arms, though results were not uniformly significant across all groups. (Minocycline + Aspirin vs. Placebo: OR = 2.93, NNT = 4.7, p (one-tailed) = 0.034; Effect of Aspirin alone (All Arms): OR = 3.67, NNT = 4.0, p (two-tailed) = 0.019. A 3-way interaction between aspirin, minocycline, and IL-6 levels showed that patients with higher inflammatory markers responded better to minocycline alone. Cytokine antagonists Elevated cytokine levels appear to contribute to depressive symptoms and suicidal behaviour, suggesting that cytokine-blocking therapies may offer therapeutic benefit. Among these, TNF-α inhibitors are the most extensively studied. Trials assessing depressive symptoms before and after treatment, primarily in patients with psoriasis, rheumatoid arthritis, or osteoarthritis, generally show greater reductions in depression with anti-TNF-α agents than with placebo ( Kappelmann et al. 2018 ). However, these findings are difficult to interpret because improvements in mood may reflect treatment of the underlying inflammatory illness rather than a direct antidepressant effect. For example, one study reported that reductions in fatigue correlated more strongly with improvements in depression than did changes in psoriasis severity or joint symptoms ( Tyring et al. 2006 ), although the very low baseline level of depressive symptoms may have influenced these associations. Overall, current evidence suggests that anti-TNF-α therapies may reduce depressive symptoms in patients with inflammatory disorders, but it remains unclear whether the effect is mediated by improvements in systemic inflammation, disease burden, or fatigue. Tocilizumab, an IL-6 receptor antagonist, has also been associated with changes in depressive symptoms in patients receiving treatment for rheumatoid arthritis ( Venkiteshwaran 2009 ). One notable exception to these patterns is the study, which evaluated infliximab, an anti-TNF-α chimeric monoclonal antibody, in patients with treatment-resistant major depressive disorder without active systemic inflammatory disease ( Raison et al. 2013 ). In this study, 60 medically stable patients with major depressive disorder were randomised to three infusions of infliximab or placebo at baseline and weeks two and six of a 12-week study. There were no differences in the change in HRSD score between the groups. However, there was a significant interaction between log baseline hsCRP, a marker of systemic inflammation, and response to infliximab, such that those with higher baseline hsCRP levels had much greater change in HRSD scores. In addition, baseline blood concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders compared with non-responders, and those who responded to infliximab had greater decreases in hsCRP than placebo responders. These findings indicate that infliximab may benefit only those depressed patients who exhibit systemic inflammation. Conversely, several case reports describe the emergence or worsening of depression, panic symptoms, or suicidal ideation following infliximab treatment for inflammatory diseases such as rheumatoid arthritis ( Thillard et al. 2020 ) Crohn’s disease ( Shayowitz et al. 2019 ), ulcerative colitis ( Kontoangelos et al. 2021 ), and ankylosing spondylitis ( Ulual et al. 2023 ). Although some cases involved additional psychosocial stressors, infliximab was considered a potential precipitating factor for self-injurious behaviour. Because infliximab does not cross the blood–brain barrier, any antidepressant effects are presumed to arise from modulation of peripheral inflammation ( Raison et al. 2013 ). This interpretation aligns with mechanistic models involving IDO activation, reduced tryptophan availability, and increased production of neuroactive kynurenine metabolites such as quinolinic acid. Although cytokine-blocking therapies (e.g. anti–TNF-α, IL-6 inhibitors) are being explored for depression and inflammation-related psychiatric symptoms, direct evidence for reducing suicidal behaviour remains limited. The strongest findings suggest potential benefit only in individuals with elevated inflammation, with no consistent effect across general clinical populations. Conclusions and future directions There is growing evidence that systemic inflammation is linked to suicidality, although this association appears to apply primarily to a biologically distinct subset of affected individuals rather than to all patients with depressive or psychiatric disorders. Emerging work highlights that inflammatory dysregulation may represent a convergent pathway through which environmental stressors, genetic vulnerability, and neurobiological alterations interact to increase suicide risk. Figure 1 provides an overview of the major biological pathways through which inflammation may influence suicidal thoughts and behaviours, illustrating interactions among peripheral immune activation, neuroinflammatory signalling, glutamatergic dysfunction, monoaminergic disturbances, and neuroendocrine abnormalities. Figure 1. Open in a new tab Pharmacotherapies for inflammation-associated pathways reported to be dysregulated in suicidal behaviour. Arachidonic acid is converted into prostaglandins and other mediators capable of causing inflammation, primarily by COX-2. Therefore, drugs that inhibit this conversion are one of the most potent choices of treatment. Glucocorticoid receptor (GR) resistance hastens the negative feedback of cortisol, thereby leading to its overstimulation. In response to stress, activated microglia release proinflammatory cytokines (PIC), which, in conjunction with cortisol, further stimulate the kynurenine pathway, favouring the conversion of tryptophan (TRYP) to quinolinic acid (QUIN) via kynurenine. Consequently, antidepressants such as tricyclics, lithium, or ketamine either prevent microglial activation or the release of PIC by them. QUIN elicits inflammatory signals and acts as an NMDA receptor agonist, leading to oxidative stress and excitotoxicity. Ketamine acts as an NMDA antagonist and prevents QUIN-mediated over-stimulation of its receptors. Autonomic inflammation reflex stressors lead to the release of catecholamines and acetylcholine via the stimulation of the sympathetic and parasympathetic nervous systems. The released neurotransmitters are capable of binding to cholinergic and adrenergic receptors on immune and endothelial cells. Adrenergic activation of these cells causes the release of cytokines, which in turn leads to inflammation. Lithium and cytokine antagonists are potential treatment arms wherein the former can shunt the release of GSK-3, and the latter can oppose or neutralise inflammatory cytokines. Although pro-inflammatory endophenotypes do not characterise the majority of patients with suicidality, several inflammatory markers have consistently emerged across clinical, translational, and post-mortem studies. Elevations in IL-1β, IL-6, TNF-α, and hsCRP are among the most robust abnormalities observed, supporting the potential implication of heightened systemic and central immune activation in subsets of individuals presenting with suicidal ideation or behaviour. Additional biomarkers – such as the tryptophan-to-quinolinic acid ratio, an index of indoleamine 2,3-dioxygenase (IDO) pathway activation – further refine this inflammatory profile. Alongside these pro-inflammatory signals, alterations in anti-inflammatory cytokines, including IL-2 and IL-10, may provide added specificity by indicating compensatory responses or distinct immunobiological phenotypes. Careful characterisation of these pro- and anti-inflammatory patterns may ultimately help delineate biologically meaningful subgroups of patients in whom inflammation contributes directly to suicide vulnerability. A deeper understanding of these inflammatory phenotypes is also critical for developing predictive biomarkers of treatment response. Individuals with elevated inflammatory markers often demonstrate attenuated response to traditional antidepressants yet may preferentially benefit from interventions targeting immune dysregulation. Although anti-inflammatory treatments, including COX-2 inhibitors, cytokine antagonists, and agents modulating the kynurenine pathway, have shown promising effects in reducing depressive symptoms among patients with elevated inflammation, their ability to reduce suicidal behaviour specifically remains less well established. Current data suggest potential benefit, but findings remain preliminary and heterogeneous, with limited studies directly examining suicidality as a primary outcome. At present, lithium and ketamine/esketamine remain the only treatments with substantial documented anti-suicidal properties that may, in part, operate through anti-inflammatory or immunomodulatory mechanisms. Lithium has been shown to inhibit GSK-3, reduce pro-inflammatory cytokine production, and modulate microglial activation, while ketamine and esketamine rapidly reduce inflammatory cytokines and counteract quinolinic acid–mediated NMDA receptor overactivation. Whether these immunomodulatory actions play a causal role in their antisuicidal effects or represent parallel mechanisms occurring alongside other neurobiological processes remains a key question for future investigation. Looking forward, determining whether targeted anti-inflammatory therapies can reduce suicidality in individuals with clear evidence of systemic or neuroinflammation represents an important and timely research direction with significant existing gaps. Precision-based approaches integrating inflammatory biomarkers, neuroimaging signatures, genetic susceptibility, and clinical presentation may enable the identification of patients most likely to benefit from immunomodulatory interventions. Such approaches hold the potential to shift suicide prevention strategies towards more individualised, biologically informed treatment models. Limitations The pharmacological interventions discussed in this review are predominantly evaluated within the framework of inflammatory and immune-related mechanisms that have been implicated in suicidality and suicidal behaviour. However, the existing literature is characterised by substantial heterogeneity across multiple domains, including study design, sample size, diagnostic composition, clinical severity, biomarker selection, and outcome ascertainment. This variability complicates direct comparison across studies and limits the generalisability of findings to broader clinical populations. In particular, many investigations draw from diagnostically mixed samples or focus on comorbid medical or inflammatory conditions, making it difficult to disentangle effects that are specific to suicidality from those attributable to underlying psychiatric or systemic illness. In addition, suicidal thoughts and behaviours are frequently assessed using secondary or indirect measures, such as depression severity scales or post-hoc analyses of clinical trials that were not originally designed to evaluate suicidality as a primary endpoint. As a result, conclusions regarding antisuicidal efficacy are often inferential rather than definitive. Prospective, suicide-focused outcomes – including the onset, persistence, or recurrence of suicidal ideation, attempts, or behaviour – are rarely incorporated as primary study objectives. This limitation is particularly relevant given the episodic, state-dependent, and multifactorial nature of suicidality, which may not be adequately captured by broader symptom-based assessments. Furthermore, the causal relationships linking inflammation, psychiatric pathology, and suicidal behaviour remain incompletely understood. It is unclear whether inflammatory abnormalities function as antecedent risk factors that increase vulnerability to suicidality, act as mediators through which psychosocial stress and psychopathology exert their effects, or merely represent epiphenomena reflecting illness burden, medication exposure, or medical comorbidity. These uncertainties underscore the importance of temporal resolution and mechanistic clarity, which are often lacking in cross-sectional or retrospective study designs. Collectively, these limitations highlight the pressing need for well-designed, longitudinal, and biomarker-guided clinical trials that explicitly prioritise suicide-related outcomes. Such studies should incorporate repeated assessments of inflammatory markers alongside rigorous, standardised measures of suicidal ideation and behaviour, while accounting for relevant confounders such as medication status, metabolic risk, and psychosocial stressors. Advancing this line of research will be essential for clarifying the therapeutic potential of immunomodulatory strategies and determining whether targeting inflammation can meaningfully contribute to suicide prevention in biologically defined subgroups of patients. Acknowledgements Chittaranjan Behera: Writing – original draft, data curation, Srishti Gupta: Writing – review & editing, data curation. Richard Shelton: Writing – review & editing, Yogesh Dwivedi: Writing – original draft, review & editing, conceptualisation, supervision, project administration, and funding acquisition. Funding This work was supported by funding from the National Institute of Mental Health (R01MH130539, R01MH124248, R01MH118884, R01MH128994, R01MH107183, R01MH137153, R56MH138596) to Dr. Dwivedi. Statement of interest Richard Shelton, M.D., is supported by AbbVie Inc., Alto Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Denovo Biopharma, Gate Neuroscience, InMune Bio, Intra-Cellular Therapies, Johnson & Johnson Innovative Medicine, LivaNova PLC, Navitor Pharmaceuticals, Neumora, Neurocrine Biosciences, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Sumitomo Pharma America, and Supernus Pharmaceuticals. He is also a consultant for Boehringer Ingelheim, Denovo Biopharma, Equulus Therapeutics, Evecxia Therapeutics LLC, Johnson & Johnson Innovative Medicine, Neurorx, Novartis AG, Otsuka Pharmaceuticals, Seelos Therapeutics, Inc., Sumitomo Pharma America, and Supernus Pharmaceuticals and receives royalties from Springer-Nature Group and Wolters-Kluwer NV. Yogesh Dwivedi, Ph.D., received royalties from Taylor and Francis for an edited book. Dr. Dwivedi has received grants from the American Foundation for Suicide Prevention and NIH. Other authors declare no conflict of interest with this work. Footnotes Declaration of generative AI and AI-assisted technologies in the writing process No AI tool was used to generate the manuscript. Data availability statement No data was used for the research described in the article. References Abbar M et al. 2022. Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial. BMJ. 376:e067194. 10.1136/bmj-2021-067194 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Abbasi S-H, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S. 2012. Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord. 141(2-3):308–314. [ DOI ] [ PubMed ] [ Google Scholar ] Addae JI, Stone TW. 2022. Quinolinic acid and related excitotoxins: mechanisms of neurotoxicity and disease relevance. In: Kostrzewa RM, editor. Handbook of neurotoxicity. Springer International Publishing; p. 839–860. [ Google Scholar ] Afifi TO et al. 2008. Population attributable fractions of psychiatric disorders and suicide ideation and attempts associated with adverse childhood experiences. Am J Public Health. 98(5):946–952. 10.2105/AJPH.2007.120253 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Ahmed GK, Elserogy YM, Elfadl GMA, Ghada Abdelsalam K, Ali MA. 2023. Antidepressant and anti-suicidal effects of ketamine in treatment-resistant depression associated with psychiatric and personality comorbidities: a double-blind randomized trial. J Affect Disord. 325:127– 134. 10.1016/j.jad.2023.01.005 [ DOI ] [ PubMed ] [ Google Scholar ] Ahrens B, Müller-Oerlinghausen B. 2001. Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry. 34(4):132–136. 10.1055/s-2001-15878 [ DOI ] [ PubMed ] [ Google Scholar ] Al Jurdi RK, Swann A, Mathew SJ. 2015. Psychopharmacological agents and suicide risk reduction: ketamine and other approaches. Curr Psychiatry Rep. 17(10):81. 10.1007/s11920-015-0614-9 [ DOI ] [ PubMed ] [ Google Scholar ] Anzolin AP et al. 2024. Subcutaneous ketamine reduces suicide risk and improves functioning in depression: a proof-of-concept study. Psychiatry Res. 337:115915. 10.1016/j.psychres.2024.115915 [ DOI ] [ PubMed ] [ Google Scholar ] Baharikhoob P, Kolla NJ. 2020. Microglial dysregulation and suicidality: a stress-diathesis perspective. Front Psychiatry. 11:781. 10.3389/fpsyt.2020.00781 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Baldini V et al. 2025. Inflammatory markers and suicidal behavior: a comprehensive review of emerging evidence. Ann Gen Psychiatry. 24(1):36. 10.1186/s12991-025-00575-9 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Ballard ED et al. 2014. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 58:161–166. 10.1016/j.jpsychires.2014.07.027 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Bell F 2023. Acute suicidal ideation in the context of esket- amine maintenance therapy. AJP Residents’ Journal. 18(3):15–17. 10.1176/appi.ajp-rj.2023.180305 [ DOI ] [ Google Scholar ] Benkelfat C 1994. Mood-lowering effect of tryptophan depletion: enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry. 51(9):687. 10.1001/archpsyc.1994.03950090019003 [ DOI ] [ PubMed ] [ Google Scholar ] Berardelli I et al. 2020. The involvement of hypothalamuspituitary-adrenal (HPA) axis in suicide risk. Brain Sci. 10(9):653. 10.3390/brainsci10090653 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Berger AJ, Dieudonné S, Ascher P. 1998. Glycine uptake governs glycine site occupancy at NMDA receptors of excitatory synapses. J Neurophysiol. 80(6):3336–3340. 10.1152/jn.1998.80.6.3336 [ DOI ] [ PubMed ] [ Google Scholar ] Beurel E, Jope RS. 2014. Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits. Transl Psychiatry. 4(12):e488-e488–e488. 10.1038/tp.2014.129 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Bipath P, Levay PF, Viljoen M. 2015. The kynurenine pathway activities in a sub-Saharan HIV/AIDS population. BMC Infect Dis. 15(1):346. 10.1186/s12879-015-1087-5 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Black C, Miller BJ. 2015. Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. Biol Psychiatry. 78(1):28–37. 10.1016/j.biopsych.2014.10.014 [ DOI ] [ PubMed ] [ Google Scholar ] Bornstein SR. 2000. Cytokines and the adrenal cortex: basic research and clinical implications. Current Opinion in Endocrinology, Diabetes and Obesity. 7(3):128–137. 10.1097/00060793-200006000-00005 [ DOI ] [ Google Scholar ] Boros F, Vécsei L. 2020. Progress in the development of kynurenine and quinoline-3-carboxamide-derived drugs. Expert Opin Investig Drugs. 29(11):1223–1247. 10.1080/13543784.2020.1813716 [ DOI ] [ PubMed ] [ Google Scholar ] Bortolato M et al. 2013. The role of the serotonergic system at the interface of aggression and suicide. Neuroscience. 236:160–185. 10.1016/j.neuroscience.2013.01.015 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Bostwick JM, Pabbati C, Geske JR, McKean AJ. 2016. Suicide attempt as a risk factor for completed suicide: even more lethal than we knew. Am J Psychiatry. 173(11):1094–1100. 10.1176/appi.ajp.2016.15070854 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Bousquet C, Chesnokova V, Kariagina A, Ferrand A, Melmed S. 2001. cAMP neuropeptide agonists induce pituitary suppressor of cytokine signaling-3: novel negative feedback mechanism for corticotroph cytokine action. Mol Endocrinol. 15(11):1880–18 10.1210/mend.15.11.0733 [ DOI ] [ PubMed ] [ Google Scholar ] Bramness JG et al. 2023. Levels of IL-6 are associated with lifetime attempted suicide in alcohol use disorder patients. Neuropsychiatr Dis Treat. 19:2141–2148. 10.2147/NDT.S413101 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Brundin L, Bryleva EY, Thirtamara Rajamani K. 2017. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacology. 42(1):271–283. 10.1038/npp.2016.116 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Bryleva EY, Brundin L. 2017. Kynurenine pathway metabolites and suicidality. Neuropharmacology. 112(Pt B):324–330. 10.1016/j.neuropharm.2016.01.034 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Campbell BM, Charych E, Lee AW, Moller T. 2014. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci. 8:12. 10.3389/fnins.2014.00012 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Can AT et al. 2023. Insights into the neurobiology of suicidality: explicating the role of glutamatergic systems through the lens of ketamine. Psychiatry Clin Neurosci. 77(10):513– 529. 10.1111/pcn.13572 [ DOI ] [ PubMed ] [ Google Scholar ] Canuso CM et al. 2018. Efficacy and safety of intranasal es- ketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 175(7):620–630. 10.1176/appi.ajp.2018.17060720 [ DOI ] [ PubMed ] [ Google Scholar ] Canuso CM et al. 2021. Esketamine nasal spray for the rapid reduction of depressive symptoms in major depressive disorder with acute suicidal ideation or behavior. J Clin Psychopharmacol. 41(5):516–524. 10.1097/JCP.0000000000001465 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Capuron L et al. 2002. Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry. 7(5):468–473. 10.1038/sj.mp.4000995 [ DOI ] [ PubMed ] [ Google Scholar ] Capuron L et al. 2003. Interferon-alpha–induced changes in tryptophan metabolism. Biol Psychiatry. 54(9):906–914. 10.1016/S0006-3223(03)00173-2 [ DOI ] [ PubMed ] [ Google Scholar ] Cesario A, Rocca B, Rutella S. 2011. The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 In chronic inflammation and cancer. Curr Med Chem. 18(15):2263–2271. 10.2174/092986711795656063 [ DOI ] [ PubMed ] [ Google Scholar ] Chang Y, Chen T-L, Sheu J-R, Chen R-M. 2005. Suppressive effects of ketamine on macrophage functions. Toxicol Appl Pharmacol. 204(1):27–35. 10.1016/j.taap.2004.08.011 [ DOI ] [ PubMed ] [ Google Scholar ] Chen M-H, Bai Y-M, Hsu J-W, Huang K-L, Tsai S-J. 2024. Proinflammatory cytokine levels, cognitive function, and suicidal symptoms of adolescents and young adults with major depressive disorder. Eur Arch Psychiatry Clin Neurosci. 274(7):1681–1687. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Chen PH et al. 2023. Mood stabilizers and risk of all-cause, natural, and suicide mortality in bipolar disorder: a nationwide cohort study. Acta Psychiatr Scand. 147(3):234–247. 10.1111/acps.13519 [ DOI ] [ PubMed ] [ Google Scholar ] Chen T-L, Chang C-C, Lin Y-L, Ueng Y-F, Chen R-M. 2009. Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1β gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells. Toxicol Appl Pharmacol. 240(1):15–25. 10.1016/j.taap.2009.06.013 [ DOI ] [ PubMed ] [ Google Scholar ] Chen W-Y et al. 2024. Clozapine and its protective effect on all-cause, natural, and suicide mortality in patients with schizophrenia: a nationwide cohort study in Taiwan. Schizophr Res. 268:150–160. 10.1016/j.schres.2023.07.014 [ DOI ] [ PubMed ] [ Google Scholar ] Christmas DM, Potokar J, Davies SJ. 2011. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatr Dis Treat. 7:431–439. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Coelho R, Viola TW, Walss‐Bass C, Brietzke E, Grassi-Oliveira R. 2014. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand. 129(3):180–192. 10.1111/acps.12217 [ DOI ] [ PubMed ] [ Google Scholar ] Collins JC, McFarland BH. 2008. Divalproex, lithium and suicide among Medicaid patients with bipolar disorder. J Affect Disord. 107(1–3):23–28. 10.1016/j.jad.2007.07.014 [ DOI ] [ PubMed ] [ Google Scholar ] Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. 2012. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? a systematic review and meta-analysis. Anesth Analg. 115(4):934–943. 10.1213/ANE.0b013e3182662e30 [ DOI ] [ PubMed ] [ Google Scholar ] Danese A et al. 2008. Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry. 65(4):409–415. 10.1001/archpsyc.65.4.409 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Danese A et al. 2011. Biological embedding of stress through inflammation processes in childhood. Mol Psychiatry. 16(3):244–246. 10.1038/mp.2010.5 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. 2007. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci USA. 104(4):1319–1324. 10.1073/pnas.0610362104 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] De Berardis D et al. 2010. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature. Int J Immunopathol Pharmacol. 23(2):417–422. 10.1177/039463201002300204 [ DOI ] [ PubMed ] [ Google Scholar ] De Kock M, Loix S, Lavand’homme P. 2013. Ketamine and peripheral inflammation. CNS Neurosci Ther. 19(6):403–410. 10.1111/cns.12104 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] de Medeiros Alves V et al. 2017. Suicide attempt in mental disorders (MeDi): association with 5-HTT, IL-10 and TNF-alpha polymorphisms. J Psychiatr Res. 91:36–46. 10.1016/j.jpsychires.2017.02.022 [ DOI ] [ PubMed ] [ Google Scholar ] De Simone S et al. 2022. Suicide and neurotrophin factors: a systematic review of the correlation between BDNF and GDNF and self-killing. Healthcare (Basel). 11(1):78. 10.3390/healthcare11010078 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Delgado PL et al. 1999. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 46(2):212–220. 10.1016/s0006-3223(99)00014-1 [ DOI ] [ PubMed ] [ Google Scholar ] Demirci OL et al. 2025. Comparison of the kynurenine/tryptophan ratio with the beck suicide intent scale in patients admitted to the emergency department due to suicide attempt. J Clin Med. 14(19):6859. 10.3390/jcm14196859 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Dervic K et al. 2023. Antisuicidal effect of lithum in bipolar disorder: is there an age-specific effect? J Affect Disord. 341:8–11. 10.1016/j.jad.2023.08.107 [ DOI ] [ PubMed ] [ Google Scholar ] Desai Boström AE et al. 2023. Regional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents. Nat Commun. 14(1):1281. 10.1038/s41467-023-36973-4 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Diazgranados N et al. 2010. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 67(8):793–802. 10.1001/archgenpsychiatry.2010.90 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Domany Y, McCullumsmith CB. 2022. Single, fixed-dose intranasal ketamine for alleviation of acute suicidal ideation. an emergency department, trans-diagnostic approach: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Arch Suicide Res. 26(3):1250–1265. 10.1080/13811118.2021.1878078 [ DOI ] [ PubMed ] [ Google Scholar ] Dumais A et al. 2005. Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men. Am J Psychiatry. 162(11): 2116–2124. 10.1176/appi.ajp.162.11.2116 [ DOI ] [ PubMed ] [ Google Scholar ] Dwivedi Y 2009. Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr Dis Treat. 5:433–449. 10.2147/ndt.s5700 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Erhardt S et al. 2013. Connecting inflammation with glutamate agonism in suicidality. Neuropsychopharmacology. 38(5):743–752. 10.1038/npp.2012.248 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Fairless R, Bading H, Diem R. 2021. Pathophysiological ionotropic glutamate signalling in neuroinflammatory disease as a therapeutic target. Front Neurosci. 15:741280. 10.3389/fnins.2021.741280 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Fan W et al. 2017. Ketamine rapidly relieves acute suicidal ideation in cancer patients: a randomized controlled clinical trial. Oncotarget. 8(2):2356–2360. 10.18632/oncotarget.13743 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Feng Y, Bowden BF, Kapoor V. 2000. Screening marine natural products for selective inhibitors of key kynurenine pathway enzymes. Redox Rep. 5(2-3):95–97. 10.1179/135100000101535636 [ DOI ] [ PubMed ] [ Google Scholar ] Francija E et al. 2019. Disruption of the NMDA receptor GluN2A subunit abolishes inflammation-induced depression. Behav Brain Res. 359:550–559. 10.1016/j.bbr.2018.10.011 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Galtress T, Garcia A, Kirkpatrick K. 2012. INDIVIDUAL DIFFERENCES IN IMPULSIVE CHOICE AND TIMING IN RATS. J Exp Anal Behav. 98(1):65–87. 10.1901/jeab.2012.98-65 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Gárate I et al. 2013. Stress-Induced Neuroinflammation: role of the Toll-Like Receptor-4 Pathway. Biol Psychiatry. 73(1):32–43. 10.1016/j.biopsych.2012.07.005 [ DOI ] [ PubMed ] [ Google Scholar ] Gárate I et al. 2014. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation. 11(1):8. 10.1186/1742-2094-11-8 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] García-Gutiérrez MS et al. 2025. Alterations of pro- and anti-inflammatory cytokines balance and superoxide dismutase in the dorsolateral prefrontal cortex of suicide decedents. Neurotherapeutics. 22(5):e00634. 10.1016/j.neurot.2025.e00634 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Gershon S, Chengappa KR, Malhi GS. 2009. Lithium specificity in bipolar illness: a classic agent for the classic disorder. Bipolar Disord. 11 Suppl 2(s2):34–44. 10.1111/j.1399-5618.2009.00709.x [ DOI ] [ PubMed ] [ Google Scholar ] Giridharan V et al. 2020. Clozapine prevents poly (I: c) induced inflammation by modulating nlrp3 pathway in microglial cells. Cells. 9(3):577. 10.3390/cells9030577 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Girlanda F et al. 2014. Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: results and lessons of an underpowered randomised clinical trial. BMC Res Notes. 7(1):731. 10.1186/1756-0500-7-731 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Gladstone GL et al. 2001. Indicators of suicide over 10 years in a specialist mood disorders unit sample. J Clin Psychiatry. 62(12):945–951. 10.4088/JCP.v62n1205 [ DOI ] [ PubMed ] [ Google Scholar ] Goel N, Workman JL, Lee TT, Innala L, Viau V. 2014. Sex differences in the HPA axis. Compr Physiol. 4(3):1121–1155. 10.1002/j.2040-4603.2014.tb00575.x [ DOI ] [ PubMed ] [ Google Scholar ] Goodwin FK et al. 2003. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 290(11):1467–1473. 10.1001/jama.290.11.1467 [ DOI ] [ PubMed ] [ Google Scholar ] Grunebaum MF et al. 2018. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 175(4):327–335. 10.1176/appi.ajp.2017.17060647 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Guillemin GJ, Smith DG, Smythe GA, Armati PJ, Brew GJ. et al. 2003. Expression of the kynurenine pathway enzymes in human microglia and macrophages. In: Allegri G, Costa CVL, Ragazzi E, editors. Developments in tryptophan and serotonin metabolism. Springer US; p. 105–112. 10.1007/978-1-4615-0135-0_12 [ DOI ] [ PubMed ] [ Google Scholar ] Haduch A, Bromek E, Kuban W, Daniel WA. 2023. The engagement of cytochrome P450 enzymes in tryptophan metabolism. Metabolites. 13(5):629. 10.3390/metabo13050629 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Hafeman DM et al. 2020. Lithium versus other mood-stabilizing medications in a longitudinal study of youth diagnosed with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 59(10):1146–1155. 10.1016/j.jaac.2019.06.013 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Haikazian S et al. 2025. Real world effectiveness of maintenance ketamine infusions for treatment-resistant depression in major depressive disorder and bipolar disorder. Psychiatry Res. 352:116691. 10.1016/j.psy-chres.2025.116691 [ DOI ] [ PubMed ] [ Google Scholar ] Hanke ML, Kielian T. 2011. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond). 121(9):367–387. 10.1042/CS20110164 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Hashimoto K 2019. Rapid-acting antidepressant ketamine, its metabolites and other candidates: a historical overview and future perspective. Psychiatry Clin Neurosci. 73(10):613–627. 10.1111/pcn.12902 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Hernández-Díaz Y et al. 2021. Association and genetic expression between genes involved in hpa axis and suicide behavior: a systematic review. Genes (Basel). 12(10):1608. 10.3390/genes12101608 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Herzog S et al. 2025. Neuroinflammation, stress-related suicidal ideation, and negative mood in depression. JAMA Psychiatry. 82(1):85–93. 10.1001/jamapsychiatry.2024.3543 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Hoertel N et al. 2021. Cerebrospinal fluid levels of monoamines among suicide attempters: a systematic review and random-effects meta-analysis. J Psychiatr Res. 136:224–235. 10.1016/j.jpsychires.2021.01.045 [ DOI ] [ PubMed ] [ Google Scholar ] Hollander E, Pallanti S, Allen A, Sood E, Rossi NB. 2005. Does sustained-release lithium reduce impulsive gambling and affective instability versus placebo in pathological gamblers with bipolar spectrum disorders? Am J Psychiatry. 162(1):137–145. 10.1176/appi.ajp.162.1.137 [ DOI ] [ PubMed ] [ Google Scholar ] Iyengar RL et al. 2013. NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med. 126(11):1017.e1011-1017–e1018. 10.1016/j.amjmed.2013.02.037 [ DOI ] [ PubMed ] [ Google Scholar ] Janelidze S, Mattei D, Westrin Å, Träskman-Bendz L, Brundin L. 2011. Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behav Immun. 25(2):335–339. 10.1016/j.bbi.2010.10.010 [ DOI ] [ PubMed ] [ Google Scholar ] Jawad MY et al. 2023. The role of ketamine in the treatment of bipolar depression: a scoping review. Brain Sci. 13(6):909. 10.3390/brainsci13060909 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Jiménez E et al. 2013. Genetic variability at IMPA2, INPP1 and GSK3β increases the risk of suicidal behavior in bipolar patients. Eur Neuropsychopharmacol. 23(11):1452–1462. 10.1016/j.euroneuro.2013.01.007 [ DOI ] [ PubMed ] [ Google Scholar ] Jiménez E et al. 2014. Association between GSK3β gene and increased impulsivity in bipolar disorder. Eur Neuropsychopharmacol. 24(4):510–518. 10.1016/j.euroneuro.2014.01.005 [ DOI ] [ PubMed ] [ Google Scholar ] Jin K, Qian C, Lin J, Liu B. 2023. Cyclooxygenase-2-prostaglandin E2 pathway: a key player in tumor-associated immune cells [Review. Front Oncol. 13:1099811. volumeEnglish. 10.3389/fonc.2023.1099811 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Jope RS, Yuskaitis CJ, Beurel E. 2007. Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res. 32(4-5):577–595. 10.1007/s11064-006-9128-5 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. 2018. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 23(2):335–343. 10.1038/mp.2016.167 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Katz IR et al. 2022. Lithium treatment in the prevention of repeat suicide-related outcomes in veterans with major depression or bipolar disorder: a randomized clinical trial. JAMA Psychiatry. 79(1):24–32. 10.1001/ja-mapsychiatry.2021.3170 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Kaushik R et al. 2024. Cytokine gene polymorphisms and suicide risk in an Indian ancestral population: a case-control study. World J Biol Psychiatry. 25(9):547–559. 10.1080/15622975.2024.2410492 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Kaushik R et al. 2025. Association of peripheral and cerebral inflammatory markers with suicidal deaths in Indian population. Psychoneuroendocrinology. 172:107268. 10.1016/j.psyneuen.2024.107268 [ DOI ] [ PubMed ] [ Google Scholar ] Kemp JA et al. 1988. 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci U S A. 85(17):6547–6550. 10.1073/pnas.85.17.6547 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Kim Y-K et al. 2008. Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 32(2):356–361. 10.1016/j.pnpbp.2007.08.041 [ DOI ] [ PubMed ] [ Google Scholar ] Köhler O et al. 2014. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 71(12):1381–1391. 10.1001/jamapsychiatry.2014.1611 [ DOI ] [ PubMed ] [ Google Scholar ] Kontoangelos K et al. 2021. Suicidal thoughts in a patient after administration of infliximab. Psychiatriki. 32(3):247–250. 10.22365/jpsych.2021.011 [ DOI ] [ PubMed ] [ Google Scholar ] Kopra E, Mondelli V, Pariante C, Nikkheslat N. 2021. Ketamine’s effect on inflammation and kynurenine pathway in depression: a systematic review. J Psychopharmacol. 35(8):934–945. 10.1177/02698811211026426 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Kovacsics CE, Gottesman II, Gould TD. 2009. Lithium’s antisuicidal efficacy: elucidation of neurobiological targets using endophenotype strategies. Annu Rev Pharmacol Toxicol. 49(1):175–198. 10.1146/annurev.pharm-tox.011008.145557 [ DOI ] [ PubMed ] [ Google Scholar ] Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. 2019. Ketamine: a paradigm shift for depression research and treatment. Neuron. 101(5):774–778. 10.1016/j.neuron.2019.02.005 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Krystal JH, Sanacora G, Duman RS. 2013. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry. 73(12):1133–1141. 10.1016/j.biopsych.2013.03.026 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Lampson LA. 1987. Molecular bases of the immune response to neural antigens. Trends Neurosci. 10(5):211–216. 10.1016/0166-2236(87)90153-6 [ DOI ] [ Google Scholar ] Larkin PB et al. 2016. Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. Biochim Biophys Acta. 1860(11 Pt A):2345–2354. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Lauterbach E et al. 2008. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand. 118(6):469–479. 10.1111/j.1600-0447. 2008.01266.x [ DOI ] [ PubMed ] [ Google Scholar ] Lee BJ et al. 2023. The protective effect of clozapine on suicide: a population mortality study of statewide autopsy records in Maryland. J Clin Psychiatry. 84(3):46188 eng. 10.4088/JCP.22m14587 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Leith WM, Lambert WE, Boehnlein JK, Freeman MD. 2019. The association between gabapentin and suicidality in bipolar patients. Int Clin Psychopharmacol. 34(1):27–32. 10.1097/YIC.0000000000000242 [ DOI ] [ PubMed ] [ Google Scholar ] Leonard BE. 2005. The HPA and immune axes in stress: the involvement of the serotonergic system. Eur Psychiatr. 20(S3): S302–S306. 10.1016/S0924-9338(05)80180-4 [ DOI ] [ PubMed ] [ Google Scholar ] Lin PY, Tsai G. 2004. Association between serotonin transporter gene promoter polymorphism and suicide: results of a meta-analysis. Biol Psychiatry. 55(10):1023–1030. 10.1016/j.biopsych.2004.02.006 [ DOI ] [ PubMed ] [ Google Scholar ] Lindqvist D et al. 2009. Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry. 66(3):287–292. 10.1016/j.biopsych.2009.01.030 [ DOI ] [ PubMed ] [ Google Scholar ] Maes M, Leonard BE, Myint AM, Kubera M, Verkerk R. 2011. The new ‘5-HT’ hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 35(3):702–721. 10.1016/j.pnpbp.2010.12.017 [ DOI ] [ PubMed ] [ Google Scholar ] Mahmood Z et al. 2020. The effect of acute exercise on interleukin-6 and hypothalamic-pituitary-adrenal axis responses in patients with coronary artery disease. Sci Rep. 10(1):21390. 10.1038/s41598-020-78286-2 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Malhi GS et al. 2018. Understanding suicide: focusing on its mechanisms through a lithium lens. J Affect Disord. 241:338–347. 10.1016/j.jad.2018.08.036 [ DOI ] [ PubMed ] [ Google Scholar ] Mann JJ et al. 2000. A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry. 57(8):729–738. 10.1001/archpsyc.57.8.729 [ DOI ] [ PubMed ] [ Google Scholar ] Mann JJ et al. 2019. Quantification of 5-HT(1A) and 5-HT(2A) receptor binding in depressed suicide attempters and non-attempters. Arch Suicide Res. 23(1):122–133. 10.1080/13811118.2017.1417185 [ DOI ] [ PubMed ] [ Google Scholar ] Mann JJ, Arango V, Marzuk PM, Theccanat S, Reis DJ. 1989. Evidence for the 5-HT hypothesis of suicide a review of post-mortem studies. Br J Psychiatry. 155(S8):7–14. 10.1192/S000712500029171X [ DOI ] [ PubMed ] [ Google Scholar ] Mann JJ, Michel CA, Auerbach RP. 2021. Improving Suicide prevention through evidence-based strategies: a systematic review. Am J Psychiatry. 178(7):611–624. 10.1176/appi.ajp.2020.20060864 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] March J et al. 2004. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA. 292(7):807–820. 10.1001/jama.292.7.807 [ DOI ] [ PubMed ] [ Google Scholar ] Mariani N, Everson J, Pariante CM, Borsini A. 2022. Modulation of microglial activation by antidepressants. J Psychopharmacol. 36(2):131–150. 10.1177/02698811211069110 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Masdrakis VG, Baldwin DS. 2023. Prevention of suicide by clozapine in mental disorders: systematic review. Eur Neuropsychopharmacol. 69:4–23. 10.1016/j.euroneuro.2022.12.011 [ DOI ] [ PubMed ] [ Google Scholar ] Melhem NM et al. 2022. Brain 5-HT1A receptor PET Binding, cortisol responses to stress, and the familial transmission of suicidal behavior. Int J Neuropsychopharmacol. 25(1):36–45. 10.1093/ijnp/pyab060 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Meltzer HY. 2003. Clozapine treatment for suicidality in Schizophrenia International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 60(1):82. [ DOI ] [ PubMed ] [ Google Scholar ] Mesripour A, Shahnooshi S, Hajhashemi V. 2019. Celecoxib, ibuprofen, and indomethacin alleviate depression-like behavior induced by interferon-alfa in mice. J Complement Integr Med. 17(1):20190016 eng. 10.1515/jcim-2019-0016 [ DOI ] [ PubMed ] [ Google Scholar ] Messaoud A et al. 2022. Investigation of the relationship among cortisol, pro-inflammatory cytokines, and the degradation of tryptophan into kynurenine in patients with major depression and suicidal behavior. Curr Top Med Chem. 22(25):2119–2125. 10.2174/1568026621666210909160210 [ DOI ] [ PubMed ] [ Google Scholar ] Miller AH, Maletic V, Raison CL. 2009. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 65(9):732–741. 10.1016/j.biopsych.2008.11.029 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Miller AH, Raison CL. 2016. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 16(1):22–34. 10.1038/nri.2015.5 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Miller M, Swanson SA, Azrael D, Pate V, Stürmer T. 2014. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med. 174(6):899–909. 10.1001/jamainternmed.2014.1053 [ DOI ] [ PubMed ] [ Google Scholar ] Mithaiwala MN, Santana-Coelho D, Porter GA, O’Connor JC. 2021. Neuroinflammation and the Kynurenine Pathway in CNS Disease: molecular Mechanisms and Therapeutic Implications. Cells. 10(6):1548. 10.3390/cells10061548 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Moore P et al. 2000. Clinical and Physiological Consequences of Rapid Tryptophan Depletion. Neuropsychopharmacology. 23(6):601–622. 10.1016/S0893-133X(00)00161-5 [ DOI ] [ PubMed ] [ Google Scholar ] Moshfeghinia R et al. 2025. Pro-inflammatory cytokines level in depressed patients with suicidal behaviour: a systematic review and meta-analysis. Ann Gen Psychiatry. 24(1):71. 10.1186/s12991-025-00609-2 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Mosili P, Mkhize BC, Sibiya NH, Ngubane PS, Khathi A. 2024. Review of the direct and indirect effects of hyperglycemia on the HPA axis in T2DM and the co-occurrence of depression. BMJ Open Diabetes Res Care. 12(1):e003218. 10.1136/bmjdrc-2022-003218 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Muneer A 2020. Kynurenine pathway of tryptophan metabolism in neuropsychiatric disorders: pathophysiologic and therapeutic considerations. Clin Psychopharmacol Neurosci. 18(4):507–526. 10.9758/cpn.2020.18.4.507 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Na K-S, Lee KJ, Lee JS, Cho YS, Jung H-Y. 2014. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 48:79–85. 10.1016/j.pnpbp.2013.09.006 [ DOI ] [ PubMed ] [ Google Scholar ] Nassar A, Azab AN. 2014. Effects of lithium on inflammation. ACS Chem Neurosci. 5(6):451–458. 10.1021/cn500038f [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Nettis MA et al. 2023. The interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression. J Psychopharmacol. 37(6):531–538. 10.1177/02698811231173588 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Ng VWS et al. 2023. Association between the mood stabilizing treatment of bipolar disorder and risk of suicide attempts: a self-controlled case series study. Psychiatry Res. 325:115236. 10.1016/j.psychres.2023.115236 [ DOI ] [ PubMed ] [ Google Scholar ] NIMH. 2026. https://www.nimh.nih.gov/health/statistics/suicide#part_10459 Noroozi R et al. 2018. Interleukin (IL)-8 polymorphisms contribute in suicide behavior. Cytokine. 111:28–32. 10.1016/j.cyto.2018.07.036 [ DOI ] [ PubMed ] [ Google Scholar ] O’Connor JC et al. 2009. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 14(5):511–522. 10.1038/sj.mp.4002148 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] O’Neill LA. 2006. How Toll-like receptors signal: what we know and what we don’t know. Curr Opin Immunol. 18(1):3–9. 10.1016/j.coi.2005.11.012 [ DOI ] [ PubMed ] [ Google Scholar ] Oquendo MA et al. 2011. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 168(10):1050–1056. 10.1176/appi.ajp.2011.11010163 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Packard AEB, Egan AE, Ulrich-Lai YM. 2016. HPA axis interactions with behavioral systems. Compr Physiol. 6(4):1897–1934. 10.1002/j.2040-4603.2016.tb00722.x [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Pandey GN et al. 2009. GSK-3β gene expression in human postmortem brain: regional distribution, effects of age and suicide. Neurochem Res. 34(2):274–285. 10.1007/s11064-008-9770-1 [ DOI ] [ PubMed ] [ Google Scholar ] Pandey GN et al. 2012. Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. J Psychiatr Res. 46(1):57–63. 10.1016/j.jpsychires.2011.08.006 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Pandey GN, Rizavi HS, Bhaumik R, Ren X. 2019. Innate immunity in the postmortem brain of depressed and suicide subjects: role of Toll-like receptors. Brain Behav Immun. 75:101–111. 10.1016/j.bbi.2018.09.024 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y. 2014. Toll-like receptors in the depressed and suicide brain. J Psychiatr Res. 53:62–68. 10.1016/j.jpsychires.2014.01.021 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Panzenhagen A et al. 2023. W71. Inflammatory markers and suicide behaviour: a systematic review and meta-analYSIS. Eur Neuropsychopharmacol. 75:S141–S142. 10.1016/j.euroneuro.2023.08.258 [ DOI ] [ Google Scholar ] Papadimitriou A, Priftis KN. 2009. Regulation of the hypothalamic-pituitary-adrenal axis. Neuroimmunomodulation. 16(5):265–271. 10.1159/000216184 [ DOI ] [ PubMed ] [ Google Scholar ] Patel S, Keating BA, Dale RC. 2022. Anti-inflammatory properties of commonly used psychiatric drugs. Front Neurosci. volume16:1039379. 2022. English. 10.3389/fnins.2022.1039379 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Plöderl M et al. 2026. Effects of ketamine and esketamine on death, suicidal behaviour, and suicidal ideation in psychiatric disorders: a systematic review and meta-analysis. medRxiv.2025.2008.2019.25333796. 10.1101/2025.08.19.25333796 [ DOI ] [ Google Scholar ] Popov A, Schultze JL. 2008. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med (Berl). 86(2):145–160. 10.1007/s00109-007-0262-6 [ DOI ] [ PubMed ] [ Google Scholar ] Popova V et al. 2019. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 176(6):428–438. 10.1176/appi.ajp.2019.19020172 [ DOI ] [ PubMed ] [ Google Scholar ] Price RB, Nock MK, Charney DS, Mathew SJ. 2009. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 66(5):522–526. 10.1016/j.biopsych.2009.04.029 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Raison CL et al. 2013. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 70(1):31–41. 10.1001/2013.jamapsychiatry.4 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Rajkumar RP. 2024. Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration. Explor Neuroprot Ther. 4(1):11–37. 10.37349/ent.2024.00068 [ DOI ] [ Google Scholar ] Ricciotti E, FitzGerald GA. 2011. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 31(5):986–1000. 10.1161/ATVBAHA.110.207449 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Rucci P et al. 2002. Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. Am J Psychiatry. 159(7):1160–1164. 10.1176/appi.ajp.159.7.1160 [ DOI ] [ PubMed ] [ Google Scholar ] Sălcudean A et al. 2025. Neuroinflammation-a crucial factor in the pathophysiology of depression-a comprehensive review. Biomolecules. 15(4):502. 10.3390/biom15040502 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Sales PMG, Schrage E, Coico R, Pato M. 2023. Linking nervous and immune systems in psychiatric illness: a meta-analysis of the kynurenine pathway. Brain Res. 1800:148190. 10.1016/j.brainres.2022.148190 [ DOI ] [ PubMed ] [ Google Scholar ] Sani G et al. 2011. Suicide in a large population of former psychiatric inpatients. Psychiatry Clin Neurosci. 65(3):286–295. 10.1111/j.1440-1819.2011.02205.x [ DOI ] [ PubMed ] [ Google Scholar ] Savitz J et al. 2012. Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2 × 2 clinical trial. BMJ Open. 2(1):e000643. 10.1136/bmjopen-2011-000643 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Serafini G et al. 2020. A specific inflammatory profile underlying suicide risk? systematic review of the main literature findings. Int J Environ Res Public Health. 17(7):2393. 10.3390/ijerph17072393 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Serafini G, Howland RH, Rovedi F, Girardi P, Amore M. 2014. The role of ketamine in treatment-resistant depression: a systematic review. Curr Neuropharmacol. 12(5):444–461. 10.2174/1570159X12666140619204251 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Serafini G, Pompili M, Girardi P, Amore M. 2016. The impact of neuroinflammation and inflammatory cytokines in depression and suicidal behavior. Eur Psychiatr. 33(S1):S160–S160. 10.1016/j.eurpsy.2016.01.311 [ DOI ] [ Google Scholar ] Serafini G, Rihmer Z, Amore M. 2015. The role of glutamate excitotoxicity and neuroinflammation in depression and suicidal behavior: focus on microglia cells [Report. Neuroimmunol Neuroinflammation. 2(3):127. English. 10.4103/2347-8659.157955 [ DOI ] [ Google Scholar ] Seraj A, Reyazuddin M, Gaur RK, Andrade C. 2025. Oral ketamine for rapid reduction of suicidal ideation in major depressive disorder: a midazolam-controlled randomized clinical trial. Asian J Psychiatr. 106:104413. 10.1016/j.ajp.2025.104413 [ DOI ] [ PubMed ] [ Google Scholar ] Sethi R et al. 2019. Neurobiology and therapeutic potential of cyclooxygenase-2 (COX-2) inhibitors for inflammation in neuropsychiatric disorders. Front Psychiatry. 10:605. volu-meEnglish. 10.3389/fpsyt.2019.00605 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Shah IR, Manzoor S, Hussain A, Majid S, Khan K. 2025. Association of interleukin-6 (IL-6) with suicide attempt. Ind Psychiatry J. 34(3):433–437. 10.4103/ipj.ipj_77_25 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Sharma R et al. 2021. Cerebrospinal fluid monoamine metabolite concentrations in suicide attempt: a meta-analysis. Asian J Psychiatr. 62:102711. 10.1016/j.ajp.2021.102711 [ DOI ] [ PubMed ] [ Google Scholar ] Shayowitz M, Bressler M, Ricardo AP, Grudnikoff E. 2019. Infliximab-induced depression and suicidal behavior in adolescent with Crohn’s disease: case report and review of literature. Pediatr Qual Saf. 4(6):e229. 10.1097/pq9.0000000000000229 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Shelton RC, Miller AH. 2010. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol. 91(4):275–299. 10.1016/j.pneurobio.2010.04.004 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Siegel AN et al. 2021. Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: a systematic review. J Psychiatr Res. 137:426–436. 10.1016/j.jpsychires.2021.03.009 [ DOI ] [ PubMed ] [ Google Scholar ] Silverman MN, Pearce BD, Miller AH. 2003. Cytokines and hpa axis regulation. In: Kronfol Z, editor. Cytokines and mental health. Springer US; p. 85–122. 10.1007/978-1-4615-0323-1_5 [ DOI ] [ Google Scholar ] Singh JB et al. 2016. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 173(8):816–826. 10.1176/appi.ajp.2016.16010037 [ DOI ] [ PubMed ] [ Google Scholar ] Sitges M, Gómez CD, Aldana BI. 2014. Sertraline reduces IL-1β and TNF-α mrna expression and overcomes their rise induced by seizures in the rat hippocampus. PLoS One. 9(11):e111665. 10.1371/journal.pone.0111665 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Song J et al. 2017. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry. 174(8):795–802. 10.1176/appi.ajp.2017.16050542 [ DOI ] [ PubMed ] [ Google Scholar ] Spencer HF et al. 2022. Effects of an intravenous ketamine infusion on inflammatory cytokine levels in male and female Sprague–Dawley rats. J Neuroinflammation. 19(1):75. 10.1186/s12974-022-02434-w [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Spiga F, Walker JJ, Terry JR, Lightman SL. 2014. HPA axis-rhythms. Compr Physiol. 4(3):1273–1298. 10.1002/cphy.c140003 [ DOI ] [ PubMed ] [ Google Scholar ] Stanley B et al. 2000. Association of aggressive behavior with altered serotonergic function in patients who are not suicidal. Am J Psychiatry. 157(4):609–614. 10.1176/appi.ajp.157.4.609 [ DOI ] [ PubMed ] [ Google Scholar ] Steiner J et al. 2011. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation. 8(1):94. 10.1186/1742-2094-8-94 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Stone TW. 2001. Kynurenines in the CNS: from endogenous obscurity to therapeutic importance. Prog Neurobiol. 64(2):185–218. 10.1016/s0301-0082(00)00032-0 [ DOI ] [ PubMed ] [ Google Scholar ] Strong KL, Jing Y, Prosser AR, Traynelis SF, Liotta DC. 2014. NMDA receptor modulators: an updated patent review (2013 – 2014). Expert Opin Ther Pat. 24(12):1349–1366. 10.1517/13543776.2014.972938 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Sublette ME et al. 2011. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. 25(6):1272–1278. 10.1016/j.bbi.2011.05.002 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Sun S et al. 2023. Association of interleukin-6 with suicidal ideation in veterans: a longitudinal perspective [Original Research]. Front Psychiatry. 14:1231031. volumeEnglish. 10.3389/fpsyt.2023.1231031 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Szmulewicz A et al. 2023. Estimating the per-protocol effect of lithium on suicidality in a randomized trial of individuals with depression or bipolar disorder. J Psychopharmacol. 37(6):539–544. 10.1177/02698811231166460 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Thillard EM et al. 2020. Psychiatric adverse events associated with infliximab: a cohort study from the French nationwide discharge abstract database. Front Pharmacol. 11:513. 10.3389/fphar.2020.00513 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Tian X et al. 2024. Association between peripheral plasma cytokine levels and suicidal ideation in first-episode, drug-naïve major depressive disorder. Psychoneuroendocrinology. 165:107042. 10.1016/j.psyneuen.2024.107042 [ DOI ] [ PubMed ] [ Google Scholar ] Tsai C-J et al. 2016. The rapid suicide protection of mood stabilizers on patients with bipolar disorder: a nationwide observational cohort study in Taiwan. J Affect Disord. 196:71–77. 10.1016/j.jad.2016.02.014 [ DOI ] [ PubMed ] [ Google Scholar ] Tu H et al. 2007. Interleukin-10 regulated gene expression in cells of hypothalamic-pituitary-adrenal axis origin. Cell Mol Neurobiol. 27(2):161–170. 10.1007/s10571-006-9137-6 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Turecki G. 2005. Dissecting the suicide phenotype: the role of impulsive–aggressive behaviours: 2003 CCNP Young Investigator Award Paper. J Psychiatry Neurosci. 30(6):398–408. 10.1139/jpn.0551 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Turnbull AV, Rivier C. 1995. Regulation of the HPA axis by cytokines. Brain Behav Immun. 9(4):253–275. 10.1006/brbi.1995.1026 [ DOI ] [ PubMed ] [ Google Scholar ] Turnbull AV, Rivier CL. 1999. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev. 79(1):1–71. 10.1152/physrev.1999.79.1.1 [ DOI ] [ PubMed ] [ Google Scholar ] Tyring S et al. 2006. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 367(9504):29–35. 10.1016/S0140-6736(05)67763-X [ DOI ] [ PubMed ] [ Google Scholar ] Ulual P, Burhan H, Güçlü O. 2023. Infliximab induced severe depression and suicidal thoughts in patient with bipolar disorder. Eur Psychiatr. 66(S1):S762–S763. 10.1192/j.eurpsy.2023.1607 [ DOI ] [ Google Scholar ] Vanicek T et al. 2022. Intravenous esketamine leads to an increase in impulsive and suicidal behaviour in a patient with recurrent major depression and borderline personality disorder. World J Biol Psychiatry. 23(9):715–718. 10.1080/15622975.2022.2031287 [ DOI ] [ PubMed ] [ Google Scholar ] Venkiteshwaran A. 2009. Tocilizumab. MAbs. 1(5):432–438. 10.4161/mabs.1.5.9497 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Walker AK et al. 2013. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology. 38(9):1609–1616. 10.1038/npp.2013.71 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Wang X, Xu J, Zhang Y, Xu W, Gao J. 2025. Associations between peripheral plasma cytokine levels and patterns of non-suicidal self-injury methods among Chinese outpatient adolescents: a latent class analysis. BMC Psychiatry. 25(1):953. 10.1186/s12888-025-07398-8 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Waszak PM, Opalko J, Olszańska N, Zagożdżon P. 2025. Anti-suicidal effects of lithium, ketamine, and clozapine—a 10-year systematic review. Pharmaceuticals. 18(5):742. 10.3390/ph18050742 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] WHO. 2025. https://wwwwhoint/news-room/fact-sheets/detail/suicide Wilkinson ST et al. 2018. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 175(2):150–158. 10.1176/appi.ajp.2017.17040472 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Worbe Y, Savulich G, Voon V, Fernandez-Egea E, Robbins TW. 2014. Serotonin depletion induces ‘waiting impulsivity’ on the human four-choice serial reaction time task: cross-species translational significance. Neuropsychopharmacology. 39(6):1519–1526. 10.1038/npp.2013.351 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Wu H, Gong J, Liu Y. 2018. Indoleamine 2, 3-dioxygenase regulation of immune response. Mol Med Rep. 17(4):4867–4873. 10.3892/mmr.2018.8537 [ DOI ] [ PubMed ] [ Google Scholar ] Yang J-j et al. 2015. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry. 77(3):e19–e20. 10.1016/j.bio-psych.2014.06.021 [ DOI ] [ PubMed ] [ Google Scholar ] Yang S et al. 2025. The correlation of inflammation, tryptophan-kynurenine pathway, and suicide risk in adolescent depression. Eur Child Adolesc Psychiatry. 34(5):1557–1567. 10.1007/s00787-024-02579-4 [ DOI ] [ PubMed ] [ Google Scholar ] Yerevanian BI, Koek RJ, Mintz J. 2007. Bipolar pharmacotherapy and suicidal behavior. Part I: lithium, divalproex and carbamazepine. J Affect Disord. 103(1-3):5–11. 10.1016/j.jad.2007.05.019 [ DOI ] [ PubMed ] [ Google Scholar ] Yıldız M, Orak U, Aydoğdu R. 2023. Enduring effects of early life traumas on adult suicidal ideation. J Child Adolesc Trauma. 16(2):297–307. 10.1007/s40653-022-00482-1 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Yin J, Valin KL, Dixon ML, Leavenworth JW. 2017. The role of microglia and macrophages in cns homeostasis, autoimmunity, and cancer. J Immunol Res. 2017:5150678. 10.1155/2017/5150678 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Yin Y et al. 2025. A history of suicide attempts among individuals with schizophrenia is associated with tryptophan degradation via the salivary kynurenine pathway. BMC Psychiatry. 25(1):1157. 10.1186/s12888-025-07574-w [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Zanos P et al. 2015. The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/GlycineB-site inhibition. J Pharmacol Exp Ther. 355(1):76–85. 10.1124/jpet.115.225664 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Zarate CA et al. 2006. A randomized trial of an n-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 63(8):856–864. 10.1001/archpsyc.63.8.856 [ DOI ] [ PubMed ] [ Google Scholar ] Zarate CA et al. 2012. Replication of Ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 71(11):939–946. 10.1016/j.biopsych.2011.12.010 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Zhao L et al. 2025. Associations between suicide attempts and clinical, metabolic, and inflammatory markers in Chinese patients with long-term schizophrenia. Front Psychiatry. 16(2025):1651246. 10.3389/fp-syt.2025.1651246 [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] Zhou Y et al. 2024. Effect of repeated intravenous esket-amine on adolescents with major depressive disorder and suicidal ideation: a randomized active-placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 63(5):507–518. 10.1016/j.jaac.2023.05.031 [ DOI ] [ PubMed ] [ Google Scholar ] Zhou Y, Zheng W, Guo F, Wu S, Zhong C. 2025. The anti-inflammation pharmacodynamics of lithium: therapy of bipolar disorder. J Psychopharmacol. 39(6):533–544. 10.1177/02698811251326942 [ DOI ] [ PubMed ] [ Google Scholar ] Zhu C-B, Blakely RD, Hewlett WA. 2006. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology. 31(10):2121–2131. 10.1038/sj.npp.1301029 [ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Data Availability Statement No data was used for the research described in the article. 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