An epidemiological perspective on depression and suicide
Suffering from chronic or traumatic mental distress is one of the most contributing risk factors for the aetiology of mental disorders [1] including Major Depressive Disorder (MDD). Although about 25% of all disability-adjusted life years lost in Europe are due to mental disorders [2], relatively little is known about the underlying pathophysiological mechanisms. As a consequence, mental disorders remain a strong socioeconomic burden to all societies [3] characterized by relatively poor treatment outcomes. The impact of this burden is highlighted by reports that up to 15% of the general population develop at least one depressive episode in a lifetime [1]. This highlights and underlines the need for strong scientific efforts to promote the identification of preventive, predictive and personalized medical (3PM) treatment options in affective disorders including MDD as a paradigm shift from today’s reactive psychiatric services.
Epidemiological research identified risk factors for MDD, reporting age, sex, socioeconomic status, social support, and lifestyle factors as relevant variables [4]. MDD is not only associated with impaired life quality [5] but it is further associated with premature morbidity and mortality due to e.g. suicidal behaviour [6, 7]. In Europe, the yearly loss of lives includes about 60,000 individuals who die by suicide. Even worse, for each completed suicide twenty other non-fatal suicide attempts can be considered statistically [8]. This unacceptable high number of cases further highlights the utmost urgent need to promote and establish the concept of 3PM in psychiatric healthcare, especially predictive and preventive strategies in those associated with suicidality. In contrast to the risk for MDD, both suicidal risk and fatal suicide attempts are more strongly associated with the male sex [9]. Additionally, men have a higher risk to perform the transition from suicide idealization to completing suicide [10]. Adolescent suicide has also been related to the impact of different sociocultural, psychological, psychopathological, and biological factors (for a review see [11]). A distinct link between psychiatric conditions and suicide risk has been reported: About 90% of all suicide completers (SC) are estimated to have a psychiatric disorder at the timepoint of death [12, 13]. Here, MDD contributes approximately 60% to the total number of deaths [14, 15]. Although suicidal behaviour is not limited to MDD, it plays a very important role due to the highest risk of attempting or dying by suicide in this group of individuals [16]. The impact of suicide in combination with MDD is reflected in findings showing a worldwide rate of suicide of about 800,000 per year [8]. Again, this very high number of yearly life losses emphasizes also the need for better predictive and preventive strategies and 3PM implementation towards personalization of medical services in psychiatric services to significantly reduce the very high number of suicides around the globe.
Missing biomarker availability in depression and suicide
Depression and suicidal behaviour are interrelated, stress-associated mental health conditions, each lacking biological verifiability. Missing biomarker availability for both conditions leads to negative medical outcomes of 3PM-related aspects in terms of treatment efficacy, remission stability and relapse probability. For example, suicidal behaviour and ideation contribute to the severity of MDD and worsen the therapeutical access and the efficacy of antidepressant treatment. As a consequence, about 25% of depressed individuals commit suicide while having contact with psychiatric services at the time of their death [17, 18]. Here, predictive biomarkers for a psychobiological stress burden would help to prevent at least cases of severe depression and associated suicide risk. Known psychosocial risk factors for fatal suicide attempts include social and financial problems, traumatic life events, and the loss of a family member or friend [19]. However, a biologically-embedded 3PM approach to identify and monitor physiological dysregulation of stress response mechanisms as a consequence of chronic or traumatic stress exposure in the context of MDD and suicide risk is most urgently needed, but still missing. Therefore, more interdisciplinary research on suicide risk and completed suicide is necessary to identify new biomarker candidates, and the psychoneuroendocrine stress response has been intensively targeted as one potential starting point for this approach.
Cortisol and the endocrine stress response
As part of an acute response, the body’s neuroendocrine stress response is triggered by environmental stressors, resulting in the stimulation of the hypothalamic-pituitary-adrenocortical (HPA) axis to release the steroid hormone cortisol from the adrenal glands into the bloodstream. Under conditions of sufficient chronicity, amplitude and/or frequency, a stressor can trigger a maladaptive regulation of the stress-response system [20], resulting in alterations of the HPA-axis signalling and regulation as reflected in persistent changes in cortisol levels. From a more holistic perspective, the dysregulation of the neuroendocrine axis leads to (mal)adaptative changes also in other biological systems, including the central and the autonomous nervous system, and the immune system. Therefore, stress-related pathological burden is discussed to affect the body on a systemic level, suspecting MDD as a disease that negatively affects the body’s functionality as a whole [21].
Research findings on cortisol alterations in depression
Alterations of HPA signalling and resulting cortisol concentrations have been reported in many stress-related conditions. Studies investigating MDD showed hypercortisolism states [22, 23], but also opposite/mixed findings [24, 25] or even no differences to non-stressed control groups were found [26–28]. This inconsistency of observations can be related to differences in the selected biomaterial collected for analysis, differences in sample preparation as well as technical and/or methodological differences used for quantitative steroid analysis. Towards achieving a technical and methodological standard, harmonization of protocols and analytical procedures is a prerequisite for the promotion of 3PM concepts in clinical psychology and psychiatry. Another explanation for the reported discrepancies might lie in demographic, socioeconomic, and lifestyle differences of participants including age, sex, gender, physical activity, nutrition, the chronicity and strength of psychological stress burden, and social support between the studies. From a biological perspective, the diurnal regulation of neuroendocrine cortisol release further causes difficulties in standardizing the time point of sample collection in human research related e.g. to the wake-up response, sleep patterns, and related regulatory changes of the circadian rhythm [29]. One methodological approach to overcome these limitations is represented by the usage of human scalp hair for the measurement of hair cortisol concentrations (HCC), which will be introduced next.
Research on hair cortisol in chronic-stress conditions
The assessment of cortisol in scalp hair allows the characterization of HPA-mediated stress responses in a retrospective manner over periods ranging from weeks to months depending on the length of hair strands used for HCC quantification. As an extension of conventional methodological approaches, hair cortisol overcomes the limitation of a snapshot impression of circulating cortisol concentrations in the periphery (e.g., blood, saliva) or cortisol secretion over a relatively short period (urine) of less than 1 day [30]. With a reported average hair growth of 1cm per month [31–33], cortisol concentrations in 1cm hair segments allow the retrospective assessment of average cortisol levels over approximately the past four weeks, and 3cm hair strands over the past three months, respectively. Easy procedures of collection (non-invasive), storage (room temperature) and analytical handling (standardized operating procedures) of samples together with relatively high compliance of individuals and patients for sampling highlights hair as a very promising matrix toward 3PM approaches in psychobiomedical (stress) research. Among other areas of application, the usage of hair is already present in forensic, environmental, doping, and toxicology research [31–34] and most recently there is increasing data also from stress-related and psychopathological stress research. Here, higher HCC have been reported e.g. in caregiving relatives of patients with dementia and chronically ill individuals [35], long-term unemployed vs. employed individuals [36], individuals with posttraumatic stress disorder (PTSD) [37], women with childhood maltreatment [38] and individuals with depression [39–43]. However, based on the relatively low number of studies, also mixed results and heterogeneous findings were reported for HCC in depressed patients. A systematic review and meta-analyses by Psarraki and colleagues [44] summarized the available literature and discussed strengths and limitations of the approach.
In comparison to the biology of MDD, today relatively little is known about the pathophysiological underpinnings of suicidal behaviour and suicide attempts. But similar to MDD, literature provided evidence for an association between alterations in HPA regulation and suicide [45–48]. For example, higher levels of corticotropin-releasing hormone (CRH) and vasopressin found in the frontal lobe, the raphe nuclei, and the locus ceruleus of SC strengthened the perspective of a contributing role of HPA-axis functioning in suicide (for a review see [12]). Furthermore, the observed decreased density of CRH receptor 1 in the frontal cortex maypossibly be linked to an adaptive mechanism in response to increased release of CRH. On the level of gene expression, reduced levels of glucocorticoid receptor mRNA were found in the amygdala and the prefrontal cortex associated with suicide [49]. Altogether, these post-mortem findings are in line with results from animal studies using chronic stress models [50]. To the best of our knowledge, no data is available on HCC in SC. However, a possible (and easy obtainable) biomarker correlate of suicidal risk - with the additional possibility to discriminate between depressed and non-depression suicide attempts - would be an important 3PM-oriented predictive as well as preventive tool in psychiatric research. Consequently, we aimed to test the usage of HCC as a correlate of stress-related HPA-axis (mal)adaptation first in the context of depression, which might help to further characterize and better understand the endocrine consequences of MDD. This might potentially provide a powerful tool to track neuroendocrine changes in the process of psychotherapy-based interventions in future studies already implementing the 3PM concept in mental disorders also considering the aforementioned biopsychosocial factors of risk and resilience. Furthermore, we investigated HCC in a group of SC to – at best - provide HCC as a possible indicator candidate for endocrine alteration reflecting an increased risk for committing suicide. Here, we did not only investigate possible changes in cortisol signalling but also wanted to test whether cortisol concentrations in hair are statistically associated with the severity of depressive symptoms. In general, a possible biomarker correlate of suicidal risk - with the additional possibility to discriminate between depressed and non-depression suicide attempts - would be an important 3PM-oriented predictive as well as preventive tool in psychiatric research. We hypothesized that HCC is elevated in both MDD and SC compared to a mentally stable, non-depressed group of age-matched controls. Furthermore, we expected that in individuals who completed suicide, HCC further exceeds the level of that observed in individuals with MDD, which might contribute to the risk for the “final exit“-behaviour by committing suicide. As a consequence, we report a first exploratory approach to characterize HCC in the context of depression and suicide to also stimulate more 3PM-oriented investigations in this very important but rather neglected field of biopsychomedical research.