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Molecular Psychiatry
https://doi.org/10.1038/s41380-021-01171-5
EXPERT REVIEW
Psychobiological risk factors for suicidal thoughts and behaviors
in adolescence: a consideration of the role of puberty
Tiffany C. Ho1,2 ●Anthony J. Gifuni1,3 ●Ian H. Gotlib1
Received: 17 April 2020 / Revised: 3 May 2021 / Accepted: 11 May 2021
© The Author(s) 2021. This article is published with open access
Abstract
Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize
the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs)
during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal
events that occur during puberty have significant effects on the organization and development of brain systems implicated in
the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex,
and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal
hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with
a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing,
warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the
neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the
pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more
effective, sex-specific, psychiatric interventions for adolescents.
Introduction
Suicide is the second leading cause of death among ado-
lescents ages 10–24 years worldwide [1] and accounts for
17.7% of all deaths in youth ages 15–24 years in the United
States [2]. Although suicide has a relatively low prevalence,
over the past 10 years suicide rates in the US have increased
by 76% in youth ages 15–19 years and, more alarmingly, by
300% in youth ages 10–14 years [3]. Despite the urgency of
suicide as a public health problem, research examining
predictors of suicidal thoughts and behaviors (STBs) has
had limited clinical impact, particularly in adolescents
[4,5]. Adolescents report a higher proportion of suicidal
ideation and attempts than do adults, making this a critical
developmental period during which to identify early risk
factors for STBs [6]. Indeed, the fact that adolescent sam-
ples represent only 20% of the literature on predictors of
STBs further underscores the need for more research with
this age group [5].
While clinicians and researchers recognize that predictors
of STBs are multidimensional—including genetic, epigenetic,
neurobiological, psychosocial, and environmental factors—
the marked increase in the prevalence of STBs (and mental
health conditions more generally) during adolescence [7]
suggests that this developmental period, in which the con-
fluence of these multidimensional influences contributes to
elevated risk, is unique [8,9]. In this context, we contend that
one critical factor is puberty. The onset of puberty initiates a
neuroendocrine cascade that shapes the maturation of neural
circuits that underlie a range of socioemotional and cognitive
functioning, including emotion regulation and impulse con-
trol. Impaired emotion regulation and impulse control both
significantly contribute to the emergence of mental disorders
in the face of environmental risk factors (e.g., life stress) that
influence neurodevelopmental trajectories, result in the gen-
eration and experience of additional psychosocial stress, and,
thus, may represent an important pathway to developing
*Tiffany C. Ho
tiffany.ho@ucsf.edu
1Department of Psychology, Stanford University, Stanford, CA,
USA
2Department of Psychiatry and Weill Institute for Neuroscience,
University of California, San Francisco, San Francisco, CA, USA
3Psychiatry Department and Douglas Mental Health University
Institute, McGill University, Montréal, QC, Canada
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STBs. Other notable aspects of development, such as pubertal
timing, and factors that may drive atypical pubertal timing
(e.g., exposure to early adversity), are also recognized as
important in affecting the development of adolescent-onset
psychiatric disorders, including STBs [10]. Indeed, atypical
pubertal timing results not only in corresponding changes in
neuroendocrine systems but also significant shifts in social
identity and perceived status may explain sex differences in
the emergence and course of STBs (and related mental health
conditions that substantially increase the risk of STBs).
The goal of this review paper is to elucidate how pubertal
changes contribute to STBs in adolescence. While we do
not regard puberty-related processes as primary determi-
nants of STBs, we posit that exposure to sex hormones
during adolescence initiates a period of plasticity in neural
circuits that are sensitive to social context (including social
stressors that amplify emotion dysregulation and impulse
control in ways that increase risk for STBs) and that may be
target mechanisms for treatment of STBs, We further con-
tend that these processes are especially critical to consider
in adolescents who have existing vulnerabilities, including
neurobiological sensitivity to hormonal changes, exposure
to adverse psychosocial experiences during early develop-
ment, and underlying mental disorders. In the following
sections, we: (1) present an overarching framework and
highlight specific brain circuits involved in social cognition,
emotion regulation, and impulse control that are relevant to
understanding STBs in adolescence; (2) review basic
experimental findings in adults that show the effect of
pubertal hormones on behaviors relevant to suicide risk and
survey the conflicting correlational literature on hormones
with STBs in adolescents; (3) discuss the role of pubertal
timing and sex differences in these processes; and (4)
advance recommendations for future research in this area.
Puberty as a driver of neuroendocrine
mechanisms relevant for understanding
adolescent STBs
Contemporary theories of suicide have been informed pri-
marily by data from adults [11,12], it is unclear whether
these theories—or specific components of associated mod-
els—extend to adolescents. Moreover, few theories of sui-
cidality explicitly integrate biological factors, including
endocrine or neural factors (with exceptions [12–14]). Here,
we posit that adolescent STBs result from a pathological
response to stress during a time when the neurobiological
systems that regulate stress are recalibrating. There is
extensive evidence that STBs in adolescents are often pre-
ceded by life stressors, particularly stressors characterized
by interpersonal rejection, loss, or conflict [15–17]. Social
rejection in particular is a commonly experienced stressor
during adolescence due to unstable romantic and peer
relationships, and is a potent trigger for negative emotions
[18,19]. In this context, emotion-related impulsivity—the
tendency to react impulsively during experiences of
heighted affective states [20]—may contribute to adolescent
risk for STBs. Indeed, both peer-related stressors [21,22]
and emotion-related impulsivity [23] have been shown
separately to predict STBs in adolescents.
We argue here that hormonal changes during puberty alter
the development of brain circuits implicated in the regulation
of social stressors. The brain is a target organ for all of the
pubertal hormones we review, and receptors for these hor-
mones are expressed abundantly in several key structures that
comprise brain networks governing social cognition, emotion
regulation, and impulse control generally (and social rejection
and emotion-related impulsivity specifically) [24,25],
including the amygdala, hippocampus, striatum, anterior
cingulate cortex (ACC), medial prefrontal cortex (mPFC), and
orbitofrontal cortex (OFC). The amygdala, hippocampus, and
ACC comprise a network of regions implicated in detecting
social salience; the amygdala and mPFC comprise a key
emotion regulatory circuit; the striatum and frontal regions
including OFC comprise circuits underlying reward valuation
and impulse control. It is important to note that many of these
regions already exhibit sexual dimorphism during adoles-
cence, including larger amygdala and hippocampal volumes
in boys, greater variance in the hippocampus and striatum in
boys than in girls, sex differences in white matter organization
of callosal, cerebellar, and long-range association tracts (for a
review, see [26]), and sex differences in the developmental
trajectories of frontoparietal networks [27]. Moreover, several
of these regions have been highlighted in a recent review of
neuroimaging markers associated with STBs across the life-
span [28]; however, those authors did not consider the
importance of pubertal development in explaining the neu-
roendocrine basis of the emergence of STBs. We contend that
this is a critical factor to consider, given emerging evidence
that sex differences in these brain circuits during adolescence
appear to be explained, at least in part, by changes in pubertal
hormones [29,30]. Thus, we contend that the social land-
scape, and most notably environmental stressors, experienced
by boys and girls begins to differ during puberty, and that
these differences, in conjunction with sex-specific hormonal
effects on brain maturation, may explain important sex dif-
ferences in STBs that emerge by mid-adolescence.
Pubertal hormones and suicide-relevant
thoughts and behaviors
Puberty is composed of two phases: adrenarche and gona-
darche. During adrenarche, which typically begins around
ages 7–8 years, the adrenal glands produce increasing levels
T. C. Ho et al.
of the hormones dehydroepiandrosterone (DHEA) and tes-
tosterone [31,32]. Gonadarche is a longer process that typi-
cally takes 4–5 years, beginning around ages 9–10 and
occurring on average a year earlier in girls than in boys [33].
Gonadarche is triggered by the activation of hypothalamic-
pituitary-gonadal (HPG) axis, which leads to rising levels of
luteinizing hormone (LH) and follicle-stimulating hormone
(FSH). The release of LH and FSH initiates the development
of the gonads, which, in turn, leads to increases in sex
hormones—specifically, testosterone in boys and estradiol
(the predominant estrogen during adolescence) and proges-
terone in girls—and, by early to mid-adolescence, the
development of secondary sex characteristics and other phy-
sical changes [32]. Importantly, these hormones cross the
blood brain barrier, influence brain development, and affect a
wide variety of signaling pathways (e.g., neurotransmitter
activity) that underlie mood and cognition [25]. Thus, puberty
involves transformation across virtually every psychobiolo-
gical domain—endocrine, neural, physical, cognitive, and
socioemotional—and represents a vulnerable time during
which STBs may emerge.
Prevalence rates of STBs begin to increase after age 12 but
peak in later adolescence, suggesting that it is not simply the
rise in these hormones that accounts for the increase in STBs,
given that these endocrine changes begin much earlier than
age 12. Instead, the organizational effects of pubertal hor-
mones play a major role in risk for STBs in adolescence.
Organizational effects are those that occur during sensitive
periods of development that lay the foundation for sex-typical
brain and behavioral phenotypes and, thus, have an impact
even in the absence of circulating levels of the hormones. In
contrast, activational effects facilitate the expression of
behaviors under specific contexts but are temporary and occur
only when the hormones in question are present [34]. Evi-
dence for organizational effects of hormones during adoles-
cence comes from studies demonstrating that the same
developmental processes (e.g., neurogenesis, synaptic prun-
ing, dendritic branching, apoptosis) that occur during the
perinatal period as a result of surging levels of gonadal hor-
mones also occur during puberty [35,36]. These studies
suggest that puberty opens a sensitive window for experience-
dependent plasticity in neural circuits that underlie higher-
order processing of social stimuli, thereby rendering adoles-
cence—a time of increased exposure to social stressors—a
vulnerable period for the onset of stress-related mental health
problems (Fig. 1). At the same time, it is possible that
ongoing fluctuations in hormone levels are also related to
STB risk through their activational effects on neurotransmitter
systems, particularly in the context of responding to social
stressors, and that these effects are more relevant for adoles-
cents with a neurobiological sensitivity to hormonal changes.
Below, we review studies investigating ovarian (estradiol
and progesterone), testicular (testosterone), and adrenal
(DHEA) hormones in relation to STBs and, importantly,
their impact on the structural development and function of
specific brain circuits implicated in social cognition, emo-
tion regulation, and impulse control. A summary of this
section is outlined in Table 1and Fig. 1B. Before reviewing
the correlational literature in adolescents, within each
respective section, we first review basic experimental stu-
dies that provide insight concerning the effects of estradiol,
progesterone, testosterone, and DHEA on human behaviors
relevant to suicide risk in adults in order to provide a more
reliable context for the actions of these hormones.
Finally, because ovarian hormones have been investi-
gated almost exclusively in females in this context and,
similarly, androgen hormones overwhelmingly in males,
our review of the association of these hormones with brain
and behavioral outcomes inherently raises issues of sex
differences or sex-specific effects in these processes;
we discuss these issues in more detail in a later section
(D. Consideration of sex differences).
Ovarian hormones (estradiol and progesterone)
Estradiol, progesterone, and their neurosteroid metabolites
all increase and begin to fluctuate cyclically in girls during
puberty [34]. Consequently, the vast majority of research in
this area has focused on females (for reviews, see [14,37]).
To provide a context for understanding the effects of
estradiol and progesterone administration on behaviors
relevant to suicide risk, we will first briefly review studies
that controlled hormone conditions in women with affective
symptoms and premenstrual dysphoric disorder (PMDD),
for whom suicide risk is elevated compared to the general
population [38,39].
Decades of research have shown that there are no dif-
ferences between women with and without PMDD in
ovarian hormone levels or related neurosteroids (e.g., allo-
pregnanolone) but that suppressing ovarian hormones
reduces or eliminates symptoms of PMDD (for a review,
see [40]). A recent study that controlled for ovarian hor-
mone secretion and exposure in women with PMDD has
helped to clarify these two seemingly opposing findings
[41]. In that study, women with PMDD who responded to a
gonadotropin-releasing hormone agonist treatment were
given placebo for one month before being administered
continuous estradiol/progesterone for three months;
researchers found that changes from low to high levels of
ovarian hormones, but not absolute levels of ovarian hor-
mones, were associated with increases in negative affect
[41]. Together, these data suggest that neurobiological
sensitivity to hormone changes is an important factor that
may explain certain clinical phenomena, such as PMDD and
suicide risk. Indeed, a recent review has covered this topic
extensively in adult women, demonstrating that cyclical
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
hormone changes may play an important role in “acute risk
for daily suicidal ideation, planning, and intent”in indivi-
duals with sensitivity to hormone changes [14]. We have
extended this theoretical model to adolescents, proposing
that in those who possess a neurobiological sensitivity to
hormonal changes, the normative fluctuations during this
transitional period, coupled with adolescent-typical experi-
ences of greater exposure to life stressors, may exacerbate
the effects of these processes on emotion regulatory and
impulse control circuits. Indeed, results from studies that
have investigated suicide risk in adult women across the
menstrual cycle have been inconsistent. These studies have
typically assessed levels of estradiol and progesterone
during different phases of the menstrual cycle [42–44], and
in women with low levels of estradiol and progesterone
(e.g., amenorrhea or menopause [45]). While some
investigators have reported that a higher risk of suicide
attempts and more severe suicidal thoughts and intentions
are associated with relatively low or declining levels of
estradiol and progesterone (i.e., during the early follicular/
menstrual or pre-menstrual phases), other researchers have
not found differences in estradiol or progesterone between
depressed women with and without STBs [46] or effects of
the menstrual cycle on suicide attempts in women with
PMDD [39].
The fact that there has been no evidence of differences in
ovarian hormone levels or in cyclical changes in female
adolescents with and without STBs is consistent with the
previously aforementioned studies in adult women with
reproductive mood disorders where the effect of menstrual
cycle and/or ovarian hormone levels on STBs in adult
women is absent. One interpretation is that it is the
Fig. 1 Summary of prevalence rates of suicidal ideation,
concentration of sex steroids, and brain volume as a function of
age and typical associations between pubertal hormones and brain
structures reported the extant literature. A) Graphical depictions of
prevalence rates of suicidal ideation, concentrations of sex steroids,
and brain volume as a function of age. Shaded region indicates
puberty. The schematized trajectories of gray matter volume adjusted
for total brain volume are based on data reported in [162]. B) Summary
of typical associations between pubertal hormones and brain structures
from both adolescent and adult samples. ACC anterior cingulate cor-
tex, AMYG amygdala, HPC hippocampus, MPFC medial prefrontal
cortex, OFC orbitofrontal cortex, STM striatum.
T. C. Ho et al.
Table 1 Summary of studies examining gonadal and adrenal hormones in relation to suicide attempts and suicidal ideation.
Publication Sample size and characteristics Age (years) Sex Psychiatric condition Suicide-related
outcome Study design and methods Findings Additional notes
Afzali et al. 2012 81 suicide attempters Mean =23.63
SD =8.41
Range =15–55
F Assorted
(25 Past mental disorder, 22
Previous suicide attempt)
History of Suicide
Attempts Structured interview over
6 months after attempt Suicide attempts were not
associated with menstrual
cycle phase.
Patients with irregular
menstrual cycles were
excluded.
Baca-Garcia et al.
2010a281 suicide attempters
176 healthy controls Mean =30.8
SD =8.8
Range =18–92
F Assorted
(229 Mood disorder, 229
SUD, 275 Previous
psychiatric treatment)
Recent Suicide
Attempts and Recent
Suicidal Ideation
Blood sample within 24 h of
attempt: estradiol,
progesterone, LH, FSH
Suicide attempts were was
more likely during the
follicular phase.
Suicide intent severity was
elevated during low-estrogen/
low-progesterone states (pre-
menstrual phase, amenorreha,
menopause)
Butterfield
et al. 2005 130 inpatients Mean =49.4
SD =8.13 M PTSD Recent History of
Suicide Attempts (past
6 months) and
Suicidal Ideation
Blood: DHEA,
androstenedione,
testosterone, estradiol
Suicide attempters had higher
DHEA than nonattempters
Cayköylü et al.
2004a52 suicide attempters
50 healthy controls Mean =26.51
SD =7.82
Range =Not
Reported
F Assorted
(8 PMDD, 1 SCZ,
2 MDD, 1 OCD)
Recent Suicide
Attempts Blood sample within 12 h
of attempt: estradiol,
progesterone
Menstrual status determined
with self-report.
Suicide attempts were more
frequent during the
follicular phase.
Estradiol and progesterone
levels were not different in
suicide attempters compared to
healthy controls.
Patients attempting suicide
with OD or admitted to the
ICU were excluded.
Chatzittofis
et al. 2013 28 suicide attempters
(10 female, 18 male)
19 healthy controls
(7 female, 12 male)
SA:
Mean =44
SD =14.6
Range =26–66
HC:
Mean =30
SD =Not Reported
range =23–48
Both Assorted
(14 Mood disorder,
4 Anxiety Disorder,
9 SUD, 19 PD)
History of Suicide
Attempts CSF: DHEA-S, DHEA,
cortisol, and 5-HIAA In males, suicide attempters
had higher CSF DHEA-S
levels compared to healthy
controls.
In females, no significant
differences.
Exposure to early adversity
(e.g., interpersonal violence)
correlated negatively with
cortisol/DHEA-S ratio
Dogra et al. 2007a217 suicide decedents
237 non-suicide decedents 45% of suicide
dececents
ages 21–30
Bimodal
distribution in the
non-suicide
decedents: 23%
ages 20–25, 23%
ages 30–35
Range =11–45
F Not Reported Suicide Death Autopsy
Menstrual status determined
by visual examination of the
uterine cavity
54.46% of non-pregnant
women who died by suicide
were menstruating versus
6.75% in the non-suicide
decedent group
Fouriestié et al.
1986a108 suicide attempters Mean =25.3
SD =4.0
Range =Not
Reported
F Assorted
(9 with previous psychiatric
admission, 15 treated with
neuroleptic and/or
antidepressant medication,
9 treated with anxiolytics,
15 with previous suicide
attempts)
Recent Suicide
Attempts Blood sample within 12 h
of attempt: estradiol and
progesterone
Suicide attempts were more
likely to happen during phases
with low estradiol, during the
first week of the menstrual
cycle (42%) and after the
fourth week (12%).
Frequency of suicide attempts
did not vary significantly
during the menstrual cycle in
OC users.
Patients admitted to the ICU
were excluded.
Gustavsson
et al. 2003 43 suicide attempters Mean=38.0
SD =12.0
Range =Not
Reported
M Assorted
(14 SUD, 9 DDNOS, 10
MDD, 4 Dysthymia,
9 Adjustment disorder,
4 Anxiety disorder, 2
Psychosis)
Recent Suicide
Attempts CSF in days (5–57 days,
mean =16) following
suicide attempt: testosterone
Suicide attempters with
depressive disorders showed
higher CSF testosterone than
those with other psychiatric
diagnoses.
CSF testosterone positively
correlated with irritability
and negatively correlated
with social desirability.
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
Table 1 (continued)
Publication Sample size and characteristics Age (years) Sex Psychiatric condition Suicide-related
outcome Study design and methods Findings Additional notes
Papadopoulou et al.
2018a70 suicide attempters Mean =35.5
SD =8.9
Range =18–52
F Assorted
(28 MDD, 13 BD, 14
Psychosis, 15 PD or
adjustment disorder)
Recent Suicide
Attempts Blood sample within 72 h of
suicide attempt or within 48
h after transfer to the ICU:
progesterone, LH, FSH
Menstrual status determined
with progesterone levels, LH
and FSH were used to rule
out menopausal status
Suicide attempts were more
frequent in the last 4 days of
days of luteal phase and during
the 4 days of menses.
No effect of menstrual status
on lethality (violent vs non-
violent mode of attempt) or
psychiatric diagnosis.
Markianos et al.
2009a15 suicide attempters
(intentional jumps)
18 accident victims
(falling from a height)
40 healthy controls
SA:
Mean =39.9,
SD =14.3,
Range =22–62
Non-SA: Mean =
37.6 SD =15.2
Range =20–66
HC:
Mean =31.6
SD =9.0
Range =25–59
M Assorted
(10 SCZ, 5 MDD) History of Suicide
Attempts Blood: testosterone,
LH, FSH Suicide attempters had lower
levels of testosterone (trending,
p=0.065) and LH compared
to accident victims.
Both suicide attempters and
accident victims had lower
levels of testosterone and LH
compared to HC.
Martin et al. 1997b81 female and 79 male
adolescents Mean =16.0
SD =1.0
Range =15–19
Both Not Reported History of Suicide
Attempts and Suicidal
Ideation
Blood: progesterone In males, progesterone was
higher in those with past
suicide attempts and with
suicide ideation.
In females, progesterone levels
negatively correlated with past
suicide attempts and disclosed
suicide ideation
SUD excluded from
analyses.
Roland et al. 1986 39 suicide decedents
48 non-suicide (sudden death)
decedents
SA:
Mean =39.1
SD =18.3
Range =15–76
HC:
Mean =51.5
SD =13.8
Range =12–79
M Not Reported Suicide Death Autopsy
Blood: testosterone Suicide decedents showed
higher levels of testosterone
compared to non-suicide
decedents.
Sher et al. 2012 67 patients with bipolar
disorders and at least one past
suicide attempt (51 female,
16 male)
Mean =34.5
SD =9.9
Range =18–75
Both Bipolar Disorder History of Suicide
Attempts Blood: testosterone Testosterone levels positively
correlated with the number of
past suicide attempts, while
controlling for sex.
Testosterone levels were also
positively correlated with
number of manic episodes,
while controlling for sex.
Sher et al. 2014 51 patients with bipolar
disorder and at least one past
suicide attempt
Mean =33.2
SD =9.6 F Bipolar Disorder History of and
Prospective Suicide
Attempts (prospective
follow-up for up to
2.5 years)
Blood: testosterone At baseline, testosterone levels
positively correlated with the
number of suicide attempts and
past major depressive episodes.
Higher testosterone levels
predicted suicide attempts in
the follow-up period.
Sher et al. 2018a17 combat veterans with post-
deployment suicide attempt (0
female, 17 male) and 17 non-
suicidal combat veterans
(2 female, 15 male)
SA:
Mean =37.5
SD =11.6
Non-SA: Mean =
35.7 SD =10.8
Both PTSD History of Suicides
Attempt and Suicidal
Ideation
Blood: DHEA, DHEA-S Suicide attempters had lower
levels of DHEA and DHEA-S
compared with nonattempters.
Suicidal ideation negatively
correlated with DHEA and
DHEA-S levels across all
participants.
Suicidal ideation negatively
correlated with DHEA-S levels
in nonattempters.
DHEA/DHEA-S ratios
positively correlate
with adolescent and adult
aggresion scores in suicide
attempters.
T. C. Ho et al.
Table 1 (continued)
Publication Sample size and characteristics Age (years) Sex Psychiatric condition Suicide-related
outcome Study design and methods Findings Additional notes
Stefansson
et al. 2016 28 suicide attempters
(10 female, 18 male)
19 healthy controls
(7 female, 12 male)
SA:
Mean =44.0
SD =14.6
Range =23–66
HC:
Mean =30.0
SD =Not Reported
Range =23–48
Both Assorted (MDD,
PTSD, SUD) Recent Suicide
Attempts and
Prospective Suicide
Death (prospective 21-
year follow-up)
CSF and blood in days
(mean =8.6, range =
2–17 days) following suicide
attempt: testosterone, cortisol
In males, CSF and blood
testosterone levels were higher
in suicide attempters compared
to healthy controls.
In females, no differences.
In males, CSF testosterone/
cortisol ratio positively
correlated with impulsivity
and aggressiveness in the
suicide attempters.
No differences associated
with MDD, PD, or SUD
Tripodianakis
et al. 2006 80 suicide attempters
(29 with schizophrenia)
56 healthy controls
29 nonattempters with
schizophrenia
SA:
Mean =34.4
SD =12.6
HC:
Mean =35.3
SD =8.7
M Schizophrenia History of Suicide
Attempts Blood: testosterone,
LH, FSH Suicide attempters had lower
blood testosterone compared to
healthy controls.
Attempters with schizophrenia
had lower levels of testosterone
compared to nonattempters
with schizophrenia.
Attempters who used a
violent method had lower
testosterone levels than non-
violent attempters.
Zhang et al. 2015 245 suicide attempters
(172 female, 73 male)
245 healthy controls
(172 female, 73 male)
SA:
Mean =42.9
SD =Not Reported
Range =16–50
HC:
Mean =37
SD =Not Reported
Range =14–53
Both Not Reported History of Suicide
Attempts Blood: testosterone In males, testosterone was
higher in male suicide
attempters compared to healthy
controls.
In females, no significant
differences.
Ffemale, FH follicular hormone, DDNOS depressive disorder not otherwise specified, ICU intensive care unit, LH lutenizing hormone, Mmale, MDD major depressive disorder, OC oral
contraceptive, OD overdose, OCD obsessive-compulsive disorder, PTSD post-traumatic stress disorder, SA suicide attempt, SCZ Schizophrenia, SD standard deviation, SUD substance use
disorder.
aLow-quality study due to limited sample size and/or limitations in study design (e.g., single-timepoint cross-sectional associations between ovarian hormones and suicidal thoughts and
behaviors).
bAdolescent sample.
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
neurobiological sensitivity to changes in estradiol and
progesterone—rather than between-person differences in
levels of these hormones—that represents a key trait-like
source of variance for understanding suicide risk in the
context of puberty, a time when the stability of these hor-
mone dynamics is still in flux [47]. Intensive (e.g., daily
samples) longitudinal studies conducted in adult women
have also provided little evidence that hormone levels at a
single point in time are correlated with levels within the
same cycle and also for subsequent cycles, particularly for
estradiol [48,49]. It is also important to note that both
between-person and within-person variability of ovarian
hormone levels are affected by multiple confounds that
investigators ought to consider, including, but not limited,
to cycle length [50], diurnal effects [51], cycle phase
[48,49], effects of study participation [48], anovulation
[52], culture and/or diet [53], and personal and family
medical history (e.g., polycystic ovary syndrome, breast
cancer [48,54]). Nevertheless, dense-sampling studies have
demonstrated robust between-person effects of menstrual
phase, such that progesterone is reliably higher in the luteal
phase relative to the follicular phase and, albeit to a lesser
extent, estradiol is higher in the follicular phase relative to
the luteal phase [48,49]. We note in Table 1which studies
employ non-experimental cross-sectional designs and that
attempt to relate ovarian hormones without consideration of
these relevant factors (e.g., cycle phase).
Given these limitations in measuring ovarian hormones,
it is not surprising that little is known about the effects of
estradiol and progesterone on the human brain in general,
much less on the circuits we have hypothesized are impli-
cated in STB risk. Nonetheless, there is evidence that
estrogen receptors are expressed strongly in brain regions
involved in social cognition broadly and social rejection
specifically, including the amygdala, hippocampus, ACC,
and vmPFC [55–58]. Several studies have also found that
women with comparably higher levels of estradiol (endo-
genous or synthetic) show greater amygdala-based resting-
state functional connectivity and activation in ACC and
vmPFC, which are key regions involved in processing
salient information [59–61]. Similarly, longitudinal studies
with naturally cycling women have documented larger
hippocampal gray matter volumes during periods of rela-
tively high estradiol (late follicular/preovulatory phases)
than of relatively low estradiol early follicular/premenstrual
phases [62,63].
There is also evidence from functional magnetic reso-
nance imaging (fMRI) studies wherein groups of women
during different phases of their menstrual cycle are com-
pared that show that relatively higher levels of estradiol
(pre-ovulatory phase) are associated with greater activation
of the hippocampus during both cognitive tasks [64] and
affective stress tests [65], and with stronger functional
connectivity of the hippocampus with brain regions
involved in processing salient information [63]. Similarly,
higher levels of progesterone (luteal phase) have also been
found to be associated with activation of the striatum and
PFC during cognitive processing [64]. Finally, results from
fMRI studies utilizing dense-sampling designs of naturally
cycling women have reported intriguing, albeit inconsistent,
results. One study found no effects of estradiol across the
menstrual cycle on intrinsic connectivity patterns [66],
whereas another found that higher levels of estradiol drove
stronger subsequent connectivity within attention networks
(specifically among brain circuits that are implicated in
internally focused attentional states and externally focused
attentional states) [67]. In contrast, one study found that
progesterone mediated patterns of positive functional con-
nectivity between the hippocampus and PFC [66] whereas
another study found that higher levels of progesterone was
associated with lower connectivity across all networks [67].
It is clear that additional research is needed to clarify the
magnitude and directionality of the effects of estradiol and
progesterone on patterns of brain connectivity, particularly
in adolescents, and their effects on longer-term neurode-
velopmental trajectories. It is also critical that researchers
work to characterize the extent to which these hormones
effect brain circuits specific to STBs, or alternatively,
whether they are implicated in mental illness risk more
broadly. Nevertheless, the studies we have reviewed pro-
vide initial evidence that brain circuits that support the
regulation of affectively salient stimuli are sensitive to the
effects of estradiol and progesterone; importantly, these
same circuits have also been shown to be affected in adults
and adolescents with STBs [28,68].
Additional research is also needed to elucidate the pre-
cise neural mechanisms by which estradiol may impact the
development of brain circuits, including its effects on neu-
rotransmitters. Estradiol has also been found to alter ser-
otonin transmission, binding, and metabolism by increasing
the production of tryptophan and inhibiting the expression
of the serotonin reuptake transporter gene (for a review, see
[69]). Serotoninergic abnormalities in the number of ser-
otonergic neurons and in serotonin transportation, receptor
binding, and levels have all been found in victims of suicide
[70,71] (for a review, see [72]). Serotonin has been shown
to be associated with cortisol reactivity to stressors [73]
and positively associated with greater 5-HT1A receptor
binding—which could contribute to lower serotonin sig-
naling by inhibiting further serotonin release into the
synapse—in depressed patients who died by suicide versus
both depressed and psychiatrically healthy individuals who
did not die by suicide [74]. Similarly, allopregnanolone, a
progesterone metabolite, binds to GABAAreceptors, which
mediates the majority of inhibitory signaling in the brain
[75] and plays an important role in downregulating the
T. C. Ho et al.
HPA-axis in response to acute stressors [76]. Several stu-
dies have found that stress exposure alters the availability of
GABAAreceptors as well as their composition and sensi-
tivity to neurosteroid regulation, which, in turn, can influ-
ence subsequent responses to stress [77–79]. Emerging data
has also implicated GABA dysfunction in STBs, whereby
depressed patients who died by suicide showed a higher
expression of genes that encode for proteins involved in
GABAergic synaptic transmission in the ACC and a lower
expression of these genes in the dorsolateral PFC than did
both depressed and psychiatrically healthy individuals who
did not die by suicide [80]. Future work is needed to
explicitly investigate the extent to which patterns of struc-
tural or functional connectivity of circuits involving the
amygdala, hippocampus, ACC, and PFC that are develop-
ing in response to puberty-related changes in estradiol and
progesterone (and related neurosteroids) exhibit corre-
sponding changes in neurotransmitter systems that support
socioemotional processes relevant to STB risk.
Testosterone
Unlike ovarian hormones, which have been studied pri-
marily in female adolescents, investigators have found in
both sexes that levels of androgens are associated with
appetitive behaviors, aggression, competition, and other
related social behaviors that are relevant to STB risk
[81,82]. In female adolescents, the sex steroid with the
most androgenic activity is DHEA, which is produced by
the adrenal cortex (discussed separately in the following
section); in males adolescents, it is testosterone [31,32].
In contrast to the data published thus far on ovarian
hormones, there is evidence of strong within-person relia-
bility and stability in testosterone levels in both men and
women. Indeed, some researchers contend that levels of
testosterone are trait-like [83]. Perhaps not surprising, tes-
tosterone has been linked more strongly with STB risk, and
specifically with suicide attempts, than has any other pub-
ertal hormone (see Table 1). However, the empirical find-
ings thus far have been mixed (for opposing reviews, see
[84,85]). Several researchers have theorized that testoster-
one is linked to suicidal behaviors through its modulation of
emotion-related impulsivity and impulsive aggression,
which are considered to be among the most robust predis-
posing traits to suicidal behaviors in youth [86]. In drawing
from the literature of studies in which testosterone is
administered and behaviors are subsequently assessed, as
well as studies that link changes in social interactions with
changes in endogenous testosterone, there appear to be
reliable effects of testosterone on socially motivated beha-
viors, including exerting dominance and displays of
aggression (either physically or non-physically) and other
social status seeking behaviors (for a review, see [87]).
While testosterone exert complex effects on interpersonal
behavior, longitudinal studies show that the puberty-related
increases in testosterone are not accompanied by a con-
current rise in aggressive behaviors [83,88,89]. Additional
studies in animals as well as in humans [90] suggest that
testosterone levels correlate more closely with social dom-
inance, rather than aggressive behaviors. Hence, testoster-
one may be an important moderator of the behavioral
response to events associated with loss of social status [91],
which are known precipitants of STBs. In the context of
adolescent STB risk, it may very well be that testosterone is
a driver of heightened sensitivity to social context, which
can lead to significant emotion dysregulation and impulse
control and, in turn, elevated STB risk.
Consistent with these points is evidence that elevated
testosterone has also been found in male adults to be
associated with psychological states and individual traits
associated with suicide risk, including depression severity,
irritability, and impulsive aggression [92,93]. Researchers
have found higher levels of testosterone in both male and
female suicide attempters than in their same-sex non-
attempting counterparts [94], and in post-mortem samples
of suicide completers compared to individuals who died
from other causes [95]. In a recent study, male, but not
female, young adults who attempted suicide had higher
levels of testosterone than did age- and sex-matched healthy
volunteers [92]. Thus, there studies do not preclude the
possibility that testosterone levels are higher in individuals
with a mental disorder than they are in healthy persons. One
study found in women with bipolar disorder with a history
of suicide attempt that higher testosterone levels predicted
subsequent suicide attempts [96]. Interestingly, in another
sample of men and women with bipolar disorder, higher
levels of testosterone were associated with number of sui-
cide attempts only after controlling for sex [97]. In contrast,
other studies have found lower levels of testosterone both in
male suicide attempters relative to psychiatric healthy
controls [98] and in patients who were hospitalized due to
accidents [99]. One possible discrepancy for these findings
involves the measurement of testosterone in plasma versus
cerebrospinal fluid; studies assaying plasma testosterone
have typically reported inverse associations with suicide
attempts. Nevertheless, it is clear that adequate clinical
controls (attempters or completers relative to nonattempters
who otherwise have similar clinical histories) must be
included in research in order to clarify the results of these
studies.
As is the case with research on ovarian hormones and
STBs, no studies have examined the psychobiological
mechanisms and specific brain circuits through which tes-
tosterone may drive risk for STBs in either adolescents or
adults. Testosterone influences many of the same neuro-
transmitters as does estradiol [25]; moreover, testosterone
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
can be converted into estradiol via aromization [100],
adding additional complexity in these processes should be
addressed in future work. That said, one pathway through
which testosterone may affect mood and cognition is
through altering dopaminergic neurotransmission: several
studies have found evidence of differences between suicide
attempters and completers in dopamine receptor density,
transporter binding capacity, and metabolism [101–103],
primarily in the striatum. In fact, testosterone receptors are
widely expressed in dopaminergic neurons of the striatum
and portions of the PFC, including vmPFC and OFC [104].
Research with both macaques and humans has documented
changes in the mechanisms that underlie dopamine signal-
ing during adolescence, which may be explained, in part, by
effects of testosterone (and estrogen; for reviews, see
[105,106]). In particular, testosterone has been shown to
increase basal dopamine levels and decrease the number of
enzymes that break down dopamine in the striatum and PFC
[105]. Consequently, it is possible that adolescent-typical
increases in testosterone during puberty, especially in boys,
contribute to elevated STB risk through enhanced dopami-
nergic transmission. This is consistent with previous reports
that, compared to depressed patients who did not die by
suicide, depressed patients who die by suicide have lower
growth hormone responses to apomorphine [102,107],
which is an indication of higher dopamine transporter
binding [108]. Nonetheless, it is important to note that some
studies provide evidence of lower dopamine (measured by
lower levels of homovanillic acid and total dopamine in
urine) in patients who attempted suicide versus those who
did not, see [103], or of no significant associations between
dopamine levels/receptor binding and STBs [109].
With respect to brain development, higher levels of
pubertal testosterone have been associated with white
matter organization in tracts implicated in social cognition
and emotion regulation, including the uncinate fasciculus
(which connects the amygdala and vmPFC) and corpus
callosum in both boys [110,111] and girls [29,112].
Several researchers have documented other effects of tes-
tosterone on adolescent and young adult brain and behavior.
Human neuroimaging studies using fMRI have shown that
in healthy young men, activation in the amygdala—a brain
structure that is rich in androgen receptors [63] and is
affected by circulating androgens [64]—to fearful and angry
faces co-varies positively with individual differences in
serum testosterone concentrations [65,66] (but see [67] for
opposing results). In an experimental study, administration
of testosterone was associated with increased amygdala
reactivity to threat-related stimuli in young women [113].
These results are consistent with a longitudinal study in
adolescents that found that increased levels of pubertal
testosterone disrupted typical coupling between the amyg-
dala and OFC, leading to increased amygdala reactivity to
threat-related stimuli in both sexes [114]. Finally, whereas
in boys higher testosterone levels are associated with lower
activation in the striatum and PFC during processing of
emotional conflict, in girls higher testosterone levels are
associated with lower activation in the PCC/precuneus
[115]. Other investigators have shown in both boys and
girls that higher levels of testosterone are associated with
higher striatal activation during reward consumption [116],
and with higher striatal activation when adolescents select
smaller yet more immediate rewards [117]. In an observa-
tional longitudinal neuroimaging study in male and female
adolescents between the ages of 8–27 years, activation in
the striatum (nucleus accumbens) to rewarding stimuli
peaked during adolescence, and was associated with
accompanying changes in testosterone levels [118]. In a
recent study, in which salivary testosterone was measured in
adolescents before and after a neuroimaging scan, acute
increases in testosterone were associated with smaller dif-
ferences in activation between reward cues signaling reward
or non-reward outcomes for a given trial in vmPFC and
posterior cingulate cortex (PCC) in both sexes [119]. Thus,
by altering neural processing of both negative (e.g., threa-
tening) and positive (e.g., rewarding) valenced stimuli,
testosterone may be facilitating the expression of adolescent
sensation-seeking and risk-taking behavior [118] through
dopaminergic transmission among these subcortical and
prefrontal circuits. Certainly, these processes may not be
specific to STBs and may represent a more general diathesis
for mental disorders that are characterized by sensation-
seeking and risky behaviors; however, future research is
needed to test this possibility more explicitly.
In sum, studies to date have demonstrated that higher
levels of testosterone are associated with aspects of emotion-
related impulsivity in males with a history of suicidal
behaviors (e.g., attempts). Higher levels of testosterone are
also associated with steeper temporal discounting of rewards
driven by patterns of activation in striatal, vmPFC, and OFC
in both sexes; sex differences in the effect of testosterone on
adolescent brain circuits appear to be most prominent in
emotion-related contexts. Indeed, in adults, both endogen-
enous levels [120] and exogenous administration [121]of
testosterone enhance risk taking. The predisposition to take
risky decision has been shown to be a critical risk factor for
suicidal behavior in adults [122] and, to a lesser extent given
the sparse literature on this topic, in adolescents [123].
Hence, functional alterations in decision-making systems
induced by puberty-related rises in testosterone levels, or
their context-dependent fluctuations, might be related to
suicidal risk through an increase probability of perpetrating
highly risky and self-destructive behaviors in the face of
overwhelming stress (particularly social stressors involving
loss of desired status). Future work is needed to test expli-
citly whether higher levels of testosterone exacerbate affect
T. C. Ho et al.
striatal and PFC systems underlying maladaptive responses
to social stressors that, in turn, lead to heightened risk
for STBs.
DHEA
DHEA (and its sulfate, DHEA-S) is the most abundant
steroid hormone in humans and is a precursor to sex ster-
oids. Researchers have not yet examined the relation
between DHEA (or DHEA-S) and STBs in adolescents;
moreover, and the few studies that have been conducted
with adults differ in their measurement of DHEA. One
study showed that male suicide attempters had higher levels
of DHEA-S than did healthy controls, and that exposure to
extreme social threat (i.e., interpersonal violence) as a child
was negatively correlated with the ratio of cortisol/DHEA-S
[124]. Among adults diagnosed with PTSD, those who had
attempted suicide had significantly higher levels of DHEA
than did those without a history of attempt [125]. Another
study found that, in combat veterans, the ratio of DHEA/
DHEA-S was positively correlated with total adolescent
aggression scores, total adulthood aggression scores, and
lifetime aggression scores in those who had attempted sui-
cide but not in nonattempters [126].
Overall, these studies suggest that higher levels of DHEA
or DHEA-S may be associated with risk for STBs. Indeed,
DHEA modulates neurotransmitter systems implicated in
suicidal thoughts and mood disturbances, including acting as
an antagonist for GABA receptors, with genes widely
expressed in hippocampus, amygdala, and striatum [127].
There is also intriguing evidence that psychiatric conditions
characterized by excessive stress and elevated suicide risk
lead to a downregulation of neurosteroid biosynthesis—
including the conversion of DHEA to GABAergic metabo-
lites, such as allopregnanolone [128]—and changes in
GABAAreceptor subunit composition [129]. Thus, STB risk
may be associated with higher levels of DHEA due to an
insufficient ability to metabolize DHEA. With respect to the
effects of DHEA on the adolescent brain, however, there
have been a small number of studies. Thus, far investigators
have found that higher levels of DHEA are associated with
larger hippocampal volumes in both male and female ado-
lescents [130] and with lower white matter organization
across a broad set of white matter tracts [110]. Other studies
have found that higher DHEA levels are associated with
reduced cingulate activation and greater functional con-
nectivity between the amygdala with ACC and other regions
involved in processing salient information in adolescents
during the processing of social stimuli (e.g., viewing fearful
faces) [131]. Moreover, higher DHEA levels are associated
in girls with lower activation in cingulate regions implicated
in processing salience information and with greater exter-
nalizing problems [132], but in boys with stronger functional
connectivity between the amygdala and inferior frontal gyrus
(the opposite pattern was found in girls) and with higher
anxiety symptoms [131].
Despite the heterogeneity in clinical, developmental, and
demographic features across the studies reviewed in this
section, there appear to be consistent associations between
higher levels of DHEA and both STBs and altered structure
and function of brain circuits underlying emotion regula-
tion. In adults with clinical disorders, higher levels of
DHEA (either alone or relative to cortisol) appear to be
associated with STBs. In psychiatrically healthy adoles-
cents, higher levels of DHEA are associated with reduced
downregulation of affective signals in the amygdala from
emotion regulatory cortical regions, including the ACC and
portions of the PFC. Thus, higher levels of DHEA may
disrupt the development of emotion regulatory brain circuits
across adolescence in ways that increase risk for STBs
when individuals are exposed to interpersonal stressors
(particularly those characterized by threat). However, it is
worth noting one study of psychiatrically healthy adults in
which administration of exogenous DHEA reduced activa-
tion in the amygdala and hippocampus, increased activation
in the vmPFC, and led to stronger connectivity between the
amygdala and hippocampus during an emotion reappraisal
task; moreover, decreased activation in the hippocampus
during the task was associated with lower negative affect,
suggesting that higher levels of DHEA improve negative
mood by downregulating affective signals in the hippo-
campus [133]. Additional research is needed to examine
whether these associations hold in clinical samples of
adolescents and whether (or how) they are related to risk
for STBs.
Consideration of sex differences
Across most countries, being female increases the risk of
suicidal thoughts and related behaviors [5]. Despite this
higher prevalence of STBs in women, men are more likely to
die by suicide [134], leading to “the gender paradox of sui-
cide.”It is notable that the sex difference in suicide deaths
increases dramatically in adolescence [135], suggesting that
puberty plays an important role in explaining this difference
(although this sex difference is now narrowing among ado-
lescents [136], indicating that other factors, including envir-
onmental or cultural influences, are also likely). Whereas past-
year ideation, plans, and attempts tend to peak during mid-
adolescence (~16 years) in girls, these rates increase steadily
throughout mid- to late adolescence in boys [137,138].
As in adults [5,139], there are sex differences in suicide-
related outcomes in adolescents that are mediated in part by
differences in lethality and mental illness. In a psycholo-
gical autopsy study, adolescent male suicide victims were
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
more likely to use lethal methods and had a higher pre-
valence of conduct disorder than did female victims [140].
A recent meta-analysis of sex-specific suicide risk in ado-
lescents (ages 12–26 years) found distinct clinical and
environmental risk factors for suicide attempt in male and
female adolescents [139]. Thus, in addition to the hormonal
differences that underlie sex-specific neurodevelopmental
changes, different clinical conditions (externalizing dis-
orders in boys versus mood disorders in girls) and social
stressors (peer influence in boys versus direct trauma/vic-
timization from romantic relationships in girls) may further
explain or moderate these pathways to risk for STBs.
Because of the sparse literature, however, it is not clear
whether sex-specific risk factors are present before puberty,
whether puberty affects neuroendocrine systems in sex-
specific ways to increase risk for STBs, or whether boys and
girls are exposed to differential environmental risk factors
as a result of going through puberty. Future research should
attempt to clarify the extent to which pubertal processes
play a central role in STBs or whether they are implicated in
mental illness more generally.
While adrenal and gonadal hormones and physical
maturation are important indicators of pubertal develop-
ment, other aspects of puberty may be relevant in the
context of adolescent risk for STBs. Pubertal timing—the
age at which individuals mature relative to their peers
[141]—has been linked to individual differences in mental
disorders in adolescence [142,143]. Moreover, the timing
of pubertal onset may have a different impact on devel-
oping neuroendocrine function depending on whether it
occurs earlier or later in a given individual [34,139].
Given that girls typically enter puberty earlier than do
boys, considering the role of pubertal timing may also
elucidate sex differences in risk for STB—as well
as mental illness more generally—and accompanying
endocrine and neural processes. A growing number of
studies are reporting that early menarche is associated
with elevated risk for suicidal ideation in adolescent girls
[144–146]. In a recent longitudinal study of a large birth
cohort, earlier age of menarche was associated with
increased suicidal behaviors at 16 and 21 years of age
[147], suggesting that earlier puberty has an enduring
effect on STB risk throughout adolescence and young
adulthood. In addition, considerable evidence suggests
that pubertal timing is influenced by early life adversity
[148], which itself is a robust predictor of STBs [149].
Thus, early puberty resulting from early adversity may be
a mechanism by which suicide risk is instantiated or
exacerbated in vulnerable adolescents. Finally, it is
important to acknowledge that sexual orientation and
identification as a sexual minority are increasingly being
recognized as risk factors for STBs [150]; more research
in this area is critically needed.
Future directions
No research has yet examined whether and how pubertal
hormones affect neurodevelopmental trajectories of brain
circuits that mediate social cognition and emotion-related
impulsivity explain risk for STBs during adolescence.
Studies are needed to clarify the role of pubertal timing and
the multidimensional mechanisms—biological, social, cul-
tural—by which puberty-related processes influence risk for
STBs. An important next step for the field is to first
establish reliable associations between pubertal hormones
and adolescent brain structure and function and to then map
those associations onto neural circuits underlying STBs in
adolescents. Other critical knowledge gaps include disen-
tangling neuroendocrine mechanisms that are more closely
linked to suicidal thoughts versus attempts (and other self-
harming behaviors) and that facilitate the transition from
ideation to action [151].
Although we focused here on the effects of pubertal
hormones, we should acknowledge that there is consider-
able evidence that HPA-axis dysfunction is associated with
STBs and self-harming behaviors in adolescents
[13,21,152,153]. Puberty is also the time when HPG-axis
regulation of the HPA axis develops [154–157]. Given that
the expected suppression of the HPA axis by the HPG axis
[158] is disrupted in individuals at risk for STBs (due to
such factors altering developmental changes in stress
response and regulatory systems, including experiences of
adversity and exposure to trauma during early life [154]), it
is critical that researchers explicitly examine the role of
puberty in this context.
It is also important that researchers in this area consider
moving away from a nomothetic framework for the pre-
diction of STBs and instead adopting idiographic or person-
centered models. Puberty is a highly individualized process;
adolescents differ markedly in their hormone levels, their
neurobiological sensitivity to typical endocrine changes
[14], their pubertal timing, their neurodevelopmental tra-
jectories, and their psychological responses to maturation.
Certainly, measuring these variables at the individual level
is challenging and will have to take into account population
norms on several dimensions (e.g., ethnicity, socio-
demographic factors). Absent such data, standardization
within age bands or residualized scores (e.g., regressing
pubertal stage on age to obtain a measurement of pubertal
timing) can be used to capture individual variability (for a
treatment of these issues, see [159]). Another solution is to
use “dense sampling”approaches that leverage repeated
assessments (e.g., self-reported mood states, saliva samples,
neurobiological measurements) from the same individual in
order to capture intra-individual variation in these processes
[13], which we argue is critical for understanding the con-
tribution of ovarian hormones in risk for STBs in adolescent
T. C. Ho et al.
females. Dense-sampling has the additional advantage of
being able to identify proximal factors that lead to suicidal
states and other related high-risk events, which are often
transient and rarely captured in the laboratory or clinic
[160].
Other important study design considerations include larger
sample sizes of both sexes in order to detect sex differences
more reliably. As we alluded to in the earlier sections of our
review, there are other important confounds to consider that
will affect the reliability and validity of estimating the effects
of within-person changes in sex hormones on brain and
behavior. These confounds include genetic factors, environ-
mental influences, medical conditions, and cycle length (given
that the range of menstrual cycles and periods of anovulation
are longer in adolescents than in adults, particularly in the first
few years post-menarche [161]). Finally, understanding the
normative associations between changes in hormones with the
structural and functional development of the brain is a critical
next step that must be established before understanding how
these alterations are altered in individuals at risk for STBs.
Gaining a more comprehensive understanding of neurobio-
logical trajectories and the mechanisms of neuroplasticity in
adolescents as a consequence of puberty will also contribute
to our knowledge of sex-specific psychiatric interventions and
may help to address the heterogeneity of risk factors identified
to date [5]. For instance, the granularity of data obtained from
dense-sampling methods will facilitate the identification of
individuals with hormonal sensitivity to the typical fluctua-
tions occurring during puberty, as well as characterize within-
person pubertal processes associated with responses to social
stressors and poorer impulse control during heightened
emotional conflict. With this information, researchers and
clinicians will be able to stratify individuals on the basis of
neuroendocrine risk (e.g., those with hormone sensitivity) and
also to identify points in time (e.g., dramatic increases in
stress perception or depressive symptoms, unusual variability
in DHEA) during which an individual might benefitfrom
immediate intervention.
Summary and conclusions
Globally, suicide has surpassed all physical diseases as a
cause of death in adolescents. Puberty drives psychobiolo-
gical changes in adolescence that have not been examined
explicitly in relation to suicide risk. In this review, we
conceptualized suicidal thoughts and behaviors in adoles-
cents as resulting from pathological responses to social
stressors at a time when stress-regulatory systems are still
maturing. We argued that alterations in brain circuits—
comprised of connections among the amygdala, hippo-
campus, striatum, ACC, vmPFC, and OFC—that underlie
social cognition, emotion regulation, and impulse control
and are shaped by puberty-related changes in sex hormones.
We propose that alterations in these circuits may partially
explain the ways in which changes in sex hormones are
linked with increased suicidal thoughts and behaviors dur-
ing adolescence. However, we also highlighted critical
moderators to be considered in this model, including a
neurobiological sensitivity to fluctuations in ovarian hor-
mones, exposure to early adversity, and underlying mental
disorders (Fig. 2). To date, these specific hypotheses have
not been tested. Although there is emerging research iden-
tifying shared and unique neural circuits that underlie sui-
cidal thoughts and behaviors [68], it is paramount that that
these associations be examined in prospective studies. It
will also be important to use both experimental designs and
large-scale longitudinal studies to elucidate the extent to
which pubertal hormones affect the acute functioning of
these circuits and drive the development of these circuits
over the course of adolescence and young adulthood.
Moreover, we expect that although pubertal hormones are
not a primary driver of suicide risk, they may play an
outsized role in individuals with a neurobiological sensi-
tivity to hormonal fluctuations. Therefore, it is critical that
we identify key moderators of the paths in our model, which
we hypothesize includes neurobiological sensitivity to
hormonal fluctuations, experiences of adversity and life
Fig. 2 Conceptual model linking aspects of the pubertal transition
with risk for suicidal thoughts and behaviors. Experiences of early
adversity affect the programming and development of endocrine and
neural systems which undergo significant maturation during puberty.
Puberty-related changes in ovarian, gonadal, and other related hor-
mones shape the neural circuits underlying social cognition, emotion
regulation, and impulse control (which include structures such as the
amygdala, hippocampus, striatum, anterior cingulate cortex, and por-
tions of prefrontal cortex). Alterations in these circuits may partially
explain the ways in which changes in sex hormones are linked with the
emergence of suicidal thoughts and behaviors during adolescence.
Moderators of these processes, including a neurobiological sensitivity
to ovarian hormones, experience of ongoing life stressors, and
underlying mental disorders, are highlighted in red.
Psychobiological risk factors for suicidal thoughts and behaviors in adolescence: a consideration of. . .
stress that influence neurodevelopmental trajectories
(which, in turn, may result in generating and experiencing
additional stress), and underlying mental disorders. In
addition to conducting longitudinal studies with larger
sample sizes, we suggest that researchers also use dense-
sampling methods to identify individuals according to these
stratification parameters (e.g., hormonal sensitivity), as well
as points in time at which individuals may be at risk and
could benefit from more immediate intervention. In con-
clusion, we want to emphasize that increasing our under-
standing of pubertal science across endocrine, neural, and
psychosocial domains will yield significant insights con-
cerning how best to reduce the frequency of suicide-related
deaths during the vulnerable period of adolescence.
Acknowledgements This work was supported by the National Institute
of Mental Health (R37MH101495 to IHG, K01MH117442 to TCH),
the Fonds de Recherche du Québec—Santé (FRQS/MSSS Resident
Physician Health Research Career Training Program to AJG), Preci-
sion Health and Integrated Diagnostics Center at Stanford (PHIND to
IHG and TCH), and the Ray and Dagmar Dolby Family Fund (to
TCH). The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes of
Health. All authors report no biomedical conflicts of interest. The
funding agencies played no role in the design and conduct of the study;
collection, management, analysis, and interpretation of the data; and
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