Inflammatory markers and suicidal attempts in depressed patients: A review

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.

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 plasma^76,78 and CSF⁹⁶ concentrations. No significant groups differences were reported for IL-4,⁷⁶ TGF-1β^76,78 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 plasma^77,78 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
Inflammatory markers	In vivo	In vitro	In vivo	In vitro	Postmortem suicidal patients versus controls
IL-4	No significant differences²³	Decreased³³	No significant differences²³	Decreased³⁴	Increased³⁷
IL-1β	–	–	No significant differences²⁶	–	Increased³⁷
IFN-γ	No significant differences²³	–	Increased²³	Increased³⁴	–
IFN-γ	No significant differences²³	–	Increased²³	Decreased³⁴	–
IL-8	–	–	Decreased²⁷	–	–
			No significant differences²⁶
			Decreased in anxiety²⁸
IL-6	Increased^24,25	Decreased³³	No significant differences^23,27,29	Increased³⁴	Increased³⁷
IL-6	No significant differences²³	Decreased³³	Increased^24–26	Increased³⁴	Increased³⁷
IL-10	No significant differences²⁵	–	Increased²⁵	–	–
TGF-1β	No significant differences²³	–	No significant differences^23,25	Increased^34,35	–
TGF-1β	No significant differences²³	–	No significant differences^23,25	No significant differences³⁶	–
IL-2	Decreased²⁴	Decreased³³	Decreased²⁴	–	–
IL-12	–	–	–	Increased³⁶	–
IL-5	–	Decreased³³	–	–	–
TNF-α	Increased²³	–	Increased²⁴	–	Increased^37,38
	Decreased²⁴		No significant differences^23,25		No significant differences³⁹
			No significant differences²⁶
CRP	Increased²⁵	–	No significant differences²⁹	–	–
VEGF	–	–	Decreased²⁴	–	–
ERS	–	–	No significant differences²⁹	–	–
Fibrinogen	–	–	No significant differences²⁹	–	–
IL-13	–	–	–	–	Increased³⁹

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

American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Publishing.

Réka

Zoltán

Kálmán

(2012) The blue side of glutamatergic neurotransmission: NMDA receptor antagonists as possible novel therapeutics for major depression. Neuropsychopharmacologia Hungarica 14: 29–40.

Greer

Kurian

Trivedi

(2010) Defining and measuring functional recovery from depression. CNS Drugs 24: 267–284.

Pompili

Serafini

Innamorati

. (2011) Suicide risk in first episode psychosis: A selective review of the current literature. Schizophrenia Research 129: 1–11.

Pompili

Innamorati

Rihmer

. Cyclothymic-depressive anxious temperament pattern is related to suicide risk in 346 patients with major mood disorders. Journal of Affective Disorders 136: 405–411.

Pompili

Rihmer

Akiskal

. (2012) Temperaments mediate suicide risk and psychopathology among patients with bipolar disorders. Comprehensive Psychiatry 53: 280–285.

Serafini

Pompili

Innamorati

. (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.

Innamorati

Pompili

Gonda

. (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.

Mann

Apter

Bertolote

. (2005) Suicide prevention strategies: A systematic review. Journal of the American Medical Association 294: 2064–2074.

10.

Brezo

Paris

Tremblay

. (2007) Identifying correlates of suicide attempts in suicidal ideators: A population-based study. Psychological Medicine 37: 1551–1562.

11.

Arsenault-Lapierre

Kim

Turecki

(2004) Psychiatric diagnoses in 3275 suicides: A meta-analysis. BMC Psychiatry 4: 37.

12.

Ackerman

Martino

Heyman

. (1998) Stressor induced alteration of cytokine production in multiple sclerosis patients and controls. Psychosomatic Medicine 60: 484–491.

13.

Maes

(1999) Major depression and activation of the inflammatory response system. Advances in Experimental Medicine and Biology 461: 25–46.

14.

Maes

Meltzer

Bosmans

. (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.

15.

Krupp

Rizvi

(2002) Symptomatic therapy for underrecognized manifestations of multiple sclerosis. Neurology 58: S32–39.

16.

Lieb

Bronisch

Hofler

. (2005) Maternal suicidality and risk of suicidality in offspring: Findings from a community study. American Journal of Psychiatry 162: 1665–1671.

17.

Blum

Sudhinaraset

Emerson

(2012) Youth at risk: Suicidal thoughts and attempts in Vietnam, China, and Taiwan. Journal of Adolescent Health 50: S37–S44.

18.

Mann

(2013) The serotonergic system in mood disorders and suicidal behaviour. Philosophical Transactions of the Royal Society of London Series B 368: 20120537.

19.

Bach

Arango

(2012) Neuroanatomy of serotonergic abnormalities in suicide. In: Dwivedi

(ed) The Neurobiological Basis of Suicide. Boca Raton, FL: CRC Press, pp. 15–17.

20.

Brezo

Klempan

Turecki

(2008) The genetics of suicide: A critical review of molecular studies. Psychiatric Clinics of North America 31: 179–203.

21.

Fergusson

Woodward

Horwood

(2000) Risk factors and life processes associated with the onset of suicidal behaviour during adolescence and early adulthood. Psychological Medicine 30: 23–39.

22.

Smith

Gamble

Cort

. (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.

23.

Stanley

Virgilio

Gershon

(1982) Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science 216: 1337–1339.

24.

Arango

Underwood

Boldrini

. (2001) Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 25: 892–900.

25.

Miller

Hesselgrave

Ogden

. (2013) Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder. Biological Psychiatry 74: 287–295.

26.

Yanowitch

Coccaro

(2011) The neurochemistry of human aggression. Advances in Genetics 75: 151–169.

27.

Brezo

Bureau

Mérette

. (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.

28.

Smith

Fairburn

Cowen

(1997) Relapse of depression after rapid depletion of tryptophan. Lancet 349: 915–919.

29.

Benkelfat

Ellenbogen

Dean

. (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.

30.

Sequeira

Gwadry

Ffrench-Mullen

. (2006) Implication of SSAT by gene expression and genetic variation in suicide and major depression. Archives of General Psychiatry 63: 35–48.

31.

Chen

Fiori

Moquin

. (2010) Evidence of altered polyamine concentrations in cerebral cortex of suicide completers. Neuropsychopharmacology 35: 1477–1484.

32.

Fiori

Bureau

Labbe

. (2011) Global gene expression profiling of the polyamine system in suicide completers. International Journal of Neuropsychopharmacology 14: 595–605.

33.

Klempan

Rujescu

Mérette

. (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.

34.

Karssen

Her

. (2007) Stress-induced changes in primate prefrontal profiles of gene expression. Molecular Psychiatry 12: 1089–1102.

35.

Raison

Capuron

Miller

(2006) Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends in Immunology 27: 24–31.

36.

Howren

Lamkin

Suls

(2009) Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis. Psychosomatic Medicine 71: 171–186.

37.

Shelton

Claiborne

Sidoryk-Wegrzynowicz

. (2011) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Molecular Psychiatry 16: 751–762.

38.

Constant

Castera

Dantzer

. (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.

39.

Sublette

Galfalvy

Fuchs

. (2011) Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behavior Immunity 25: 1272–1278.

40.

Isung

Aeinehband

Mobarrez

. (2012) Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Translational Psychiatry 2: e196.

41.

Grassi-Oliveira

Brieztke

Teixeira

. (2002) Peripheral chemokine levels in women with recurrent major depression with suicidal ideation. Revista Brasileira de Psiquiatria 34: 71–75.

42.

Janelidze

Ventorp

Erhardt

. (2013) Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters. Psychoneuroendocrinology 38(6): 853–862.

43.

De Berardis

Serroni

Campanella

. (in press) Alexithymia, suicide ideation, C-reactive protein and serum lipid levels among outpatients with generalized anxiety disorder. Archives of Suicide Research.

44.

De Berardis

Conti

Serroni

. (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.

45.

Sequeira

Mamdani

Ernst

. (2009) Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One 4: e6585.

46.

Choudary

Molnar

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.

47.

Larkin

Beautrais

(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.

48.

Price

Iosifescu

Murrough

. (2014) Effects of ketamine on explicit and implicit suicidal cognition: A randomized controlled trial in treatment-resistant depression. Depression and Anxiety 31: 335–343.

49.

Czeh

Fuchs

Flugge

(2013) Altered glial plasticity in animal models for mood disorders. Current Drug Targets 14: 1249–1261.

50.

Banasr

Chowdhury

Terwilliger

. (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.

51.

Rajkowska

(2000) Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells. Biological Psychiatry 48: 766–777.

52.

Torres-Platas

Hercher

Davoli

. (2011) Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology 36: 2650–2658.

53.

Dere

De Souza-Silva

Frisch

. (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.

54.

Frisch

Theis

De Souza Silva

. (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.

55.

Raadsheer

van Heerikhuize

Lucassen

. (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.

56.

Raadsheer

Hoogendijk

Stam

. (1994) Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60: 436–444.

57.

Wang

Kamphuis

Huitinga

. (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.

58.

Nemeroff

Widerlöv

Bissette

. (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226: 1342–1344.

59.

Nemeroff

Owens

Bissette

. (1998) Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Archives of General Psychiatry 45: 577–579.

60.

Lopez

Palkovits

Arató

. (1992) Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoid receptor mRNA in pituitaries of suicide victims. Neuroendocrinology 56: 491–501.

61.

Dumser

Barocka

Schubert

(1998) Weight of adrenal glands may be increased in persons who commit suicide. American Journal of Forensic Medicine and Pathology 19: 72–76.

62.

Szigethy

Conwell

Forbes

. (1994) Adrenal weight and morphology in victims of completed suicide. Biological Psychiatry 36: 374–380.

63.

McGirr

Diaconu

Berlim

. (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.

64.

Labonte

Suderman

Maussion

. (2012) Genome-wide epigenetic regulation by early-life trauma. Archives of General Psychiatry 69: 722–731.

65.

Labonte

Suderman

Maussion

. (2013) Genome-wide methylation changes in the brains of suicide completers. American Journal of Psychiatry 170: 511–520.

66.

Weder

Zhang

Jensen

. (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.

67.

Roth

Lubin

Funk

. (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry 65: 760–769.

68.

Roth

Zoladz

Sweatt

. (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.

69.

Heim

Shugart

Craighead

. (2010) Neurobiological and psychiatric consequences of child abuse and neglect. Developmental Psychobiology 52: 671–690.

70.

McGowan

Sasaki

D’Alessio

. (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience 12: 342–348.

71.

Conradt

Lester

Appleton

. (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.

72.

Perroud

Paoloni-Giacobino

Prada

. (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.

73.

Serafini

Pompili

Elena Seretti

. (2013) The role of inflammatory cytokines in suicidal behavior: A systematic review. European Neuropsychopharmacology 23(12): 1672–1686.

74.

Ducasse

Olié

Guillaume

. (2015) A meta-analysis of cytokines in suicidal behavior. Brain Behavior Immunology 46: 203–211.

75.

Black

Miller

(2015) Meta-analysis of cytokines and chemokines in suicidality: Distinguishing suicidal versus nonsuicidal patients. Biological Psychiatry 78: 28–37.

76.

Poznanski

Mokros

(1996) Children’s Depression Rating Scale–Revised (CDRS-R). Los Angeles, CA: WPS.

77.

Kaufman

Birmaher

Brent

. (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.

78.

Shaffer

Gould

Brasic

. (1985) A Children’s Global Assessment Scale (CGAS) (for children 4–16 years of age). Psychopharmacology Bulletin 21: 747–748.

79.

Beck

Ward

Mendelson

. (1961) An inventory for measuring depression. Archives of General Psychiatry 4(6): 561–571.

80.

Beck

Kovacs

Weissman

(1979) Assessment of suicidal intention: The scale for suicide ideation. Journal of Consulting and Clinical Psychology 47: 343–352.

81.

Asberg

Montgomery

Perris

. (1978) A comprehensive psychopathological rating scale. Acta Psychiatrica Scandinavica Supplementum 271: 5–27.

82.

Stanley

Traskman-Bendz

Stanley

(1986) The suicide assessment scale: A scale evaluating change in suicidal behavior. Psychopharmacology Bulletin 22: 200–205.

83.

Tyrer

Owen

Cicchetti

(1984) The brief scale for anxiety: A subdivision of the comprehensive psychopathological rating scale. Journal of Neurology Neurosurgery and Psychiatry 47: 970–975.

84.

First

(1997) Structured clinical interview for DSM-IV axis I disorders (SCID-I). Washington, DC: American Psychiatric Press.

85.

First

(1997) Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press.

86.

World Health Organization (WHO) (2002) The alcohol, smoking and substance involvement screening test (ASSIST): Development, reliability and feasibility. Addiction 97(9): 1183–1194.

87.

Sheehan

Lecrubier

Sheehan

. (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.

88.

Hamilton

(1960) A rating scale for depression. Journal of Neurology Neurosurgery and Psychiatry 23: 56–62.

89.

Overall

Gorham

(1962) The brief psychiatric rating scale. Psychology Reports 10: 799–812.

90.

Weisman

Worden

(1972) Risk-rescue rating in suicide assessment. Archives of General Psychiatry 26: 553–560.

91.

Berman

Shepherd

Silverman

(2003) The LSARS-II: Lethality of suicide attempt rating scale-updated. Suicide & Life-Threatening Behavior 33: 261–276.

92.

Smith

Conroy

Ehler

(1984) Lethality of suicide attempt rating scale. Suicide & Life-Threatening Behavior 14: 215–242.

93.

Gabbay

Klein

Guttman

. (2009) A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. Journal of Child and Adolescent Psychopharmacology 19: 423–430.

94.

Janelidze

Mattei

Westrin

. (2011) Cytokine levels in the blood may distinguish suicide attempters from depressed patients. Brain Behavior Immunology 25: 335–339.

95.

O’Donovan

Rush

Hoatam

. (2013) Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder. Depression and Anxiety 30: 307–314.

96.

Lindqvist

Janelidze

Hagell

. (2009) Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biological Psychiatry 66: 287–292.

97.

Janelidze

Suchankova

Ekman

. (2015) Low IL-8 is associated with anxiety in suicidal patients: Genetic variation and decreased protein levels. Acta Psychiatrica Scandinavica 131: 269–278.

98.

Vargas

Nunes

Pizzo de Castro

. (2013) Oxidative stress and lowered total anti-oxidant status are associated with a history of suicide attempts. Journal of Affective Disorders 150: 923–930.

99.

Isung

Mobarrez

Nordström

. (2012) Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide. World Journal of Biological Psychiatry 13: 468–473.

100.

Chen

. (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.

101.

Nassberger

Traskman-Bendz

(1993) Increased soluble interleukin-2 receptor concentrations in suicide attempters. Acta Psychiatrica Scandinavica 88: 48–52.

102.

Mendlovic

Mozes

Eilat

. (1999) Immune activation in non-treated suicidal major depression. Immunology Letters 67: 105–108.

103.

Kim

Lee

Kim

. (2008) Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Progress in Neuropsychopharmacology & Biological Psychiatry 32: 356–361.

104.

Lee

Kim

(2010) Transforming growth factor-beta1 and major depressive disorder with and without attempted suicide: Preliminary study. Psychiatry Research 178: 92–96.

105.

Lee

Kim

(2006) The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive disorder. International Immunopharmacology 6(8): 1298–1304.

106.

Pandey

Rizavi

Ren

. (2012) Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims. Journal of Psychiatric Research 46: 57–63.

107.

Boehm

Fischer

Bohnert

(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.

108.

Tonelli

Stiller

Rujescu

. (2008) Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatrica Scandinavica 117: 198–206.