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Decreased Cortisol Levels in Adolescent Girls With Conduct Disorder
Kathleen Pajer, MD, MPH;
William Gardner, PhD;
Robert T. Rubin, MD, PhD;
James Perel, PhD;
Stephen Neal, BS
Arch Gen Psychiatry. 2001;58:297-302.
ABSTRACT
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Background Female adolescent antisocial behavior is increasing, but little is known
about the neuroendocrinologic aspects of this disorder. On the basis of reports
of decreased cortisol levels in antisocial males, we investigated morning
plasma cortisol levels in adolescent girls with conduct disorder (CD).
Methods Three plasma samples for cortisol levels were taken every 20 minutes
between 8 and 9 AM in 47 adolescent girls with CD (mean ± SD age, 16.5
± 0.9 years) and 37 normal control girls (mean age, 16.0 ± 0.8
years). All blood was drawn within 72 hours after the onset of menstrual flow.
Results Girls with CD had significantly lower cortisol levels than girls in
the normal control group at all 3 sampling times. This finding was not due
to procedural factors, demographic characteristics, or the use of medications.
The girls with CD who had no other psychiatric problems had lower cortisol
levels than girls with other disorders or those in the normal control group.
In the multiple regression analysis, having CD predicted 10% of the variance
in cortisol levels.
Conclusions Morning plasma cortisol levels were significantly diminished in adolescent
girls with CD. Decreased cortisol levels appear to be most strongly associated
with antisocial girls who do not have other psychiatric disorders.
INTRODUCTION
FEMALE ADOLESCENT antisocial behavior is prevalent, whether defined
as conduct disorder (CD) or delinquency. Conduct disorder is the second most
common diagnosis given to adolescent girls,1
and one third of adolescent female psychiatric patients receive the diagnosis.2 In the general population, nearly 10% of 15- to 17-year-old
girls meet criteria for CD.3, 4
The delinquency rate for adolescent girls and the proportion of arrests of
females for violent crimes have increased dramatically in the past 2 decades.5, 6 Adolescent antisocial behavior is financially
and emotionally costly to the teens and their families, and to society.7 Antisocial girls become women with rates of criminal
behavior up to 40 times greater than those of other women, a high risk of
early death, complex psychiatric problems, a high rate of substance abuse,
poor adult physical health, and intergenerational transmission of antisocial
behavior.8
Unfortunately, current treatments for female antisocial behavior are
ineffective.9, 10, 11, 12, 13, 14, 15
Treatments may fail, in part, because little is known about biological correlates
of female antisocial behavior. All previous research on neuroendocrinologic
function in antisocial disorders has studied males.
One of the most provocative neuroendocrinologic abnormalities reported
in antisocial males is decreased cortisol secretion. Low plasma cortisol levels
in response to experimental stressors was first described among adult male
criminals referred to a maximum-security hospital.16
These men were more violent than a criminal control group, who responded normally
to the stressors with an increase in cortisol levels. Ninety-three percent
of these hyporesponders had histories of repeated physical violence. Sixty-seven
percent of the hyporesponders had committed murder, compared with only 14%
of the criminal control group. Similarly, Virkkunen17
found that violent male criminals had decreased cortisol secretion, but that
cortisol levels were normal in nonviolent criminals and noncriminal violent
men.
Antisocial behavior in boys has also been associated with low resting
cortisol levels, especially in boys exhibiting physical aggression.18, 19, 20 Similarly, both resting
salivary cortisol levels and the cortisol response to psychological stimuli
were negatively correlated with symptoms of CD in aggressive and impulsive
sons of substance-abusing fathers.21, 22
Given that low cortisol levels have been found in antisocial males,
we investigated whether they are also low in antisocial females. We chose
to determine morning cortisol levels because cortisol secretion follows a
circadian rhythm and secretion peaks in most people between 8 and 9 AM.23 We focused on teenage girls who were in the final
stage of puberty, and who met criteria for repeated antisocial behavior.
SUBJECTS AND METHODS
SUBJECTS
We recruited 15- to 17-year-old girls to ensure that as many girls as
possible would be in Tanner stage V and yet not out of adolescence. Girls
were recruited predominantly from the community, through newspaper ads and
posters. The ads sought girls with behavior problems such as "truancy, fighting,
stealing, and lying." The ads also indicated that we were interested in girls
without these problems. Three hundred fifty-four girls were contacted through
ads and posters, through friends already in the study (n = 7), or through
contacts in clinics (n = 6).
Intake appointments were made after a brief telephone screening and
explanation of the project. One hundred fifty-one girls completed intake appointments.
Each girl was interviewed concurrently with a parent or guardian who knew
her history (the majority of adult informants were mothers or fathers). The
intake appointment was used to determine eligibility for the study and to
collect baseline nonbiological data.
In addition, a structured psychiatric interview (see below) was used
to classify girls into the conduct disorder (CD) or normal control (NC) group.
Exclusion criteria for both groups were age outside the 15- to 17-year range,
pubertal development less than Tanner stage V, history of head trauma with
loss of consciousness for more than 15 minutes, serious medical illness that
could affect hypothalamic-pituitary-adrenal (HPA) axis function (eg, diabetes,
thyroid disorders, renal disease), IQ less than 65, or a history of psychosis.
Additional exclusion criteria for the NC group were the presence of any lifetime
psychiatric disorder or any symptom of CD. Since we were trying to recruit
a sample that would be as representative as possible of girls in the general
population who matched girls with CD, we did not exclude girls in the NC group
who smoked cigarettes or had experimented with alcohol, marijuana, or other
drugs. We defined experimentation as not having used these substances more
than 5 times throughout a girl's life and having no social or physical sequelae
of use; no NC girl exceeded these criteria.
Ninety-three girls (52 in the CD group and 41 in the NC group) were
found eligible and agreed to participate. We dropped 5 girls (3 in the CD
group and 2 in the NC group) from the neuroendocrine protocol because we could
not obtain a blood sample within 4 menstrual cycles of the baseline data collection.
Four girls (2 in the CD group and 2 in the NC group) refused to give blood
either initially or after an adverse event (vein collapsing, fainting). Thus,
the final sample size for the neuroendocrine data presented in this article
was 84 (47 in the CD group and 37 in the NC group).
ASSESSMENTS
After explaining both stages of the study, we obtained written, informed
consent from each girl and her parent or guardian. The intake interview was
conducted separately with each girl and her parent. Data were collected about
the following topics: family demographics, medical and developmental history
of the girl, school experiences, psychosocial history, family function, family
psychiatric history (parent only), and Tanner pubertal stage self-report (girl
only). Psychiatric diagnosis was determined from the computerized version
of the NIMH (National Institute of Mental Health) Diagnostic Interview Schedule
for Children, Version 2.3 (DISC), Parent and Youth Versions.24
All interviewers held bachelor's or postgraduate degrees. They were trained
by the principal investigator (K.P.), who in turn had been trained by the
developers of the DISC.
As indicated above, the DISC was used to classify girls into 2 groups.
On the basis of concerns regarding the validity of using the aggression and
age at onset DSM-IV criteria to diagnose female CD,1 we modified the DISC slightly. First, we rephrased
the question on fighting to read "Do you often get into fights?" rather than
"Do you often start fights?" Second, our diagnostic algorithm required that
antisocial behaviors be demonstrated for at least 1 year before the interview,
but onset before age 13 years was dropped from the items to which it is attached
in the DSM-IV criteria.
Subjects were given a diagnosis based on meeting criteria from either
the youth or the parent report. It is difficult to know who is the more accurate
informant at this age because some adolescents may share their feelings and
activities with their parents, and others may not. Moreover, some adolescents
exaggerate reports of what they do, while others minimize them. Therefore,
we considered data from all sources to be equally valid.
PROCEDURES
If a girl met criteria for either group, she was asked to participate
in neuroendocrinologic testing. To control for any menstrual cycle effects
on HPA axis activity, we drew all blood within the first 72 hours after the
onset of menstrual flow.25, 26, 27, 28
Each girl participating in stage 2 was asked to call the study office as soon
as she started her next menstrual period. When contacted, we arranged for
an early-morning phlebotomy appointment within 72 hours of when she had begun
her period. Fifty-two percent of the subjects had their blood drawn in their
homes or at another designated meeting place (eg, school). The others were
done at the study office. We inserted an indwelling catheter into the antecubital
fossa of one arm. Samples were taken immediately on insertion (time 0), 20
minutes later (time 1), and 40 minutes later (time 2). Time 2 samples were
used in the analyses. They were likely to be the most reliable estimates of
morning basal secretion, since 40 minutes should have allowed the HPA axis
to recover from the stress of catheter insertion. The catheter was kept patent
with a saline flush between samples. Sixty-seven percent of the blood draws
occurred before 9 AM (this time, however, was not significantly associated
with CD vs NC status). However, because of the unpredictable schedules and
behavior of these subjects, some girls had their blood drawn later than 9
AM, with starting times ranging to 11:15 AM. Most girls were studied within
1 menstrual cycle of baseline data collection, but erratic menses and scheduling
difficulties resulted in some subjects having their blood drawn 2 to 4 cycles
later.
All cortisol assays were performed without regard to diagnostic status.
Plasma cortisol levels were determined with radioimmunoassay by means of a
commercially available kit (Nichols Institute, San Juan Capistrano, Calif).
Interassay variability, intra-assay variability, and assay sensitivity were
6.1%, 4.7%, and 1.4 nmol/L, respectively.29
Ten girls were taking medroxyprogesterone acetate and 5 were using oral
contraceptives. One girl in the NC group signed up for the study and was pregnant
by the time she was ready for neuroendocrinologic testing. Since the menstrual
cycle in all 16 of these girls was suppressed, we drew blood when it was convenient
for them, and as close as possible to the intake interview. We then tested
for effects of these variables in the data analysis.
Because hypocortisolemia in antisocial men may be particularly related
to violence, we categorized the girls with CD as aggressive or nonaggressive
on the basis of the presence of 1 or more aggressive behaviors in either the
parent or youth DISC report (fighting, cruelty to animals or people, carrying
or using a weapon, fire-setting, stealing with confrontation, police arrests
for assault). Each behavior described by the girl or her parent was assigned
1 point, and the final score for aggressive CD was the sum of these points.
Girls with CD were also divided into 3 groups defined by the presence of psychiatric
comorbidity: CD and no comorbidity, CD and oppositional defiant disorder only,
and CD and multiple diagnoses.
The protocol was approved by the institutional review boards at Allegheny
General Hospital and the University of Pittsburgh Medical School, Pittsburgh,
Pa. The girls and their parents were paid $20 for baseline testing, and each
girl received $50 on completion of the neuroendocrinologic testing.
DATA ANALYSIS
Any variable not displaying a normal distribution was log-transformed,
including plasma cortisol level. Comparisons between the 2 groups were tested
for statistical significance by using unpaired t
tests, univariate and repeated-measures analyses of variance, correlation
coefficients, or  2, depending on whether the variables were
interval or nominal. All tests were 2-tailed, and statistical significance
was set at P .05.
Cortisol levels are associated with many factors, including the time
of day, time of year, and place when blood was drawn,30
demographic factors,31, 32, 33, 34, 35, 36
taking oral contraceptives,28, 37
being pregnant,38, 39, 40
and other psychiatric conditions, including posttraumatic stress disorder
(PTSD).41 Statistically controlling for all
of these factors would absorb more degrees of freedom than we could afford
with our sample. Therefore, we calculated propensity scores42
(ie, the probability of CD vs NC membership) by logistically regressing group
status on the above covariates. We then controlled for CD vs NC differences
on the covariates by calculating a linear regression of cortisol on group
status and the propensity score. By including the propensity score in the
regression, we controlled for that information in the covariates that increased
the likelihood of group membership. SPSS (SPSS Inc, Chicago, Ill) was used
to conduct the analyses.
RESULTS
SUBJECT CHARACTERISTICS
The girls in the CD group were, on average, 6 months older than the
NC girls (Table 1). Because all
girls were in Tanner stage V, we doubt that this finding is clinically significant.
The CD group included slightly higher proportions of African American girls
and girls of lower socioeconomic status. Rates of smoking, alcohol, and drug
experimentation were also higher among girls with CD, particularly experimentation
with drugs other than marijuana (primarily hallucinogens). Girls with CD had
high rates of comorbid substance abuse, internalizing, and oppositional defiant
disorders, although few of the girls with CD had comorbid attention-deficit/hyperactivity
disorder.
CD VS NC DIFFERENCES IN PLASMA CORTISOL
Mean plasma cortisol levels were significantly lower in the CD group
at all 3 time samples (Figure 1).
A repeated-measures analysis of variance was performed, and the effect of
group status was significant: F1,82 = 8.40, P = .005. Results of t tests on log-transformed
cortisol variables, which included corrections for unequal within-group error
variances, showed t71.3 = 2.13, P = .04 at time 0; t75.8 = 2.74, P = .008 at time 1; and t78.4 = 3.08, P = .003 at time
2. The fractional degrees of freedom reflect corrections for unequal variance.
Results were similar when the analysis was repeated without the girl who was
pregnant. They were also similar when analyses were repeated without a girl
who took lithium carbonate, a girl who took sertraline hydrochloride, girls
who took oral contraceptives, girls who took medroxyprogesterone, and girls
with PTSD. The effect sizes were substantial: time 0, d = 0.48; time 1, d = 0.61; and time 2, d = 0.67; where d = (CD - NC)/SDpooled. Cortisol level was not significantly associated
with age, ethnicity, socioeconomic status, or use of oral contraceptives.
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Cortisol levels in the girls with conduct disorder (CD) vs the normal
control (NC) group. Each error bar represents 1 SD.
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To control for NC vs CD differences on other variables that might affect
cortisol level, we estimated propensity scores to summarize these differences
(see above). We then computed a linear regression of time 2 cortisol level
on CD vs NC group status and the propensity score. In this regression, belonging
to the CD group lowered cortisol level by 185.1 nmol/L (t81 = 2.53; P = .01), despite our having controlled for the group differences
represented by the propensity score.
PLASMA CORTISOL: AGGRESSION AND PSYCHIATRIC COMORBIDITY
Thirty-seven girls met the criteria for aggressive CD, with the number
of aggressive behaviors ranging from 1 to 10 (mean and median, 3 behaviors).
The mean of the plasma levels of cortisol in the aggressive CD group (n =
37) was 336.9 ± 173.5 nmol/L compared with a mean of 386.5 ±
102.6 nmol/L in the nonaggressive CD group (n = 10). However, this difference
was not statistically significant (t45 = 1.92; P = .07).
To determine whether decreased cortisol level was simply a correlate
of severe psychopathology, as manifested by multiple diagnoses, we examined
the mean cortisol levels in the following groups: NC (n = 37) (467.4 ±
212.2 nmol/L), CD with no comorbidity (n = 12) (291.9 ± 131.6 nmol/L),
CD with ODD only (n = 6) (338.8 ± 103.2 nmol/L), and CD with multiple
diagnoses (n = 29) (372.2 ± 179.1 nmol/L). It is clear that the girls
with CD who had no comorbidity, not the girls with multiple comorbid diagnoses,
had the lowest mean cortisol level. Only 2 girls had comorbid PTSD, but their
cortisol levels were the lowest 2 in the sample. However, these 2 subjects
also met criteria for major depression, separation anxiety disorder, and generalized
anxiety disorder.
COMMENT
This is the first study, to our knowledge, of cortisol levels in antisocial
girls. It confirmed our hypothesis that adolescent girls with CD would have
lower morning cortisol levels than girls without any psychiatric disorder.
Thus, it appears that adolescent antisocial girls may have HPA axis dysregulation
similar to that found in antisocial boys and men.
The difference in mean cortisol levels between the CD and NC groups
is much larger than those reported in previous studies on males.16, 17
Not all researchers have found a negative correlation between cortisol levels
and antisocial behavior in boys. Mean plasma cortisol levels drawn for morning
baseline levels before a fenfluramine challenge were not different in a mixed
group of prepubertal and adolescent boys who had "disruptive behavior disorders"
compared with normal controls.43 In 2 samples
of boys with attention-deficit/hyperactivity disorder, the majority of whom
had comorbid CD or oppositional defiant disorder, urinary free cortisol levels44 and plasma cortisol levels45
were no different than levels in NC subjects. However, all of these samples
were composed of boys spanning the age range from latency to adolescence and
who had been selected on the basis of disruptive behavior or attention-deficit/hyperactivity
disorder, rather than repeated acts of antisocial behavior. Our more robust
effect may be due to our sampling strategy, which selected a homogeneous group
of late-adolescent girls who were in Tanner stage V and who had exhibited
a pattern of repeated antisocial acts for at least 1 year. Our design further
limited intersubject variance secondary to sampling time and menstrual cycle
effects by standardizing these factors across subjects. However, it is also
possible that the difference in cortisol levels between antisocial and normal
subjects may be more pronounced in females because normal women have higher
basal and reactive levels of cortisol than do normal men.46, 47, 48
The girls with CD displayed substantial psychiatric comorbidity, a finding
consistent with other reports in the literature.49, 50, 51, 52
Nonetheless, we were able to demonstrate that the relationship between cortisol
level and CD was not simply a reflection of severity of psychopathology, because
subjects without other diagnoses actually had the lowest mean cortisol levels.
The finding that antisocial females have low cortisol levels raises
important clinical questions. First, low cortisol levels may put these girls
at risk for later autoimmune diseases, some types of atopic illnesses, increased
inflammation, and infections with extracellular pathogens.53, 54, 55, 56, 57, 58, 59, 60, 61
This may partially explain the poor adult health of women who had been antisocial
adolescents.8, 62, 63, 64, 65, 66
Second, low cortisol level may be a diagnostic marker for subtypes of
girls with CD. To determine whether a biological correlate of a behavioral
syndrome is a diagnostic clinical marker, one must first show that the relationship
between the two is not due to a confounding factor. We have extended the previous
work in males by demonstrating that the association between cortisol and CD
is not due to factors such as season or race. The next step is to demonstrate
that the biological finding discriminates between subgroups within the spectrum
of a diagnostic category.67, 68
We did find that girls with aggressive CD had lower mean cortisol levels than
girls with nonaggressive CD did, but this difference was not statistically
significant. However, only 10 girls with CD were not aggressive. Thus, the
question of whether low cortisol level is a marker for aggressive CD in girls
remains unanswered.
On the basis of a study reporting a high rate of PTSD in a sample of
incarcerated adolescent females69 and data
suggesting low cortisol levels in subjects with PTSD,41
we also investigated whether low cortisol level was a marker for antisocial
girls with PTSD. The girls with CD with comorbid PTSD had the lowest cortisol
levels in our sample, but there were only 2 of them and they also met criteria
for several other diagnoses. Furthermore, the NC vs CD differences remained
when these 2 cases were deleted from analyses. This important issue should
be addressed in a study with larger numbers of antisocial girls with PTSD.
Our design permitted us to examine many alternative explanations for
the group difference in cortisol levels. One limitation of our study, however,
is that we could not exclude sleep disturbance as an explanation for the difference
between the CD and NC groups. If the girls with CD are less well supervised
and their lives more chaotic, it is possible that, as a group, they may routinely
go to sleep later than midnight. This could shift their circadian rhythm such
that the 8 to 9 AM blood-drawing time may still be in the prepeak phase of
their HPA axis cycle.70 This question merits
further research.
To date, there have been no studies of the mechanisms underlying decreased
cortisol levels in antisocial subjects. However, animal and human data suggest
that the ratio of corticotropin-releasing hormone to arginine vasopressin
may be lower than normal in aggressive subjects, particularly in animals who
have been bullied and become bullies themselves.71, 72
This explanation may account for both the aggression and PTSD aspects of our
findings. Although this research has focused on males, one clinical study
of pregnant teens did report that the girls with CD had lower plasma levels
of corticotropin-releasing hormone than the pregnant controls without CD.73
Future studies on HPA axis function in these girls should focus on describing
the basal state of cortisol secretion throughout the rest of the 24-hour cycle,
determining if their HPA axis responds normally to experimentally induced
stressors, and methodically investigating the function of each component of
the HPA axis (eg, response to corticotropin-releasing hormone, assessment
of glucocorticoid receptor function). Research on potential mechanisms may
result in more effective pharmacologic interventions or facilitate the identification
of subgroups of girls with CD who respond to different types of treatments.
AUTHOR INFORMATION
Accepted for publication September 25, 2000.
This study was supported by grant MH01285-04 from the National Institute
of Mental Health, Bethesda, Md (Dr Pajer).
We are grateful for the efforts of Judith Navratil, Barbara LeBeau,
Deborah McCaskill, and Phyllis Wanetick, MSN, in collecting these data. We
also thank the subjects for their participation.
From the Departments of Psychiatry (Drs Pajer, Gardner, and Perel and
Mr Neal) and Medicine (Dr Gardner), University of Pittsburgh School of Medicine,
Pittsburgh, Pa; and Center for Neurosciences Research, Allegheny General Hospital,
Pittsburgh (Dr Rubin).
Corresponding author and reprints: Kathleen Pajer, MD, MPH, Department
of Psychiatry, University of Pittsburgh School of Medicine, 3811 O'Hara St,
Suite 430, Pittsburgh, PA 15213 (pajerka{at}msx.upmc.edu).
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