Low Cortisol and Risk for PTSD in Adult Offspring of Holocaust Survivors
by Rachel Yehuda, Ph.D., Linda M. Bierer, M.D., James Schmeidler, Ph.D.,
Daniel H. Aferiat, M.S.W., Ilana Breslau, M.A. and Susan Dolan, B.A.
The American
Journal of Psychiatry, Volume
157, No. 8, August 2000:1229-1235.
INTRODUCTION
We previously suggested that children of Holocaust survivors constitute
a high-risk group for posttraumatic stress disorder (PTSD), since they
were found to have a greater prevalence of lifetime PTSD compared to
demographically similar persons who have experienced equivalent numbers
and types of events that meet the DSM-IV definition of trauma (1). Adult
children of Holocaust survivors also showed a greater prevalence of mood
and other anxiety disorders [1]. PTSD in children of
Holocaust survivors appeared to be strongly related to parental PTSD.
In a sample of Holocaust survivors and their children in which PTSD could
be evaluated directly, lifetime PTSD was present in the children of parents
with chronic PTSD but not in the children of parents who either had never
developed PTSD or had recovered from PTSD within several years after
World War II [2].
The idea that familial contributions can increase the likelihood of developing
PTSD is supported not only by the observations summarized above but also
by studies showing a relationship between psychological responses in
trauma survivors and family history of psychopathology (reviewed in reference 3).
As early as 1918, Wolfsohn demonstrated that 74% of 100 patients with
war neuroses reported a family history of psychoneurosis compared to
none of 100 matched comparison subjects [4]. These observations
were replicated by other investigators, who found similar associations
in World War I [5–7] and World War II [8]
veterans and their families, and by a later study of traumatized civilians
exposed to disaster [9]. The findings of these studies
all described a significantly higher rate of familial mental illness
in symptomatic trauma survivors with PTSD (or "shell shock")
compared to either nonexposed subjects or similarly exposed survivors
who did not develop posttraumatic syndromes. More recent community-based
studies have confirmed that respondents with PTSD were three times more
likely than trauma survivors without PTSD to report family mental illness,
particularly anxiety, depression, psychosis, and antisocial behavior
[10]. Perhaps most compelling, however, is the finding
of an increased prevalence of PTSD among trauma survivors who also had
a twin with PTSD compared to trauma survivors whose exposed twin did
not develop PTSD [11]. The risk for developing PTSD
after trauma exposure was significantly greater for monozygotic than
for dizygotic twins, suggesting a role for genetic factors in conferring
susceptibility to the development of these symptoms [12],
possibly by influencing biological substrates associated with the pathophysiologic
response to stress in PTSD.
Low ambient cortisol levels have been found in many groups of trauma
survivors with PTSD [13–18]. The observation of low
cortisol levels in PTSD was initially considered counterintuitive, because
cortisol levels have generally been found to be high in conditions of
acute and chronic stress and in certain types of psychiatric disorders
that are associated with stress (e.g., major depressive disorder) (reviewed
in references 19, 20). In cases of
chronic stress or chronic illness such as depression, increased cortisol
levels usually indicate that the hypothalamic-pituitary-adrenal (HPA)
axis has grown resistant to the effects of cortisol.
This cortisol resistance can be measured by the extent of "nonsuppression" of
cortisol after the administration of dexamethasone. Indeed, about half
of patients with major depressive disorder demonstrate a nonsuppression
of cortisol on the dexamethasone suppression test [21].
In contrast, low cortisol levels in PTSD are associated with enhanced
cortisol suppression after dexamethasone administration [22],
suggesting that the HPA axis may actually be overly responsive to stimulation
(see reference 23 for review). The hypothesis that
the HPA axis may be hypersensitive in PTSD is consistent with the more
general phenomenology of increased reactivity to both explicit and implicit
trauma reminders (e.g., reference 24) and as well as
a more generalized hypervigilance in trauma survivors with this disorder.
According to current convention, phenomenological and biological differences
between trauma survivors with and without PTSD are generally considered
to be either consequences of the traumatic event or correlates of PTSD.
However, given the evidence for familial transmission of vulnerability
to PTSD or the more general idea of the existence of risk factors for
the development of PTSD, it is reasonable to consider the possibility
that variables that distinguish between trauma survivors with and without
PTSD might also reflect risk factors for the development of PTSD and,
as such, may be useful predictors of who will develop PTSD after exposure
to trauma [25, 26].
The study of cortisol levels in the putative high-risk group of adult
children of Holocaust survivors, especially those whose parents have
PTSD, and comparison subjects provides an opportunity for determining
the relationship between cortisol and putative risk factors for PTSD.
Thus, in the study reported here, we evaluated 24-hour urinary cortisol
levels in 35 adult children of Holocaust survivors and 15 comparison
subjects. The evaluation of cortisol requires a consideration not only
of the risk factor of parental trauma and PTSD, but also of the characteristics
of the subject, particularly in regard to their own trauma exposure,
presence of PTSD, or other psychiatric disorders. We therefore evaluated
the association of cortisol to trauma exposure, parental survivor status,
parental PTSD, personal PTSD, and other psychiatric diagnoses.
Method
Subjects
The study was approved by the Institutional Review Board of the Mount
Sinai School of Medicine in New York City. All subjects provided written
informed consent before their participation. Thirty-five offspring of
Holocaust survivors (six men and 29 women) and 15 comparison subjects
(eight men and seven women) participated in the study. The offspring
were between the ages of 26 and 50 years, and the comparison subjects
were between 23 and 51. Offspring were defined as having been raised
by at least one biological parent who survived the Nazi Holocaust, but
the majority (N=28) were raised by two biological parents who were survivors.
The comparison subjects were Jewish, within the same age range, and did
not have a parent who was a Holocaust survivor. The majority of the comparison
subjects had two American-born parents, but two comparison subjects had
one parent born in Israel.
There were two types of recruitment for the study. The clinical sample
consisted of offspring who had participated in short-term group psychotherapy
in the Mount Sinai Specialized Treatment Program for Holocaust Survivors
and Their Families (N=19). The nonclinical sample consisted of volunteers
solicited from lists obtained from the Jewish community (i.e., recruitment
that did not identify the offspring status of subjects) or who had responded
to newspaper advertisements and community group announcements for research
participants. The nonclinical sample included both offspring (N=16) and
comparison (N=15) subjects. Our previous study showed no substantial
differences between offspring recruited by using these two methods in
trauma history or in personal or parental history of PTSD (1). There
were no formal exclusions for current or past psychiatric problems because
we were interested in examining the contribution of such problems to
cortisol levels. However, no subject in either group met criteria for
a past or current psychotic disorder or substance dependence. Thus, the
only past or current diagnoses present in the sample were substance abuse
and mood, anxiety, and eating disorders. An earlier preliminary report
of cortisol levels from a subset of this sample was reported in Yehuda
et al. [27, 28].
Medical information on all subjects was obtained by the use of a medical
checklist and was reviewed by a staff physician. Patients with major
active medical conditions were excluded from the study, as were patients
who had used benzodiazepines, lithium, b-blockers, or psychotropic medications
within 2 months of the study. Subjects were not withdrawn from medications
to participate in this protocol. One of the offspring had irregular and
brief use of paroxetine, and one subject had taken trazodone as needed
for sleep within 2 months of the study. Two subjects (one offspring and
one comparison subject) reported occasional use of nonsteroidal asthma
medication, five women (four offspring and one comparison subject) were
taking either estrogen replacement or birth control pills, and three
women (two offspring and one comparison subject) were taking low-dose
levothyroxine sodium.
Clinical Assessment
Past and current lifetime trauma was assessed by using the Trauma History
Questionnaire (B. Green, unpublished manuscript, 1995). The questionnaire
lists 23 potentially traumatic (mostly potentially life-threatening)
events, such as crime, physical and sexual assaults, and disaster, and
includes an open-ended question for specifying other extraordinarily
stressful situations or events. Subjects were asked the number of times
they experienced each of these events and at what ages. The events were
classified into four categories—crime, sexual abuse, disaster, and other—and
then further classified as low-magnitude (e.g., mugging without a weapon,
motor vehicle accident without injury) and high-magnitude (e.g., assault,
rape) events. For events in the "other" category, repeated
instances of hearing about traumatic events of the same type were counted
only once.
After reviewing the responses to this questionnaire, the clinical rater
asked the subject to identify the most traumatic life event from the
list and used this event as the basis of inquiry about PTSD symptoms.
PTSD symptoms were assessed by using the Clinician Administered PTSD
Scale [29] and DSM-IV symptom criteria. If no event
was present, or if no event was deemed life-threatening or as having
resulted in a subjective response of intense fear, helplessness, or horror,
the Clinician Administered PTSD Scale was not administered, and individual
items were automatically scored as zero. Psychiatric diagnoses other
than PTSD were made according to DSM-IV criteria by using the Structured
Clinical Interview for DSM-IV (SCID) [30]. The full
diagnostic interview was performed for only subjects who endorsed a positive
response on one or more of the mental health screening questions at the
beginning of the interview.
Parental PTSD was assessed in one of two ways. For 11 of the 35 offspring
subjects, parents were interviewed directly by the investigators, who
used the Clinician Administered PTSD Scale. (These parents could be interviewed
because they participated in other ongoing research on Holocaust survivors
at the Mount Sinai Traumatic Stress Studies Program.) For other subjects,
determination of parental PTSD was made by the offspring, who completed
a parental stress history assessment developed for this study. The scale
required offspring to first describe the nature of the parent’s Holocaust-related
experience (i.e., concentration camp, ghetto, hidden in forest, etc.)
and then complete a checklist based on the 17 DSM-IV symptoms of PTSD
for each parent. The offspring estimated the average severity of each
of the parent’s symptoms, on the basis of recall from their childhood,
adolescent, and early adult years. PTSD symptoms were rated on a 4-point
Likert-type scale that had anchors similar to those on the Clinician
Administered PTSD Scale. Although the accuracy of an adult child’s estimate
of the actual extent of parental PTSD symptoms is difficult to ascertain,
particularly because PTSD symptoms may have fluctuated over the life
course of the parent and some symptoms may not have been observable to
the child and would therefore be underestimated, the questionnaire provided
an index of the subjective perception of the parent’s symptoms. It is
noteworthy that this subjective assessment correlated well with our diagnostic
conclusions when the parent could be rated with the Clinician Administered
PTSD Scale. Nine of the 11 subjects whose parents we interviewed had
completed the parental stress history scale. In each of these cases,
our raters and the offspring generated the same conclusions regarding
the presence or absence of PTSD.
In addition to this interview, subjects completed the Civilian Mississippi
Scale [31] to determine the global effect of stressful
events on individuals’ lives. This scale provides a continuous measure
of PTSD-like symptoms. Subjects also completed the Symptom Checklist
(SCL-90) [32] to provide an estimate of general psychiatric
symptom severity. The depression and anxiety subscales of this instrument
were of interest for this study.
Cortisol Assessment
Urine was collected beginning at wake-up in 24-hour portions in 2-liter
polyethylene bottles kept in freezers in the subjects’ residences to
ensure stability of cortisol, as previously described [18].
Collections were scheduled to occur on days that were anticipated not
to be particularly stressful to obtain samples that would reflect basal
secretion (Mason et al. [13]). Typically, subjects
planned to be at home for the 24-hour period to facilitate collection.
Urinary free cortisol levels were determined by using an extraction procedure
and radioimmunoassay kit from Clinical Assays, Inc. (Cambridge, Mass)
(interassay coefficient of variation=4.0).
Statistical Analysis
One-way analysis of variance (ANOVA) was performed to determine group
differences in age, height, weight, gender, education, and 24-hour urine
volumes, as well as trauma exposure and clinical symptoms. The primary
dependent variable in this study was cortisol level, which was substantially
skewed; taking the log of cortisol level produced more nearly normally
distributed values. Log-transformed cortisol levels of offspring and
comparison subjects were used for all statistical analyses, but means
and standard deviations of untransformed values are presented. Group
means in cortisol levels were compared by using ANOVA. To further investigate
whether group differences were attributable to demographic variables,
gender, or trauma exposure, analysis of covariance (ANCOVA) or two-way
ANOVA was performed. ANCOVAs, controlling for age, were performed to
compare exposure to types of trauma between offspring and comparison
subjects, as cumulative exposure may increase with age.
Additional analyses were performed to distinguish among the offspring
by using characteristics that were either not evaluated (parental PTSD)
or not present (lifetime PTSD, current major psychiatric diagnosis) among
comparison subjects. Because all offspring with lifetime PTSD had a parent
with PTSD, both variables could not be employed in factorial ANOVA. Instead,
a trichotomy was constructed consisting of offspring 1) without parental
PTSD or lifetime PTSD, 2) with parental PTSD but no lifetime PTSD, and
3) with both parental PTSD and their own lifetime PTSD. One-way ANOVA
was performed to investigate cortisol differences in these three offspring
groups and in comparison subjects. Another one-way ANOVA was performed
to compare differences in log-transformed cortisol levels among offspring
with and without current psychiatric diagnoses and comparison subjects.
Two-way ANOVA was used to investigate whether the differences in log-transformed
cortisol levels found among the three offspring types were affected by
the presence of a current psychiatric diagnosis other than PTSD. Post
hoc testing for the ANOVAs was performed using Tukey’s honestly significant
difference test or Dunnett’s T3, if variances were unequal among the
groups.
To complement these ANOVAs, correlational analyses with log-transformed
cortisol levels were performed for offspring by using dichotomous indices
of parental and lifetime PTSD and current psychiatric diagnosis. Parallel
analyses were performed by using the Mississippi PTSD scale as a continuous
measure of current PTSD symptoms in place of the dichotomous characterization
of lifetime PTSD.
Results
The mean ages for children of Holocaust survivors and comparison subjects
were 40.9 years (SD=6.4) and 32.7 years (SD=8.0), respectively (F=14.59,
df=1, 48, p<0.001). Children of Holocaust survivors did not differ
from comparison subjects in education (mean=17.0 years, SD=1.7, and mean=16.8
years, SD=3.2, respectively) (F=0.04, df=1, 40, n.s.). An ANOVA analyzing
the effects of group and gender failed to reveal significant group differences
for height (F=0.28, df=1, 45, n.s.) or weight (F=3.66, df=1, 43, p=0.06).
Significant gender effects were observed for height (F=20.10, df=1, 45,
p<0.001) and weight (F=8.67, df=1, 43, p=0.005), but no interaction
of group and gender was observed for either height (F=0.42, df=1, 45,
n.s.) or weight (F=0.02, df=1, 43, n.s.). Offspring did not differ from
comparison subjects in 24-hour urine volume (t=0.70, df=43, n.s.) or
urinary cortisol concentration (t=1.36, df=43, n.s.).
Children of Holocaust survivors did not differ from comparison subjects
in the types of lifetime traumatic experiences, as assessed by the Trauma
History Questionnaire (Table 1). The mean number of traumatic events
reported by children of Holocaust survivors (mean=4.1, SD=3.8) and comparison
subjects (mean=3.9, SD=3.2) did not differ, covarying for age (F=0.38,
df=1, 47, n.s.). However, offspring were more likely to develop PTSD
after traumatic experiences. None of the comparison subjects met criteria
for lifetime PTSD in response to their traumatic life experiences. In
contrast, 28.6% of offspring (10 of 35 offspring) had lifetime PTSD,
and two had current PTSD.
Table 2 and Table 3 provide a summary of self-reported symptom severity
of the offspring, grouped by presence or absence of lifetime PTSD and
current psychiatric diagnosis, and of the comparison subjects. Offspring
with lifetime PTSD had significantly higher scores on the Mississippi
PTSD scale than offspring without lifetime PTSD and comparison subjects,
who did not differ significantly from each other. Offspring with lifetime
PTSD also reported more psychiatric symptom severity than comparison
subjects, as reflected by the SCL-90 total score. Offspring without lifetime
PTSD were not significantly different from either of the other two groups
on this measure. Significant group differences were observed on the depression
and anxiety subscales of the SCL-90. Post hoc tests revealed significant
differences in the number of current depressive symptoms endorsed by
offspring with PTSD and comparison subjects, but no significant pair-wise
group differences in anxiety ratings.
Twelve of the 35 offspring of Holocaust survivors met criteria for at
least one current psychiatric diagnosis other than PTSD at the time of
the evaluation. Five subjects had a mood disorder (either major depressive
disorder or dysthymia) with generalized anxiety disorder, three met criteria
for only a mood disorder, one had major depressive disorder with body
dysmorphic disorder, one had dysthymia with an eating disorder, one met
criteria for obsessive-compulsive disorder, and one had anorexia nervosa.
Although these illnesses tended to be chronic, their severities were
generally in the mild to moderate range at the time of assessment; only
one subject had been treated with an antidepressant or psychotropic medication
for any of these conditions within the previous 6 months. Three of the
12 subjects also had lifetime PTSD; one of these had current PTSD. None
of the comparison subjects met the diagnostic criteria for current or
past major psychiatric disorder.
Offspring were classified by the presence or absence of current psychiatric
diagnoses and compared on symptom rating scales to the comparison subjects
(Table 2). Scores on the Mississippi PTSD scale were highest in the offspring
with psychiatric diagnoses, three of whom also had lifetime PTSD. However,
there were no differences between offspring with or without current psychiatric
disorder on SCL-90 total scores or on the depression and anxiety subscales.
Assessment of parental PTSD indicated that 71.4% of the offspring (25
of 35 offspring) had at least one parent with chronic PTSD. All 10 offspring
meeting criteria for lifetime PTSD were among these 25 offspring. Furthermore,
for all 10 offspring with lifetime PTSD, both parents were Holocaust
survivors.
As a group, children of Holocaust survivors showed significantly lower
24-hour urinary cortisol excretion (mean=48.3 mg/day, SD=27.0) than comparison
subjects (mean=65.1 mg/day, SD=25.7) (F=5.62, df=1, 48, p=0.02), based
on log-transformed cortisol values. When age was used as a covariate,
this group difference was not substantially changed (F=5.13, df=1, 47,
p=0.03). Covarying for the total number of traumatic life events in addition
to age did not affect the group difference in cortisol level (F=5.11,
df=1, 46, p=0.03). When gender was used as a main effect in a two-way
ANOVA, the group difference was reduced (F=2.91, df=1, 46, p=0.10). However,
there was no gender difference (F=0.66, df=1, 46, n.s.) or interaction
of group and gender (F=0.15, df=1, 46, n.s.). There was no further reduction
of significance when height and weight were added as covariates (F=2.94,
df=1, 41, p=0.09). When education was used as a covariate, the group
difference was still significant (F=4.41, df=1, 39, p=0.04).
Pooled within-group associations of cortisol level with other demographic
observations were assessed by partial correlations, controlling for group.
Log-transformed cortisol levels were not significantly correlated with
age (r=–0.06, df=47, n.s.) or education (r=–0.15, df=39, n.s.). Partial
correlations were not significant for total number of traumatic events
(r=–0.04, df=46, n.s.), controlling for age in addition to group, or
for height (r=0.22, df=43, n.s.) or weight (r=0.09, df=43, n.s.), controlling
for gender in addition to group.
We divided the offspring sample into three categories: offspring with
PTSD and parental PTSD, offspring without PTSD but with parental PTSD,
and offspring without either PTSD or parental PTSD. Because all offspring
with PTSD also had parental PTSD, it was not possible to distinguish
fully between these two characteristics. A one-way ANOVA indicated significant
differences in cortisol level among the comparison subjects and these
three offspring categories (F=6.72, df=3, 46, p=0.001), as illustrated
in Figure 1. Dunnett’s T3 post hoc tests showed that offspring with both
parental PTSD and their own PTSD differed from offspring without parental
PTSD or their own PTSD (p=0.003), and also from comparison subjects (p=0.006).
When offspring were characterized by current psychiatric diagnosis, one-way
ANOVA demonstrated differences in log-transformed cortisol levels among
three groups, defined as offspring with (mean=63.1 mg/day, SD=33.2) and
without (mean=40.6 mg/day, SD=19.8) current psychiatric diagnoses and
comparison subjects (mean=65.1 mg/day, SD=25) (F=6.22, df=2, 47, p=0.004).
Post hoc tests of log cortisol level that used Tukey’s honestly significant
difference test indicated that offspring with no current psychiatric
diagnoses showed significantly lower mean 24-hour levels of cortisol
excretion than offspring with psychiatric diagnoses (p=0.04) and comparison
subjects (p=0.006).
A two-way ANOVA analyzing presence of current psychiatric diagnosis other
than PTSD among offspring trichotomized by presence of parental PTSD
and their own PTSD demonstrated significant main effects for both offspring
group (F=4.60, df=2, 29, p=0.02) and diagnosis (F=4.34, df=1, 29, p=0.05)
but a nonsignificant interaction (F=1.99, df=2, 29, n.s.). Table 4 presents
the mean cortisol levels for offspring grouped by lifetime PTSD, parental
PTSD, and current diagnoses. Cortisol levels were generally low in offspring
with both their own and parental PTSD and high in offspring with neither.
Cortisol levels were generally higher in the groups with psychiatric
diagnoses. Pair-wise comparisons of groups using Tukey’s honestly significant
difference test of log cortisol levels demonstrated that, for the three
groups without psychiatric diagnoses, offspring with both parental PTSD
and lifetime PTSD had lower values than offspring with parental PTSD
but no lifetime PTSD (p=0.04) and offspring with neither parental or
lifetime PTSD (p=0.03).
Bivariate correlations demonstrated that in the offspring group, cortisol
levels were more strongly negatively correlated with having parental
PTSD (r=–0.50, df=33, p=0.002) than with lifetime PTSD (r=–0.34, df=33,
p=0.05) and were positively correlated with having a current psychiatric
diagnosis (r=0.37, df=33, p=0.03). After controlling for parental PTSD,
the correlation between log-transformed cortisol level and lifetime PTSD
was no longer significant (r=–0.16, df=32, n.s.). On the other hand,
the relationship between log-transformed cortisol level and parental
PTSD was maintained even after controlling for lifetime PTSD in the offspring
(r=–0.41, df=32, p=0.02). The relationship between log-transformed cortisol
level and parental PTSD was similarly demonstrated after controlling
for current PTSD symptoms as reflected by the Mississippi PTSD scale
(r=–0.48, df=32, p=0.03). The Mississippi scale score was, however, not
significantly correlated with log-transformed cortisol level among the
entire offspring sample (r=–0.20, df=33, n.s.). It is interesting to
note that this index of PTSD symptoms was only moderately correlated
with a diagnosis of PTSD among the offspring (r=0.36, df=33, p=0.03),
indicating that PTSD symptoms were present in offspring even in the absence
of a PTSD diagnosis (Table 2).
Discussion
The results demonstrate that some putative risk factors are associated
with cortisol levels in offspring of Holocaust survivors, whereas other
risk factors are not. Low cortisol levels in offspring were associated
with parental PTSD but not with parental exposure to Holocaust-related
trauma. This is consistent with our previous finding that risk for PTSD
among offspring was related to parental PTSD status and not to exposure
of the parent to the Holocaust [2].
Likewise, cortisol levels were associated with the development of PTSD
in the offspring but not with the offspring’s exposure to trauma. Because
the development of PTSD in the offspring was limited to offspring with
parental PTSD, it was not possible to distinguish completely between
the effect of parental PTSD and the individual’s own PTSD. Nonetheless,
it appears that parental PTSD is an even more important correlate of
cortisol levels in the offspring than whether or not the offspring developed
his or her own PTSD after exposure to a traumatic event, as there was
a significant correlation between cortisol level and parental PTSD even
after controlling for the lifetime PTSD status of the offspring. Conversely,
the correlation between PTSD and cortisol level in the offspring was
no longer significant after controlling for parental PTSD.
This pattern of associations does not imply that the offspring’s own
PTSD was unrelated to cortisol level. Offspring with both parental PTSD
and lifetime PTSD had significantly lower cortisol levels than either
offspring without lifetime PTSD or comparison subjects. Offspring with
only parental PTSD, but not lifetime PTSD, had an intermediate level
of cortisol, which in this small sample was not significantly different
from the levels in other groups. Thus, parental PTSD alone did not fully
account for low cortisol levels in offspring.
In the context of discussions about biological correlates of risk, however,
lifetime PTSD—that is, whether an individual ever developed PTSD—may
be a more relevant variable than the current PTSD status at any given
time after exposure to a traumatic event. The importance of this variable
is illustrated by its association with current symptoms, not only as
measured by the Mississippi PTSD scale but also by the SCL-90 total score
and SCL-90 depression and anxiety subscale scores. Indeed, offspring
with lifetime PTSD were more symptomatic in terms of current depression
and anxiety symptoms than offspring without lifetime PTSD, while the
presence of a current psychiatric disorder did not differentiate symptoms
of the SCL-90. The association between lifetime PTSD and current psychiatric
symptoms suggests that historical variables may be critical in determining
current responses to the environment. Further, these results indicate
that cortisol level, which has been considered to be a "state-related" measure
because it is profoundly affected by day-to-day provocation, can be a
legitimate correlate of historical variables such as past PTSD or even
parental PTSD.
In this context, it should be noted that increased cortisol levels have
been found in first-degree relatives of depressed patients and have been
implicated as a risk factor for the development of major depressive disorder
(33, 34). In fact, a variety of HPA parameters have been examined and
found to be altered in nondepressed probands at genetic high risk for
depression in a manner consistent with alterations observed in the depressed
relatives, albeit not to the same extent [33, 34].
Moreover, the HPA alterations were found to be stable when assessed 4
years later in the same high-risk probands [35]. These
studies demonstrate that cortisol parameters can be viewed as vulnerability
markers in probands with high familial risk for depression. Indeed, although
PTSD and also parental PTSD appear to be associated with low cortisol
levels, other psychiatric disorders such as major depressive disorder
have been associated with increased cortisol levels (for review, see
references 19 and 20). Having a psychiatric disorder is certainly a plausible
outcome after exposure to trauma [36] and is compatible
with and, some argue, predictive of [37] the development
of PTSD. In the current study, having a psychiatric diagnosis other than
PTSD at the time of assessment was generally associated with levels of
cortisol as high as those observed in comparison subjects. There were
too few subjects in the sample to permit an analysis of cortisol by diagnosis,
but this type of analysis may be of interest in future studies.
Nonetheless, in considering why cortisol levels were not significantly
higher in offspring with psychiatric disorder compared with healthy volunteers,
as one might expect based on the psychiatric literature, it may be that
the cohort of subjects in this study, while meeting criteria for these
disorders, were not symptomatic enough to show the cortisol elevations
typically associated with psychiatric disorders. Supporting this view
is the observation that there were no substantial differences in SCL-90
scores, particularly scores on the depression and anxiety subscales,
for offspring with a psychiatric diagnosis compared to offspring without
a psychiatric diagnosis or comparison subjects. Indeed, our exclusion
of subjects taking psychotropic medications within the past 2 months
may have generated a less symptomatic sample.
Alternatively, it may be that cortisol levels might have been more elevated
in offspring with psychiatric disorder were it not for the presence of
other factors that are associated with low cortisol levels. Indeed, having
parental PTSD, and especially having lifetime PTSD in addition to parental
PTSD, was generally associated with low cortisol levels. In the groups
with parental PTSD and a current psychiatric diagnosis other than PTSD,
the cortisol level was low for those with a lifetime PTSD diagnosis and
high for those without a lifetime PTSD diagnosis. The message here is
that a variety of intercorrelated factors contributing to risk for PTSD
may be associated with different effects on cortisol. Thus, our findings
represent the beginning of an exploration of this complex issue, which
should be pursued to more carefully examine relationships among these
factors and their individual or collective impact on risk and cortisol.
In considering unanswered questions and methodological limitations of
the study, the reader should be reminded that the major risk factor examined
in this study—that of parental PTSD—was largely based on the subjective
assessment of the parent’s PTSD by the offspring rather than by a direct
examination of the parent. Yet, the subjective nature of the assessment
may not be a serious methodological flaw in the context of examining
the impact of parental status on the offspring. Indeed, the offspring’s
subjective evaluation may be at least as relevant to this issue as the
objective reality of the parents’ symptoms. PTSD may exert effects on
the family because of the obvious distress of the afflicted parent. Although
family members may not always know what intrusive thoughts are being
recalled at any given time by the trauma survivor parent, family members
may certainly notice the parent’s distractibility, frequent references
to the Holocaust, distress at reminders of the Holocaust, or explosive
outbursts, or they may notice the effects of constriction of affect and
numbing in the parent’s life. It is important to note that although some
offspring claimed their parents did not speak of the Holocaust, many
of them still believed their parents were impaired by their experiences.
It may be that witnessing symptoms, even in the absence of knowledge
about the historical details of their parents’ lives, is a salient aspect
of conferring on offspring the vulnerability to PTSD after trauma exposure,
as suggested by Solomon et al. [38]. However, the converse
case—a failure by the offspring to recognize parental PTSD—may not necessarily
imply the absence of PTSD in that parent but only a lack of awareness
of parental symptoms. This issue, too, can be addressed in a larger study
examining the variability of cortisol levels in those who report no parental
PTSD. Ultimately, it will be possible to determine whether a low cortisol
level is differentially associated with subjective assessment or actual
presence of PTSD in the parent(s) through direct examination of survivors
and children.
Whatever the perception of offspring regarding parental psychopathology,
parental rearing practices may be substantially affected by the presence
of PTSD in one or both parents. Nongenomic transmission of stress response
characteristics has been demonstrated in rats, and this process includes
both a behavioral and neuroendocrine response bias [39, 40].
Moreover, this effect of maternal behavior has recently been shown to
persist across multiple generations [41] and to be
associated with increased hippocampal glucocorticoid receptor expression.
Thus, putative animal models exist that provide a template for generating
hypotheses concerning the intergenerational transmission of stress vulnerability.
The current findings represent the first clinical demonstration of this
phenomenon that we are aware of. Clearly, additional studies are warranted
to further explore this initial observation of the association of cortisol
levels with the risk factor of parental PTSD.
FOOTNOTES
Received July 29, 1999; revision received Jan. 19, 2000; accepted Mar.
9, 2000. From the Traumatic Stress Studies Program, Department of Psychiatry,
Mount Sinai School of Medicine, New York City; and the Psychiatry Department,
Veterans Affairs Medical Center. Address reprint requests to Dr. Yehuda,
Psychiatry 116A, Veterans Affairs Medical Center, 130 West Kingsbridge
Rd., Bronx, NY 10468; rachel.yehuda@med.va.gov (e-mail).This work was
supported by NIMH grant MH-49555 and Merit Review funding to Dr. Yehuda.The
authors thank Abbie Elkin for recruiting and screening subjects and the
staff at the Specialized Treatment Program for Holocaust Survivors and
Their Families, particularly Robert Grossman, M.D., medical director,
for help with medical and diagnostic evaluations. The authors thank Alan
Lehman, M.S.W., and Karen Binder-Brynes for their help in diagnostic
assessments.
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