Abnormal Stress Responsiveness and Suicidal Behavior: A Risk Phenotype

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:

1

Columbia University, Department of Psychiatry

2

New York State Psychiatric Institute

Corresponding author: J.

Steinberg,

1051

Riverside

Dr.

[email protected] ; Phone: 646-774-7501

York,

NY

10032;

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Abstract

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Louisa

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Louisa J. Steinberg1, J. John Mann1,2

Suicidal behavior is a major cause of morbidity and mortality in psychiatric illness. However, only

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a subset of patients with psychiatric illnesses, such as major depressive disorder (MDD), commit suicide. This raises the question of how those who manifest suicidal behavior differ from those

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who do not. In the context of a stress-diathesis model of suicidal behavior, the reaction to stress 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

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risk for suicide in major depression. Suicide attempters are distinguished from non-attempters by 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 HPA axis dysfunction, which in turn can be traced back to genetic predisposition, and early life

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stress-related epigenetic mechanisms.

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.

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

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Mann, 2013; Mann et al., 1999; Oquendo et al., 2014). Some traits that form the diathesis for suicidal behavior have been identified from differences between suicide attempters and psychiatric

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controls. These traits include: greater mood dysregulation and greater subjective distress, more pronounced reactive aggressive traits, impaired problem solving and learning, and distortion of

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perceived social cues (van Heeringen and Mann, 2014). As a consequence, when faced with the decision of whether to seek symptom relief through treatment or through suicide, this population

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is more likely to choose suicide.

The basis for these trait difference remains to be fully described. Risk suicidal behavior is

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associated with greater depression severity (Hawton et al., 2013) and declines with subjective 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 pituitary adrenal (HPA) axis (Figure 1). Abnormal HPA axis function is an important predictor of

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suicide risk in major depression (van Heeringen and Mann, 2014; Mann et al., 2006a; Melhem et 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

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levels (O’Connor et al., 2016). However, this may differ in those who complete suicide, as opposed 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

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corticotropin releasing factor (CRF), indicating over-secretion of CRF, and lower expression of CRF receptors in prefrontal cortex (Arató et al., 1989; Nemeroff et al., 1988; Szigethy et al., 1994).

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Studies also suggest that patients with mood disorders who have impaired cortisol suppression on the dexamethasone suppression test, and therefore release more cortisol in response to CRF, are at

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higher risk for subsequent suicide (Coryell and Schlesser, 2001; van Heeringen, 2003; Kunugi et al., 2006; Mann et al., 2006a; Pfennig et al., 2005; Westrin, 2000; Yerevanian et al., 2004).

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Excessive 24-hour urinary excretion of corticosteroids has been observed in depressed patients at 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

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major depression, especially when characterized by clinical features linked to the risk of suicide 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 antidepressant medications. However, antidepressant trials of the glucocorticoid receptor (GR)

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antagonist mifepristone in psychotic depression have yielded mixed results (Block et al., 2017, 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

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within the HPA system specifically involving the GR. GRs have low affinity for glucocorticoids 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

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feedback at lower, resting levels of cortisol (De Kloet et al., 1998; de Kloet et al., 2016). Chronic, mild stress has been linked to increased trafficking of GRs to the nucleus via the chaperone protein

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FKBP5 (Guidotti et al., 2013), and this chaperone protein appears to be upregulated in postmortem brain tissue of suicide decedents (Yin et al., 2016). Furthermore, certain FKBP5 gene variants may

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confer increased risk for depression and PTSD in those with early life trauma (Wang et al., 2018), as well as increased risk for suicide (Breen et al., 2016; Fudalej et al., 2015; Hernández-Díaz et

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al., 2019; Roy et al., 2010, 2012). Suicide decedents with reported childhood abuse, a form of 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-

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psychiatric controls postmortem (McGowan et al., 2009). This indicates an impairment of the 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; Miller et al., 2009). Inflammatory cytokines stimulate the release of CRF and ACTH in the brain,

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and cortisol peripherally (Miller et al., 2009; Silverman and Sternberg, 2012). Furthermore, 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

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in rats (Fish et al., 2004; Liu et al., 1997; Zhang et al., 2013). This suggests that a hyperactive HPA axis may be primed by early life adversity and potentially mediates a linkage between early trauma,

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and subsequent mood disorders and suicide.

Early life adverse experiences may also interact with genes to prime the stress-response circuits

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via gene-environment interactions. These people carry a lifelong predisposition for a hyperactive HPA axis response to an environmental stressor. Single nucleotide polymorphisms in the

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corticotropin releasing hormone receptor-1 gene (CRHR1) and serotonin transporter gene (5HTTLPR) have been linked to increased risk for suicide when paired with either early stressful

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life events in women, or stressful life events at any time in men (Ben-Efraim et al., 2011; Caspi et 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

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glucocorticoid levels (Yin et al., 2016). Furthermore, response to treatment with a corticotropinreleasing 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 childhood experiences can prime the HPA axis for excessive responses into adulthood and impact

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treatment responsiveness in psychiatric disorders. 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

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suppression of glucocorticoid secretion in response to dexamethasone (Coryell and Tsuang, 1992; Sharma et al., 1988; Yeragani, 1990). HPA axis gene polymorphisms, specifically corticotropinreleasing hormone binding protein (CRHBP), the BclI polymorphism in glucocorticoid receptor

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gene (NC3R1), and corticotropin-releasing hormone receptor type 1 (CRHR1) genotype, may modulate risk for suicide in schizophrenia as well. CRHBP heterozygotes were found to be at

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increased risk for suicide, while NC3R1 genotype 11 was protective against suicide. CRHBP and CRHR1 showed a genotype interaction such that CRHBP genotype 11 and CRHR1 genotype 22

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in combination were associated with lower suicide severity (De Luca et al., 2010). Furthermore, it appears that this HPA axis hyperactivity is attenuated with antipsychotic treatment, possibly

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through inhibition of the CRF promoter, and that this is potentially related to improvement in 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

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antipsychotics in reducing ACTH and cortisol secretion (Cohrs et al., 2006; Markianos et al., 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.

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).

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

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this patient population, but studies were often confounded by comorbid depression diagnoses (Baxter et al., 1984; Beeber et al., 1984; De la Fuente and Mendlewicz, 1996; Kontaxakis et al.,

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1987; Lahmeyer et al., 1988; Sternbach et al., 1983). Patients with BPD additionally appear to have a blunted cortisol response to both pharmacological and psychosocial stressors (Drews et al.,

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2019). Studies on how HPA axis function and stress responses in this disorder relate to suicidality are, however, also mostly performed in subjects with co-occurring MDD or PTSD, therefore

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clouding the picture.

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How Can HPA Axis Affect the Risk for Suicidal Behavior? 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 Scott, 2005; Duval et al., 2006; Juruena et al., 2018; Mickey et al., 2018; Nelson and Davis, 1997;

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Pintor et al., 2013; Posener et al., 2000; Schatzberg et al., 2014; Staner et al., 1992). Moreover, 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

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(Boldrini et al., 2009, 2012; Dranovsky and Hen, 2006). We found that greater cortisol stress responses are correlated with higher 5-HT1A binding in hippocampus, precuneus, putamen, insula, temporal cortex, lateral occipital cortex, middle frontal gyrus, amygdala, parahippocampal gyrus

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and ventral orbital prefrontal cortex (Steinberg et al., 2019). Higher 5-HT1A receptor binding and lower serotonin transporter binding are associated with higher cortisol levels and with higher

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lethality suicidal behavior and related phenomenology of suicide intent and ideation (Miller et al., 2013; Oquendo et al., 2016; Sullivan et al., 2015). Higher 5-HT1A binding correlates with lethality

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of suicidal behavior and with suicidal ideation, supporting the hypothesis that autoreceptor upregulation, leading to less serotonin release, is a contributor to greater suicide risk (Oquendo et

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al., 2016; Sullivan et al., 2015). What remains unclear is how higher 5-HT1A binding, particularly 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

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mediate direct effects, but it is also possible that stress directly affects both systems in parallel.

HPA Axis and Cognition

Steroids affect cognition and may impact learning and decision-making (Forget et al., 2016;

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Lupien and McEwen, 1997; Vogel et al., 2016; Yamakawa et al., 2016; Yu, 2016; Zoladz et al., 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).

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HPA Axis and Aggressive Impulsive Traits

HPA hypersensitivity has also been linked to increased childhood and adolescent reactive

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aggression, i.e. aggression that is triggered by perceived threats and serves to protect (van Bokhoven et al., 2005; Lopez-Duran et al., 2009). Adult subjects with more pronounced impulsive-

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aggression traits demonstrate cortisol hypersecretion on the Trier Social Stress Task, indicating that these individuals are more vulnerable to social stressors (Melhem et al., 2015). However, this

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has not always been replicated for depressed subjects, specifically (Wichmann et al., 2017). Moreover, aggressive behavior is linked to lower serotonergic tone based on lower CSF 5-

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hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, in those convicted of 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

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the HPA axis, which may be linked to early adverse life events, is also associated with increased 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. Another effect of childhood adversity may be on the serotonergic system. The HPA axis hyper-

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responsiveness and impaired serotonin function may both in turn affect mood regulation, cognition 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

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danger (Korte et al., 2005).

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Impact of an Abnormal HPA Axis on Decision-Making

Suicide is an abnormal response to stress (J. J. Mann and D. Currier, 2002), and both are related

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to impaired decision making, which may bias those at risk for attempting suicide towards making an attempt instead of pursuing treatment. Increased vulnerability to stress, as shown by an over-

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active HPA axis, predicts risk of future suicide (Mann et al., 2006a). HPA axis function in turn affects serotonergic input into some of the brain regions involved in decision making (Lanfumey

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et al., 2008), and thereby may alter both mood regulation and decision-making. Suicide attempters 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

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their reward value (Dombrovski et al., 2019). Delayed discounting, which is the decline in the 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 found in groups at higher risk of suicide attempts including more impulsive individuals, and in

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substance use disorders, including alcoholism (Amlung et al., 2017; MacKillop, 2016; Moody et 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).

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Dias-Ferreira and colleagues subjected adult rats to chronic variable stress for a period of 21 days. 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

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reward was dissociated from pressing for one of the levers in order to extinguish the learned actionreward relationship. While control animals quickly abandoned pressing the reward-degraded lever

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in favor of the rewarding lever, stressed animals continued to press the degraded lever at nearly the same rate. Since, the rats have no deficits in learning, the authors suggested that this represented

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a bias towards non-adaptive habitual action as opposed to goal-directed action. Stressed animals were found to have atrophy of the mPFC associated with shortening and decreased branching of

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the apical dendrites of pyramidal cells. Furthermore, there was an increase in dendrite length and 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

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echoed in data from human studies, where individuals exposed to chronic stress show insensitivity 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, increases their rate of disadvantageous choices compared to controls (Koot et al., 2013). This,

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again, is mirrored in human subjects, where administration of hydrocortisone increased risk-taking 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

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et al., 1993, 1996; Ordway et al., 1994a, 1994b). Therefore, the reports of a lack of association 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.

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(2009) found that lower CSF norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG) levels, in depressed subjects predicted future suicide attempts, as well as higher attempt

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lethality. They also found that CSF MHPG did not relate to recent suicide attempts, even as close as 3 months prior to the study – which may explain previous negative results found in retrospective

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designs. Furthermore, low CSF MHPG has also been linked to greater subjective depression severity, hopelessness, and increased suicidal ideation (Galfalvy et al., 2009).These

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neurobiological abnormalities in the noradrenergic stress-response circuit therefore appear to put

Summary

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a subset of patients at higher risk of committing a high lethality suicide attempt.

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 early life-stress, which can also generate HPA axis hyper-reactivity in at-risk patients, making

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them more vulnerable to stress as adults. HPA axis over-activity also predicts risk of suicide in major depression. Genetic and epigenetic effects underlie the HPA axis over-activity. HPA overactivity in turn, affects aggressive traits, mood regulation, antidepressant response and decisionmaking 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.

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Acknowledgements and Disclosures:

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

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

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Mental Hygiene.

References Adinoff, B., Krebaum, S.R., Chandler, P.A., Ye, W., Brown, M.B., and Williams, M.J. (2005). Dissection of hypothalamic-pituitary-adrenal axis pathology in 1-month-abstinent alcoholdependent men, part 1: adrenocortical and pituitary glucocorticoid responsiveness. Alcohol. Clin. Exp. Res. 29, 517–527. Amlung, M., Vedelago, L., Acker, J., Balodis, I., and MacKillop, J. (2017). Steep delay discounting and addictive behavior: a meta-analysis of continuous associations. Addict. Abingdon Engl. 112, 51–62.

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of

Appelhof, B.C., Huyser, J., Verweij, M., Brouwer, J.P., van Dyck, R., Fliers, E., Hoogendijk, W.J.G., Tijssen, J.G.P., Wiersinga, W.M., and Schene, A.H. (2006). Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression). Biol. Psychiatry 59, 696–701.

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Arango, V., Ernsberger, P., Sved, A.F., and Mann, J.J. (1993). Quantitative autoradiography of alpha 1- and alpha 2-adrenergic receptors in the cerebral cortex of controls and suicide victims. Brain Res. 630, 271–282.

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Arango, V., Underwood, M.D., and Mann, J.J. (1996). Fewer pigmented locus coeruleus neurons in suicide victims: preliminary results. Biol. Psychiatry 39, 112–120.

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Arató, M., Bánki, C.M., Bissette, G., and Nemeroff, C.B. (1989). Elevated CSF CRF in suicide victims. Biol. Psychiatry 25, 355–359.

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Arsenault-Lapierre, G., Kim, C., and Turecki, G. (2004). Psychiatric diagnoses in 3275 suicides: a meta-analysis. BMC Psychiatry 4, 37. Barraclough, B., Bunch, J., Nelson, B., and Sainsbury, P. (1974). A hundred cases of suicide: clinical aspects. Br. J. Psychiatry J. Ment. Sci. 125, 355–373.

Jo

Basta-Kaim, A., Budziszewska, B., Jaworska-Feil, L., Tetich, M., Kubera, M., Leśkiewicz, M., Otczyk, M., and Lasoń, W. (2006). Antipsychotic drugs inhibit the human corticotropinreleasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 31, 853–865. Batty, G.D., Bell, S., Stamatakis, E., and Kivimäki, M. (2016). Association of Systemic Inflammation With Risk of Completed Suicide in the General Population. JAMA Psychiatry 73, 993–995. Batty, G.D., Jung, K.J., Lee, S., Back, J.H., and Jee, S.H. (2018). Systemic inflammation and suicide risk: cohort study of 419 527 Korean men and women. J. Epidemiol. Community Health.

Bauer, M.E., and Teixeira, A.L. (2018). Inflammation in psychiatric disorders: what comes first? Ann. N. Y. Acad. Sci. Baxter, L., Edell, W., Gerner, R., Fairbanks, L., and Gwirtsman, H. (1984). Dexamethasone suppression test and Axis I diagnoses of inpatients with DSM-III borderline personality disorder. J. Clin. Psychiatry 45, 150–153. Beeber, A.R., Kline, M.D., Pies, R.W., and Manring, J.M. (1984). Dexamethasone suppression test in hospitalized depressed patients with borderline personality disorder. J. Nerv. Ment. Dis. 172, 301–303.

of

Belanoff, J.K., Kalehzan, M., Sund, B., Fleming Ficek, S.K., and Schatzberg, A.F. (2001). Cortisol activity and cognitive changes in psychotic major depression. Am. J. Psychiatry 158, 1612– 1616.

-p

ro

Belay, H., Burton, C.L., Lovic, V., Meaney, M.J., Sokolowski, M., and Fleming, A.S. (2011). Early adversity and serotonin transporter genotype interact with hippocampal glucocorticoid receptor mRNA expression, corticosterone, and behavior in adult male rats. Behav. Neurosci. 125, 150–160.

re

Ben-Efraim, Y.J., Wasserman, D., Wasserman, J., and Sokolowski, M. (2011). Geneenvironment interactions between CRHR1 variants and physical assault in suicide attempts. Genes Brain Behav. 10, 663–672.

lP

Bertolote, J.M., and Fleischmann, A. (2002). Suicide and psychiatric diagnosis: a worldwide perspective. World Psychiatry Off. J. World Psychiatr. Assoc. WPA 1, 181–185. Blaine, S.K., and Sinha, R. (2017). Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders. Neuropharmacology 122, 136–147.

ur na

Block, T., Petrides, G., Kushner, H., Kalin, N., Belanoff, J., and Schatzberg, A. (2017). Mifepristone Plasma Level and Glucocorticoid Receptor Antagonism Associated With Response in Patients With Psychotic Depression. J. Clin. Psychopharmacol. 37, 505–511.

Jo

Block, T.S., Kushner, H., Kalin, N., Nelson, C., Belanoff, J., and Schatzberg, A. (2018). Combined Analysis of Mifepristone for Psychotic Depression: Plasma Levels Associated With Clinical Response. Biol. Psychiatry. van Bokhoven, I., Van Goozen, S.H.M., van Engeland, H., Schaal, B., Arseneault, L., Séguin, J.R., Nagin, D.S., Vitaro, F., and Tremblay, R.E. (2005). Salivary cortisol and aggression in a population-based longitudinal study of adolescent males. J. Neural Transm. 112, 1083–1096. Boldrini, M., Underwood, M.D., Hen, R., Rosoklija, G.B., Dwork, A.J., John Mann, J., and Arango, V. (2009). Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 34, 2376–2389.

Boldrini, M., Hen, R., Underwood, M.D., Rosoklija, G.B., Dwork, A.J., Mann, J.J., and Arango, V. (2012). Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol. Psychiatry 72, 562–571. Bradley, A.J., and Dinan, T.G. (2010). A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortality. J. Psychopharmacol. Oxf. Engl. 24, 91–118. Breen, M.E., Gaynor, S.C., Monson, E.T., de Klerk, K., Parsons, M.G., Braun, T.A., DeLuca, A.P., Zandi, P.P., Potash, J.B., and Willour, V.L. (2016). Targeted Sequencing of FKBP5 in Suicide Attempters with Bipolar Disorder. PloS One 11, e0169158.

ro

of

Brent, D.A., Perper, J.A., Moritz, G., Baugher, M., Schweers, J., and Roth, C. (1993). Firearms and adolescent suicide. A community case-control study. Am. J. Dis. Child. 1960 147, 1066– 1071.

-p

Brown, R.P., Stoll, P.M., Stokes, P.E., Frances, A., Sweeney, J., Kocsis, J.H., and Mann, J.J. (1988). Adrenocortical hyperactivity in depression: effects of agitation, delusions, melancholia, and other illness variables. Psychiatry Res. 23, 167–178.

re

Brundin, L., Bryleva, E.Y., and Thirtamara Rajamani, K. (2017). Role of Inflammation in Suicide: From Mechanisms to Treatment. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 42, 271–283.

lP

Bunney, W.E., Fawcett, J.A., Davis, J.M., and Gifford, S. (1969). Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Arch. Gen. Psychiatry 21, 138–150. Buydens-Branchey, L., and Branchey, M.H. (1992). Cortisol in alcoholics with a disordered aggression control. Psychoneuroendocrinology 17, 45–54.

ur na

Cáceda, R., Griffin, W.S.T., and Delgado, P.L. (2018). A probe in the connection between inflammation, cognition and suicide. J. Psychopharmacol. Oxf. Engl. 32, 482–488. Cameron, O.G., Addy, R.O., and Malitz, D. (1985). Effects of ACTH and prednisone on mood: incidence and time of onset. Int. J. Psychiatry Med. 15, 213–223.

Jo

Cao, B., Wang, J., Zhang, X., Yang, X., Poon, D.C.-H., Jelfs, B., Chan, R.H.M., Wu, J.C.-Y., and Li, Y. (2016). Impairment of decision making and disruption of synchrony between basolateral amygdala and anterior cingulate cortex in the maternally separated rat. Neurobiol. Learn. Mem. 136, 74–85. Caroff, S., Winokur, A., Rieger, W., Schweizer, E., and Amsterdam, J. (1983). Response to dexamethasone in psychotic depression. Psychiatry Res. 8, 59–64. Caspi, A., Sugden, K., Moffitt, T.E., Taylor, A., Craig, I.W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389.

Cattane, N., Rossi, R., Lanfredi, M., and Cattaneo, A. (2017). Borderline personality disorder and childhood trauma: exploring the affected biological systems and mechanisms. BMC Psychiatry 17, 221. Chalmers, D.T., Kwak, S.P., Mansour, A., Akil, H., and Watson, S.J. (1993). Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression. J. Neurosci. Off. J. Soc. Neurosci. 13, 914–923. Chen, C., and Grigoriadis, D.E. (2005). NBI 30775 (R121919), an orally active antagonist of the corticotropin-releasing factor (CRF) type-1 receptor for the treatment of anxiety and depression. Drug Dev. Res. 65, 216–226.

ro

of

Cohrs, S., Röher, C., Jordan, W., Meier, A., Huether, G., Wuttke, W., Rüther, E., and Rodenbeck, A. (2006). The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects. Psychopharmacology (Berl.) 185, 11–18.

-p

Coryell, W., and Schlesser, M. (2001). The dexamethasone suppression test and suicide prediction. Am. J. Psychiatry 158, 748–753. Coryell, W., and Tsuang, D. (1992). Hypothalamic-pituitary-adrenal axis hyperactivity and psychosis: recovery during an 8-year follow-up. Am. J. Psychiatry 149, 1033–1039.

lP

re

Costa, A., Bono, G., Martignoni, E., Merlo, P., Sances, G., and Nappi, G. (1996). An assessment of hypothalamo-pituitary-adrenal axis functioning in non-depressed, early abstinent alcoholics. Psychoneuroendocrinology 21, 263–275. Curtin, S.C., Warner, M., and Hedegaard, H. (2016). Increase in Suicide in the United States, 1999-2014. NCHS Data Brief 1–8.

ur na

Dai, X., Thavundayil, J., and Gianoulakis, C. (2002). Response of the hypothalamic-pituitaryadrenal axis to stress in the absence and presence of ethanol in subjects at high and low risk of alcoholism. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 27, 442– 452. De Kloet, E.R., Vreugdenhil, E., Oitzl, M.S., and Joëls, M. (1998). Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301.

Jo

De la Fuente, J.M., and Mendlewicz, J. (1996). TRH stimulation and dexamethasone suppression in borderline personality disorder. Biol. Psychiatry 40, 412–418. De Luca, V., Tharmalingam, S., Zai, C., Potapova, N., Strauss, J., Vincent, J., and Kennedy, J.L. (2010). Association of HPA axis genes with suicidal behaviour in schizophrenia. J. Psychopharmacol. Oxf. Engl. 24, 677–682. Denson, T.F., Mehta, P.H., and Ho Tan, D. (2013). Endogenous testosterone and cortisol jointly influence reactive aggression in women. Psychoneuroendocrinology 38, 416–424.

Dias-Ferreira, E., Sousa, J.C., Melo, I., Morgado, P., Mesquita, A.R., Cerqueira, J.J., Costa, R.M., and Sousa, N. (2009). Chronic stress causes frontostriatal reorganization and affects decision-making. Science 325, 621–625. Dinan, T.G., and Scott, L.V. (2005). Anatomy of melancholia: focus on hypothalamic-pituitaryadrenal axis overactivity and the role of vasopressin. J. Anat. 207, 259–264. Dombrovski, A.Y., Szanto, K., Siegle, G.J., Wallace, M.L., Forman, S.D., Sahakian, B., Reynolds, C.F., and Clark, L. (2011). Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age. Biol. Psychiatry 70, 138–144.

of

Dombrovski, A.Y., Szanto, K., Clark, L., Reynolds, C.F., and Siegle, G.J. (2013). Reward Signals, Attempted Suicide, and Impulsivity in Late-Life Depression. JAMA Psychiatry 70, 1020.

ro

Dombrovski, A.Y., Hallquist, M.N., Brown, V.M., Wilson, J., and Szanto, K. (2019). Value-Based Choice, Contingency Learning, and Suicidal Behavior in Mid- and Late-Life Depression. Biol. Psychiatry 85, 506–516.

-p

Dorpat, T.L., and Ripley, H.S. (1960). A study of suicide in the Seattle area. Compr. Psychiatry 1, 349–359.

re

Dranovsky, A., and Hen, R. (2006). Hippocampal neurogenesis: regulation by stress and antidepressants. Biol. Psychiatry 59, 1136–1143.

lP

Dratcu, L., and Calil, H.M. (1989). The dexamethasone suppression test: its relationship to diagnoses, severity of depression and response to treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 13, 99–117.

ur na

Drews, E., Fertuck, E.A., Koenig, J., Kaess, M., and Arntz, A. (2019). Hypothalamic-pituitaryadrenal axis functioning in borderline personality disorder: A meta-analysis. Neurosci. Biobehav. Rev. 96, 316–334. Dunlop, B.W., Binder, E.B., Iosifescu, D., Mathew, S.J., Neylan, T.C., Pape, J.C., Carrillo-Roa, T., Green, C., Kinkead, B., Grigoriadis, D., et al. (2017). Corticotropin-Releasing Factor Receptor 1 Antagonism Is Ineffective for Women With Posttraumatic Stress Disorder. Biol. Psychiatry 82, 866–874.

Jo

Duval, F., Mokrani, M.-C., Monreal-Ortiz, J.A., Fattah, S., Champeval, C., Schulz, P., and Macher, J.-P. (2006). Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: dopaminergic, noradrenergic and thyroid correlates. Psychoneuroendocrinology 31, 876–888. Fish, E.W., Shahrokh, D., Bagot, R., Caldji, C., Bredy, T., Szyf, M., and Meaney, M.J. (2004). Epigenetic programming of stress responses through variations in maternal care. Ann. N. Y. Acad. Sci. 1036, 167–180.

Forget, H., Lacroix, A., Bourdeau, I., and Cohen, H. (2016). Long-term cognitive effects of glucocorticoid excess in Cushing’s syndrome. Psychoneuroendocrinology 65, 26–33. Forster, G.L., Pringle, R.B., Mouw, N.J., Vuong, S.M., Watt, M.J., Burke, A.R., Lowry, C.A., Summers, C.H., and Renner, K.J. (2008). Corticotropin-releasing factor in the dorsal raphe nucleus increases medial prefrontal cortical serotonin via type 2 receptors and median raphe nucleus activity. Eur. J. Neurosci. 28, 299–310.

of

Fudalej, S., Kopera, M., Wołyńczyk-Gmaj, D., Fudalej, M., Krajewski, P., Wasilewska, K., Szymański, K., Chojnicka, I., Podgórska, A., Wojnar, M., et al. (2015). Association between FKBP5 Functional Polymorphisms and Completed Suicide. Neuropsychobiology 72, 126– 131.

ro

Galfalvy, H., Currier, D., Oquendo, M.A., Sullivan, G., Huang, Y.-Y., and John Mann, J. (2009). Lower CSF MHPG predicts short-term risk for suicide attempt. Int. J. Neuropsychopharmacol. 12, 1327.

-p

Gotlib, I.H., Joormann, J., Minor, K.L., and Hallmayer, J. (2008). HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol. Psychiatry 63, 847–851.

re

Greenberg, P.E., Fournier, A.-A., Sisitsky, T., Pike, C.T., and Kessler, R.C. (2015). The economic burden of adults with major depressive disorder in the United States (2005 and 2010). J. Clin. Psychiatry 76, 155–162.

ur na

lP

Guidotti, G., Calabrese, F., Anacker, C., Racagni, G., Pariante, C.M., and Riva, M.A. (2013). Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 38, 616–627. Hardeveld, F., Spijker, J., Vreeburg, S.A., Graaf, R.D., Hendriks, S.M., Licht, C.M.M., Nolen, W.A., Penninx, B.W.J.H., and Beekman, A.T.F. (2014). Increased cortisol awakening response was associated with time to recurrence of major depressive disorder. Psychoneuroendocrinology 50, 62–71.

Jo

Haroon, E., Raison, C.L., and Miller, A.H. (2012). Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 37, 137–162. Hawton, K., Casañas I Comabella, C., Haw, C., and Saunders, K. (2013). Risk factors for suicide in individuals with depression: a systematic review. J. Affect. Disord. 147, 17–28. van Heeringen, K. (2003). The neurobiology of suicide and suicidality. Can. J. Psychiatry Rev. Can. Psychiatr. 48, 292–300. van Heeringen, K., and Mann, J.J. (2014). The neurobiology of suicide. Lancet Psychiatry 1, 63–72.

Hernández-Díaz, Y., González-Castro, T.B., Tovilla-Zárate, C.A., Juárez-Rojop, I.E., LópezNarváez, M.L., Pérez-Hernández, N., Rodríguez-Pérez, J.M., and Genis-Mendoza, A.D. (2019). Association between FKBP5 polymorphisms and depressive disorders or suicidal behavior: A systematic review and meta-analysis study. Psychiatry Res. 271, 658–668. Holsboer, F., and Ising, M. (2008). Central CRH system in depression and anxiety--evidence from clinical studies with CRH1 receptor antagonists. Eur. J. Pharmacol. 583, 350–357. Isometsä, E., Henriksson, M., Marttunen, M., Heikkinen, M., Aro, H., Kuoppasalmi, K., and Lönnqvist, J. (1995). Mental disorders in young and middle aged men who commit suicide. BMJ 310, 1366–1367.

ro

of

J. J. Mann, and D. Currier (2002). Relationships of Genes and Early-Life Experience to the Neurobiology of Suicidal Behavior. In International Handbook of Suicide Prevention: Research, Policy and Practice., (John Wiley & Sons), p.

-p

Jokinen, J., Ouda, J., and Nordström, P. (2010). Noradrenergic function and HPA axis dysregulation in suicidal behaviour. Psychoneuroendocrinology 35, 1536–1542.

re

Jollant, F., Bellivier, F., Leboyer, M., Astruc, B., Torres, S., Verdier, R., Castelnau, D., Malafosse, A., and Courtet, P. (2005). Impaired decision making in suicide attempters. Am. J. Psychiatry 162, 304–310.

lP

Juruena, M.F., Bocharova, M., Agustini, B., and Young, A.H. (2018). Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review. J. Affect. Disord. 233, 45–67. Kahneman, D., and Tversky, A. (1979). Prospect Theory: An Analysis of Decision under Risk. Econometrica 47, 263.

ur na

Kalinichev, M., Easterling, K.W., Plotsky, P.M., and Holtzman, S.G. (2002). Long-lasting changes in stress-induced corticosterone response and anxiety-like behaviors as a consequence of neonatal maternal separation in Long–Evans rats. Pharmacol. Biochem. Behav. 73, 131–140.

Jo

Keilp, J.G., Ellis, S.P., Gorlyn, M., Burke, A.K., Oquendo, M.A., Mann, J.J., and Grunebaum, M.F. (2017). Suicidal ideation declines with improvement in the subjective symptoms of major depression. J. Affect. Disord. 227, 65–70. King, A., Munisamy, G., de Wit, H., and Lin, S. (2006). Attenuated cortisol response to alcohol in heavy social drinkers. Int. J. Psychophysiol. Off. J. Int. Organ. Psychophysiol. 59, 203–209. de Kloet, E.R., Otte, C., Kumsta, R., Kok, L., Hillegers, M.H.J., Hasselmann, H., Kliegel, D., and Joëls, M. (2016). Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor. J. Neuroendocrinol. 28.

Kluen, L.M., Agorastos, A., Wiedemann, K., and Schwabe, L. (2017). Cortisol boosts risky decision-making behavior in men but not in women. Psychoneuroendocrinology 84, 181– 189. Kontaxakis, V., Markianos, M., Vaslamatzis, G., Markidis, M., Kanellos, P., and Stefanis, C. (1987). Multiple neuroendocrinological responses in borderline personality disorder patients. Acta Psychiatr. Scand. 76, 593–597. Koot, S., Baars, A., Hesseling, P., van den Bos, R., and Joëls, M. (2013). Time-dependent effects of corticosterone on reward-based decision-making in a rodent model of the Iowa Gambling Task. Neuropharmacology 70, 306–315.

ro

of

Korte, S.M., Koolhaas, J.M., Wingfield, J.C., and McEwen, B.S. (2005). The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci. Biobehav. Rev. 29, 3–38.

-p

Kunugi, H., Ida, I., Owashi, T., Kimura, M., Inoue, Y., Nakagawa, S., Yabana, T., Urushibara, T., Kanai, R., Aihara, M., et al. (2006). Assessment of the dexamethasone/CRH test as a statedependent marker for hypothalamic-pituitary-adrenal (HPA) axis abnormalities in major depressive episode: a Multicenter Study. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 31, 212–220.

lP

re

Kuroda, Y., Watanabe, Y., Albeck, D.S., Hastings, N.B., and McEwen, B.S. (1994). Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain. Brain Res. 648, 157– 161.

ur na

Ladd, C.O., Huot, R.L., Thrivikraman, K.., Nemeroff, C.B., and Plotsky, P.M. (2004). Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mrna and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol. Psychiatry 55, 367–375. Ladd, C.O., Thrivikraman, K.V., Huot, R.L., and Plotsky, P.M. (2005). Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling-maternal separation as neonates. Psychoneuroendocrinology 30, 520–533.

Jo

Lahmeyer, H.W., Val, E., Gaviria, F.M., Prasad, R.B., Pandey, G.N., Rodgers, P., Weiler, M.A., and Altman, E.G. (1988). EEG sleep, lithium transport, dexamethasone suppression, and monoamine oxidase activity in borderline personality disorder. Psychiatry Res. 25, 19–30. Lammers, C.H., Garcia-Borreguero, D., Schmider, J., Gotthardt, U., Dettling, M., Holsboer, F., and Heuser, I.J. (1995). Combined dexamethasone/corticotropin-releasing hormone test in patients with schizophrenia and in normal controls: II. Biol. Psychiatry 38, 803–807. Lanfumey, L., Mongeau, R., Cohen-Salmon, C., and Hamon, M. (2008). Corticosteroidserotonin interactions in the neurobiological mechanisms of stress-related disorders. Neurosci. Biobehav. Rev. 32, 1174–1184.

Lenow, J.K., Constantino, S.M., Daw, N.D., and Phelps, E.A. (2017). Chronic and Acute Stress Promote Overexploitation in Serial Decision Making. J. Neurosci. Off. J. Soc. Neurosci. 37, 5681–5689. Lester, D. (1995). The concentration of neurotransmitter metabolites in the cerebrospinal fluid of suicidal individuals: a meta-analysis. Pharmacopsychiatry 28, 45–50. Lidz, T., Carter, J.D., Lewis, B.I., and Surratt, C. (1952). Effects of ACTH and cortisone on mood and mentation. Psychosom. Med. 14, 363–377.

of

Lieb, K., Rexhausen, J.E., Kahl, K.G., Schweiger, U., Philipsen, A., Hellhammer, D.H., and Bohus, M. (2004). Increased diurnal salivary cortisol in women with borderline personality disorder. J. Psychiatr. Res. 38, 559–565.

ro

Lindqvist, D., Janelidze, S., Erhardt, S., Träskman-Bendz, L., Engström, G., and Brundin, L. (2011). CSF biomarkers in suicide attempters - a principal component analysis: CSF biomarkers in suicide attempters. Acta Psychiatr. Scand. 124, 52–61.

-p

Lindy, D.C., Walsh, B.T., Roose, S.P., Gladis, M., and Glassman, A.H. (1985). The dexamethasone suppression test in bulimia. Am. J. Psychiatry 142, 1375–1376.

re

Lippmann, M., Bress, A., Nemeroff, C.B., Plotsky, P.M., and Monteggia, L.M. (2007). Long-term behavioural and molecular alterations associated with maternal separation in rats: Molecular adaptations after maternal separation. Eur. J. Neurosci. 25, 3091–3098.

lP

Liu, D., Diorio, J., Tannenbaum, B., Caldji, C., Francis, D., Freedman, A., Sharma, S., Pearson, D., Plotsky, P.M., and Meaney, M.J. (1997). Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science 277, 1659–1662.

ur na

Lopez-Duran, N.L., Olson, S.L., Hajal, N.J., Felt, B.T., and Vazquez, D.M. (2009). Hypothalamic Pituitary Adrenal Axis Functioning in Reactive and Proactive Aggression in Children. J. Abnorm. Child Psychol. 37, 169–182.

Jo

Lowry, C.A., Rodda, J.E., Lightman, S.L., and Ingram, C.D. (2000). Corticotropin-Releasing Factor Increases In VitroFiring Rates of Serotonergic Neurons in the Rat Dorsal Raphe Nucleus: Evidence for Activation of a Topographically Organized Mesolimbocortical Serotonergic System. J. Neurosci. 20, 7728–7736. Lukkes, J.L., Forster, G.L., Renner, K.J., and Summers, C.H. (2008). Corticoptropin-releasing factor 1 and 2 receptors in the dorsal raphe differentially affect serotonin release in the nucleus accumbens. Eur. J. Pharmacol. 578, 185–193. Lupien, S.J., and McEwen, B.S. (1997). The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Res. Brain Res. Rev. 24, 1–27. MacKillop, J. (2016). The Behavioral Economics and Neuroeconomics of Alcohol Use Disorders. Alcohol. Clin. Exp. Res. 40, 672–685.

Mann, J.J. (2013). The serotonergic system in mood disorders and suicidal behaviour. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 368, 20120537. Mann, J.J., and Currier, D. (2007). A Review of Prospective Studies of Biologic Predictors of Suicidal Behavior in Mood Disorders. Arch. Suicide Res. 11, 3–16. Mann, J.J., Malone, K.M., Sweeney, J.A., Brown, R.P., Linnoila, M., Stanley, B., and Stanley, M. (1996). Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 15, 576–586.

of

Mann, J.J., Waternaux, C., Haas, G.L., and Malone, K.M. (1999). Toward a clinical model of suicidal behavior in psychiatric patients. Am. J. Psychiatry 156, 181–189.

ro

Mann, J.J., Currier, D., Stanley, B., Oquendo, M.A., Amsel, L.V., and Ellis, S.P. (2006a). Can biological tests assist prediction of suicide in mood disorders? Int. J. Neuropsychopharmacol. 9, 465.

-p

Mann, K., Rossbach, W., Müller, M.J., Müller-Siecheneder, F., Pott, T., Linde, I., Dittmann, R.W., and Hiemke, C. (2006b). Nocturnal hormone profiles in patients with schizophrenia treated with olanzapine. Psychoneuroendocrinology 31, 256–264.

lP

re

Markianos, M., Hatzimanolis, J., and Lykouras, L. (1999). Switch from neuroleptics to clozapine does not influence pituitary-gonadal axis hormone levels in male schizophrenic patients. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 9, 533–536. Martire, M., Pistritto, G., and Preziosi, P. (1989). Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus. J. Neural Transm. 78, 109–120.

ur na

McEvoy, J.P., Lieberman, J.A., Stroup, T.S., Davis, S.M., Meltzer, H.Y., Rosenheck, R.A., Swartz, M.S., Perkins, D.O., Keefe, R.S.E., Davis, C.E., et al. (2006). Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am. J. Psychiatry 163, 600–610.

Jo

McGowan, P.O., Sasaki, A., D’Alessio, A.C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., and Meaney, M.J. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 12, 342–348. McKlveen, J.M., Morano, R.L., Fitzgerald, M., Zoubovsky, S., Cassella, S.N., Scheimann, J.R., Ghosal, S., Mahbod, P., Packard, B.A., Myers, B., et al. (2016). Chronic Stress Increases Prefrontal Inhibition: A Mechanism for Stress-Induced Prefrontal Dysfunction. Biol. Psychiatry 80, 754–764. Meador-Woodruff, J.H., Greden, J.F., Grunhaus, L., and Haskett, R.F. (1988). Dexamethasone suppression test status and severity of depression. Biol. Psychiatry 24, 693–696.

Mechawar, N., and Savitz, J. (2016). Neuropathology of mood disorders: do we see the stigmata of inflammation? Transl. Psychiatry 6, e946. Meijer, O.C., and de Kloet, E.R. (1994). Corticosterone suppresses the expression of 5-HT1A receptor mRNA in rat dentate gyrus. Eur. J. Pharmacol. 266, 255–261. Melhem, N.M., Keilp, J.G., Porta, G., Oquendo, M.A., Burke, A., Stanley, B., Cooper, T.B., Mann, J.J., and Brent, D.A. (2015). Blunted HPA axis activity in suicide attempters compared to those at high risk for suicidal behavior. Neuropsychopharmacology.

of

Melhem, N.M., Munroe, S., Marsland, A., Gray, K., Brent, D., Porta, G., Douaihy, A., Laudenslager, M.L., DePietro, F., Diler, R., et al. (2017). Blunted HPA axis activity prior to suicide attempt and increased inflammation in attempters. Psychoneuroendocrinology 77, 284–294.

-p

ro

Meltzer, H.Y., Alphs, L., Green, A.I., Altamura, A.C., Anand, R., Bertoldi, A., Bourgeois, M., Chouinard, G., Islam, M.Z., Kane, J., et al. (2003). Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch. Gen. Psychiatry 60, 82–91.

re

Mickey, B.J., Ginsburg, Y., Sitzmann, A.F., Grayhack, C., Sen, S., Kirschbaum, C., Maixner, D.F., and Abelson, J.L. (2018). Cortisol trajectory, melancholia, and response to electroconvulsive therapy. J. Psychiatr. Res. 103, 46–53.

lP

Miller, A.H., Maletic, V., and Raison, C.L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732–741.

ur na

Miller, J.M., Hesselgrave, N., Ogden, R.T., Sullivan, G.M., Oquendo, M.A., Mann, J.J., and Parsey, R.V. (2013). Positron Emission Tomography Quantification of Serotonin Transporter in Suicide Attempters with Major Depressive Disorder. Biol. Psychiatry 74, 287–295. Moody, L., Franck, C., and Bickel, W.K. (2016). Comorbid depression, antisocial personality, and substance dependence: Relationship with delay discounting. Drug Alcohol Depend. 160, 190–196.

Jo

Nelson, J.C., and Davis, J.M. (1997). DST studies in psychotic depression: a meta-analysis. Am. J. Psychiatry 154, 1497–1503. Nemeroff, C.B., Owens, M.J., Bissette, G., Andorn, A.C., and Stanley, M. (1988). Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch. Gen. Psychiatry 45, 577–579. Nordström, P., Samuelsson, M., Asberg, M., Träskman-Bendz, L., Aberg-Wistedt, A., Nordin, C., and Bertilsson, L. (1994). CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life. Threat. Behav. 24, 1–9.

O’Connor, D.B., Ferguson, E., Green, J.A., O’Carroll, R.E., and O’Connor, R.C. (2016). Cortisol levels and suicidal behavior: A meta-analysis. Psychoneuroendocrinology 63, 370–379. O’Connor, D.B., Green, J.A., Ferguson, E., O’Carroll, R.E., and O’Connor, R.C. (2017). Cortisol reactivity and suicidal behavior: Investigating the role of hypothalamic-pituitary-adrenal axis responses to stress in suicide attempters and ideators. Psychoneuroendocrinology 75, 183–191. Oquendo, M.A., Sullivan, G.M., Sudol, K., Baca-Garcia, E., Stanley, B.H., Sublette, M.E., and Mann, J.J. (2014). Toward a biosignature for suicide. Am. J. Psychiatry 171, 1259–1277.

ro

of

Oquendo, M.A., Galfalvy, H., Sullivan, G.M., Miller, J.M., Milak, M.M., Sublette, M.E., CisnerosTrujillo, S., Burke, A.K., Parsey, R.V., and Mann, J.J. (2016). Positron Emission Tomographic Imaging of the Serotonergic System and Prediction of Risk and Lethality of Future Suicidal Behavior. JAMA Psychiatry 73, 1048.

-p

Ordway, G.A., Widdowson, P.S., Smith, K.S., and Halaris, A. (1994a). Agonist binding to alpha 2-adrenoceptors is elevated in the locus coeruleus from victims of suicide. J. Neurochem. 63, 617–624.

re

Ordway, G.A., Smith, K.S., and Haycock, J.W. (1994b). Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims. J. Neurochem. 62, 680–685.

lP

Ostroff, R., Giller, E., Bonese, K., Ebersole, E., Harkness, L., and Mason, J. (1982). Neuroendocrine risk factors of suicidal behavior. Am. J. Psychiatry 139, 1323–1325. Papadopoulou, A., Douzenis, A., Christodoulou, C., Gournellis, R., Papageorgiou, C., and Markianos, M. (2017). Association of Plasma Cortisol Levels with Clinical Characteristics of Suicide Attempters. Neuropsychobiology 76, 161–165.

ur na

Park, R.J., and Kim, Y.H. (2017). Association between high sensitivity CRP and suicidal ideation in the Korean general population. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 27, 885–891.

Jo

Pfennig, A., Kunzel, H.E., Kern, N., Ising, M., Majer, M., Fuchs, B., Ernst, G., Holsboer, F., and Binder, E.B. (2005). Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression. Biol. Psychiatry 57, 336–342. Pintor, L., Torres, X., Bailles, E., Navarro, V., de Osaba, M.J.M., Belmonte, A., and Gastó, C. (2013). CRF test in melancholic depressive patients with partial versus complete relapses: a 2-year follow-up study. Nord. J. Psychiatry 67, 177–184. Posener, J.A., DeBattista, C., Williams, G.H., Chmura Kraemer, H., Kalehzan, B.M., and Schatzberg, A.F. (2000). 24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression. Arch. Gen. Psychiatry 57, 755–760.

Quadros, I.M., Hwa, L.S., Shimamoto, A., Carlson, J., DeBold, J.F., and Miczek, K.A. (2014). Prevention of alcohol-heightened aggression by CRF-R1 antagonists in mice: critical role for DRN-PFC serotonin pathway. Neuropsychopharmacology 39, 2874–2883. Rausch, J., Gäbel, A., Nagy, K., Kleindienst, N., Herpertz, S.C., and Bertsch, K. (2015). Increased testosterone levels and cortisol awakening responses in patients with borderline personality disorder: gender and trait aggressiveness matter. Psychoneuroendocrinology 55, 116–127. Ribeiro, S.C., Tandon, R., Grunhaus, L., and Greden, J.F. (1993). The DST as a predictor of outcome in depression: a meta-analysis. Am. J. Psychiatry 150, 1618–1629.

of

Robins, E., Murphy, G.E., Wilkinson, R.H., Gassner, S., and Kayes, J. (1959). Some clinical considerations in the prevention of suicide based on a study of 134 successful suicides. Am. J. Public Health Nations Health 49, 888–899.

ro

Roy, A., Virkkunen, M., Guthrie, S., and Linnoila, M. (1986). Indices of serotonin and glucose metabolism in violent offenders, arsonists, and alcoholics. Ann. N. Y. Acad. Sci. 487, 202–220.

-p

Roy, A., Gorodetsky, E., Yuan, Q., Goldman, D., and Enoch, M.-A. (2010). Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 35, 1674–1683.

lP

re

Roy, A., Hodgkinson, C.A., Deluca, V., Goldman, D., and Enoch, M.-A. (2012). Two HPA axis genes, CRHBP and FKBP5, interact with childhood trauma to increase the risk for suicidal behavior. J. Psychiatr. Res. 46, 72–79. Ryan, M.C.M., Sharifi, N., Condren, R., and Thakore, J.H. (2004). Evidence of basal pituitaryadrenal overactivity in first episode, drug naïve patients with schizophrenia. Psychoneuroendocrinology 29, 1065–1070.

ur na

van Santen, A., Vreeburg, S.A., Van der Does, A.J.W., Spinhoven, P., Zitman, F.G., and Penninx, B.W.J.H. (2011). Psychological traits and the cortisol awakening response: results from the Netherlands Study of Depression and Anxiety. Psychoneuroendocrinology 36, 240–248.

Jo

Schatzberg, A.F., Keller, J., Tennakoon, L., Lembke, A., Williams, G., Kraemer, F.B., Sarginson, J.E., Lazzeroni, L.C., and Murphy, G.M. (2014). HPA axis genetic variation, cortisol and psychosis in major depression. Mol. Psychiatry 19, 220–227. Schoenfeld, T.J., McCausland, H.C., Morris, H.D., Padmanaban, V., and Cameron, H.A. (2017). Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume. Biol. Psychiatry 82, 914–923. Scott, L.N., Levy, K.N., and Granger, D.A. (2013). Biobehavioral reactivity to social evaluative stress in women with borderline personality disorder. Personal. Disord. 4, 91–100.

Sharma, R.P., Pandey, G.N., Janicak, P.G., Peterson, J., Comaty, J.E., and Davis, J.M. (1988). The effect of diagnosis and age on the DST: a metaanalytic approach. Biol. Psychiatry 24, 555– 568. Silverman, M.N., and Sternberg, E.M. (2012). Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann. N. Y. Acad. Sci. 1261, 55–63. Soares, J.M., Sampaio, A., Ferreira, L.M., Santos, N.C., Marques, F., Palha, J.A., Cerqueira, J.J., and Sousa, N. (2012). Stress-induced changes in human decision-making are reversible. Transl. Psychiatry 2, e131.

ro

of

Sorocco, K.H., Lovallo, W.R., Vincent, A.S., and Collins, F.L. (2006). Blunted hypothalamicpituitary-adrenocortical axis responsivity to stress in persons with a family history of alcoholism. Int. J. Psychophysiol. Off. J. Int. Organ. Psychophysiol. 59, 210–217.

-p

Staner, L., Maes, M., Bouillon, E., and Linkowski, P. (1992). Biological correlates of the Newcastle Scale in depressive illness: a multivariate approach. Acta Psychiatr. Scand. 85, 345–350.

re

Starkman, M.N., Schteingart, D.E., and Schork, M.A. (1981). Depressed mood and other psychiatric manifestations of Cushing’s syndrome: relationship to hormone levels. Psychosom. Med. 43, 3–18.

lP

Steinberg, L.J., Rubin-Falcone, H., Galfalvy, H.C., Kaufman, J., Miller, J.M., Sublette, M.E., Cooper, T.B., Min, E., Keilp, J.G., Stanley, B.H., et al. (2019). Cortisol Stress Response and in Vivo PET Imaging of Human Brain Serotonin 1A Receptor Binding. Int. J. Neuropsychopharmacol. 22, 329–338.

ur na

Sternbach, H.A., Fleming, J., Extein, I., Pottash, A.L., and Gold, M.S. (1983). The dexamethasone suppression and thyrotropin-releasing hormone tests in depressed borderline patients. Psychoneuroendocrinology 8, 459–462. Strakowski, S.M., McElroy, S.L., Keck, P.E., and West, S.A. (1996). Suicidality among patients with mixed and manic bipolar disorder. Am. J. Psychiatry 153, 674–676.

Jo

Sullivan, G.M., Oquendo, M.A., Milak, M., Miller, J.M., Burke, A., Ogden, R.T., Parsey, R.V., and Mann, J.J. (2015). Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder. JAMA Psychiatry 72, 169–178. Swinburn, C.R., Wakefield, J.M., Newman, S.P., and Jones, P.W. (1988). Evidence of prednisolone induced mood change ('steroid euphoria’) in patients with chronic obstructive airways disease. Br. J. Clin. Pharmacol. 26, 709–713. Szigethy, E., Conwell, Y., Forbes, N.T., Cox, C., and Caine, E.D. (1994). Adrenal Weight and Morphology in Victims of Completed Suicide. Biol. Psychiatry 36, 374–380.

Takahashi, A., Shimamoto, A., Boyson, C.O., DeBold, J.F., and Miczek, K.A. (2010). GABAB Receptor Modulation of Serotonin Neurons in the Dorsal Raphe Nucleus and Escalation of Aggression in Mice. J. Neurosci. 30, 11771–11780. Takahashi, A., Quadros, I.M., de Almeida, R.M.M., and Miczek, K.A. (2011). Brain serotonin receptors and transporters: initiation vs. termination of escalated aggression. Psychopharmacology (Berl.) 213, 183–212. Takahashi, A., Lee, R.X., Iwasato, T., Itohara, S., Arima, H., Bettler, B., Miczek, K.A., and Koide, T. (2015). Glutamate Input in the Dorsal Raphe Nucleus As a Determinant of Escalated Aggression in Male Mice. J. Neurosci. 35, 6452–6463.

ro

of

Ventura-Juncá, R., Symon, A., López, P., Fiedler, J.L., Rojas, G., Heskia, C., Lara, P., Marín, F., Guajardo, V., Araya, A.V., et al. (2014). Relationship of cortisol levels and genetic polymorphisms to antidepressant response to placebo and fluoxetine in patients with major depressive disorder: a prospective study. BMC Psychiatry 14, 220.

-p

Vinberg, M., Miskowiak, K., and Kessing, L.V. (2014). Serotonin transporter genotype, salivary cortisol, neuroticism and life events: impact on subsequent psychopathology in healthy twins at high and low risk for affective disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 48, 193–198.

lP

re

Vogel, S., Klumpers, F., Schröder, T.N., Oplaat, K.T., Krugers, H.J., Oitzl, M.S., Joëls, M., Doeller, C.F., and Fernández, G. (2016). Stress Induces a Shift Towards Striatum-Dependent StimulusResponse Learning via the Mineralocorticoid Receptor. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol.

ur na

Vrshek-Schallhorn, S., Doane, L.D., Mineka, S., Zinbarg, R.E., Craske, M.G., and Adam, E.K. (2013). The cortisol awakening response predicts major depression: predictive stability over a 4-year follow-up and effect of depression history. Psychol. Med. 43, 483–493. Wand, G., McCaul, M.E., Gotjen, D., Reynolds, J., and Lee, S. (2001). Confirmation that offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitaryadrenal axis activation induced by naloxone compared with offspring without a family history of alcohol dependence. Alcohol. Clin. Exp. Res. 25, 1134–1139.

Jo

Wand, G.S., Mangold, D., Ali, M., and Giggey, P. (1999). Adrenocortical responses and family history of alcoholism. Alcohol. Clin. Exp. Res. 23, 1185–1190. Wang, Q., Shelton, R.C., and Dwivedi, Y. (2018). Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. J. Affect. Disord. 225, 422–428. Westrin, A. (2000). Stress system alterations and mood disorders in suicidal patients. A review. Biomed. Pharmacother. Biomedecine Pharmacother. 54, 142–145.

Westrin, A., Ekman, R., and Träskman-Bendz, L. (1999). Alterations of corticotropin releasing hormone (CRH) and neuropeptide Y (NPY) plasma levels in mood disorder patients with a recent suicide attempt. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 9, 205–211. Wichmann, S., Kirschbaum, C., Böhme, C., and Petrowski, K. (2017). Cortisol stress response in post-traumatic stress disorder, panic disorder, and major depressive disorder patients. Psychoneuroendocrinology 83, 135–141.

of

Yamakawa, K., Ohira, H., Matsunaga, M., and Isowa, T. (2016). Prolonged Effects of Acute Stress on Decision-Making under Risk: A Human Psychophysiological Study. Front. Hum. Neurosci. 10, 444.

ro

Yeragani, V.K. (1990). The incidence of abnormal dexamethasone suppression in schizophrenia: a review and a meta-analytic comparison with the incidence in normal controls. Can. J. Psychiatry Rev. Can. Psychiatr. 35, 128–132.

-p

Yerevanian, B.I., Feusner, J.D., Koek, R.J., and Mintz, J. (2004). The dexamethasone suppression test as a predictor of suicidal behavior in unipolar depression. J. Affect. Disord. 83, 103–108.

lP

re

Yin, H., Galfalvy, H., Pantazatos, S.P., Huang, Y.-Y., Rosoklija, G.B., Dwork, A.J., Burke, A., Arango, V., Oquendo, M.A., and Mann, J.J. (2016). GLUCOCORTICOID RECEPTOR-RELATED GENES: GENOTYPE AND BRAIN GENE EXPRESSION RELATIONSHIPS TO SUICIDE AND MAJOR DEPRESSIVE DISORDER. Depress. Anxiety 33, 531–540. Yu, R. (2016). Stress potentiates decision biases: A stress induced deliberation-to-intuition (SIDI) model. Neurobiol. Stress 3, 83–95.

ur na

Zhang, T.Y., Labonté, B., Wen, X.L., Turecki, G., and Meaney, M.J. (2013). Epigenetic mechanisms for the early environmental regulation of hippocampal glucocorticoid receptor gene expression in rodents and humans. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 38, 111–123.

Jo

Zhang, X.Y., Zhou, D.F., Cao, L.Y., Wu, G.Y., and Shen, Y.C. (2005). Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 30, 1532–1538. Zhong, P., and Ciaranello, R.D. (1995). Transcriptional regulation of hippocampal 5-HT1a receptors by corticosteroid hormones. Brain Res. Mol. Brain Res. 29, 23–34. Zimmermann, U., Spring, K., Wittchen, H.-U., Himmerich, H., Landgraf, R., Uhr, M., and Holsboer, F. (2004). Arginine vasopressin and adrenocorticotropin secretion in response to psychosocial stress is attenuated by ethanol in sons of alcohol-dependent fathers. J. Psychiatr. Res. 38, 385–393.

Zobel, A.W., Nickel, T., Künzel, H.E., Ackl, N., Sonntag, A., Ising, M., and Holsboer, F. (2000). Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181.

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Zoladz, P.R., Dailey, A.M., Nagle, H.E., Fiely, M.K., Mosley, B.E., Brown, C.M., Duffy, T.J., Scharf, A.R., Earley, M.B., and Rorabaugh, B.R. (2016). FKBP5 Polymorphisms Influence PreLearning Stress-Induced Alterations of Learning and Memory. Eur. J. Neurosci.

Expresses GRs

Hypothalamus PVN Higher tissue levels in suicide decedents Decreased receptor expression in prefrontal cortex Stimulated by inflammatory cytokines

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CRF/CRH

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Anterior Pituitary

ACTH

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Stimulated by inflammatory cytokines

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+ Adrenal Cortex

Low affinity

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High affinity

Cortisol

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Increased secretion = risk factor for suicide

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MR

Increased DNA methylation of GR gene with childhood adversity

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Heavier suicide decedents

GR

Lower expression levels with childhood adversity

FKBP5

Upregulated in suicide decedents

Nucleus Gene 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 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.