Redefining suicidal behaviour – Rating scales and biomarkers

Risk assessment of suicidal behaviour is one of the most important tasks in clinical psychiatry and a major determinant of subsequent care and treatment selections. To date, suicide risk assessment is based solely on clinical evaluations, which inevitably leads to subjective interpretations and decisions by the psychiatrist. In order to find more robust instruments in the evaluation of suicidality it is important to search for objective correlates of different aspects of suicidal behavior. The main aim of the present thesis was to investigate neurobiological and clinical characteristics in a group of suicide attempters in order to gain a further understanding of the mechanisms underlying suicidal behavior. The patients, who were all treated at a psychiatric ward of the Lund University Hospital after a suicide attempt, participated in a research program including clinical and biochemical investigations, as well as expert and self -ratings. While free of psychotropic medications, the patients underwent lumbar punctures and Dexamethasone Suppression Tests (DST). Diagnostic interviews and ratings of different aspects of psychopathology were carried out at the psychiatric ward. A subset of the patients participated in a clinical follow-up approximately 12 years after the suicide attempt, this time in an outpatient setting. Salivary samples were collected in conjunction with the follow-up. Biomarkers from the stress-, immune-, and the monoaminergic systems were analyzed in cerebrospinal fluid (CSF), saliva and blood, and subsequently analyzed in relation to different aspects of suicidal behaviour and psychiatric symptoms. The most salient findings were that: 1. Low post-DST cortisol levels were associated with high suicidal intent among patients with Major Depressive Disorder (MDD). 2. Low salivary cortisol levels were found in suicide attempters approximately years after the index suicide attempt. Low salivary cortisol was associated with repetition of suicidal behaviour and severe psychiatric symptoms. 3. Suicide attempters had significantly higher CSF levels of pro- inflammatory cytokine Interleukin (IL)-6 compared to healthy individuals, and the highest levels were found in violent suicide attempters and patients with MDD. 4. Levels of CSF-Kynurenic acid (Kyna), an end-metabolite of tryptophan through the kynurenine-pathway, did not significantly differ between suicide attempters and controls. High Kyna levels were, however, associated with high IL-6 levels and a diagnosis of MDD. 5. By using Principal component analysis (PCA) we found that a combination of IL-6, 5-Hydroxyindoleacetic acid (serotonin metabolite), and Homovanillic acid (dopamine metabolite) was associated with severe suicidal behaviour and risk for future completed suicide. We found that suicide attempters display elevated levels of the proinflammatory cytokine IL-6 in CSF. We therefore suggest that neuroinflammation may be involved in the pathophysiology of suicidal behaviour. The results from the PCA further confirm that IL-6 seems to play an important role for suicidal behaviour, an effect perhaps mediated via the monoaminergic system. In addition, our results suggest that low Hypothalamic-Pituitary-Adrenal (HPA)- axis activity is associated with more severe forms of suicidal behaviour in our sample of patients. This might be due to long-term stress resulting in an “HPA- axis burnout”. We propose a neurobiological model for suicidal behaviour linking long-term stress with HPA-axis burnout, which in turn might lead to a shift towards immune activation. We further suggest a dynamic relationship between the immune system and monoamines, where an acute immune response may result in increased monoamine turnover whereas long-lasting, low-grade inflammation, in contrast, may lead to a monoamine depletion. Our findings may in the long run have important clinical implications. For example, we are planning to start a treatment study in which suicidal patients will receive anti-inflammatory agents added to their regular medicine. We hope that this combination will improve their psychiatric symptoms and that this will show in blood and CSF samples. Another potential clinical implication is the use of biomarkers in psychiatry. Suicide risk assessment is one clinical situation in which biomarkers would be useful as a tool in the clinical evaluation. Indeed, inflammatory markers such as IL-6 are candidates for this purpose, although further studies are warranted in order to identify biomarkers with sufficient sensitivity and specificity to be used in the clinic.