The World Journal of Biological Psychiatry, 2012; 13: 468–473
BRIEF REPORT
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Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide
JOSEF ISUNG1, FARIBORZ MOBARREZ2, PETER NORDSTRÖM1, MARIE ÅSBERG2 & JUSSI JOKINEN1 1Department
of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden, and 2Department of Clinical Sciences, Karolinska Institute, Stockholm, Sweden
Abstract Objectives. Immunological differences have previously been associated with depression and suicidal behaviour. Several cytokines have been identified as potentially important in understanding the pathophysiology of mood disorders and suicidality. Here we aimed to identify new inflammatory biomarkers for suicide prediction. Methods. Plasma concentrations of interleukin (IL) 1-a, IL1-b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFNG), tumor necrosis factor-a (TNF-a), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) were measured in 58 suicide attempters with a high throughput automated biochip immunoassay system. Patients were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Suicide Intent Scale (SIS). All patients were followed up for cause of death. Results. We found significantly lower levels of VEGF in the seven patients who upon a mean follow-up of 13 years were found to have completed suicide. VEGF also showed a trend for negative correlation with the planning subscale of SIS. A trend could be shown for lower IL-2 and for higher IFNG levels in suicide victims. Conclusions. Our study provides further support for a role of inflammation in the pathophysiology of suicidality. VEGF may be related with suicide risk. Key words: VEGF, IFNG, suicide, depression, cytokines
Introduction A dysregulation of the hypothalamic-pituitary-adrenal system (HPAS) and increased concentrations of proinflammatory cytokines have been described in major depressive disorder (MDD) and in suicide-related behaviour (Jokinen et al. 2007; Kim et al. 2008; Gabbay et al. 2009; Lindqvist et al. 2009; Janelidze et al. 2010). Post mortem samples of suicide victims have shown microgliosis and increased mRNA levels of proinflammatory cytokines in the brain adding support to immunological involvement in the pathophysiology of suicidal behaviour (Steiner et al. 2008;Tonelli et al. 2008). Recent reports suggest that vascular endothelial growth factor (VEGF) may also be dysregulated during states of stress and depression (Åsberg et al. 2009; Gormanns et al. 2011). Several studies have proposed mechanisms for how induction of depressive states can be understood via cytokine
regulation of metabolic pathways in the brain, and genetic studies have also shown cytokine polymorphisms associated with depression and suicide risk (Tonelli et al. 2008; Miller et al. 2009; Omrani et al. 2009; Oxenkrug 2010). The aim of this study was to assess if cytokine and growth factor levels are associated with suicide risk in patients with previous suicide attempt followed-up for 13 years.
Methods Study setting Patients having their clinical follow-up after a suicide attempt at the Karolinska University Hospital were proposed to participate in a study of biological and psychological risk factors for suicidal behaviour. The
Correspondence: Jussi Jokinen, MD, PhD, Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, R5, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: ⫹ 46 8 51776759. Fax: ⫹ 46 8 303706. E-mail:
[email protected] (Received 12 April 2011; accepted 14 September 2011) ISSN 1562-2975 print/ISSN 1814-1412 online © 2012 Informa Healthcare DOI: 10.3109/15622975.2011.624549
Low plasma VEGF and suicide 469 Regional Ethical Review Board in Stockholm approved the study protocol (Dnr 93-211) and the participants gave their written informed consent to the study.
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Subjects This is a retrospective cohort study involving 58 suicide attempters (23 men, mean age 39 years, SD ⫽ 12.7, range 20–69; and 35 women, mean age 36 years, SD ⫽ 12, range 18–68). Inclusion criteria were a recent suicide attempt (within a time limit of 1 month), adequate capacity to communicate verbally and in writing in the Swedish language and an age of 18 years or older. Exclusion criteria were schizophrenia spectrum psychosis, dementia, mental retardation and intravenous drug abuse. Suicide attempt was defined as any nonfatal, self injurious behaviour with some intent to cause death. Eleven patients had used a violent suicide attempt method. The participants were interviewed by a trained psychiatrist using the SCID I research version interview to establish diagnosis according to DSM-III (American Psychiatric Association). Axis II diagnoses were established with SCID-II interview. Ninety-three percent of participants had at least one current Axis I psychiatric diagnosis; 78% of patients fulfilled criteria for mood disorder, 7% for adjustment disorder and 3% for anxiety disorders, one patient had substance-related disorder and one an unspecified psychiatric disorder (not psychotic); 24% of the patients had a co morbid substancerelated disorder (mostly alcohol dependence) and 39% fulfilled criteria for a personality disorder. Fiftysix patients (97%) were drug-free; two patients were on antidepressant medication (SSRI). Blood sampling procedures Blood samples were collected in conjunction to the suicide attempt, between 07:30 and 08:00 h after a night of fasting and bed rest. Blood samples were collected from all seasons throughout the year between 1993 and 1998. The same conditions applied to all the samples. The blood was centrifuged within 5 min in room temperature (1000 ⫻ g during 10 min). Plasma was collected and stored at –80°C until cytokine measurements. Samples had never been thawed prior to the cytokine analysis in 2010. The following cytokines and growth factors were analyzed: interleukin (IL) 1-a , IL1-b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFNG), tumor necrosis factor-a (TNF-a), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) with
a high throughput automated biochip immunoassay system, EvidenceH, Randox Laboratories Ltd (Crumlin, UK). Biochip Array technology is used to perform simultaneous quantitative detection of multiple analytes from a single sample. The technology is the Randox Biochip, a solid-state device containing an array of discrete test regions of immobilised antibodies specific to different cytokines and growth factors. A sandwich chemiluminescent immunoassay is employed for the cytokine array. The light signal generated from each of the test regions on the biochip is detected using digital imaging technology and the concentration of analyte present in a patient sample or control was calculated from a calibration curve. All the values obtained in this study were in the range of the standard/calibration curve, since this is the high-sensitivity kit, each calibration begins at 0 pg/ml. The inter, intra-assay variation is less than 10% according to manufacturer. Quality control procedures were all implemented in the cytokine profiles that had passed predefined acceptance criteria to guarantee a high degree of precision. Clinical assessments Beck`s Suicide Intent Scale (SIS), is an instrument using 15 items designed to examine the factual aspects of the suicide attempt; such as the patients thoughts and feelings and the circumstances at the time of the suicide attempt (Beck et al. 1974). The mean score of SIS was 16.2 (median 16, SD 5.8, range 2–26). One two-factor model of the SIS (Factor 1: Lethal intent; and Factor 2: Planning) (Mieczkowski et al. 1993) was tested separately. To evaluate severity of depression, the Montgomery– Åsberg Depression Rating Scale (MADRS) was used (Montgomery and Åsberg 1979). The mean score of MADRS was 16 (median 17, SD 9, range 0–37). Table I shows demographic data and clinical ratings for the study participants.
Table I. Demographic data and clinical ratings for the study participants.
Variable Age, mean ⫾ SD Gender, male/female BMI, mean ⫾ SD MADRS, median (IQR) SIS, median (IQR)
Surviving suicide attempters (N ⫽ 51)
Suicide victims (N ⫽ 7)
37 ⫾ 12.3 19/32 24.3 ⫾ 3.9 17 (10–23) 15.7 (11–21)
37 ⫾ 12.6 4/3 26.3 ⫾ 3.1 12.1 (3–21) 20.1 (18–22)
BMI, body mass index; IQR, interquartile range; MADRS, Montgomery– sberg Depression Rating Scale; SD, standard deviation; SIS, Suicide Intent Scale.
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Outcomes
Cytokine levels and suicide risk
By use of the unique personal identification number all patients were linked to the Cause of Death register, maintained by the National Board of Health and Welfare in Sweden (http://www.socialstyrelsen.se). Seven patients had committed suicide before January 2009; suicides were ascertained from the death certificates. Five patients committed suicide within 6 years, two patients died of suicide after 11 years from entering to the study (time to suicide: median 4 years, mean 6 years, range 1.7–12.8 years). The follow-up time ranged between 11 and 15 years. There was no age difference between suicides and survivors.
Seven suicides (12%) occurred during the follow-up time: three women (8.7%) and four men (17%). The major finding was that mean VEGF distinguished between suicides (Mean ⫹ SE) (14.6 ⫾ 7 pg/ml) and survivors (24.9 ⫾ 2.6 pg/ml) (n ⫽ 58, P ⫽ 0.033, Kruskal–Wallis test) (see Table II). When age, gender and BMI were used as covariates in a regression analysis, the regression model with VEGF was significant (n ⫽ 58, χ2 ⫽ 10, df ⫽ 4, P ⫽ 0.040). VEGF was a significant predictor for suicide (P ⫽ 0.045). Suicide victims had lower levels of IL-2 (Mean ⫹ SE) (0.4 ⫾ 0.49 pg/ml) compared to survivors (1.2 ⫾ 0.18 pg/ml) (n ⫽ 58, P ⫽ 0.037, Kruskal–Wallis test). When age, gender and BMI were used as covariates in a regression analysis, the regression model with IL-2 did not remain significant (n ⫽ 58, χ2 ⫽ 6.8, df ⫽ 4, P ⫽ 0.14). IL-2 showed a trend to be a predictor for suicide (P ⫽ 0.099). There was a trend for higher IFNG levels in suicide victims compared to survivors (n ⫽ 58, P ⫽ 0.063, Kruskal–Wallis test).
Data analysis Two male patients were identified as multivariate outliers by using Mahalanobis distance (Tabachnick and Fidell 2007). The exclusion of these individuals did not affect the results and they were included in all statistical analyses. Characteristics of the population were described by using the mean, the median and the range for quantitative variables. The Shapiro–Wilk test was used to test whether data were normally distributed. The data for all cytokines displayed skewness above 2; therefore nonparametric statistics (Kruskal–Wallis test) in continuous variables was applied for between-group comparisons suicide victims vs. survivors. Tests of nonparametric correlations were performed using Spearman rho. Regression analysis was performed to control for age, gender and body mass index (BMI). Pearson Chi-square and Fisher’s exact test were used for cross tabulations of categorical variables. Statistical analyses were performed using JMP VI software, SAS Institute inc., Cary, NC, USA. The P value was set at ⬍ 0.05.
Results Cytokines: demographics Age and BMI showed a significant positive correlation to plasma IL-6 levels (Spearman ρ ⫽ 0.44 for age; ρ ⫽ 0.32 for BMI) and a trend to significant positive correlation to VEGF levels (Spearman ρ ⫽ 0.25 for age; ρ ⫽ 0.18 for BMI). The correlation between storage time and VEGF levels was non significant (Spearman ρ ⫽ – 0.03, P ⫽ 0.81). There was no significant effect of degree of depression (MADRS score), co-morbid diagnosis of personality disorder or substance abuse diagnosis on the cytokine levels in the suicide attempters.
Cytokines and Suicide Intent Plasma VEGF showed a trend for negative correlation with the Planning subscale of suicide intent (ρ ⫽ – 0.24, P ⫽ 0.076). Plasma IFNG showed a significant positive correlation with SIS (ρ ⫽ 0.26, P ⫽ 0.048) and with the Planning subscale (ρ ⫽ 0.28, P ⫽ 0.038). IL-2 did not correlate with suicide intent. Figure 1 shows VEGF levels and Suicide Intent scores in suicide victims and survivors. Table II. Cytokine levels in suicide victims and surviving suicide attempters. Cytokines mean ⫾ SD pg/ml
Surviving suicide attempters (N ⫽ 51)
Suicide victims (N ⫽ 7)
P valuea
IL 1-a IL1-b IL-2 IL-4 IL-6 IL-8 IL-10 VEGF IFNG TNF-a MCP-1 EGF
0.14 ⫾ 0.14 1.0 ⫾ 1.88 1.16 ⫾ 1.33 1.61 ⫾ 1.22 1.38 ⫾ 0.97 2.20 ⫾ 1.78 0.52 ⫾ 0.48 24.9 ⫾ 19.5 1.04 ⫾ 0.93 3.07 ⫾ 1.58 136.59 ⫾ 84.70 24.29 ⫾ 17.97
0.12 ⫾ 0.04 0.39 ⫾ 0.49 0.44 ⫾ 0.84 1.28 ⫾ 0.60 1.82 ⫾ 2.84 1.80 ⫾ 1.23 3.27 ⫾ 7.38 14.58 ⫾ 6.03 1.69 ⫾ 1.51 2.48 ⫾ 1.36 112.37 ⫾ 6.51 24.97 ⫾ 21.55
0.52 0.33 0.037* 0.90 0.30 0.75 0.18 0.033* 0.063 0.11 0.53 0.88
Interleukin (IL) 1-a, IL1-b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFNG), tumor necrosis factor-a (TNF-a), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). aKruskal–Wallis’ test.
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Low plasma VEGF and suicide 471
Figure 1. Plasma VEGF measurements and Suicide Intent scores for each individual. Suicide victims marked with stars.
Discussion In this follow-up study of suicide attempters, we found a significant association between low levels of VEGF in plasma and subsequent risk for suicide. Furthermore, we found a trend for decreased IL-2 concentrations and increased IFNG concentrations in plasma in suicide victims compared to survivors. To the best of our knowledge this is the first time VEGF has been associated with suicide risk. Our study suggests that dysregulation of VEGF may be related to suicide risk. Interestingly there was a trend for negative correlation between VEGF levels and the planning subscale of SIS. The suicide attempters with the lowest levels of VEGF had made more planned suicide attempts. We have recently reported that both SIS and the planning subscale predicted subsequent suicide (Stefansson et al. 2012). Furthermore, plasma IFNG levels, which showed a trend to be higher in suicide victims, correlated positively with SIS and the Planning subscale. There was no significant effect of depression severity, co-morbid diagnosis of personality disorder or substance abuse diagnosis on the cytokine levels in the suicide attempters. VEGF is a key angiogenic protein (Vogel 2005). Later studies have elucidated VEGF to have a role both in neuroprotection and neurogenesis, and it has been recognized as a true neurotrophic factor (Warner-Schmidt and Duman 2008; Ortuzar et al. 2010). Neurogenesis in the hippocampus region is a known effect of antidepressants as well as of electroconvulsive treatment (ECT) and proposed to be of therapeutic importance (Warner-Schmidt and Duman 2008). Studies on rodent depression models have provided support for VEGF to be a target for
how biological therapies exert their effect in the hippocampus region, shown both for antidepressants and for ECT (Warner-Schmidt and Duman 2007; Segi-Nishida et al. 2008; Greene et al. 2009). In humans VEGF belongs to a family of proteins, whereVEGF-A is the prototypical member.VEGF121 and VEGF165 are the predominant brain isoforms (Warner-Schmidt and Duman 2008). There are also known single nucleotide polymorphisms which in one study have been shown to correlate with hippocampus morphology (Blumberg et al. 2008). Furthermore, a recent study reported an association between VEGF polymorphism and treatment resistant depression (Viikki et al. 2010). At present it is not known if VEGF levels in brain and blood are correlated which may explain different findings in human and animal studies. In humans VEGF levels have previously been associated with MDD and stress-related disorders. High levels of VEGF mRNA in peripheral leukocytes showed a significant correlation with depression level (Iga et al. 2007). Significantly higher levels of VEGF in plasma have been reported in women with prolonged sick leave due to stress-related disorders (Åsberg et al. 2009). Studies in rodents have reported that VEGF expression in the hippocampus was down regulated in response to chronic stress (Heine et al. 2005). Preclinical studies have also provided support for VEGF to be down regulated in response to corticosteroids (Koedam et al. 2002; Greenberger et al. 2010). Dexamethasone nonsuppression in hyperreactive HPA axis is associated with long-term suicide risk in suicide attempters (Jokinen et al. 2007), interestingly women with stress-related disorders showed marked hyporeactivity of the HPA axis using the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test (Wahlberg et al. 2009). Two studies have reported high levels of VEGF correlating with depression (Kahl et al. 2009; Takebayashi et al. 2010). Treatment of cultured cortical astrocytes with fluoxetine upregulated VEGF indicating that fluoxetine may contribute to normalize the trophic and metabolic support to neurons in major depression (Allaman et al. 2011). Two recent clinical studies linked increase of VEGF levels in plasma to antidepressive effect of ECT and sleep deprivation in depressed patients (Ibrahim et al. 2011; Minelli et al. 2011). We also found a trend for lower levels of IL-2 and for higher levels of IFNG in suicide victims. Previously, low IL-2 levels have been reported in patients with suicide attempt compared to non-suicidal MDD patients (Kim et al. 2008; Janelidze et al. 2010). Elevated concentrations of soluble IL-2 receptor (sIL-2R) have been previously observed in suicide attempters (Nassberger and Traskman-Bendz 1993). This has been proposed to explain lower IL-2 levels
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since binding of sIL-2R leads to internalization of the sIL- 2R/IL-2 complex and then lysosomal degradation (Smith 1988; Smith and Popmihajlov 2008). High IFNG have previously been reported in patients with MDD compared to controls (Kim et al. 2008; Gabbay et al. 2009) although to our knowledge it has not previously been linked to suicide-related behaviour. Interestingly IFNG polymorphism however has recently been associated with suicide in males (Omrani et al. 2009). The results of our study could be a new contribution in the quest for biomarkers in assessing suicide risk if replicated in an independent sample. The strength in this study was that 97% of the patients were free of medication. Low levels of VEGF in suicide victims remained significant even after controlling for age, sex and BMI. Degradation of several cytokines has previously been observed after 4 years of storage at –80°C (de Jager et al. 2009) indicating that the difference in storage time could represent a limitation of the present study. However, we found no correlation between VEGF levels and sample storage time. Another limitation is that data on smoking habits and exercise were not available. Furthermore, as this is an exploratory study, we did not correct for multiple testing. Why low levels of VEGF in plasma may be associated with suicide risk is as yet unknown. The differential results regarding plasma levels in several studies could possibly be an illustration of VEGF:s complex role and involvement in regulatory mechanisms both peripherally and centrally. It could also represent a dysregulation at a higher level, where association between regulation of HPA axis and VEGF levels would be worth another study. VEGF is already proposed to be an important target in antidepressive treatment, where more research could be conducted on pharmaceuticals specifically targeted for VEGF associated pathways. In summary, our study of plasma cytokines and suicide risk provides some more evidence for immunological dysregulation as a mechanism in the pathophysiology of suicidal behaviour in patients with mood disorder.
Acknowledgements We wish to thank Dr Kaj Forslund for clinical assessments. Funding for this study was provided by the Swedish Research Council (Project number K200961P-21304-04-4; K2009-61X-21305-01-1).
Statement of Interest None to declare.
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