Elsevier

Journal of Affective Disorders

Volume 257, 1 October 2019, Pages 10-16
Journal of Affective Disorders

Research paper
Cortisol response to stress as a predictor for suicidal ideation in youth

https://doi.org/10.1016/j.jad.2019.06.053Get rights and content

Highlights

  • Suicidal Ideation is associated with higher cortisol reactivity to stress.

  • Higher baseline cortisol may predict future Suicidal Ideation.

  • HPA axis is related to bereavement and suicidal ideation.

Abstracts

Objective

To examine the association between cortisol response to stress and suicidal ideation (SI) cross-sectionally and longitudinally in our sample of bereaved and non-bereaved youth.

Methods

The sample included 114 youth bereaved by sudden parental death and 109 non-bereaved controls, mean age of 12.3 (SD = 3.6), evaluated at four time-points over an average follow-up period of 7 years. The Trier Social Stress Test (TSST) was conducted on average 6 years after bereavement. We used latent class analyses to examine the trajectories of SI over follow-up and up to the time of the TSST and compare them on cortisol measures. We examined whether cortisol measures predicted future SI at 18.5 months on average after the TSST.

Results

Bereavement was associated with higher cortisol reactivity after controlling for covariates [β = 0.96, 95% CI (0.28, 1.65), p < 0.01, d = 0.41]. Cortisol reactivity to stress was higher in those belonging to the high SI trajectory [β = 1.23, 95% CI (0.41, 2.06), p = 0.004, d = 0.23] compared to the low SI trajectory. Higher baseline cortisol showed small to medium effect size in predicting future SI [β = 2.34, 95% CI (0.17, 4.51), p = 0.03, d = 0.38].

Conclusion

The persistence of SI is associated with higher cortisol reactivity to stress, and higher baseline cortisol may predict future SI. These results emphasize the importance of HPA-axis activity in youth exposed to major stressors, and those with SI. More research is needed to further clarify biological mechanisms linking SI and behavior, bereavement, and HPA axis response to stress, to better identify at-risk subjects for targeted prevention and intervention efforts.

Introduction

Parental death occurs in 4% of youth under the age of 18 and is an extremely stressful form of childhood adversity (Administration, 2000). It has a major impact on the psychological development of children and increases the risk for a wide range of psychopathology, including depression, post-traumatic stress disorder (PTSD), anxiety, conduct problems, substance abuse, and functional impairment, all of which are risk factors for suicidal behavior (Kaplow et al., 2010; Brent et al., 2009). Parental death from any cause during childhood was found to be a significant risk factor for suicide among offspring, especially in those who were bereaved by suicide (Guldin et al., 2015; Pitman et al., 2016; Pitman et al., 2014).

While the association between parental death and risk for suicidal behavior has been well-established, the mechanisms by which parental death leads to increased risk for suicidal behavior are not known. One possible mechanism is via alterations in the hypothalamic–pituitary–adrenal axis (HPA) axis. In fact, parental death has also been associated with altered HPA axis response to stress (Dietz et al., 2013). Altered basal cortisol or cortisol response to stress have also been linked to risk for suicidal behavior (van Heeringen and Mann, 2014). However, there are no studies that concomitantly link parental death, alterations in HPA axis function, and risk for suicidal behavior.

Studies suggest that HPA axis dysregulation occurs more commonly in individuals who lost their parents as children (Luecken et al., 2014). Adults who experienced parental death during childhood had been reported to have higher diurnal cortisol, especially if they experienced childhood abuse and family conflict (Nicolson, 2004). Children who lost a caregiver in the 9/11 terrorist attack exhibited persistently higher basal cortisol levels compared to non-bereaved children (Pfeffer et al., 2007). We previously showed that sudden parental death is associated with higher total cortisol output in response to social stress in bereaved youth (Dietz et al., 2013).

The role of the HPA-axis in suicidal behavior was robustly demonstrated in a meta-analysis where non-suppression in response to the Dexamethasone Suppression Test (DST) was related to a 4.5-fold increased risk for suicide in adult inpatients (Mann et al., 2006). Melhem and colleagues found lower baseline and total cortisol output during the Trier Social Stress Test (TSST) in early-onset suicide attempters compared to high-risk subjects who never attempted suicide and healthy controls (Melhem et al., 2016). This blunted HPA axis profile was observed mostly in suicide attempters who also had a family history of an attempt. O'Connor et al. reported similar findings in demonstrating that suicide attempters, especially those with a family history of suicidal behavior, and those who made the attempt within the last year, had the lowest total cortisol output in response to the TSST compared to controls (O'Connor et al., 2017). O'Connor et al. also found that blunted cortisol response to the TSST in suicide attempters was associated with a higher level of suicidal ideation one month after the TSST. Similarly, Keilp et al. found that adult suicide attempters had lower baseline cortisol levels compared to non-attempters (Keilp et al., 2016) and McGirr et al. found blunted cortisol response in first-degree relatives of those who died by suicide compared to controls (McGirr et al., 2010).

Melhem et al. extended these findings to show that blunted HPA axis activity most likely precedes suicide attempt (Melhem et al., 2017). They found that psychiatric inpatients admitted for a suicide attempt had lower hair cortisol concentrations (HCC), which provides a measure of overall cortisol production in previous months, compared to those admitted for suicidal ideation but had never attempted suicide and to healthy controls. Specifically, in the above-noted study, HCC obtained from 2–3 cm hair segments closest to the scalp reflected cortisol levels for the prior 2–3 months, which would have been prior to the attempt in Melhem et al.’s study design. However, other studies found that hyper-responsiveness of the HPA axis to social stress was associated with current and future suicidal ideation (Giletta et al., 2015). These discrepant findings could be due to differences in outcome measures (ideation vs. attempt), age differences, and the population studied with respect to their burden of psychopathology, history of childhood adversity, and whether they were responding to acute or chronic stress.

Thus, the relationships of the HPA axis to both suicidality and bereavement have been investigated independently. Here, we examine the relationship of HPA-axis response to stress and suicidal ideation in our sample of children bereaved by sudden parental death. We hypothesize that bereavement and suicidal ideation will each, independently be related to baseline cortisol, total cortisol output, and cortisol reactivity in response to the TSST, and that cortisol measures will predict future suicidal ideation.

Section snippets

Study sample

The sample in this paper is drawn from our longitudinal study on the impact of sudden parental death on children and families. A total of 427 bereaved and non-bereaved youth were enrolled in the study, of whom 223 (52%) completed the acute laboratory social stress task and were available for follow-up. The 223 youths included 114 offspring from 79 parentally-bereaved families and 109 offspring from 65 non-bereaved families with a mean age of 12.3 (standard deviation [SD] = 3.6, range: 6–25

Relationships of bereavement and suicidal ideation at the time of the TSST on individual cortisol measures

Table 1 shows that bereavement and suicidal ideation at the time of TSST were not significantly associated with any of the cortisol measures at p < 0.017. Younger and Caucasian participants had a significantly higher baseline and total cortisol output. Smoking on the day of the TSST was negatively associated with cortisol reactivity. When controlling for covariates, there were no main effects of suicidal ideation on any of the cortisol measures. Bereavement was associated with higher cortisol

Discussion

There were no significant relationships between baseline cortisol, total cortisol output, and cortisol reactivity with suicidal ideation at the time of the TSST. However, participants belonging to the high suicidal ideation trajectory showed greater cortisol reactivity. There were no significant interactions between bereavement and suicidal ideation on each of the cortisol measures. As hypothesized, we found that parental bereavement was associated with greater cortisol reactivity.

These results

CRediT authorship contribution statement

Amit Shalev: Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review & editing. Giovanna Porta: Data curation, Formal analysis, Investigation, Methodology, Project administration, Software, Supervision, Validation, Visualization, Writing - review & editing. Candice Biernesser: Project administration, Supervision, Validation, Writing - review & editing. Jamie Zelazny: Project administration, Supervision, Validation, Writing -

Conflict of interest

Dr. David Brent receives research support from the National Institutes of Mental Health, American Foundation for Suicide Prevention, the Once Upon a Time Foundation, and the Beckwith Foundation, receives royalties from Guilford Press, from the electronic self-rated version of the C-SSRS from eRT, Inc., and from performing duties as an UptoDate Psychiatry Section Editor, and receives consulting fees from Healthwise. Dr. Nadine Melhem is supported by the National Institutes of Mental Health,

Acknowledgments

This study was supported by grants R01-MH65368 and K01-MH077930 from the National Institute of Mental Health (NIMH); and by a Young Investigator Award from the American Foundation for Suicide Prevention. The authors would like to thank the studies’ participants and their families and to the Herman Dana Foundation which provided stipend for the research activities of the corresponding author.

References (49)

  • A. McGirr et al.

    Personal and family history of suicidal behaviour is associated with lower peripheral cortisol in depressed outpatients

    J. Affect. Disord.

    (2011)
  • N.M. Melhem et al.

    Blunted HPA axis activity prior to suicide attempt and increased inflammation in attempters

    Psychoneuroendocrinology

    (2017)
  • N.A. Nicolson

    Childhood parental loss and cortisol levels in adult men

    Psychoneuroendocrinology

    (2004)
  • D.B. O'Connor et al.

    Cortisol reactivity and suicidal behavior: investigating the role of hypothalamic-pituitary-adrenal axis responses to stress in suicide attempters and ideators

    Psychoneuroendocrinology

    (2017)
  • C.R. Pfeffer et al.

    Salivary cortisol and psychopathology in children bereaved by the september 11, 2001 terror attacks

    Biol. Psychiatry

    (2007)
  • A. Pfennig et al.

    Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression

    Biol. Psychiatry

    (2005)
  • A. Pitman et al.

    Effects of suicide bereavement on mental health and suicide risk

    Lancet Psychiatry

    (2014)
  • J.C. Pruessner et al.

    Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change

    Psychoneuroendocrinology

    (2003)
  • K. van Heeringen et al.

    The neurobiology of suicide

    Lancet Psychiatry

    (2014)
  • B.I. Yerevanian et al.

    The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression

    J. Affect. Disord.

    (2004)
  • S.S. Administration

    Intermediate Assumptions of the 2000 Trustees Report

    (2000)
  • A.P. Association et al.
    (2000)
  • D. Brent et al.

    The incidence and course of depression in bereaved youth 21 months after the loss of a parent to suicide, accident, or sudden natural death

    Am. J. Psychiatry

    (2009)
  • A. de Belmont Hollingshead

    Four Factor Index of Social Status: Yale University

    (1975)
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