Journal Pre-proof

Abnormal Stress Responsiveness and Suicidal Behavior: A Risk

Phenotype

Louisa J. Steinberg, J. John Mann

PII: S2666-1446(20)30001-0
DOI: https://doi.org/10.1016/j.bionps.2020.100011
Reference: BIONPS 100011

To appear in: Biomarkers in Neuropsychiatry

Received Date: 16 October 2019

Revised Date: 3 January 2020
Accepted Date: 7 January 2020

Please cite this article as: Steinberg LJ, Mann JJ, Abnormal Stress Responsiveness and
Suicidal Behavior: A Risk Phenotype, Biomarkers in Neuropsychiatry (2020),
doi: https://doi.org/10.1016/j.bionps.2020.100011

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Abnormal Stress Responsiveness and Suicidal Behavior: A Risk Phenotype

Authorship:
Louisa J. Steinberg1, J. John Mann1,2

1
Columbia University, Department of Psychiatry
2
New York State Psychiatric Institute

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Corresponding author:
Louisa J. Steinberg, 1051 Riverside Dr. New York, NY 10032;
louisa.steinberg@nyspi.columbia.edu ; Phone: 646-774-7501

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Abstract

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Suicidal behavior is a major cause of morbidity and mortality in psychiatric illness. However, only
a subset of patients with psychiatric illnesses, such as major depressive disorder (MDD), commit
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suicide. This raises the question of how those who manifest suicidal behavior differ from those
who do not. In the context of a stress-diathesis model of suicidal behavior, the reaction to stress
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has often been overlooked. The hypothalamic-pituitary-adrenal (HPA) axis dysfunction is

proposed as an index of a disordered response to stress that thereby is part of the pathogenesis of
risk for suicide in major depression. Suicide attempters are distinguished from non-attempters by
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a cluster of traits that include greater mood dysregulation and subjective distress, more pronounced
reactive aggressive traits, impaired problem solving and learning, and distortion of perceived
social cues. In this review, we show how these traits and risk for suicide are potentially linked to
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HPA axis dysfunction, which in turn can be traced back to genetic predisposition, and early life
stress-related epigenetic mechanisms.
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Introduction

Suicidal behavior is a major cause of morbidity and mortality in psychiatric illness. The United
States’ suicide rate increased 33.7% from 2000-2016 (Curtin et al., 2016). Prevention efforts need
to be focused most intensively on the groups at highest risk. About 90% of suicides occur within
the context of a psychiatric illness, and mood disorders account for about 60% of the diagnoses
(Barraclough et al., 1974; Brent et al., 1993; Dorpat and Ripley, 1960; Isometsä et al., 1995; Robins
et al., 1959; Strakowski et al., 1996). Given that the prevalence of adults with major depressive
disorder in the United States is approximately 7% (Greenberg et al., 2015), we estimate that based
on 2015 CDC data that about 25,000 suicides in the USA resulted from mood disorders,
representing a prevalence of about .008% of the general population.

Since only a subset of depressed patients commit suicide or make serious nonfatal suicide attempts,

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prevention requires determination of who is in this high-risk group. We have sought to describe
this difference using a stress diathesis model of suicidal behavior (van Heeringen and Mann, 2014;
Mann, 2013; Mann et al., 1999; Oquendo et al., 2014). Some traits that form the diathesis for

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suicidal behavior have been identified from differences between suicide attempters and psychiatric
controls. These traits include: greater mood dysregulation and greater subjective distress, more

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pronounced reactive aggressive traits, impaired problem solving and learning, and distortion of
perceived social cues (van Heeringen and Mann, 2014). As a consequence, when faced with the
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decision of whether to seek symptom relief through treatment or through suicide, this population
is more likely to choose suicide.
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The basis for these trait difference remains to be fully described. Risk suicidal behavior is
associated with greater depression severity (Hawton et al., 2013) and declines with subjective
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improvement of symptoms (Keilp et al., 2017). One striking characteristic of suicide completers
compared to those that engage in non-fatal suicidal behavior appears to be altered responses to
stress. The most prominent biological system involved in stress response is the hypothalamic
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pituitary adrenal (HPA) axis (Figure 1). Abnormal HPA axis function is an important predictor of
suicide risk in major depression (van Heeringen and Mann, 2014; Mann et al., 2006a; Melhem et
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al., 2015; Oquendo et al., 2014; Yin et al., 2016), common in severe major depression (Brown et
al., 1988; Dratcu and Calil, 1989; Meador-Woodruff et al., 1988), and also associated with
aggressive traits (Buydens-Branchey and Branchey, 1992; Denson et al., 2013; Lopez-Duran et
al., 2009; Rausch et al., 2015; van Santen et al., 2011). We therefore examine the causes and
consequences of HPA axis dysfunction and how it may impact risk of suicidal behavior.
HPA Axis and Suicidal Behavior

Suicidal behavior is associated with lower resting cortisol levels and blunted cortisol responses to
stressors (Melhem et al., 2015, 2017; O’Connor et al., 2017; Papadopoulou et al., 2017).
Interestingly, this effect may dependent on age, with older suicide attempters demonstrating lower
cortisol levels than controls, while younger suicide attempters demonstrating elevated cortisol
levels (O’Connor et al., 2016). However, this may differ in those who complete suicide, as opposed

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to non-fatal suicide attempters. Some postmortem studies of suicide completers have found
evidence of an over-active HPA axis including heavier adrenal glands, higher tissue levels of
corticotropin releasing factor (CRF), indicating over-secretion of CRF, and lower expression of

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CRF receptors in prefrontal cortex (Arató et al., 1989; Nemeroff et al., 1988; Szigethy et al., 1994).
Studies also suggest that patients with mood disorders who have impaired cortisol suppression on

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the dexamethasone suppression test, and therefore release more cortisol in response to CRF, are at
higher risk for subsequent suicide (Coryell and Schlesser, 2001; van Heeringen, 2003; Kunugi et
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al., 2006; Mann et al., 2006a; Pfennig et al., 2005; Westrin, 2000; Yerevanian et al., 2004).
Excessive 24-hour urinary excretion of corticosteroids has been observed in depressed patients at
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risk for future suicidal behavior (Bunney et al., 1969; Ostroff et al., 1982). Some studies of HPA
axis feedback inhibition using the dexamethasone suppression test show impairment in severe
major depression, especially when characterized by clinical features linked to the risk of suicide
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such as melancholia, psychotic features or psychomotor agitation (Brown et al., 1988; Lindy et al.,
1985). Given the link of HPA axis hyper-responsiveness to suicide risk in major depression, the
possibility of targeting the HPA as a therapeutic target is an important option beyond the use of
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antidepressant medications. However, antidepressant trials of the glucocorticoid receptor (GR)

antagonist mifepristone in psychotic depression have yielded mixed results (Block et al., 2017,
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2018). Trials of CRF-1 antagonists have suggested effectiveness for the treatment of depression
and anxiety, risk factors for suicide, but were discontinued due to safety concerns (Chen and
Grigoriadis, 2005; Zobel et al., 2000). No studies have addressed suicidal behavior as the primary
outcome measure. Together, these findings suggest the presence of excessive cortisol response to
stress in patients at risk for completing suicide, and raise the question of whether excessive cortisol
contributes to altered emotion regulation, learning deficiency, altered decision-making and
distorted social perceptions.

Causes of HPA Axis Abnormalities in Major Depression

One mechanism for this HPA dysregulation appears to lie in attenuated feedback mechanisms
within the HPA system specifically involving the GR. GRs have low affinity for glucocorticoids

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and tend to regulate feedback inhibition at high levels of cortisol, as found during a stress response.
The mineralocorticoid receptor (MR) has a higher affinity for glucocorticoids and regulates
feedback at lower, resting levels of cortisol (De Kloet et al., 1998; de Kloet et al., 2016). Chronic,

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mild stress has been linked to increased trafficking of GRs to the nucleus via the chaperone protein
FKBP5 (Guidotti et al., 2013), and this chaperone protein appears to be upregulated in postmortem

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brain tissue of suicide decedents (Yin et al., 2016). Furthermore, certain FKBP5 gene variants may
confer increased risk for depression and PTSD in those with early life trauma (Wang et al., 2018),
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as well as increased risk for suicide (Breen et al., 2016; Fudalej et al., 2015; Hernández-Díaz et
al., 2019; Roy et al., 2010, 2012). Suicide decedents with reported childhood abuse, a form of
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severe or chronic stress, have increased DNA methylation and lower expression levels of the GR
gene compared with suicide decedents having no reported childhood adversity and with non-
psychiatric controls postmortem (McGowan et al., 2009). This indicates an impairment of the
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normal feedback mechanism mediated via epigenetic effects on GRs (Ladd et al., 2004).
Inflammation also modulates the HPA axis and has been implicated in the development of major
depressive disorder (Bauer and Teixeira, 2018; Haroon et al., 2012; Mechawar and Savitz, 2016;
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Miller et al., 2009). Inflammatory cytokines stimulate the release of CRF and ACTH in the brain,
and cortisol peripherally (Miller et al., 2009; Silverman and Sternberg, 2012). Furthermore,
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cytokines are thought to decrease monoamine neurotransmitter synthesis, promote excitotoxicity,

and decrease release of neurotrophic factors, and therefore may contribute to the genesis of
depression through multiple pathways (Haroon et al., 2012; Miller et al., 2009). Data on the
association between inflammation suicide remain mixed, and may depend on gender (Batty et al.,
2016, 2018; Brundin et al., 2017; Cáceda et al., 2018; Melhem et al., 2017; Park and Kim, 2017).
Human postmortem studies cannot answer the question of causal relationships which includes
determining which comes first: major depression or impairment in HPA axis feedback? In animal
studies, HPA axis hyper-reactivity has been linked to early-life stressors, such as prolonged
maternal separation (Belay et al., 2011; Kalinichev et al., 2002; Ladd et al., 2004, 2005; Lippmann
et al., 2007). Pups that undergo prolonged separations from their mothers exhibit dysregulated
HPA responses as adults, that may be modulated by serotonin transporter genotype (Belay et al.,
2011). Maternal separation results in DNA methylation of the GR gene and decreased expression
in rats (Fish et al., 2004; Liu et al., 1997; Zhang et al., 2013). This suggests that a hyperactive HPA

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axis may be primed by early life adversity and potentially mediates a linkage between early trauma,
and subsequent mood disorders and suicide.

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Early life adverse experiences may also interact with genes to prime the stress-response circuits
via gene-environment interactions. These people carry a lifelong predisposition for a hyperactive

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HPA axis response to an environmental stressor. Single nucleotide polymorphisms in the
corticotropin releasing hormone receptor-1 gene (CRHR1) and serotonin transporter gene (5-
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HTTLPR) have been linked to increased risk for suicide when paired with either early stressful
life events in women, or stressful life events at any time in men (Ben-Efraim et al., 2011; Caspi et
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al., 2003). Genetic studies have linked low expressing variants of NR3C1, a nuclear GR, and gene
variants in chaperone proteins SKA2 and HDAC6 to suicide and feedback regulation of
glucocorticoid levels (Yin et al., 2016). Furthermore, response to treatment with a corticotropin-
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releasing factor receptor 1 antagonist in post-traumatic stress disorder (PTSD) is moderated by an

interaction between a specific single nucleotide polymorphism of the receptor gene, rs110402, and
moderate to severe childhood abuse (Dunlop et al., 2017). Interactions between genotype and early
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childhood experiences can prime the HPA axis for excessive responses into adulthood and impact
treatment responsiveness in psychiatric disorders.
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HPA Axis Abnormalities in Other Psychiatric Disorders associated with Suicide

While mood disorders appear to be the most heavily represented psychiatric diagnoses in suicide
decedents, other leading diagnoses are substance use disorders, schizophrenia, and personality
disorder (Bertolote and Fleischmann, 2002). This may differ by gender, with mood disorders being
more common in women, and substance use and personality disorders seen more frequently in
male decedents (Arsenault-Lapierre et al., 2004). There is robust evidence that HPA axis
dysregulation also plays a role in schizophrenia, as well as alcohol use disorder and borderline
personality disorder, the most heavily studied of the substance use and personality disorders
(Blaine and Sinha, 2017; Bradley and Dinan, 2010; Cattane et al., 2017; Drews et al., 2019).

Akin to mood disorder, some studies show that schizophrenic patients also exhibit higher basal
HPA axis activity (Lammers et al., 1995; Ryan et al., 2004; Zhang et al., 2005) and impaired
suppression of glucocorticoid secretion in response to dexamethasone (Coryell and Tsuang, 1992;

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Sharma et al., 1988; Yeragani, 1990). HPA axis gene polymorphisms, specifically corticotropin-
releasing hormone binding protein (CRHBP), the BclI polymorphism in glucocorticoid receptor
gene (NC3R1), and corticotropin-releasing hormone receptor type 1 (CRHR1) genotype, may

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modulate risk for suicide in schizophrenia as well. CRHBP heterozygotes were found to be at
increased risk for suicide, while NC3R1 genotype 11 was protective against suicide. CRHBP and

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CRHR1 showed a genotype interaction such that CRHBP genotype 11 and CRHR1 genotype 22
in combination were associated with lower suicide severity (De Luca et al., 2010). Furthermore, it
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appears that this HPA axis hyperactivity is attenuated with antipsychotic treatment, possibly
through inhibition of the CRF promoter, and that this is potentially related to improvement in
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negative symptoms (Basta-Kaim et al., 2006; Lammers et al., 1995; Mann et al., 2006b; Zhang et
al., 2005). Second generation antipsychotics may be more effective than first generation
antipsychotics in reducing ACTH and cortisol secretion (Cohrs et al., 2006; Markianos et al.,
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1999), though how this relates to suicidality has not been reported. Clozapine is thought to have
anti-suicidal properties compared to other second-generation antipsychotics (Meltzer et al., 2003),
which may be related to its superior treatment efficacy (McEvoy et al., 2006), but there is no data
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relating this to HPA axis measures that we are aware of.

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In contrast to MDD and schizophrenia, alcohol use disorder (AUD) appears to be associated with
a lower basal HPA axis activity. Healthy subjects with a positive family history of AUD
(AUDFH+) have lower baseline ACTH levels and demonstrate a slower recovery of plasma ACTH
after stress (Dai et al., 2002). AUDFH+ also demonstrate blunted cortisol stress responsiveness,
which is thought to be modulated by the opiate system (Wand et al., 2001, 1999), as well as
personality traits (Sorocco et al., 2006). Additionally, their plasma ACTH response to stress is
attenuated after ingestion of alcohol, which is not observed in those without family history of AUD
(Dai et al., 2002; Zimmermann et al., 2004). Subject with AUD who are not intoxicated also
display attenuated cortisol responses to ACTH compared to healthy controls (Adinoff et al., 2005;
Costa et al., 1996). Of course, alcohol consumption in and of itself also leads to HPA axis
activation, with secretion of ACTH and cortisol, though this appears to be blunted with heavy
habitual alcohol use (King et al., 2006).

Borderline personality disorder (BPD) has also been associated with higher basal HPA axis activity

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with higher baseline cortisol levels (Drews et al., 2019; Lieb et al., 2004; Scott et al., 2013).
Dexamethasone suppression studies have suggested a high rate of impaired HPA axis feedback in
this patient population, but studies were often confounded by comorbid depression diagnoses

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(Baxter et al., 1984; Beeber et al., 1984; De la Fuente and Mendlewicz, 1996; Kontaxakis et al.,
1987; Lahmeyer et al., 1988; Sternbach et al., 1983). Patients with BPD additionally appear to

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have a blunted cortisol response to both pharmacological and psychosocial stressors (Drews et al.,
2019). Studies on how HPA axis function and stress responses in this disorder relate to suicidality
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are, however, also mostly performed in subjects with co-occurring MDD or PTSD, therefore
clouding the picture.
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How Can HPA Axis Affect the Risk for Suicidal Behavior?
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HPA axis dysfunction, particular impaired GR feedback inhibition is associated with major
depression more closely when the episode is characterized by melancholic features, psychomotor
agitation or delusions (Belanoff et al., 2001; Brown et al., 1988; Caroff et al., 1983; Dinan and
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Scott, 2005; Duval et al., 2006; Juruena et al., 2018; Mickey et al., 2018; Nelson and Davis, 1997;
Pintor et al., 2013; Posener et al., 2000; Schatzberg et al., 2014; Staner et al., 1992). Moreover,
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HPA axis dysfunction is associated with greater risk of relapse (Appelhof et al., 2006; Hardeveld
et al., 2014; Vrshek-Schallhorn et al., 2013). Melancholic features, psychomotor agitation and
delusions are associated with greater risk of suicide and may mediate the part of the relationship
of HPA axis dysfunction and suicide.
Animal work has demonstrated that CRF directly acts upon the dorsal raphe nucleus to modulate
serotonergic tone in brain areas such as prefrontal cortex and nucleus accumbens (Forster et al.,
2008; Lowry et al., 2000; Lukkes et al., 2008; Quadros et al., 2014). Cortisol appears to reduce
expression of 5-HT1A receptors in hippocampus (Chalmers et al., 1993; Kuroda et al., 1994;
Martire et al., 1989; Meijer and de Kloet, 1994; Zhong and Ciaranello, 1995), which may cause
alterations in mood and memory. Those effects may be related to the 5-HT1A receptors mediating
trophic effects on dentate gyrus granule neurons, and thereby the antidepressant effect of SSRIs
(Boldrini et al., 2009, 2012; Dranovsky and Hen, 2006). We found that greater cortisol stress

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responses are correlated with higher 5-HT1A binding in hippocampus, precuneus, putamen, insula,
temporal cortex, lateral occipital cortex, middle frontal gyrus, amygdala, parahippocampal gyrus
and ventral orbital prefrontal cortex (Steinberg et al., 2019). Higher 5-HT1A receptor binding and

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lower serotonin transporter binding are associated with higher cortisol levels and with higher
lethality suicidal behavior and related phenomenology of suicide intent and ideation (Miller et al.,

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2013; Oquendo et al., 2016; Sullivan et al., 2015). Higher 5-HT1A binding correlates with lethality
of suicidal behavior and with suicidal ideation, supporting the hypothesis that autoreceptor
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upregulation, leading to less serotonin release, is a contributor to greater suicide risk (Oquendo et
al., 2016; Sullivan et al., 2015). What remains unclear is how higher 5-HT1A binding, particularly
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higher autoreceptor binding, and cortisol are related to each other. Glucocorticoid response
elements on the 5-HT1A gene promotor and serotonin moderation of HPA axis function can
mediate direct effects, but it is also possible that stress directly affects both systems in parallel.
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HPA Axis and Cognition

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Steroids affect cognition and may impact learning and decision-making (Forget et al., 2016;
Lupien and McEwen, 1997; Vogel et al., 2016; Yamakawa et al., 2016; Yu, 2016; Zoladz et al.,
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2016) (Belanoff Schatzberg 2001). Chronic, unpredictable stress has been shown to reduce
hippocampal volume in animals, which may affect learning and memory (Schoenfeld et al., 2017).
The HPA axis index, dexamethasone resistance, predicts the risk of death by suicide in mood
disorders with an odds ratio of 4.6 and that effect is independent of the serotonin system as assessed
by CSF 5-HIAA, which also predicts risk of suicide in major depression (citation) (Mann and
Currier, 2007; Mann et al., 1996). Steroid over-secretion and dexamethasone resistance as indices
of GR feedback impairment, are associated with more severe mood disorders and with unstable
responses to antidepressant treatment (Coryell and Schlesser, 2001; Gotlib et al., 2008; Melhem et
al., 2015; Ribeiro et al., 1993; Ventura-Juncá et al., 2014; Vinberg et al., 2014). ACTH, CRH, and
artificial glucocorticoids such as prednisolone, alter mood as well as cognition (Cameron et al.,
1985; Holsboer and Ising, 2008; Lidz et al., 1952; Starkman et al., 1981; Swinburn et al., 1988;
Westrin et al., 1999).

HPA Axis and Aggressive Impulsive Traits

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HPA hypersensitivity has also been linked to increased childhood and adolescent reactive
aggression, i.e. aggression that is triggered by perceived threats and serves to protect (van

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Bokhoven et al., 2005; Lopez-Duran et al., 2009). Adult subjects with more pronounced impulsive-
aggression traits demonstrate cortisol hypersecretion on the Trier Social Stress Task, indicating

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that these individuals are more vulnerable to social stressors (Melhem et al., 2015). However, this
has not always been replicated for depressed subjects, specifically (Wichmann et al., 2017).
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Moreover, aggressive behavior is linked to lower serotonergic tone based on lower CSF 5-
hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, in those convicted of
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homicide and arson (Roy et al., 1986). Decreased serotonin release is in turn modulated by CRF
levels in studies of aggression (Takahashi et al., 2010, 2011, 2015). Therefore, dysregulation of
the HPA axis, which may be linked to early adverse life events, is also associated with increased
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aggressive behavior and unstable mood, both risk factors for suicide, and both also associated with
early adversity. Such a set of relationships suggests that childhood adversity results in a
constellation of effects, HPA axis over-activity, mood disorders and aggressive impulsive traits.
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Another effect of childhood adversity may be on the serotonergic system. The HPA axis hyper-
responsiveness and impaired serotonin function may both in turn affect mood regulation, cognition
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and aggressive impulsive traits.

Increased aggressive traits and greater HPA axis response range may involve greater risk for
suicide in man but in the animal kingdom in general, these traits may have been preserved because
they confer a survival advantage: individuals with higher aggression favor a fight-or-flight
response, as opposed to a freeze-and-hide response. These individuals demonstrate a greater
modulation in their diurnal cortisol secretion, increased sympathetic drive under stress, and
increased activation of the hypothalamic-pituitary-gonadal axis. In contrast, low-aggression
individuals tend to show freeze-and-hide behavior, have greater tonic resting HPA axis activity,
and higher anxiety levels. Interestingly, however, they also manifest more mossy-fiber synapses
in the hippocampus, which may allow them to integrate and process higher complexity
information, conferring a survival advantage as they may be better at detecting cues of impending
danger (Korte et al., 2005).

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Impact of an Abnormal HPA Axis on Decision-Making

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Suicide is an abnormal response to stress (J. J. Mann and D. Currier, 2002), and both are related
to impaired decision making, which may bias those at risk for attempting suicide towards making

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an attempt instead of pursuing treatment. Increased vulnerability to stress, as shown by an over-
active HPA axis, predicts risk of future suicide (Mann et al., 2006a). HPA axis function in turn
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affects serotonergic input into some of the brain regions involved in decision making (Lanfumey
et al., 2008), and thereby may alter both mood regulation and decision-making. Suicide attempters
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display impaired reward base learning, which may be linked to impaired value comparison:
suicide attempters have difficulty distinguishing between options that similarly close in terms of
their reward value (Dombrovski et al., 2019). Delayed discounting, which is the decline in the
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perceived value of the reward in proportion to the time interval before it is available, and the impact
of the perceived value of a reward outcome depending on the certainty of the reward (Kahneman
and Tversky, 1979), may also play an important role in suicide. Greater delayed discounting is
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found in groups at higher risk of suicide attempts including more impulsive individuals, and in
substance use disorders, including alcoholism (Amlung et al., 2017; MacKillop, 2016; Moody et
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al., 2016). However, the relationship between suicidal behaviors and delay discounting is complex.
(Dombrovski et al., 2011) assessed delay discounting in an older population of healthy volunteers,
depressed non-suicidal subjects, depressed suicidal subjects subdivided into low-lethality suicide
attempters, and high-lethality suicide attempters. Low-lethality attempters had higher rates of
delay discounting compared to controls and to the non-suicidal depressed cohort, consistent with
being biased towards immediate rewards. However, high-lethality suicide attempters demonstrated
lower rates of delay discounting compared to low-lethality attempters and suicide ideators,
indicating that they were better able to delay gratification for a larger reward. This can be
reconciled through a two-step decision process model in which each decision step is influenced by
the degree of delay discounting applied by the subject.

Neuroanatomical and neurophysiological correlates of early life and chronic stress may also lead
to impaired decision-making (Cao et al., 2016; Dias-Ferreira et al., 2009; McKlveen et al., 2016).
Dias-Ferreira and colleagues subjected adult rats to chronic variable stress for a period of 21 days.

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The animals were then trained to press levers for a reward, which both stressed and control animals
did equally well, indicating that stress did not impair task learning. Subsequently, receiving the
reward was dissociated from pressing for one of the levers in order to extinguish the learned action-

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reward relationship. While control animals quickly abandoned pressing the reward-degraded lever
in favor of the rewarding lever, stressed animals continued to press the degraded lever at nearly

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the same rate. Since, the rats have no deficits in learning, the authors suggested that this represented
a bias towards non-adaptive habitual action as opposed to goal-directed action. Stressed animals
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were found to have atrophy of the mPFC associated with shortening and decreased branching of
the apical dendrites of pyramidal cells. Furthermore, there was an increase in dendrite length and
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branching of neurons in the dorsolateral striatum, a region involved in habitual behavior.

Therefore, stress biases behavior towards habitual, rather than adaptive, volitional, action. This is
echoed in data from human studies, where individuals exposed to chronic stress show insensitivity
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to contingency changes on learning tasks, favoring habitual actions that may be less adaptive
(Dombrovski et al., 2013; Jollant et al., 2005; Lenow et al., 2017; Soares et al., 2012; Yu, 2016).
Administration of corticosterone to rats prior to performing a modified Iowa Gambling Task,
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increases their rate of disadvantageous choices compared to controls (Koot et al., 2013). This,
again, is mirrored in human subjects, where administration of hydrocortisone increased risk-taking
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in male subjects on a specific risk-taking assessment task (Kluen et al., 2017).

Other Stress Response Systems and Suicidal Behavior

Abnormalities in the noradrenergic system have also been reported in a subset of patients with
unipolar depression (Schildkraut 1978, Schatzberg 1980, Samson 1994), and may play a role in
HPA axis abnormalities in this context (Roy 1986, Roy 1987). However, results from studies of
cerebrospinal fluid (CSF) levels of noradrenaline and its metabolites in the context suicidality
remain conflicting (Galfalvy et al., 2009; Jokinen et al., 2010; Lester, 1995; Lindqvist et al., 2011;
Nordström et al., 1994) (Roy 1989). Postmortem studies have shown that the brains from suicide
completers have fewer noradrenergic neurons in the rostral locus coeruleus, and also bear other
potential hallmarks of low noradrenergic tone, such as higher levels of adrenergic binding in
prefrontal cortex and higher alpha-2 adrenergic receptor binding in locus coeruleus itself (Arango
et al., 1993, 1996; Ordway et al., 1994a, 1994b). Therefore, the reports of a lack of association

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between CSF adrenergic metabolites and suicide (Jokinen et al., 2010; Lester, 1995; Lindqvist et
al., 2011; Nordström et al., 1994) are puzzling. A prospective survival study by Galfalvy et al.
(2009) found that lower CSF norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol

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(MHPG) levels, in depressed subjects predicted future suicide attempts, as well as higher attempt
lethality. They also found that CSF MHPG did not relate to recent suicide attempts, even as close

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as 3 months prior to the study – which may explain previous negative results found in retrospective
designs. Furthermore, low CSF MHPG has also been linked to greater subjective depression
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severity, hopelessness, and increased suicidal ideation (Galfalvy et al., 2009).These
neurobiological abnormalities in the noradrenergic stress-response circuit therefore appear to put
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a subset of patients at higher risk of committing a high lethality suicide attempt.

Summary
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Patients at risk for suicide display impaired mood regulation and are prone to severe episodes of
major depression, impaired decision-making, more pronounced aggressive traits, and stress
responses. These features of stress-sensitive depression and aggressive traits are also linked to
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early life-stress, which can also generate HPA axis hyper-reactivity in at-risk patients, making
them more vulnerable to stress as adults. HPA axis over-activity also predicts risk of suicide in
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major depression. Genetic and epigenetic effects underlie the HPA axis over-activity. HPA over-
activity in turn, affects aggressive traits, mood regulation, antidepressant response and decision-
making and learning, thereby impacting risk of suicide. Early adversity also impacts serotonergic
tone and brain development and results in proneness to mood disorders, more reactive aggressive
behavior, social distortions and a pattern of decision-making favoring suicidal behavior. The HPA
axis and serotonin systems have a bidirectional relationship such that their functionality is not
entirely independent. Future studies should consider the HPA axis as not only a pathogenic
pathway and predictor biomarker, but also a treatment and suicide prevention target.

Declaration of Interest
Dr. Steinberg declares no conflict of interest.
Dr. Mann receives royalties for commercial use of the C-SSRS from the Research Foundation
for Mental Hygiene.

Acknowledgements and Disclosures:

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This work was funded by NIH grant # 5P50MH090964.
Dr. Steinberg declares no conflict of interest.

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Dr. Mann receives royalties for commercial use of the C-SSRS from the Research Foundation for
Mental Hygiene.

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 Hypothalamus Expresses GRs
PVN
-
Higher tissue levels in suicide
decedents
Decreased receptor expression CRF/CRH
in prefrontal cortex
Stimulated by inflammatory
cytokines
+
Anterior Pituitary
-
Stimulated by
inflammatory cytokines ACTH

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+
Heavier suicide decedents Adrenal Cortex

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Increased secretion =
risk factor for suicide Cortisol

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High Low
affinity affinity
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Lower expression levels

MR GR with childhood adversity
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FKBP5 Upregulated in suicide

decedents
Increased DNA Nucleus
methylation of GR gene Gene
with childhood adversity transcription
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Figure 1: Overview of hypothalamic-pituitary-adrenal (HPA) axis anatomy and function.

Neurons of the paraventricular nucleus (PVN) of the hypothalamus secrete corticotropin
releasing factor (CRF), also referred to corticotropin releasing hormone (CRH), via direct
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projection to the anterior pituitary gland. This stimulates the release of

adrenocorticotropic hormone (ACTH) into the blood stream, which stimulates production
of cortisol by the adrenal cortex. Cortisol binds with high affinity to mineralocorticoid
receptors (MR) and with low affinity to glucocorticoid receptors (GR) expressed on cells
throughout the body. GRs are translocated from the cell surface to the nucleus via the
chaperone protein FKBP5 and modulate gene transcription.