Cortisol reactivity to social stress in adolescents: role of depression severity and child maltreatment.
ABSTRACT This study examined the hypothesis that depressed adolescents with a history of childhood maltreatment will show greater cortisol reactivity to psychological stress challenge than those without, and this relation will be moderated by level of depression severity. Seventy-one adolescents were exposed to the Trier Social Stress Test. Salivary cortisol was assessed at baseline, immediately before the challenge, after the challenge, and during an extended recovery period. Childhood maltreatment was assessed with a rigorous contextual interview and rating system. Adolescents with a history of maltreatment produced higher and more prolonged levels of cortisol in response to the challenge than did adolescents with no maltreatment, but only among those with a mild/moderate level of depression severity. Those with moderate/severe depression exhibited a blunted cortisol response regardless of child maltreatment history. These findings indicate that depression is a heterogeneous syndrome, and that both depression severity and child maltreatment history should be considered in studies examining biological stress reactivity.
- [Show abstract] [Hide abstract]
ABSTRACT: Terrorist attacks have been shown to precipitate posttraumatic stress disorder (PTSD) symptomatology in children and adolescents, particularly among youths with high exposure to media coverage surrounding such events. Media exposure may be particularly likely to trigger PTSD symptoms in youths with high physiological reactivity to stress or with prior psychopathology or exposure to violence. We examined the interplay between media exposure, preattack psychopathology, autonomic nervous system (ANS) reactivity, and prior violence exposure in predicting PTSD symptom onset following the terrorist attack at the 2013 Boston Marathon.Depression and Anxiety 07/2014; 31(7):551-8. · 4.29 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Childhood maltreatment has been shown to have a stronger etiological relation to depression onset in adolescence than in adulthood. We propose that a maltreatment history may more strongly sensitize individuals to the depressogenic effects of proximal stressful life events in adolescence compared to adulthood. In an amalgamated sample of 176 unipolar depressed adolescents (age 12-17) and emerging adults (age 18-29), we examined the moderating role of age group on the relation of childhood maltreatment to sensitization to stressors that occurred just prior to episode onset. Among adolescents, but not among adults, those with a maltreatment history reported a lower severity level of life events prior to episode onset than reported by those without such a history. Further, this relation was specific to emotional abuse, and not physical or sexual abuse. We suggest that the pathological mechanisms associated with translating childhood maltreatment to depression may differ across developmental periods.Journal of Adolescence 06/2014; 37(6):871-882. · 2.05 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The effects of early life adversity can be observed across the lifespan, and the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes could be mechanistic intermediaries underlying this phenomenon. The current study examined 50 adolescent males aged 12-18 in a maximum-security correctional and treatment setting. Saliva samples were collected five times a day for 2 days and assayed for cortisol, testosterone, and DHEA. Youth completed semi-structured life stress interviews and self-reports of child maltreatment to index adversity. When youth had higher testosterone levels, they had higher cortisol and DHEA levels, indicating positive "coupling" of the HPA-HPG axes. In addition, children experiencing greater life adversity had tighter coupling of the HPA-HPG axes. Additional analyses hint that coupling may be driven largely by HPG axis functioning. Results indicate that positive coupling of the HPA-HPG axis is observed within incarcerated adolescents, especially for those with the greatest life stress. © 2014 Wiley Periodicals, Inc. Dev Psychobiol.Developmental Psychobiology 09/2014; · 3.16 Impact Factor
Cortisol reactivity to social stress in adolescents:
Role of depression severity and child maltreatment
Kate L. Harknessa,*, Jeremy G. Stewarta,1, Katherine E. Wynne-Edwardsb,2
aDepartment of Psychology, Queen’s University, Kingston, ON K7L 3N6, Canada
bFaculty of Veterinary Medicine, University of Calgary, HRIC 1AC68, 3330 Hospital Drive NW, Calgary AB T2N 4N1, Canada
Received 15 December 2009; received in revised form 14 May 2010; accepted 6 July 2010
Forty years of research has consistently documented dysre-
gulation of hypothalamic-pituitary-adrenal (HPA) axis func-
tioning in the pathophysiology of adult major depressive
more, a recent meta-analysis of HPA axis function in 41
studies employing primarily adolescent samples reported
that adolescents with MDD show greater cortisol production
(or less suppression) after the dexamethasone suppression
test (DST; d = .57), as well as higher basal cortisol levels
(d = .20), in comparison to non-depressed groups (Lopez-
Duran et al., 2009).
indices of HPA axis functioning because they fail to assess the
endogenous response of the HPA axis to psychological stress
(Rao et al., 2008). Therefore, more recently investigators
have used psychological challenge paradigms such as the
Trier Social Stress Test (TSST) (Kirschbaum et al., 1993).
The TSST is one of the few available stress protocols that
Psychoneuroendocrinology (2011) 36, 173—181
Trier Social Stress Test;
childhood maltreatment will show greater cortisol reactivity to psychological stress challenge
than those without, and this relation will be moderated by level of depression severity. Seventy-
one adolescents were exposed to the Trier Social Stress Test. Salivary cortisol was assessed at
baseline, immediately before the challenge, after the challenge, and during an extended
recovery period. Childhood maltreatment was assessed with a rigorous contextual interview
and rating system. Adolescents with a history of maltreatment produced higher and more
prolonged levels of cortisol in response to the challenge than did adolescents with no maltreat-
ment, but only among those with a mild/moderate level of depression severity. Those with
moderate/severe depression exhibited a blunted cortisol response regardless of child maltreat-
ment history. These findings indicate that depression is a heterogeneous syndrome, and that both
depression severity and child maltreatment history should be considered in studies examining
biological stress reactivity.
# 2010 Elsevier Ltd. All rights reserved.
This study examined the hypothesis that depressed adolescents with a history of
E-mail addresses: firstname.lastname@example.org (K.L. Harkness),
email@example.com (J.G. Stewart), firstname.lastname@example.org
1Tel.: +1 613 533 6003; fax: +1 613 533 2499.
2Tel.: +1 403 210 6331; fax: +1 403 210 9550.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/psyneuen
0306-4530/$ — see front matter # 2010 Elsevier Ltd. All rights reserved.
combines elements of uncontrollability and high levels of
social-evaluative threat. Stress tasks containing these two
components are associated with the largest HPA axis stress
responses and the longest recovery times (Dickerson and
Meta-analytic results in adults have indicated that
depressed individuals show blunted cortisol reactivity in
response to psychological challenge, particularly in older
and more severely depressed individuals (Burke et al.,
2005). Only one study to our knowledge has compared
depressed versus non-depressed adolescents using the TSST
secretion in response to the TSSTin depressed adolescents. In
younger children, studies have found blunted cortisol reactiv-
2004). Several investigators have argued, however, that a
distinction needs to be made between child and adolescent
MDD, particularly with respect to HPA axis function (Kaufman
and Charney, 2003; Kaufman et al., 2001). Therefore, results
across these two sets of studies may not be comparable.
Nevertheless, what is consistent across most studies using
challenge paradigms in adult and pediatric MDD is a much
larger variability in cortisol response within the depressed
group versus the non-depressed individuals (Lopez-Duran
et al., 2009). It is this heterogeneity within MDD that may
help to account for inconsistencies in results across studies.
Two important sources of individual variability that have
consequences for the HPA axis system are (a) a history of
childhood maltreatment, and (b) individual differences in
depression severity. On the one hand, research in both adult
and child/adolescent samples has found that childhood mal-
treatment is associated with increased cortisol reactivity in
response to biological (e.g., corticotropin-releasing hormone
[CRH]) and psychological stress challenge (De Bellis et al.,
1994; Heim et al., 2000, 2001, 2002; Kaufman et al., 1997;
Rao et al., 2008;). On the other hand, there is a literature in
adults linking severe depression to blunted cortisol reactivity
response to stress challenge (Burke et al., 2005). Severe
melancholic depression, in particular, has been linked to
biological markers in the HPA axis (e.g., nonsuppression on
the DST), and HPA axis parameters appear to be among the
strongest discriminators of melancholic versus non-melan-
and Scott, 2005; Tsigos and Chrousos, 2002; Zimmerman
et al., 1985).
It is noteworthy that these two lines of research reveal an
opposing pattern of HPA function; that is, childhood mal-
treatment is associated with heightened reactivity, and high
depression severity is associated with blunted reactivity.
Childhood maltreatment and depression severity are, them-
selves, highly correlated (Harkness and Monroe, 2002).
Therefore, it is possible that failure to take both of these
sources of heterogeneity into account in research on the HPA
axis in MDD may at least in part explain inconsistencies in
findings across studies. To date, however, there have been no
studies examining the relation of individual differences in
depression severity to cortisol reactivity in adolescents, nor
have there been any studies in either adults or adolescents
examining the interaction of childhood maltreatment and
depression severity on HPA axis function.
The goal ofthe present study wasto examinethe relation
of childhood maltreatment, depression severity, and their
interaction, to cortisol reactivity and total cortisol expo-
sure in response to the TSST. We hypothesized that (a)
consistent with the adult literature, adolescents with
MDD will show blunted cortisol reactivity and lower total
cortisol output in response to the TSST than non-depressed
controls, particularly among those with a severe depres-
sion; (b) again, consistent with previous literature, adoles-
cents with a history of childhood maltreatment will show
greater cortisol reactivity and total cortisol exposure in
response to the TSST than those without; and (c) depression
severity will fully moderate the relation of childhood
maltreatment to cortisol reactivity: heightened cortisol
reactivity to the TSST in those with a history of child
maltreatment will only be seen in the less severely
depressed adolescents, whereas blunted cortisol reactivity
will be seen in those with a history of child maltreatment in
the context of severe depression. The latter hypothesis is
tentative given the lack of previous research examining the
relation of childhood maltreatment to HPA axis function
moderated by depression severity.
2. Methods and materials
Participants were 71 individuals (48 females) ages 12—21
years (M = 15.39, SD = 2.11) recruited from a mid-sized com-
was consistent with that of the community (89% European
ancestry). Our depressed sample was drawn from community
mental health agencies and community advertisements seek-
ing adolescents with depression. Our non-depressed sample
was recruited from local high schools and community adver-
tisements seeking healthy adolescents. Adolescents whom
we identified as depressed from the self-referrals were
referred for mental health treatment.
The depressed adolescents all met Diagnostic and Statis-
tical Manual of Mental Disorders (DSM-IV) (American Psychia-
tric Association, 1994) criteria for a current non-bipolar, non-
psychotic mood disorder. Exclusion criteria included the
presence of a psychotic disorder, bipolar disorder, substance
dependence, conduct disorder, developmental disability, or
medical disorder that could cause depression. Adolescents in
the non-depressed group were free of all current or past
Our initial sample included 92 adolescents. Of this group,
12 were excluded because they met criteria for one of the
exclusionary diagnoses, and 9 either did not complete the
childhood maltreatment interview, or were missing more
than one cortisol sample. The resulting sample of 71 did
not differ from excluded participants in terms of age, sex,
ethnicity, or parental occupation status (all ps > .44). Of the
21 adolescents who were excluded, 52% (n = 11) had been
recruited from community mental health sites, and 48%
(n = 10) were from advertisements or local high schools
(p > .90).
2.2. Assessment measures
The present study was conducted in compliance with
our University’s Health Sciences Research Ethics Board.
174 K.L. Harkness et al.
Written informed consent was obtained from all adoles-
cents, and from a parent or guardian for adolescents under
18. Interviews and questionnaires were administered by
one of three graduate students in clinical psychology.
Adolescents participated in two sessions separated by
one week to reduce participant burden. Both sessions were
conducted at the same time of day. Session 1 included the
diagnostic interview and questionnaires. Session 2 included
the TSSTand childhood maltreatment interview. The child-
hood maltreatment interview was conducted a full 2 h
following the TSST.
2.2.1. Diagnostic measure
All adolescents received the full child and adolescent
version of the Schedule of Affective Disorders and Schizo-
phrenia (K-SADS) (Kaufman et al., 2000) to evaluate the
presence of current and/or past DSM-IV Axis I diagnoses.
Interviews were conducted by senior graduate students in
clinical psychology who were trained to gold-standard
reliability status (Grove et al., 1981). This interview began
with the collection of basic demographic information,
including parental occupation. Occupations were subse-
quently rated by two independent judges on a 1- to 7-
point scale according to the Hollingshead Index of Social
raters were resolved by consensus, and the consensus
rating was used in analyses. Parent report of adolescent
symptoms was not gathered based on evidence document-
ing that parent reports of adolescent internalizing disor-
ders produce a high level of false negatives (Klein et al.,
Thirty-eight (54%) adolescents met criteria for a
current depressive disorder (n = 24 major depressive
disorder, n = 10 depressive disorder not otherwise speci-
fied, n = 4 dysthymia). Of these, 20 (53%) adolescents met
criteria for at least one comorbid Axis I disorder (see
2.2.2. Depression symptoms
Participants completed the BDI-II (Beck et al., 1996), a 21-
item questionnaire assessing the severity of depressive symp-
toms over the past two weeks. We compared three depres-
sion severity groups based on BDI-II scores: minimal
depression (BDI-II 0—13; n = 30), mild/moderate depression
(BDI-II 14—25; n = 16), and moderate/severe depression
(BDI-II 26—49; n = 25). The group labels are consistent with
those employed by Beck et al. (1996).3
2.2.3. Purbertal status
maturation (Tanner, 1962). Self-report was based on a choice
between five illustrations of breast (females) and pubic hair
(males and females) development, as validated against phy-
sician assessment for this age group (Taylor et al., 2001).
Scores could range from 1 to 5, with higher scores represent-
ing later stages. It should be noted that none of the adoles-
cent girls were pregnant at the time of the study.
2.2.4. Childhood maltreatment
Participants were interviewed using the Childhood Experi-
ence of Careand Abuse contextual semi-structured interview
and rating system (CECA) (Bifulco et al., 1994). The CECA
interviews were conducted 2 h following the TSST, thus
allowing for full recovery of cortisol function before querying
about this emotionally charged information. The following
scales were assessed: (1) antipathy — hostility or coldness
toward the child (e.g., harsh criticism or name-calling); (2)
indifference — neglect of the child’s physical and/or emo-
tional needs (e.g., not providing adequate food or clothing;
not comforting the child when upset); (3) physical abuse —
violence toward the child (e.g., punching, hitting with an
object, or threatening with a knife); and (4) sexual abuse —
non-consensual sexual contact by any perpetrator (e.g.,
fondling, oral sex, and/or penetration). All interviews were
The above scales were rated for severity (1-marked, 2-
moderate, 3-some, 4-little/none) by raters who were una-
ware of the participants’ depression status. Ratings were
anchored to the CECA manual, which includes hundreds of
examples and rating rules. CECA interviewers and raters
received extensive training and ongoing supervision in the
Descriptive characteristics of the sample by depression group.
No/mild depression (n = 30) Moderate depression (n = 16) Severe depression (n = 25)
M SDn%M SDn%M SDn%
Age at first onset
3Beck et al. (1996) suggest the following cutoffs: 0—13: minimal
depression; 14—19: mild depression; 20—28: moderate depression;
and 29—63: severe depression. We did not use the exact same
groupings as Beck et al. because we did not have sufficient sample
size to divide our sample into four groupings. Therefore, we chose
three groupings that cut the moderate group in half, putting the
lower half with the mild/moderate group and the upper half with the
Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment175
Bedford College procedures for rating the CECA by the first
author. Inter-rater reliabilities ranged from k = .86—1.0
(Harkness et al., 2006). The severity ratings of maltreatment
using the CECAwere very negatively skewed (i.e., the major-
ity of participants had ratings of 4-little/none). Therefore,
we created a composite variable — ‘‘childhood maltreat-
ment,’’ representing the presence versus absence of at least
some (level ‘3’) antipathy and/or indifference and/or phy-
sical abuse and/or sexual abuse.
2.3. Cortisol collection and Trier Social Stress
Participants were asked to refrain from eating and drinking
for 1 h prior to their arrival at the lab. All saliva was
collected in previously labeled 5 ml polypropylene vials
(PGC Scientifics Corporation, MD) by passive drool (Shirt-
cliff et al., 2001) between the hours of 3 pm and 5 pm
because this is a period of low cortisol relative to the
morning (Groschl et al., 2003). All participants were medi-
cally healthy and had not experienced an acute injury in the
preceding 24 h.4
We followed precisely the procedure outlined by Krisch-
baum, Pirke, and Hellhammer (1993) in defining the time
points for salivary sample collection during the TSST. The
TSST protocol began with a 10-min rest period to allow the
participant to adjust to the research setting. Participants
then provided a baseline saliva sample (sample a). They were
then led into the experimental room and introduced to two
research assistants who the participants were told were
members of a selection committee from a human resources
department. Participants were told that they were to pre-
pare a 5-min speech that would serve as a ‘‘job interview,’’
and that they would give their speech to the selection
committee. They were told that their speech would be
videotaped. This point in time served as the onset of the
stressor. Participants were then led back into the experi-
mental room and given 10 min to prepare, after which we
collecteda secondsample (sample b).Participants were then
led back into the experimental room where they delivered
their speech and performed an arithmetic test, which con-
sisted of serially subtracting by 13, starting from 1022, as
quickly as possible without making any mistakes. This phase
of the TSST took approximately 20 min, after which we
collected a third sample (sample c). Therefore, sample c
was collected 30 min after the onset of the stressor, the time
point of peak cortisol reactivity. A fourth sample was col-
lected 1 h later (sample d), and a fifth and final sample was
collected another hour later (sample e). Following the TSST,
participants were fully debriefed regarding the purpose of
the TSST and the nature of the deception.
2.3.1. Hormone determinations
All saliva samples were immediately placed in a freezer for
short-term storage and eventually transported, on ice, to a
secure frozen storage (?20 8C). Resulting supernatant were
assayed for cortisol using an enzyme-linked immunoassay
designed specifically for saliva (1-0102/1-0112; Salimetrics
LLC, State College, PA). All samples from one individual were
placed on the same plate so that inter-assay variability did
not contribute to quantification error. Each sample was
quantified in duplicate at 25 ml, and triplicate high and
low controls (4-COO1) were distributed across each plate
to track precision and accuracy. Samples that had a coeffi-
and Wynne-Edwards, 2001). Repetition was used to reject
one of the original duplicates but was not used in analyses.
Salivary cortisol measured by this method is highly correlated
with serum cortisol (r = .96; Salimetrics validation). In all, 24
assay runs, in four batches, were conducted. The high con-
trol, measured at1.1 mg/dL, had anintra-assay coefficient of
variation of 4.2% and an inter-assay coefficient of variation of
5.8%. The low control, measured at .1 mg/dL had an intra-
assay coefficient of variation of 6.9% and an inter-assay
coefficient of variation of 11.1%.
2.3.2. Cortisol parameters for analyses
We used sample a (‘‘rest phase’’) as participants’ baseline
against which to gauge differences across depression severity
and history of childhood maltreatment in: (a) raw baseline
cortisol concentration in
range = .04—.49, Skew = 2.20), (b) ‘cortisol reactivity,’
defined as peak cortisol concentration (sample c) minus
baseline (sample a) divided by baseline (M = .27, SD = .71,
range = ?.68—3.44, Skew = 2.14), and (c) area under the
range = ?24.25—25.63, Skew = .26). AUC is a measure of
the total cortisol output over the TSST calculated as the
sum of the area of the four trapezoids bounded by the
baseline value and framed by the cortisol concentration in
the five saliva samples from the session. Square-root trans-
formations were applied to baseline cortisol and cortisol
reactivity to normalize these variables (transformed skew
values < 1.5). The untransformed estimated marginal means
are presented in the figures for ease of interpretability.
mg/dL(M = .12,SD = .08,
self(M = ?.07, SD = 8.65,
3.1. Participant characteristics
Demographic and clinical characteristics of the three depres-
sion severity groups are presented in Table 1. There were no
significant relations of depression severity group to sex
(p = .42) or Tanner score (p = .19). However, groups differed
in age, at a trend, F(2, 68) = 2.80, p = .07, h2= .08, and
parental Hollingshead index, F(2, 68) = 7.00, p < .005,
h2= .17. Among those with a diagnosis of a depressive dis-
order, there were no significant differences between those of
moderate and severe BDI-II scores in percentage of those on a
recurrence, age at first onset, percentage of those with a
comorbid disorder, or percentage of those receiving treat-
ment (all ps > .15). Of those receiving treatment, 8 were on
an antidepressant medication. These 8 adolescents were not
4As would be expected, 25/41 (61%) of the depressed adolescents
in our sample were experiencing sleep disturbance (i.e., insomnia or
hypersomnia). These adolescents were not differentially distributed
across the mild/moderate (56%) and moderate/severe (64%) de-
pressed groups, x2(1) = .25, p = .62, or across those with (61%) versus
without (61%) childhood maltreatment, x2(1) < .001, p = .99. There-
fore, sleep disturbance cannot better account for our pattern of
176K.L. Harkness et al.
and moderate/severe depression groups (25% vs. 12%;
x2 = 1.16, p = .28) or between the groups with versus
without a history of maltreatment (12% vs. 11%; x2 =
.003, p = .96).5
Twenty-six adolescents reported a history of childhood
maltreatment (37%). Therefore, the present sample con-
sisted of the following groups: (a) no/minimal depression
with no maltreatment (n = 27); (b) no/minimal depression
with a history of maltreatment (n = 3); (c) mild/moderate
depression with no maltreatment (n = 8); (d) mild/moderate
depression with a history of maltreatment (n = 8); (e) mod-
erate/severe depression with no maltreatment (n = 10); and
(f) moderate/severe depression with a history of maltreat-
ment (n = 15).
Participants with versus without a history of childhood
maltreatment did not differ significantly in terms of sex, age,
Tanner score, or parental Hollingshead index (all ps > .15).
Among the clinically depressed adolescents, there were no
significant relations of childhood maltreatment to depression
history status, age at first onset, or treatment status (all
ps > .35). However, those with a history of maltreatment
were significantly more likely to have a comorbid diagnosis
(61% vs. 28%; x2 = 4.45, p < .05).6
The specific types of maltreatment assessed in our sample
included physical abuse (n = 7), sexual abuse (n = 6), and
emotional maltreatment (n = 24). As is typical in maltreated
samples, most adolescents reported more than one form of
maltreatment. We found no evidence for a differential dis-
depression of physical abuse (19% vs. 8%, x2 = 1.05,
p = .30), sexual abuse (19% vs. 12%, x2 = .36, p = .55), or
emotional abuse (50% vs. 56%, x2 = .14, p = .71). The
average age at start of maltreatment was 7.96 (SD = 4.89)
and at end was 14.81 (SD = 2.40), with an average duration of
11.58 years (SD = 5.46). The presence versus absence of
current maltreatment was not differentially distributed
across the mild/moderate and moderate/severe depression
groups (x2 = .17, p = .68).
3.2. Within-group cortisol reactivity over time
dL) at each time point were analyzed using a 5 (time) ? 3
depression,moderate/severedepression) ? 2(childhoodmal-
lysis of Covariance (RMANCOVA) controlling for age and
parental occupation status. There was a 2-way interaction
of time by depressed group, Wilks’ l = .72, F(8, 120) = 2.66,
p < .01, h2= .16. This was qualified by a significant 3-way
mentinthequadratictrend,F(2,63) = 3.39,p < .05,h2= .10.
Among those with no history of maltreatment, the three
depression groups did not differ in terms of the shape of their
cortisolcurvesovertime,F(2,40) = 1.18,p = .32,h2= .06(see
Fig. 1a). In contrast, among those with a history of maltreat-
ment, there remained a significant time by depression group
interaction, F(2, 21) = 3.72, p < .05, h2= .26 (see Fig. 1b). As
hypothesized, the mild/moderate depressed group with mal-
treatment showed the strongest reactivity to the stressor,
demonstrating a significant quadratic trend in the curve over
time, F(1, 7) = 8.50, p < .05, h2= .57. In contrast, and also as
hypothesized, the moderate/severe depressed group with
maltreatment showed no reactivity to the stressor, demon-
strating a significant downward linear trend in the curve over
time, F(1, 14) = 24.67, p < .001, h2= .64.
group:minimal depression, mild/moderate
3.3. Between-group cortisol parameters
As displayed in Table 2, baseline cortisol concentration was
significantly positively correlated with age, and cortisol
reactivity was significantly positively correlated with paren-
tal Hollingshead scores (i.e., related to lower parental occu-
fied by childhood maltreatment history and depression severity.
Cortisol concentrations (in mg/dL) across time strati-
5None of the adolescents in our sample were on an anxiolytic
medication. In analyses including only the depressed adolescents,
results we report below were all robust when we controlled for
antidepressant medication usage. Results are available from the
6In analyses including only the depressed adolescents, all effects
were robust when controlling for the presence versus absence of a
comorbid diagnosis. In terms of the specific comorbidities, all effects
were robust when controlling for the presence versus absence of
social phobia and alcohol/substance abuse, in separate models. The
frequencies of the remaining comorbidities were too small to merit
including these comorbidities as covariates. However, all results
were robust in separate models in which the individuals with each
of these comorbidities were excluded. Therefore, there is no evi-
dence that our pattern of results is driven by the individuals with any
of these comorbidities. Results are available from the authors.
Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment177
pation status). In addition, among the clinically depressed
adolescents, those with a comorbid diagnosis had higher
cortisol reactivity than those without. Below we report on
a series of ANCOVA models examining the effects of depres-
sionseverity group, childhoodmaltreatment, and their inter-
action to cortisol baseline, reactivity, and AUC, controlling
for age and parental Hollingshead index.
3.3.1. Cortisol baseline
The interaction of depression severity group and childhood
maltreatment was significant, F(2, 63) = 3.82, p < .05,
had a significantlyhighercortisolbaselinethanthosewithout,
but only among those with moderate/severe depression, F(1,
63) = 5.18, p < .05, h2= .08 (see Fig. 2). Indeed, among those
with a history of maltreatment, the moderately/severely
depressed, F(1, 63) = 7.84, p < .01, h2= .11, and the
h2= .08, adolescents had a significantly higher baseline than
not differ significantly (all ps > .25).
63) = 5.76, p < .05,
3.3.2. Cortisol reactivity
The interaction of depression severity group and childhood
maltreatment approached significance, F(2, 63) = 2.59,
p = .08, h2= .08. As hypothesized, the moderate/severe
depressed adolescents with maltreatment had a significantly
lower level of reactivity than those with no/minimal depres-
sion, F(1, 63) = 5.57, p < .05, h2= .08, and than those with
h2= .17 (see Fig. 3). Among those with no childhood mal-
treatment, however, the three depression groups did not
differ significantly (all ps > .07).
It is important to note that the moderate/severe and
mild/moderate groups with maltreatment did not differ in
terms of their cortisol baseline, t(21) = ?.66, p = .52.
Further, in the moderate/severe depressed and maltreated
group, baseline cortisol did not correlate significantly with
cortisol reactivity, r = ?.02, p = .94. Therefore, the blunted
reactivity seen in the moderate/severe depressed group with
maltreatment likely does not represent a ceiling effect.
F(1,63) = 13.06,p < .005,
3.3.3. Area under the curve
The interaction of depression severity group and childhood
maltreatment was significant, F(2, 63) = 3.41, p < .05,
h2= .10. Adolescents with a history of childhood maltreat-
ment had a significantly greater AUC than those without, but
only among those with mild/moderate depression, F(1,
63) = 10.42, p < .005, h2= .14 (see Fig. 4). Among those with
no childhood maltreatment, however, the three depression
groups did not differ significantly (all ps > .08).
clinical characteristics of the sample.
Age at first onset
*p < .05.
**p < .01.
treatment history and depression severity.
Mean cortisol baseline (in mg/dL) by childhood mal-
maltreatment history and depression severity.
Mean cortisol reactivity (in mg/dL) by childhood
treatment history and depression severity.
Total cortisol exposure (in mg/dL) by childhood mal-
178 K.L. Harkness et al.
effect of a history of childhood maltreatment on HPA axis
reactivity as moderated by depression severity. Consistent
with hypotheses, a history of childhood maltreatment was
associated with significantly higher cortisol reactivity and
total cortisol exposure (i.e., AUC) to a psychosocial stress
challenge. However, an intriguing differential association
between childhood maltreatment and HPA axis function
emerged when the sample was stratified by depression sever-
ity. Only those with a mild/moderate level of depression
severity (i.e., BDI-II between 14 and 25) showed increased
adolescents with a moderate/severe level of depression
(i.e., BDI-II > 25) showed significant blunting of the cortisol
response, particularly among those with a history of mal-
treatment. Indeed, cortisol levels decreased in a linear
fashion across the sampling period in moderate/severe
depression with a history of maltreatment. This pattern of
results cannot be better accounted for by socio-economic
status, age, pubertal status, or gender. Further, the mild/
moderate and moderate/severe depression groups did not
differ in baseline cortisol concentration, anti-depressant
medication status, or the presence of a comorbid disorder,
including post-traumatic stress disorder.
Our results are consistent with, and expand upon, the
literature in adult MDD. Specifically, Burke et al. (2005) also
reported blunted stress reactivity and impaired stress recov-
controls, and described a similarly flat and unresponsive pat-
tern of cortisol secretion, particularly in severe depression.
Our results suggest that this pattern generalizes to an adoles-
centsample,and may bespecifictoseveredepression.Future
research is now needed to determine whether a blunted HPA
subtypes (e.g., melancholic depression) of MDD.
In addition, our results are consistent with previous lit-
erature examining the effect of childhood maltreatment on
HPA axis function. On the one hand, greater cortisol reactiv-
ity in challenge studies has been observed in adult samples
with a history of abuse (Heim et al., 2000, 2001, 2002), as
well as in adolescent samples with a history ofadversity more
generally (e.g., early parental loss, life-threatening illness,
and abuse) (Rao et al., 2008). On the other hand, however,
studies in adolescents employing the TSST, and examining
maltreatment experiences similar to those assessed in the
present study, have reported blunted cortisol reactivity
(Carpenter et al., 2007; De Bellis et al., 1994). We suggest
based on our results that differences in the severity of the
depressed groups examined in these previous studies may
help to reconcile these conflicting findings.
The complete dissociation of cortisol response between
the mild/moderate and moderate/severe depressed adoles-
cents with maltreatment suggests that the neurobiological
stress response systems may be functioning very differently
in these two groups. Previous research has suggested that
to developing a more severe manifestation of the syndrome,
express resistance (i.e., desensitization) of glucocorticoid
receptors as a trait (Holsboer et al., 1995; Modell et al.,
1998). In these individuals, high levels of CRH release as a
result ofthestress of childhoodmaltreatment, inthecontext
of this reduced glucocorticoid negative feedback, would
ultimately lead to a downregulation in CRH receptors on
ACTH-producing cells in the anterior pituitary. As such, this
may suggest a mechanism to explain why individuals with a
severe, potentially genetically-mediated depression, and a
history of chronic adversity would be more likely to show a
blunted cortisol response to acute stress.
In contrast, maltreated individuals with mild/moderate
depressive symptoms may be experiencing the typical HPA
abnormalities that have been well documented in the con-
text of stress. That is, these individuals are able to maintain
an increased secretion of glucocorticoids to an acute stressor
despite negative feedback from glucocorticoid and mireral-
corticoid receptors. This is achieved by increased expression
of CRH and vasopressin in the paraventricular nucleus,
decrease in glucocorticoid and mineralcorticoid receptors
and hypertrophy of the adrenal glands (see Checkley, 1996
for a review). The fact that some studies have found higher
levels of CRH in the cerebrospinal fluid of depressed indivi-
duals versus healthy controls (e.g., Catala ´n et al., 1998),
whereas others have found lower CSF CRH levels in depres-
sion (e.g., Geracioti et al., 1997), also supports the proposal
that there may be two different groups of depressed indivi-
duals who may prone, respectively, to a normal versus a
blunted cortisol response to stress. Future studies examining
a broad array of neurohormonal indicators of HPA axis func-
tion are now required to more firmly determine the exact
mechanism that accounts for the dissociation in cortisol
response to stress in mild/moderate versus moderate/severe
depressed individuals with a history of maltreatment.
The present results should be interpreted in light of the
following limitations. First, the results should be replicated
with a larger sample. Nevertheless, it is important to note
that we obtained medium to large effect sizes for all com-
parisons, indicating the robustness of our effects. In parti-
cular, we had a small number of adolescents in the no/
minimal depression group who had a history of childhood
maltreatment. These adolescents had the lowest mean base-
linecortisol level. However,this result is difficult to interpret
given the size of this group. While this group did not repre-
sent the crucial comparison in the present study, future
studies confirming and expanding upon the results presented
here should nevertheless strive to include a higher number of
healthy adolescents with maltreatment histories.
Future research is also needed to stratify the sample by
socio-economic status, age, and gender. Lower socio-eco-
nomic status significantly predicted higher cortisol reactivity
inthepresent sample, andsignificant sex andage differences
in cortisol reactivity have been reported in previous samples
(Chopra et al., 2009; Gunnar et al., 2009; Kelly et al., 2008).
While our results were robust when controlling for these
demographic characteristics, this does not preclude the
possibility that the pattern reported here may be further
moderated by age, sex, or socio-economic status.
Our small sample also precluded examination of our
effects separately for different types of abuse (physical
versus sexual versus emotional). As noted earlier, we found
no evidence for a differential distribution across mild/mod-
erate and moderate/severe depression of physical abuse,
sexual abuse, or emotional abuse. Therefore, the dissocia-
tion of HPA axis function found between these two groups
Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment 179
cannot be better accounted for by a differential distribution
of maltreatment type across mild/moderate and moderate/
severedepression. Nevertheless, this isan important areafor
future research as different types of abuse may have differ-
ent neurobiological consequences.
Second, our definition of the depression groups was based
on self-report. Nevertheless, all adolescents in our mild/
moderate and moderate/severe depression groups met DSM-
IV criteria for a unipolar mood disorder based on the K-SADS
interview. Further, the BDI is a highly reliable measure
(a = .95 in the present sample) that correlates significantly
with clinician-rated severity scales (Steer et al., 1987).
Third, our study relied on retrospective self-reports of child-
hood maltreatment, which may be subject to bias. However,
it is unclear how differential biases to recall childhood mal-
treatment would lead to the specific pattern of results seen
here given that the mild/moderate and moderate/severe
depressed groups did not differ significantly in the proportion
who reported this history (50% vs. 60%; x2 = .40, p = .53).
Further, recent reports have confirmed the validity of retro-
spective reports of maltreatment using the CECA in the study
of depression (Brown et al., 2007). Fourth, in the present
study we did not collect data regarding non-psychotropic
we provide urine screenings for substance use. However, we
reported alcohol/substance abuse. Finally, future research
should employ more frequent cortisol assessment points to
provide a more fine-grained analysis of cortisol recovery.
The present study also had a number of strengths, includ-
ing the use of an ecologically valid challenge paradigm and
the use of rigorous, structured interviews to determine
clinical diagnoses and childhood maltreatment history. In
summary, the present findings suggest that HPA axis dysre-
gulation in adolescent MDD is specific to those with a history
of maltreatment, and shows an opposing pattern of response
based on the severity of depression. These results have
significant implications for our understanding of the neu-
roendocrinological pathology of MDD, and suggest that indi-
vidual differencesin both
maltreatment history should be considered in all future
studies examining HPA axis reactivity in MDD.
Role of funding sources
Mental Health Foundation (Harkness, Wynne-Edwards). The
OMHF had no further role in study design; in the collection,
analysis and interpretation of data; in the writing of the
Conflicts of interest
Dr. Harkness, Mr. Stewart, and Dr. Wynne-Edwards report no
Dr. Harkness designed the study, supervised data collection,
and wrote the manuscript. Mr. Stewart aided in conducting
the diagnostic and childhood maltreatment interviews and
undertook the statistical analyses. Dr. Wynne-Edwards wrote
the study protocol and supervised the cortisol assays.
We gratefully acknowledge the technical of Lea Bond in
performing the cortisol assays. We would also like to
acknowledge Eric Bulmash, Alexandra Sutherland, and Naza-
nin Alavi who performed the diagnostic and maltreatment
interviews, and Shannon Coyle, Lindsey Lytle, Emma Dargie,
and Lindsay Delima for their help with data coding and data
Akil, H., Haskett, R.F., Young, E.A., Grunhaus, L., Kotun, J., Wein-
berg, V., et al., 1993. Multiple HPA profiles in endogenous
depression: effect of age and sex on cortisol and beta-endorphin.
Biol. Psychiatry 33, 73—85.
American Psychiatric Association, 1994. Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Author, Washington, DC.
Beck, A.T., Brown, G., Steer, R.A., 1996. Beck Depression Inventory II
Manual. The Psychological Corporation, San Antonio, TX.
Berg, S.J., Wynne-Edwards, K.E., 2001. Changes in testosterone,
cortisol and estradiol levels in men becoming fathers. Mayo Clin.
Proc. 76, 582—592.
and Abuse (CECA): a retrospective interview measure. J. Child
Psychol. Psychiatry 31, 1419—1435.
Brown, G.W., Craig, T.K.J., Harris, T.O., Handley, R.V., Harvey, A.L.,
2007. Validity of retrospective measures of maltreatment and
depressive episodes using the Childhood Experience of Care and
Abuse (CECA) instrument — a life course study of adult chronic
depression — 2. J. Affect. Dis. 103, 217—224.
Burke, H.M., Davis, S.C., Otte, C., Mohr, D.C., 2005. Depression and
psychological response to stress: a meta-analysis. Psychoneur-
oendocrinology 30, 846—856.
Carpenter, L.L., Carvalho, J.P., Tyrka, A.R., Wier, L.M., Mello, A.F.,
Mello, M., et al., 2007. Decreased adrenocorticotropic hormone
and cortisol responses to stress in healthy adults reporting signif-
icant childhood maltreatment. Biol. Psychiatry 62, 1080—1087.
Carroll, B.J., Feinberg, M., Greden, J.F., Haskett, R.F., Steiner, J.M.,
Tarika, J., 1980. Diagnosis of endogenous depression. J. Affect.
Dis. 2, 177—194.
Carroll, B.J., Feinberg, M., Greden, J.F., Tarika, J., Albala, A.A.,
Haskett, R.F., et al., 1981. A specific laboratory test for diagnosis
of melancholia — standardization, validation, and clinical utility.
Arch. Gen. Psychiatry 38, 15—22.
Catala ´n, R., Gallart, J.M., Castellanos, J.M., Galard, R., 1998.
Plasma corticotropin-releasing factor in depressive disorders.
Biol. Psychiatry 44, 15—20.
Checkley, S., 1996. The neuroendocrinology of depression and chron-
ic stress. Br. Med. Bull. 52, 597—617.
Chopra, K.K., Ravindran, A., Kennedy, S.H., Mackenzie, B., Mat-
thews, S., Anisman, H., et al., 2009. Sex differences in hormonal
responses to a social stressor in chronic major depression. Psy-
choneuroendocrinology 34, 1235—1241.
De Bellis, M.D., Chrousos, G.P., Dorn, L.D., Burke, L., Helmers, K.,
Kling, M.A., et al., 1994. Hypothalamic-pituitary-adrenal axis
dysregulation in sexually abused girls. J. Clin. Endocr. Metab. 78,
Dickerson, S.S., Kemeny, M.E., 2004. Acute stressors and cortisol
responses: a theoretical integration and synthesis of laboratory
research. Psychol. Bull. 130, 355—391.
180 K.L. Harkness et al.
Dinan, T.G., Scott, L.V., 2005. Anatomy of melancholia: focus on
hypothalamic-pituitary-adrenal axis overactivity and the role of
vasopressin. J. Anat. 207, 259—264.
Geracioti, T.D., Loosen, P.T., Orth, D.N., 1997. Low cerebrospinal
fluid corticotropin-releasing hormone concentrations in eucorti-
solemic depression. Biol. Psychiatry 42, 165—174.
Groschl, M., Rauh, M., Dorr, H.G., 2003. Circadian rhythm of salivary
cortisol, 17 alpha-hydroxyprogesterone and progesterone in
healthy children. Clin. Chem. 49, 1688—1691.
1981. Reliability studies of psychiatric diagnosis. Arch. Gen.
Psychiatry 38, 408—413.
Gunnar, M.R., Wewerka, S., Frenn, K., Long, J.D., Griggs, C., 2009.
Developmental changes in hypothalamus-pituitary-adrenal activ-
ity over the transition to adolescence: normative changes and
associations with puberty. Dev. Psychopathol. 21, 69—85.
Harkness, K.L., Bruce, A.E., Lumley, M.N., 2006. Childhood adversity
and the sensitization to stressful life events in adolescent de-
pression. J. Abnorm. Psychol. 115, 730—741.
Harkness, K.L., Monroe, S.M., 2002. Childhood adversity and the
endogenous versus nonendogenous distinction in women with
major depression. Am. J. Psychiatry 159, 387—393.
Heim, C., Newport, D.J., Heit, S., Graham, Y.P., Wilcox, M., Bonsall,
R., et al., 2000. Pituitary-adrenal and autonomic responses to
stress in women after sexual and physical abuse in childhood.
JAMA 284, 592—597.
Heim, C., Newport, D.J., Bonsall, R., Miller, A.H., Nemeroff, C.B.,
2001. Altered pituitary-adrenal axis responses to provocative
challenge tests in adult survivors of childhood abuse. Am. J.
Psychiatry 158, 575—581.
Heim, C., Newport, D.J., Wagner, D., Wilcox, M.M., Miller, A.H.,
Nemeroff, C.B., 2002. The role of early adverse experience and
adulthood stress in the prediction of neuroendocrine stress reac-
tivity in women: a multiple regression analysis. Depress. Anxiety
Hollingshead, A.B., 1975. Four factor index of social position. Un-
published manuscript, Yale University, New Haven, CT
Holsboer, F., 2000. The corticosteroid receptor hypothesis of depres-
sion. Neuropsychopharmacology 23, 477—501.
Holsboer, F., Lauer, C.J., Schreiber, W., Krieg, J.C., 1995. Altered
hypothalamic-pituitary-adrenocortical regulation in healthy sub-
jects at high familial risk for affective disorders. Neuroendocri-
nology 62, 340—347.
Kaufman, J., Birmaher, B., Brent, D.A., Ryan, N.D., Rao, U., 2000. K-
SADS-PL. J. Am. Acad. Child Psychiatry 39, 1208—11208.
Kaufman, J., Birmaher, B., Perel, J., Dahl, R.E., Moreci, P., Nelson,
B., et al., 1997. The corticotropin-releasing hormone challenge
in depressed abused, depressed nonabused, and normal control
children. Biol. Psychiatry 42, 669—679.
Kaufman, J., Charney, D., 2003. The neurobiology of child and
adolescent depression: current knowledge and future directions.
In: Cicchetti, D., Walker, E.F. (Eds.), Neurodevelopmental
Mechanisms in Psychopathology. Cambridge University Press,
Cambridge, UK, pp. 461—490.
Kaufman, J., Martin, A., King, R.A., Charney, D., 2001. Are child-,
adolescent-, and adult-onset depression one and the same disor-
der. Biol. Psychiatry 49, 980—1001.
2008. Sex differences in emotional and physiological responses to
the Trier Social Stress Test. J. Behav. Ther. Exp. Psychiatry 39,
Kirschbaum, C., Pirke, K.M., Hellhammer, D.H., 1993. The Trier
Social Stress Test — a tool for investigating psychobiological stress
responses in a laboratory setting. Neuropsychobiology 28, 76—81.
Klein, D.N., Dougherty, L.R., Olino, T.M., 2005. Toward guidelines for
evidence-based assessment of depression in children and adoles-
cents. JCCAP 34, 412—432.
Lopez-Duran, N.L., Kovacs, M., George, C.J., 2009. Hypothalamic-
pituitary-adrenal axis dysregulation in depressed children and
adolescents: a meta-analysis. Psychoneuroendocrinology 34,
Luby, J.L., Heffelfinger, A., Mrakotsky, C., Brown, K., Hessler, M.,
Spitznagel, E., 2003. Alterations in stress cortisol reactivity in
depressed preschoolers relative to psychiatric no-disorder com-
parison groups. Arch. Gen. Psychiatry 60, 1248—1255.
Luby, J.L., Mrakotsky, C., Heffelfinger, A., Brown, K., Spitznagel, E.,
2004. Characteristics of depressed preschoolers with and without
anhedonia: evidence for a melancholic depressive subtype in
young children. Am. J. Psychiatry 168, 1998—2004.
Modell, S., Lauer, C.J., Schreiber, W., Huber, J., Krieg, J.C., Hols-
boer, F., 1998. Hormonal response pattern in the combined DEX-
CRH test is stable over time in subjects at high familial risk for
affective disorders. Neuropsychopharmacology 18, 253—262.
Rao, U., Hammen, C., Ortiz, L.R., Chen, L.A., Poland, R.E., 2008.
Effects of early and recent adverse experiences on adrenal
response to psychosocial stress in depressed adolescents. Biol.
Psychiatry 64, 521—526.
Shirtcliff, E.A., Granger, D.A., Schwartz, E.B., Curran, M.J., 2001.
Use of salivary biomarkers in biobehavioral research: cotton-
based sample collection methods can interfere with salivary
immunoassay results. Psychoneuroendocrinology 26, 165—173.
Steer, R.A., Beck, A.T., Riskind, J.H., Brown, G., 1987. Relationship
between the Beck Depression Inventory and the Hamilton Psychi-
atric Rating Scale for Depression in depressed outpatients. J.
Psychopathol. Behav. 9, 327—339.
Tanner, J.M., 1962. Growth and Adolescence,
Taylor, S.J., Whincup, P.H., Hindmarsh, P.C., Lampe, F., Odoki, K.,
Cook, D.G., 2001. Performance of a new pubertalself-assessment
questionnaire: a preliminary study. Paediatr. Perinat. Epidemiol.
Tsigos, C., Chrousos, G.P., 2002. Hypothalamic-pituitary-adrenal
axis, neuroendocrine factors and stress. J. Psychosom. Res. 53,
Zimmerman, M., Coryell, W., Pfohl, B.M., 1985. Importance of
diagnostic thresholds in familial classification: dexamethasone
suppression test and familial subtypes of depression. Arch. Gen.
Psychiatry 42, 300—304.
2nd ed. Thomas,
Cortisol reactivity to social stress in adolescents: Role of depression severity and child maltreatment 181