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editorial
. 2016 Jul 7;29(4):583–594. doi: 10.1177/0394632015623793

Inflammatory markers and suicidal attempts in depressed patients: A review

Stefano Marini 1,✉, Federica Vellante 1, Ilaria Matarazzo 1, Domenico De Berardis 1,2, Nicola Serroni 2, Daniela Gianfelice 2, Luigi Olivieri 2, Fulvia Di Renzo 2, Anna Di Marco 2, Michele Fornaro 3, Laura Orsolini 4,5, Alessandro Valchera 6, Felice Iasevoli 7, Monica Mazza 8, Giampaolo Perna 9,10,11, Giovanni Martinotti 1, Massimo Di Giannantonio 1
PMCID: PMC5806831  PMID: 26729403

Abstract

Major depressive disorder is a chronic and invalidating psychiatric illness and is associated with a greater risk of suicidal behaviors. In recent decades many data have supported a biological link between depressive states and inflammation. Pro-inflammatory cytokines have been found to rise, first of all TNF-α and IL-6. Suicidal behaviors have been consistently associated with increased levels of IL-6 and decreased levels of IL-2. The aim of this review is to investigate the relationship between inflammatory markers in depressed patients with or without suicidal attempts compared to healthy controls.

Keywords: inflammatory markers, major depressive disorder, suicidal attempts

Introduction

Major depressive disorder (MDD) is a chronic and invalidating psychiatric illness leading to both social and occupational disability.1–3 MDD patients show a greater risk of suicidal behaviors than healthy controls (HC).4–8 Even if suicidal behavior has been classified as a separate diagnosis in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5),1 suicide is often associated with co-morbid psychiatric dis-orders. For these reasons, death by suicide may be avoided following some suicide prevention strategies;9 for systematic review and meta-analysis see Brezo et al.10 and Arsenault-Lapierre et al.11

Inflammation and stressor mediators leading to excitotoxicity and oxidative damage seem to play a critical role in the pathophysiology of MDD. Different cytokines have been identified as potentially relevant in the understanding of the link between mood disorders and suicidality. In fact, untreated depressed patients have been found to present an imbalance among pro-inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α).12–14 In addition, various immunomodulators have been used to treat subclinical symptoms of depression, such as pain and fatigue, and sexual, bladder and bowel dysfunctions.15

A family history of suicide is considered a risk and a predictive factor of suicidality in offspring. Contrary to suicidal behaviour, suicidal thoughts do not seem to be directly linked to a family history of suicidal ideation.16,17

Genetic studies have also tried to build a solid theoretical basis on gene-related aspects of suicide. Particular attention has been given to the gene encoding for tryptophan hydroxylase and monoamine oxidase A;18,19 for a review see Brezo et al.20

Early-life adversities (ELA) are considered as important lifetime risks for suicidal behaviour. In fact, recent research has suggested a link between poor parent–child attachment and maladjustment in the parental role on one side, and childhood abuse on the other.21,22

Altered blood levels of serotonin seem to underlie depressive and suicide risk factors. Coupling postmortem binding studies and in vivo studies using positron emission tomography highlighted altered 5-hydroxytryptamine 1A and 2A (5HT1A, 5HT2A) receptor availability in suicidal brains, suggesting that insufficient serotonin levels in certain areas of the brain may be linked to suicidality.4,5,23 Serotonin variation has also been considered specific to suicidal behaviour, but this alteration shows only a partial overlapping in those with depressed brains.24,25 In addition, it has been found that different serotoninergic genes contribute jointly to increase the risk for depression and suicidal behaviours.26,27 Moreover, a lower serotoninergic neurotransmission has been associated with behaviour related to suicide attempts, such as impulsive and aggressive traits, irrespective of other psychiatric conditions. Variations in serotonin levels are associated with the onset of depressive and suicidal symptoms in euthymic individuals who have had previous depressive episodes, and in patients at higher risk for developing depression.28,29

Stressors derived from different origins, such as physical, emotional or hormonal stimuli, physiologically activate the same pathway of polyamine, named the polyamine stress response system. Protein levels of several components of the polyamine are altered in the cortical and subcortical brain regions in patients who had completed suicide and in psychiatric patients dead from other causes.30,31

Primate models of depression suggest that stress may induce a modification in gene expression, leading to alterations of spermidine and spermine N1-acetyltransferase (SAT1), wich is considered the rate-limiting enzyme in the catabolism of polyamines. SAT1 has been found to be decreased in the brain cortex of suicide completers, and has been considered a peripheral biomarker of suicidality.32–34

In recent decades many data have supported a biological link between depressive states and inflammation. An increase of pro-inflammatory cytokines have been highlighted, mainly of TNF and IL-6.35–37 Moreoveor, patients undergoing therapy with IFN-α have been found to often develop mood depression.38 Several reports show an association between suicidal behaviour and inflammatory cytokines even in the absence of depressive mood. Suicidal behaviour has been consistently associated with increased levels of IL-6 and decreased levels of IL-2. Decreased levels of vascular endothelial growth factor (VEGF) and increased levels of quinolonic and kinurenic acids have also been described in suicidal depressed patients.39,40 A higher peripheral inflammatory chemokine concentration has been reported in individuals with MDD and suicidal ideation than in those without suicidal ideation.41,42 Moreover, some authors reported data about the relation-ship among alexithymia, suicidal ideation and C-reactive protein,43 and data regarding the effects of antidepressants on cytokine concentrations (for a review see De Berardis et al.44).

With respect to GABAergic signaling, it seems that the genes encoding GABA type A receptors subunits and their associated binding proteins may be be upregulated in the hippocampus and in the prefrontal and anterior cingulate cortices of suicidal depressed patients.45,46 For these reasons, agents acting on the glutamatergic way are considered rapid-response antidepressants, useful in the treatment of both depressive mood and acute suicidal ideation.47,48

Many studies have analysed the role of astrocytes in psychopathology. In animal models of depression, impaired glial functions have been reported.49,50 Postmortem brain studies indicated a decreased glial cell count in the cortical grey matter of depressed patients51 and hypertrophied astrocytes in the cortical white matter of depressed patients who died by suicide.52 Expression gene studies have focused on the expression of connexin 30 (CX30) and connexin 43 (CX43), two proteins working as gap junctions and present almost only in astrocyte cells. In animal studies conducted on mice, CX30 and CX43 have shown altered reactivity to novel environment and they have been related to changes in brain neurotransmitters, including serotonin.53,54

In individuals attempting and/or completing suicide, evidence of hypothalamus pituitary adrenal (HPA) axis disfunction has been found. Postmortem studies of suicide completers revealed an increased corticotropin-releasing hormone (CRH) activity in the paraventricular nucleus,55–57 an over-expression of CRH in the cerebrospinal fluid (CSF),58 fewer CRH-binding sites in the frontal cortex, decreased glucocorticoid receptor expression in the hippocampus and increased levels of pro-opiomelanocortin (POMC) in the pituitary gland.59,60 In addition, suicide completers show increased adrenal glands weight and adrenocortical hypertrophy. Studies on relatives of suicide attempters highlighted an altered HPA axis response as well.61–63

Brain-derived neurotrophic factor (BDNF) was found to be under-expressed by hyper-methylation in stressful situations in studies involving suicide completers. Methylation studies in hippocampal cells taken from patients who died as complete suiciders and who had history of ELA show that ELA was associated with different methylation levels of genes involved in neuroprotection and neuronal growth.64,65 In pheripheral samples of living patients a different level of methylation in neuronal plasticity genes has also been suggested.66 These data are similar to those derived from animal studies, supporting an early-life environmental role in regulating genes related to neuronal plasticity. One of them is the gene coding BDNF. In female rodents stressed by introduction into a new environment with inadequate bedding material, the expression of BDNF gene was decreased in prefrontal cortex due to hyper-methylation of BDNF promoter gene.67 Similar effects were found in the dorsal hippocampus in a post-traumatic stress disorder adult rat model.68

In vivo studies on suicide completers showed that they have higher levels of methylation in the Wernicke area than HC. This higher methylation was associated with lower BDNF expression. In line with these data, some studies reported differential methylation of BDNF promoter in pheripheral samples of depressed living patients.69–72

Discussion

The aim of this review is to investigate the relationship between inflammatory markers in depressed patients with or without suicidal attempts and suicidal ideation, compared to HC (Table 1). Studies have been divided into three classes: in vivo, in vitro and postmortem. In each class, when it was possible, studies have been subdivided in: suicidal versus non-suicidal depressed patients and suicidal depressed patients versus HC (for recent systematic reviews and meta-analyses see Serafini et al.,73 Ducasse et al.74 and Black and Miller75).

Table 1.

Studies investigated in the review.

Authors Population Inflammatory markers In vivo/in vitro plasma/CSF postmortem Scales Main findings
Gabbay et al.93 12 suicidal depressed adolescents, 18 non-suicidal depressed adolescents, 15 controls IL-1β, IL-4, IL-6, TNF-α, IFN-γ In vivo plasma CDRS-R, K-SADS-PL, CGAS, BDI-II, BSS Decreased TNF-α plasma levels in suicidal depressed adolescents and non-suicidal depressed patients. Increased IFN-γ plasma levels in suicidal and non-suicidal versus controls.
Lindqvist et al.96 63 suicide attempters, 47 controls IL-1β, IL-6, IL-8, TNF-α In vivo CSF MADRS, SUAS Significantly higher CSF IL-6 levels in suicide attempters than controls. Violent suicide attempters showed the highest IL-6. Significant positive correlation between MADRS scores and CSF IL-6 levels in all patients.
Janelidze et al.94 47 suicide attempters, 17 non-suicidal depressed patients, 16 controls IL-2, IL-6, IL-8, TNF-α In vivo plasma BSA, MADRS, SUAS, CPRS Increased levels of IL-6, TNF-α and decreased IL-2 concentrations in suicide attempters compared to non-suicidal depressed patients and controls.
Isung et al.40 43 suicide attempters, 20 controls IL-8, VEGF In vivo CSF MADRS, SCID Lower CSF VEGF and IL-8 levels in suicide attempters than controls. A more severe depressive state was correlated with low CSF levels of VEGF.
Vargas et al.98 150 patients with a history of suicide attempts, 201 without suicide attempts IL-6, TNF-α, CRP, fibrinogen, ERS In vivo serum SCID, ASSIST, self-reported questionnaire for smoking status and lifetime suicidal behavior information No significant differences between both groups in CRP, fibrinogen, ERS, IL-6 and TNF-α.
O’Donovan et al.95 76 depressed patient, 48 controls IL-6, IL-10, TNF-α, TGF-1β, CRP In vivo plasma HDRS, MINI In our sample, patients with MDD who had high levels of suicidal ideation showed significantly elevated IL-6 and CRP levels in high suicidal depressed patients than in low suicidal depressed patients. Only those patients with high levels of suicidal ideation exhibited significantly higher levels of inflammation than controls.
Janelidze et al.97 206 suicide attempters, 578 controls IL-8 In vivo CSF and plasma SCID, CPRS, MADRS, BSA Significantly lower of IL-8 plasma and CSF levels in suicide attempters with anxiety than in controls. IL-8 plasma and CSF levels correlated negatively with symptoms of anxiety.
Mendlovic et al.102 6 suicidal depressed patients, 3 non-suicidal depressed patients, 9 controls IL-2, IL-4,IL-5,IL-10, IFN- γ In vitro plasma HDRS, BDI, Suicidal depressed patients secreted significantly more IFN-γ than controls. Non-suicidal depressed patients secreted significantly less IFN-γ than controls. Suicidal depressed patients secreted less IL-4 and IL-5 than non-suicidal depressed patients (not statistically significant differrence).
Lee and Kim105 48 suicidal depressed patients, 47 non-suicidal depressed patients, 91 controls TGF-1β, IL-12, In vitro plasma HDRS, BPRS TGF-1β levels were significantly higher in suicidal and non-suicidal depressed patients than in controls.
Kim et al.103 36 suicidal depressed patients, 33 non-suicidal depressed patients, 40 controls IL-2, IL-4, IL-6, IFN-γ, TGF-1β In vitro plasma HDRS, RRR, LSARS-II Significantly higher IL-6 levels in non-suicidal depressed patients than suicidal depressed patients and controls. Significantly lower IL-2 levels in suicidal depressed patients than non-suicidal patients and controls. Lower IFN-γ and IL-4 as well as higher TGF-1β in both patients groups. Significant positive correlations between IL-6, IFN-γ and HDRS scores. Significant negative correlations between IL-4 and HDRS scores in non-suicidal depression patients but not in suicidal depressed patients.
Lee et al.104 124 suicidal depressed patients, 61 non-suicidal depressed patients, 125 controls TGF-1β In vitro plasma HDRS, RRR, LARS-II Significantly higher in vitro TGF-1β levels in depressed patients than in controls.
Tonelli et al.108 34 completed suicides, 17 controls – Postmortem – Respectively increased expression of IL-4 and IL-13 in female and male suicide victims.
Boehm et al.107 40 suicidal burn victims, 48 non-suicidal deaths for burns, haemorrhagic shock, railway deaths IL-8, TNF-α, ICAM-1 Postmortem – Significantly stronger positivity of TNF-α in burn victims versus controls.
Pandey et al.106 24 teenage suicide victims, 24 teenage controls TNF-α, IL-1β, IL-6 in Brodmann area Postmortem – Significantly increased IL-1β, IL-6 and TNF-α levels in Brodmann area of suicide victims compared with controls.
Nassberger and Traskman-Bendz101 Medication-free suicide attempters IL-2 soluble receptor In vivo plasma, 24-h urine and CSF, follow-up study – High levels of the soluble IL-2 receptor concentration at follow-up in medication-free suicide attempters.
Isung et al.99 58 suicidal attempters IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, VEGF In vivo plasma, longitudinal study MADRS, SIS Suicidal patients who completed suicide had lower VEGF levels than suicidal attempters.
Li et al.100 49 responder depressed patients, 12 non-responder depressed patient, 64 controls TNF-α In vivo plasma, longitudinal study HDRS, SCID Plasma TNF-α levels significantly decreased in responder patients following venlafaxine treatment. A greater reduction in TNF-α levels correlated to a greater reduction in HDRS scores.
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CDRS-R, Children’s Depression Rating Scale-Revised;76 K-SADS-PL, Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version;77 CGAS, Children’s Global Assessment Scale;78 BDI, Beck Depression Inventory;79 BSS, Beck Scale for Suicide Ideation;80 MADRS, Montgomery-Asberg Depression Rating Scale;81 SUAS, Suicide Assessment Scale;82 BSA, Brief Scale for Anxiety;83 CPRS, Comprehensive Psychopathological Rating Scale;81 SCID, Structured Clinical Interview for DSM-IV;84,85 ASSIST, The alcohol, smoking and substance involvement screening test;86 MINI, Mini International Neuropsychiatric Instrument;87 HDRS, Hamilton Depression Rating Scale;88 BPRS, Brief Psychiatry Rating Scale;89 RRR, Risk-Rescue Rating;90 LARS-II, Lethality Suicide Attempt Rating Scale-updated.91,92

In vivo studies

When suicidal depressed patients were compared to non-suicidal depressed patiens, no significant differences in IL-4, IFN-γ and TGF-1β plasma concentrations were found by Gabbay et al.93 Contrasting results were reported for TNF-α plasma levels.76,94 O’Donovan95 found higher IL-6 and CRP plasma levels in patients with higher suicidal ideation than in patients with less suicidal thoughts. A non-significant trend was found for IL-10.78 Decreased IL-2 plasma concentrations were reported in one study.78 Increased plasma levels77 and non-significant group differences76 were found for IL-6.

Janelidze et al.77 found increased TNF-α plasma levels in suicidal patients compared to HC. No significant groups differences were reported for TNF-α plasma76,78 and CSF96 concentrations. No significant groups differences were reported for IL-4,76 TGF-1β76,78 plasma levels and IL-1β79 CSF levels. Regarding IL-6, two authors reported no significant differences between groups in plasma76 and CSF concentrations.40 Three authors found increased IL-6 plasma77,78 and CSF79 levels. Increased IFN-γ76 and IL-10 plasma levels were reported.78 Lower concentrations were reported for plasma IL-277 and CSF VEGF80 levels. CSF IL-8 concentrations were lower80 or non-significant.79 In particular, Janelidze et al.97 found lower CSF and plasma IL-8 concentrations in suicidal attempters with anxiety. Finally, Vargas et al.98 reported no significant differences between patients with and without a history of suicide in CRP, fibrinogen, erythrocyte sedimentation rate (ERS), IL-6 and TNF-α.

Some authors reported correlations between cytokine levels and psychopathological scales scores. A positive correlation between Mont-gomery Asberg Depression Rating Scale (MADRS)81 scores and CSF IL-6 levels was highlighted in all patients.79 In particular, violent suicidal attempters showed the highest IL-6 levels.79 Significant negative correlations between CSF VEGF levels and MADRS scores, and non-significant correlations between CSF IL-8 and MADRS scores were found by Isung et al.80

Some longitudinal studies reported data about VEGF, IL-2, IFN-γ and TNF-α levels. Suicidal patients who completed suicide had lower VEGF levels than suicidal attempters, but only a trend for lower IL-2 and IFN-γ levels was found.99 Plasma TNF-α levels were significantly decreased, in responder patients treated with venlafaxine. The reduction in TNF-α levels was positively related to the reduction in Hamilton Depression Rating Scale (HDRS)88 scores.100 Nassberger and Traskman-Bendz101 found high levels of soluble IL-2 receptor concentration at follow-up in medication-free suicidal attempters.

In vitro studies

Suicidal depressed patients secreted less IL-4, IL-5,102 IL-2 and IL-6103 than non-suicidal depressed patients.

The in vitro TGF-1β production was significantly higher in depressed patients, both with and without attempted suicide, than in HC,88,104 but no statistically significant differences were reported by Lee and Kim.105 Stimulated lymphocytes of suicidal depressed patients secreted significantly more IFN-γ,87 IL-1290 and IL-688 than those of HC. A lower production of IFN-γ and IL-4 in depressed patients, with or without attempted suicide, compared to HC were reported by Kim et al.88

Studies reported different correlations between cytokine concentrations and psychopathological scales scores: positive correlations among IL-6, IFN-γ and HDRS scores;88 negative correlations between IL-4 and HDRS scores;88 no correlations between IL-2 or TGF-1β levels and HDRS or Brief Psychiatry Rating Scale (BPRS)89 scores.90

Postmortem studies

In post-mortem studies,106–108 authors demonstrated associations between inflammatory cytokines and patients dead by suicide (even if most authors, except for Pandey et al., did not report whether patients were depressed or not), when compared to HC. Levels of IL-1β, IL-6 (in adolescents),92 IL-4 (in women) and IL-13 (in men)94 were significantly increased in postmortem brain samples of suicide victims compared to those of HC.93 TNF-α levels resulted also significantly increased, except for Tonelli et al.94

For a final summary see Table 2.

Table 2.

Final summary.

Main findings
Inflammatory markers Suicidal versus non-suicidal depressed patients
 Suicidal depressed patients versus controls
 Postmortem suicidal patients versus controls
In vivo In vitro In vivo In vitro
IL-4 No significant differences23 Decreased33 No significant differences23 Decreased34 Increased37
IL-1β – – No significant differences26 – Increased37
IFN-γ No significant differences23 – Increased23 Increased34 –
Decreased34
IL-8 – – Decreased27 – –
No significant differences26
Decreased in anxiety28
IL-6 Increased24,25 Decreased33 No significant differences23,27,29 Increased34 Increased37
No significant differences23 Increased24–26
IL-10 No significant differences25 – Increased25 – –
TGF-1β No significant differences23 – No significant differences23,25 Increased34,35 –
No significant differences36
IL-2 Decreased24 Decreased33 Decreased24 – –
IL-12 – – – Increased36 –
IL-5 – Decreased33 – – –
TNF-α Increased23 – Increased24 – Increased37,38
Decreased24 No significant differences23,25 No significant differences39
No significant differences26
CRP Increased25 – No significant differences29 – –
VEGF – – Decreased24 – –
ERS – – No significant differences29 – –
Fibrinogen – – No significant differences29 – –
IL-13 – – – – Increased39
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Conclusions

In the past few years, a number of studies have been performed in order to identify a biological marker associated with suicidal depressed patients. This review summarises the studies investigating the relationship between inflammatory markers in depressed patients, with or without suicidal attempts and suicidal ideation, in comparison to healthy controls. More studies have been conducted under in vivo than in vitro and in postmortem conditions. Some, but limited, data reported correlations between cytokine levels and psychopathological scales scores. Insufficient and contrasting data are available in literature so far. For these reasons, furher investigations are needed.

Footnotes

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

  • 1. American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Publishing. [Google Scholar]
  • 2. Réka S, Zoltán J, Kálmán J. (2012) The blue side of glutamatergic neurotransmission: NMDA receptor antagonists as possible novel therapeutics for major depression. Neuropsychopharmacologia Hungarica 14: 29–40. [PubMed] [Google Scholar]
  • 3. Greer TL, Kurian BT, Trivedi MH. (2010) Defining and measuring functional recovery from depression. CNS Drugs 24: 267–284. [DOI] [PubMed] [Google Scholar]
  • 4. Pompili M, Serafini G, Innamorati M, et al. (2011) Suicide risk in first episode psychosis: A selective review of the current literature. Schizophrenia Research 129: 1–11. [DOI] [PubMed] [Google Scholar]
  • 5. Pompili M, Innamorati M, Rihmer Z, et al. Cyclothymic-depressive anxious temperament pattern is related to suicide risk in 346 patients with major mood disorders. Journal of Affective Disorders 136: 405–411. [DOI] [PubMed] [Google Scholar]
  • 6. Pompili M, Rihmer Z, Akiskal H, et al. (2012) Temperaments mediate suicide risk and psychopathology among patients with bipolar disorders. Comprehensive Psychiatry 53: 280–285. [DOI] [PubMed] [Google Scholar]
  • 7. Serafini G, Pompili M, Innamorati M, et al. (2011) Affective temperamental profiles are associated with white matter hyperintensity and suicidal risk in patients with mood disorders. Journal of Affective Disorders 129: 47–55. [DOI] [PubMed] [Google Scholar]
  • 8. Innamorati M, Pompili M, Gonda X, et al. (2011) Psychometric properties of the Gotland Scale for Depression in Italian psychiatric inpatients and its utility in the prediction of suicide risk. Journal of Affective Disorders 132: 99–103. [DOI] [PubMed] [Google Scholar]
  • 9. Mann JJ, Apter A, Bertolote J, et al. (2005) Suicide prevention strategies: A systematic review. Journal of the American Medical Association 294: 2064–2074. [DOI] [PubMed] [Google Scholar]
  • 10. Brezo J, Paris J, Tremblay R, et al. (2007) Identifying correlates of suicide attempts in suicidal ideators: A population-based study. Psychological Medicine 37: 1551–1562. [DOI] [PubMed] [Google Scholar]
  • 11. Arsenault-Lapierre G, Kim C, Turecki G. (2004) Psychiatric diagnoses in 3275 suicides: A meta-analysis. BMC Psychiatry 4: 37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Ackerman KD, Martino M, Heyman R, et al. (1998) Stressor induced alteration of cytokine production in multiple sclerosis patients and controls. Psychosomatic Medicine 60: 484–491. [DOI] [PubMed] [Google Scholar]
  • 13. Maes M. (1999) Major depression and activation of the inflammatory response system. Advances in Experimental Medicine and Biology 461: 25–46. [DOI] [PubMed] [Google Scholar]
  • 14. Maes M, Meltzer HY, Bosmans E, et al. (1995) Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin- 2 and transferring receptor in major depression. Journal of Affective Disorders 34: 301–309. [DOI] [PubMed] [Google Scholar]
  • 15. Krupp LB, Rizvi SA. (2002) Symptomatic therapy for underrecognized manifestations of multiple sclerosis. Neurology 58: S32–39. [DOI] [PubMed] [Google Scholar]
  • 16. Lieb R, Bronisch T, Hofler M, et al. (2005) Maternal suicidality and risk of suicidality in offspring: Findings from a community study. American Journal of Psychiatry 162: 1665–1671. [DOI] [PubMed] [Google Scholar]
  • 17. Blum R, Sudhinaraset M, Emerson MR. (2012) Youth at risk: Suicidal thoughts and attempts in Vietnam, China, and Taiwan. Journal of Adolescent Health 50: S37–S44. [DOI] [PubMed] [Google Scholar]
  • 18. Mann JJ. (2013) The serotonergic system in mood disorders and suicidal behaviour. Philosophical Transactions of the Royal Society of London Series B 368: 20120537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Bach H, Arango V. (2012) Neuroanatomy of serotonergic abnormalities in suicide. In: Dwivedi Y. (ed) The Neurobiological Basis of Suicide. Boca Raton, FL: CRC Press, pp. 15–17. [PubMed] [Google Scholar]
  • 20. Brezo J, Klempan T, Turecki G. (2008) The genetics of suicide: A critical review of molecular studies. Psychiatric Clinics of North America 31: 179–203. [DOI] [PubMed] [Google Scholar]
  • 21. Fergusson DM, Woodward LJ, Horwood LJ. (2000) Risk factors and life processes associated with the onset of suicidal behaviour during adolescence and early adulthood. Psychological Medicine 30: 23–39. [DOI] [PubMed] [Google Scholar]
  • 22. Smith PN, Gamble SA, Cort NA, et al. (2012) The relationships of attachment style and social maladjustment to death ideation in depressed women with a history of childhood sexual abuse. Journal of Clinical Psychology 68: 78–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Stanley M, Virgilio J, Gershon S. (1982) Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science 216: 1337–1339. [DOI] [PubMed] [Google Scholar]
  • 24. Arango V, Underwood MD, Boldrini M, et al. (2001) Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 25: 892–900. [DOI] [PubMed] [Google Scholar]
  • 25. Miller JM, Hesselgrave N, Ogden RT, et al. (2013) Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biological Psychiatry 74: 287–295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Yanowitch R, Coccaro EF. (2011) The neurochemistry of human aggression. Advances in Genetics 75: 151–169. [DOI] [PubMed] [Google Scholar]
  • 27. Brezo J, Bureau A, Mérette C, et al. (2010) Differences and similarities in the serotonergic diathesis for suicide attempts and mood disorders: A 22-year longitudinal gene–environment study. Molecular Psychiatry 15: 831–843. [DOI] [PubMed] [Google Scholar]
  • 28. Smith KA, Fairburn CG, Cowen PJ. (1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349: 915–919. [DOI] [PubMed] [Google Scholar]
  • 29. Benkelfat C, Ellenbogen MA, Dean P, et al. (1994) Mood-lowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Archives of General Psychiatry 51: 687–697. [DOI] [PubMed] [Google Scholar]
  • 30. Sequeira A, Gwadry FG, Ffrench-Mullen JM, et al. (2006) Implication of SSAT by gene expression and genetic variation in suicide and major depression. Archives of General Psychiatry 63: 35–48. [DOI] [PubMed] [Google Scholar]
  • 31. Chen GG, Fiori LM, Moquin L, et al. (2010) Evidence of altered polyamine concentrations in cerebral cortex of suicide completers. Neuropsychopharmacology 35: 1477–1484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Fiori LM, Bureau A, Labbe A, et al. (2011) Global gene expression profiling of the polyamine system in suicide completers. International Journal of Neuropsychopharmacology 14: 595–605. [DOI] [PubMed] [Google Scholar]
  • 33. Klempan TA, Rujescu D, Mérette C, et al. (2009) Profiling brain expression of the spermidine/spermine N1-acetyltransferase 1 (SAT1) gene in suicide. American Journal of Medical Genetics Part B Neuropsychiatric Genetics 150B: 934–943. [DOI] [PubMed] [Google Scholar]
  • 34. Karssen AM, Her S, Li JZ, et al. (2007) Stress-induced changes in primate prefrontal profiles of gene expression. Molecular Psychiatry 12: 1089–1102. [DOI] [PubMed] [Google Scholar]
  • 35. Raison CL, Capuron L, Miller AH. (2006) Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends in Immunology 27: 24–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Howren MB, Lamkin DM, Suls J. (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosomatic Medicine 71: 171–186. [DOI] [PubMed] [Google Scholar]
  • 37. Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, et al. (2011) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Molecular Psychiatry 16: 751–762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Constant A, Castera L, Dantzer R, et al. (2005) Mood alterations during interferon-α therapy in patients with chronic hepatitis C: Evidence for an overlap between manic/hypomanic and depressive symptoms. Journal of Clinical Psychiatry 66: 1050–1057. [DOI] [PubMed] [Google Scholar]
  • 39. Sublette ME, Galfalvy HC, Fuchs D, et al. (2011) Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behavior Immunity 25: 1272–1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Isung J, Aeinehband S, Mobarrez F, et al. (2012) Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Translational Psychiatry 2: e196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Grassi-Oliveira R, Brieztke E, Teixeira A, et al. (2002) Peripheral chemokine levels in women with recurrent major depression with suicidal ideation. Revista Brasileira de Psiquiatria 34: 71–75. [DOI] [PubMed] [Google Scholar]
  • 42. Janelidze S, Ventorp F, Erhardt S, et al. (2013) Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters. Psychoneuroendocrinology 38(6): 853–862. [DOI] [PubMed] [Google Scholar]
  • 43. De Berardis D, Serroni N, Campanella D, et al. (in press) Alexithymia, suicide ideation, C-reactive protein and serum lipid levels among outpatients with generalized anxiety disorder. Archives of Suicide Research. [DOI] [PubMed] [Google Scholar]
  • 44. De Berardis D, Conti CM, Serroni N, et al. (2010) The effect of newer serotonin-noradrenalin antidepressants on cytokine production: A review of the current literature. International Journal of Immunopathology and Pharmacology 23: 417–422. [DOI] [PubMed] [Google Scholar]
  • 45. Sequeira A, Mamdani F, Ernst C, et al. (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 4: e6585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Choudary PV, Molnar M, Evans SJ, et al. (2005) Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proceedings of the National Academy of Sciences of the United States of America 102: 15653–15658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Larkin GL, Beautrais AL. (2011) A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. International Journal of Neuropsychopharmacology 14: 1127–1131. [DOI] [PubMed] [Google Scholar]
  • 48. Price RB, Iosifescu DV, Murrough JW, et al. (2014) Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression. Depression and Anxiety 31: 335–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Czeh B, Fuchs E, Flugge G. (2013) Altered glial plasticity in animal models for mood disorders. Current Drug Targets 14: 1249–1261. [DOI] [PubMed] [Google Scholar]
  • 50. Banasr M, Chowdhury GM, Terwilliger R, et al. (2010) Glial pathology in an animal model of depression: Reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Molecular Psychiatry 15: 501–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Rajkowska G. (2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biological Psychiatry 48: 766–777. [DOI] [PubMed] [Google Scholar]
  • 52. Torres-Platas SG, Hercher C, Davoli MA, et al. (2011) Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 36: 2650–2658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Dere E, De Souza-Silva MA, Frisch C, et al. (2003) Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open-field along with neurochemical changes. European Journal of Neuroscience 18: 629–638. [DOI] [PubMed] [Google Scholar]
  • 54. Frisch C, Theis M, De Souza Silva MA, et al. (2003) Mice with astrocyte-directed inactivation of connexin 43 exhibit increased exploratory behaviour, impaired motor capacities, and changes in brain acetylcholine levels. European Journal of Neuroscience 18: 2313–2318. [DOI] [PubMed] [Google Scholar]
  • 55. Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, et al. (1995) Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression. American Journal of Psychiatry 152: 1372–1376. [DOI] [PubMed] [Google Scholar]
  • 56. Raadsheer FC, Hoogendijk WJ, Stam FC, et al. (1994) Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60: 436–444. [DOI] [PubMed] [Google Scholar]
  • 57. Wang SS, Kamphuis W, Huitinga I, et al. (2008) Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: The presence of multiple receptor imbalances. Molecular Psychiatry 13: 786–799. [DOI] [PubMed] [Google Scholar]
  • 58. Nemeroff CB, Widerlöv E, Bissette G, et al. (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226: 1342–1344. [DOI] [PubMed] [Google Scholar]
  • 59. Nemeroff CB, Owens MJ, Bissette G, et al. (1998) Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Archives of General Psychiatry 45: 577–579. [DOI] [PubMed] [Google Scholar]
  • 60. Lopez JF, Palkovits M, Arató M, et al. (1992) Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoid receptor mRNA in pituitaries of suicide victims. Neuroendocrinology 56: 491–501. [DOI] [PubMed] [Google Scholar]
  • 61. Dumser T, Barocka A, Schubert E. (1998) Weight of adrenal glands May be increased in persons who commit suicide. American Journal of Forensic Medicine and Pathology 19: 72–76. [DOI] [PubMed] [Google Scholar]
  • 62. Szigethy E, Conwell Y, Forbes NT, et al. (1994) Adrenal weight and morphology in victims of completed suicide. Biological Psychiatry 36: 374–380. [DOI] [PubMed] [Google Scholar]
  • 63. McGirr A, Diaconu G, Berlim MT, et al. (2010) Dysregulation of the sympathetic nervous system, hypothalamic-pituitary-adrenal axis and executive function in individuals at risk for suicide. Journal of Psychiatry & Neuroscience 35: 399–408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Labonte B, Suderman M, Maussion G, et al. (2012) Genome-wide epigenetic regulation by early-life trauma. Archives of General Psychiatry 69: 722–731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Labonte B, Suderman M, Maussion G, et al. (2013) Genome-wide methylation changes in the brains of suicide completers. American Journal of Psychiatry 170: 511–520. [DOI] [PubMed] [Google Scholar]
  • 66. Weder N, Zhang H, Jensen K, et al. (2014) Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry. Journal of the American Academy of Child and Adolescent Psychiatry 53: 417–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Roth TL, Lubin FD, Funk AJ, et al. (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry 65: 760–769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Roth TL, Zoladz PR, Sweatt JD, et al. (2011) Epigenetic modification of hippocampal BDNF DNA in adult rats in an animal model of post-traumatic stress disorder. Journal of Psychiatric Research 45: 919–929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Heim C, Shugart M, Craighead WE, et al. (2010) Neurobiological and psychiatric consequences of child abuse and neglect. Developmental Psychobiology 52: 671–690. [DOI] [PubMed] [Google Scholar]
  • 70. McGowan PO, Sasaki A, D’Alessio AC, et al. (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience 12: 342–348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Conradt E, Lester BM, Appleton AA, et al. (2013) The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics 8: 1321–1329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Perroud N, Paoloni-Giacobino A, Prada P, et al. (2011) Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry 1: e59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Serafini G, Pompili M, Elena Seretti M, et al. (2013) The role of inflammatory cytokines in suicidal behavior: A systematic review. European Neuropsychopharmacology 23(12): 1672–1686. [DOI] [PubMed] [Google Scholar]
  • 74. Ducasse D, Olié E, Guillaume S, et al. (2015) A meta-analysis of cytokines in suicidal behavior. Brain Behavior Immunology 46: 203–211. [DOI] [PubMed] [Google Scholar]
  • 75. Black C, Miller BJ. (2015) Meta-analysis of cytokines and chemokines in suicidality: Distinguishing suicidal versus nonsuicidal patients. Biological Psychiatry 78: 28–37. [DOI] [PubMed] [Google Scholar]
  • 76. Poznanski E, Mokros H. (1996) Children’s Depression Rating Scale–Revised (CDRS-R). Los Angeles, CA: WPS. [Google Scholar]
  • 77. Kaufman J, Birmaher B, Brent D, et al. (1997) Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry 36(7): 980–988. [DOI] [PubMed] [Google Scholar]
  • 78. Shaffer D, Gould M, Brasic J, et al. (1985) A Children’s Global Assessment Scale (CGAS) (for children 4–16 years of age). Psychopharmacology Bulletin 21: 747–748. [Google Scholar]
  • 79. Beck AT, Ward CH, Mendelson M, et al. (1961) An inventory for measuring depression. Archives of General Psychiatry 4(6): 561–571. [DOI] [PubMed] [Google Scholar]
  • 80. Beck AT, Kovacs M, Weissman A. (1979) Assessment of suicidal intention: The scale for suicide ideation. Journal of Consulting and Clinical Psychology 47: 343–352. [DOI] [PubMed] [Google Scholar]
  • 81. Asberg M, Montgomery SA, Perris C, et al. (1978) A comprehensive psychopathological rating scale. Acta Psychiatrica Scandinavica Supplementum 271: 5–27. [DOI] [PubMed] [Google Scholar]
  • 82. Stanley B, Traskman-Bendz L, Stanley M. (1986) The suicide assessment scale: A scale evaluating change in suicidal behavior. Psychopharmacology Bulletin 22: 200–205. [PubMed] [Google Scholar]
  • 83. Tyrer P, Owen RT, Cicchetti DV. (1984) The brief scale for anxiety: A subdivision of the comprehensive psychopathological rating scale. Journal of Neurology Neurosurgery and Psychiatry 47: 970–975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. First M. (1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I). Washington, DC: American Psychiatric Press. [Google Scholar]
  • 85. First M. (1997) Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press. [Google Scholar]
  • 86. World Health Organization (WHO) (2002) The alcohol, smoking and substance involvement screening test (ASSIST): Development, reliability and feasibility. Addiction 97(9): 1183–1194. [DOI] [PubMed] [Google Scholar]
  • 87. Sheehan DV, Lecrubier Y, Sheehan KH, et al. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 59 (Suppl. 20): 22–33. [PubMed] [Google Scholar]
  • 88. Hamilton M. (1960) A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry 23: 56–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Overall JE, Gorham DR. (1962) The brief psychiatric rating scale. Psychology Reports 10: 799–812. [Google Scholar]
  • 90. Weisman AD, Worden JW. (1972) Risk-rescue rating in suicide assessment. Archives of General Psychiatry 26: 553–560. [DOI] [PubMed] [Google Scholar]
  • 91. Berman AL, Shepherd G, Silverman MM. (2003) The LSARS-II: Lethality of suicide attempt rating scale-updated. Suicide & Life-Threatening Behavior 33: 261–276. [DOI] [PubMed] [Google Scholar]
  • 92. Smith K, Conroy RW, Ehler BD. (1984) Lethality of suicide attempt rating scale. Suicide & Life-Threatening Behavior 14: 215–242. [DOI] [PubMed] [Google Scholar]
  • 93. Gabbay V, Klein RG, Guttman LE, et al. (2009) A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. Journal of Child and Adolescent Psychopharmacology 19: 423–430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Janelidze S, Mattei D, Westrin A, et al. (2011) Cytokine levels in the blood May distinguish suicide attempters from depressed patients. Brain Behavior Immunology 25: 335–339. [DOI] [PubMed] [Google Scholar]
  • 95. O’Donovan A, Rush G, Hoatam G, et al. (2013) Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depression and Anxiety 30: 307–314. [DOI] [PubMed] [Google Scholar]
  • 96. Lindqvist D, Janelidze S, Hagell P, et al. (2009) Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biological Psychiatry 66: 287–292. [DOI] [PubMed] [Google Scholar]
  • 97. Janelidze S, Suchankova P, Ekman A, et al. (2015) Low IL-8 is associated with anxiety in suicidal patients: Genetic variation and decreased protein levels. Acta Psychiatrica Scandinavica 131: 269–278. [DOI] [PubMed] [Google Scholar]
  • 98. Vargas HO, Nunes SO, Pizzo de Castro M, et al. (2013) Oxidative stress and lowered total anti-oxidant status are associated with a history of suicide attempts. Journal of Affective Disorders 150: 923–930. [DOI] [PubMed] [Google Scholar]
  • 99. Isung J, Mobarrez F, Nordström P, et al. (2012) Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide. World Journal of Biological Psychiatry 13: 468–473. [DOI] [PubMed] [Google Scholar]
  • 100. Li Z, Qi D, Chen J, et al. (2013) Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-alpha) in the Chinese patients with major depressive disorder: A prospective longitudinal study. Psychoneuroendocrinology 38: 107–114. [DOI] [PubMed] [Google Scholar]
  • 101. Nassberger L, Traskman-Bendz L. (1993) Increased soluble interleukin-2 receptor concentrations in suicide attempters. Acta Psychiatrica Scandinavica 88: 48–52. [DOI] [PubMed] [Google Scholar]
  • 102. Mendlovic S, Mozes E, Eilat E, et al. (1999) Immune activation in non-treated suicidal major depression. Immunology Letters 67: 105–108. [DOI] [PubMed] [Google Scholar]
  • 103. Kim YK, Lee SW, Kim SH, et al. (2008) Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Progress in Neuropsychopharmacology & Biological Psychiatry 32: 356–361. [DOI] [PubMed] [Google Scholar]
  • 104. Lee HY, Kim YK. (2010) Transforming growth factor-beta1 and major depressive disorder with and without attempted suicide: Preliminary study. Psychiatry Research 178: 92–96. [DOI] [PubMed] [Google Scholar]
  • 105. Lee KM, Kim YK. (2006) The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder. International Immunopharmacology 6(8): 1298–1304. [DOI] [PubMed] [Google Scholar]
  • 106. Pandey GN, Rizavi HS, Ren X, et al. (2012) Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. Journal of Psychiatric Research 46: 57–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Boehm J, Fischer K, Bohnert M. (2010) Putative role of TNF-alpha, interleukin-8 and ICAM-1 as indicators of an early inflammatory reaction after burn: A morphological and immunohistochemical study of lung tissue of fire victims. Journal of Clinical Pathology 63: 967–971. [DOI] [PubMed] [Google Scholar]
  • 108. Tonelli LH, Stiller J, Rujescu D, et al. (2008) Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatrica Scandinavica 117: 198–206. [DOI] [PMC free article] [PubMed] [Google Scholar]

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