Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity.

Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values<2.98E-12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho=0.49, P<0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation.

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability.

BACKGROUND: The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior. METHOD: We measured the CSF levels of HA and the soluble CD44 (sCD44) in suicide attempters (n=94) and in healthy controls (n=45) using ELISA and electrochemiluminescence assays. We also investigated other proteins known to interact with CD44, such as osteopontin and the matrix metalloproteinases MMP1, MMP3 and MMP9. RESULTS: The suicide attempters had higher CSF levels of HA (p=.003) and MMP9 (p=.004). The CSF levels of HA correlated with BBB-permeability (rho=0.410, p<.001) and MMP9 correlated with sCD44 levels (rho=0.260, p=.005). LIMITATIONS: Other relevant biological contributors to suicidal behavior is not addressed in parallel to the specific role of CD44-HA signaling. The gender distribution of the patients from whom CSF was analyzed was uneven. CONCLUSIONS: Increased BBB-permeability and HA levels might be a results of increased neuroinflammation and can play a role in the pathobiology of suicidal behavior. The CD44 signaling pathway might be considered a novel target for intervention in mood disorders.

Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels.

OBJECTIVE: Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. METHOD: We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). RESULTS: Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. CONCLUSION: We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression.

The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features (P=0.005, n=19) or schizophrenia (P=0.02, n=36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg(452) allele was associated with psychotic features during manic episodes (P=0.003). KMO Arg(452) was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg(452) associated with increased levels of CSF KYNA (P=0.03) and reduced lymphoblastoid and hippocampal KMO expression (P≤0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.

Grasping the dynamics of suicidal behaviour: combining time-geographic life charting and COPE ratings.

ACCESSIBLE SUMMARY: • A primary aim of suicide research is to gain a profound knowledge of the suicidal individual so preventive strategy can be formulated. • Time-geographic life charting used in combination with the pattern of coping strategies may be helpful when assessing risk of suicidal behaviour. • It can also be a therapeutic intervention to look back and to reflect coping styles. ABSTRACT: The aim of this study is to explore whether a time-geographic life charting, combined with a survey of a person's coping capacities over time, elucidates the pathway to suicidal behaviour, and therefore could be useful in suicide prevention. Twenty-three patients were recruited shortly after a suicide attempt. A time-geographic life charting and COPE inventory ratings were used separately and in combination. According to COPE ratings, the participants could be divided into three groups using different coping strategies: (1) adaptive, (2) maladaptive, and (3) both adaptive and maladaptive coping. Within these subgroups, three different pathways to suicidal behaviour were described and illustrated. We conclude that time-geographic life charting used in combination with the pattern of coping strategies may be helpful when assessing risk of suicidal behaviour, because this approach strengthens the comprehensive picture of the patient's life situation.

Increased IL-1ß reactivity upon a glucose challenge in patients with deliberate self-harm.

OBJECTIVE: A disturbed glucose metabolism has been observed in patients with aggressive behaviour. Interleukin (IL)-1ß is a pro-inflammatory cytokine that can induce hypoglycaemia, but has also been suggested to be involved in the generation of hostility and aggression. Our group has previously shown an altered glucose metabolism in patients with self-inflicted aggressive behaviour. We investigated the hypothesis that the levels of IL-1ß would be increased in these patients, because this might explain the aberrant glucose metabolism and add further knowledge to the aetiology of self-inflicted aggressive behaviour. METHOD: We investigated plasma cytokine changes in 13 patients with borderline personality disorder and 13 healthy controls during a 5-h glucose challenge. Plasma samples were analysed for cytokines IL-1ß, TNF-α and IL-6 using high-sensitivity multiplex ELISA. Psychiatric symptoms were rated using the Aggression Questionnaire Revised Swedish Version. RESULTS: Basal plasma levels of the three cytokines did not differ between patients and controls. All three cytokines reacted significantly upon the glucose challenge. The increase in IL-1ß levels in response to glucose was significantly greater in patients than in controls. Furthermore, IL-1ß reactivity was associated with symptoms of hostility. CONCLUSION: An increased reactivity of IL-1ß might be part of a pathogenetic mechanism in patients with deliberate self-harm.

CSF biomarkers in suicide attempters--a principal component analysis.

OBJECTIVE: The objective of the present study was to identify biological patterns (factors) among 20 cerebrospinal fluid (CSF) biomarkers in suicide attempters and subsequently analyse their association with suicidal behaviour. METHOD: We measured kynurenic acid, orexin, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol, chemokines, matrix metalloproteases and cytokines in the CSF of 124 drug-free suicide attempters. Patients were evaluated for suicidality and psychiatric symptoms using well-defined psychiatric rating scales and followed-up regarding future suicide. We used principal component analysis to identify factors among the biological substances. RESULTS: Four factors were extracted from the 20 biomarkers, explaining 52.4% of the total variance. Factors 1 and 2 were characterized by high loadings of chemokines and cytokines respectively. They were both associated with severe depressive symptoms. Factor 2 was also associated with a high suicidal intent. Factor 4 was characterized by strong loadings of the monoamine metabolites 5-HIAA and HVA, as well as orexin and interleukin-6. High scores on this factor were found in patients who performed a violent suicide attempt and in patients who subsequently completed suicide. CONCLUSION: Our results suggest that specific combinations of CSF biomarkers may discriminate between types of suicidal behaviour and indicate increased risk for future suicide.

Time geography: a model for psychiatric life charting?

Since many years, life charting has been used to describe the life course and life events of psychiatric patients. The aim of the present study was to describe and evaluate time geographic life charts of 11 former psychiatric patients in order to promote systematic descriptions of their life events over time. Information on all events which was gathered from the life charts was analysed by manifest content analysis and reduced to four categories: information received by asking only about moves, social capacity, predisposing life events and/or stressful as well as precipitating life events. Our findings showed that this kind of life charts offered a comprehensive and structured picture. They describe a detailed life situation from one time period to another, where geographical sites serve as anchors. The patients expressed satisfaction with this method of combining an interview with a time geographic life line.

Evaluation of a modified interview version and of a self-rating version of the Suicide Assessment Scale.

The Suicide Assessment Scale (SUAS) was constructed to be sensitive to change of suicidality. It was recently found to be predictive of suicide in a group of suicide attempters. The aim of the present study was to evaluate the reliability and validity of a modified interview version of SUAS with defined scores and also a new self-rating version (SUAS-S). The subjects consisted of former inpatients, 42 persons who had been admitted because of a suicide attempt about 12 years ago and 22 control patients. The subjects were rated according to the SUAS, the SUAS-S, as well as the Montgomery Asberg Depression Rating Scale (MADRS). The interrater reliability was found to be high. The SUAS correlated significantly with the MADRS, but the concordance was not consistent, which indicates that the SUAS measures something different from depression. The SUAS-S correlated significantly with the interview-rated SUAS, thus exhibiting good concurrent validity. In summary, both the modified interview version of SUAS and the SUAS-S seem to be valid, reliable and easily used suicide assessment instruments.

Social characteristics of seasonal affective disorder patients: comparison with suicide attempters with non-seasonal major depression and other mood disorder patients.

Although it is evident from numerous studies that patients with mood disorders generally have a deficient social functioning and a weak social network, little is known about these aspects of seasonal affective disorder (SAD) patients. We studied the social situation, the social network and the social functioning of SAD (n = 20) patients in comparison with matched suicide attempters (SA) with non-seasonal major depression, and with findings from other major depressive disorder (MDD) studies and community samples. The social situation and the clinical background of both the SAD and the SA groups were almost similar and the social networks were equally disadvantageous and weaker than those observed in some community/healthy populations. Furthermore, the data on global functioning and social adjustment of the SAD group were well comparable to those of other MDD patients and significantly worse than that of a community sample. Thus, the results indicate a considerable social impairment in SAD.

Psychosocial and pharmacological treatment of patients following deliberate self-harm: the methodological issues involved in evaluating effectiveness.

Development of effective treatments for patients following deliberate self-harm (self-poisoning or self-injury) is a very important element in suicide prevention. The randomized controlled trial (RCT) is the mainstay of evaluation of treatments. In a systematic review of the literature, the effectiveness of treatments based on RCTs was examined and the quality of the RCTs was assessed. Twenty trials were identified, and where possible, these were grouped on the basis of similarities among the types of treatment. In this paper, we examine the methodological aspects of the trials and consider what may be learned that will assist in the design of future studies in this field. The methodological quality of the trials was reasonable, but most trials included too few participants to detect clinically important differences in rates of repeated self-harm. In planning future trials, the following major issues should be addressed: investigators should perform power calculations to determine the number of subjects necessary to detect clinically important effects, provide information on method of randomization and interventions, use standard measures of outcome, and focus on homogeneous subgroups of patients. Improving the methodology of future studies in this field will be essential if sound evidence is to be obtained which can inform effective service provision for deliberate self-harm patients.

A follow up study of suicide attempters: increase of CSF-somatostatin but no change in CSF-CRH.

Concentrations of somatostatin and corticotrophin releasing hormone (CRH), measured in cerebrospinal fluid (CSF) have been reported to be low in suicidal patients with major depressive disorder (MDD). Often have MDD patients in general, high CSF-CRH and low CSF-somatostatin concentrations, which both seem to normalise with clinical recovery. The present study was designed to look for CSF-CRH and CSF-somatostatin alterations along with clinical changes in patients studied repeatedly after a suicide attempt. Sixteen patients with different diagnoses, initially inpatients after a suicide attempt (baseline), participated. Lumbar punctures and ratings according to the Suicidal Assessment Scale (SUAS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were performed while patients were drug-free (baseline) and after a median of 7 (5 to 9) months. At follow up MADRS- and SUAS-scores were significantly decreased (P<0.05), whereas CSF-somatostatin was significantly increased (P=0.013) and CSF-CRH had not changed significantly. Thus, the patients showed long-lasting low CSF-CRH concentrations, in spite of changed CSF-somatostatin concentrations and clinical amelioration.

Self-poisonings with drugs by adolescents in the Lund catchment area.

Our objective was to investigate which drugs young people who attempt suicide use in the Lund catchment area-eight municipalities in Skåne, southern Sweden. All patients aged up to 18 years admitted to Lund University Hospital after deliberate or probably deliberate self-poisoning from 1 January 1991 until 31 December 1995 were included. Forty-nine (58%) had used a single drug; 20 (24%) had used 3 or more drugs. Fifty-two (61%) used analgesics-paracetamol was used by 38 (45%) and propoxyphene by 17 (20%). Thirty-one (36%) had ingested psychotropics-13 used benzodiazepines, 10 antidepressants, and 8 antipsychotics. Eleven (15%) had used drugs in combination with alcohol. We conclude that it is important to follow changes in self-poisoning patterns, to monitor the effects of preventive work and discover new trends in drug use.

The suicide assessment scale: an instrument assessing suicide risk of suicide attempters.

The Suicide Assessment Scale (SUAS), a scale constructed to measure suicidality over time, was administered to 191 suicide attempters. Its predictive validity was tested. SUAS ratings were compared to ratings from other scales, and related to age and psychiatric diagnoses including co-morbidity. Eight patients committed suicide within 12 months after the SUAS assessment. Apart from advanced age, high scores in the SUAS were significant predictors of suicide. From a receiver operating characteristic (ROC) analysis, we identified cutoff SUAS scores which alone and in combination with certain diagnostic and demographic factors are of apparent value in the clinical evaluation of suicide risk after a suicide attempt.

Changes of cerebrospinal fluid monoamine metabolites during long-term antidepressant treatment.

This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment.

Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.

Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour.

Alterations of corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) plasma levels in mood disorder patients with a recent suicide attempt.

In order to receive a further understanding of stress-regulation in depressed suicide attempters, peptides that are supposed to be related to the stress system (the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system) were studied in plasma. When compared with healthy controls, cortisol was high (p<0.001) and corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) appeared to be low (p<0.001) in patients who had recently attempted suicide. Patients who had repeatedly attempted suicide had the lowest NPY. A correlation between NPY and cortisol (p<0.05) was found in suicidal patients with depression NOS, whereas beta-endorphins correlated with cortisol (p<0.01) in suicidal patients with major depressive disorder. A postdexamethasone decrease of NPY was noted in the controls but not in the patients. These results suggest stress system alterations in suicidal patients with mood disorders.

Deliberate self harm: systematic review of efficacy of psychosocial and pharmacological treatments in preventing repetition.

OBJECTIVE: To identify and synthesise the findings from all randomised controlled trials that have examined the effectiveness of treatments of patients who have deliberately harmed themselves. DESIGN: Systematic review of randomised controlled trials of psychosocial and physical treatments. Studies categorised according to type of treatment. When there was more than one investigation in a particular category a summary odds ratio was estimated with the Mantel-Haenszel method. SETTING: Randomised trials available in electronic databases in 1996, in the Cochrane Controlled Trials Register in 1997, and from hand searching of journals to 1997. SUBJECTS: Patients who had deliberately harmed themselves shortly before entry into the trials with information on repetition of behaviour. The included trials comprised 2452 randomised participants with outcome data. MAIN OUTCOME MEASURE: Repetition of self harm. RESULTS: 20 trials reported repetition of self harm as an outcome variable, classified into 10 categories. Summary odds ratio (all for comparison with standard aftercare) indicated reduced repetition for problem solving therapy (0.73; 95% confidence interval 0.45 to 1.18) and for provision of an emergency contact card in addition to standard care (0.45; 0.19 to 1.07). The summary odds ratios were 0.83 (0.61 to 1.14) for trials of intensive aftercare plus outreach and 1.19 (0.53 to 2.67) for antidepressant treatment compared with placebo. Significantly reduced rates of further self harm were observed for depot flupenthixol versus placebo in multiple repeaters (0.09; 0.02 to 0.50) and for dialectical behaviour therapy versus standard aftercare (0.24; 0.06 to 0.93). CONCLUSION: There remains considerable uncertainty about which forms of psychosocial and physical treatments of patients who harm themselves are most effective. Further larger trials of treatments are needed.