Effects of Parental PTSD on the Cortisol Response to Dexamethasone Administration in Their Adult Offspring

Table 1 shows that offspring of Holocaust survivors with PTSD were older than comparison subjects, but no group differences were noted in demographic variables or lifetime exposure to a traumatic event meeting PTSD criterion A. Offspring of Holocaust survivors with PTSD had higher Childhood Trauma Questionnaire and Civilian Mississippi Scale scores, and were significantly more likely to have past PTSD than the other two groups. No subject met criteria for current PTSD.

Significant group differences were also present in pre- and post-dexamethasone cortisol values. Repeated measures ANCOVA revealed a significant group-by-day interaction (F=3.66, df=2, 35, p<0.04), which was confirmed by pairwise comparisons that controlled for age, BMI, and dexamethasone levels to reflect greater cortisol suppression in offspring with parental PTSD than in offspring without parental PTSD (F=4.92, df=1, 20, p<0.04) or comparison subjects (F=5.56, df=1, 24, p<0.03), but not between offspring without parental PTSD and comparison subjects (p<0.54). There were no significant group differences in dexamethasone concentrations after age and BMI were controlled, nor was dexamethasone significantly associated with post-dexamethasone cortisol.

The total number of parental PTSD symptoms was significantly correlated with 1) severity of trauma-related symptoms (r=0.53, df=37, p=0.001), as rated on the Civilian Mississippi Scale; 2) childhood emotional abuse (r=0.33, df=36, p=0.041) and physical neglect (r=0.38, df=36, p<0.02), as measured by the Childhood Trauma Questionnaire; and 3) total Childhood Trauma Questionnaire score (r=0.41, df=36, p<0.02). Similarly, offspring Civilian Mississippi Scale scores were correlated with the childhood emotional abuse (r=0.55, df=36, p<0.0005), physical neglect (r=0.49, df=36, p=0.002), and total Childhood Trauma Questionnaire (r=0.52, df=36, p=0.001) scores.

It is important to note that the extent of parental PTSD symptoms was significantly associated with offspring post-dexamethasone cortisol after we controlled for offspring Civilian Mississippi Scale scores, presence or absence of lifetime PTSD, total Childhood Trauma Questionnaire scores, and dexamethasone levels (r=–0.35, df=32, p<0.05).

The association between cortisol suppression and parental PTSD is noteworthy in that, unlike ambient mean 24-hour cortisol excretion rates, which are thought to constitute relatively stable measures, the cortisol response to dexamethasone has often been linked to more transient phenomena related to symptom severity and has been shown to normalize in successfully treated depressed patients (11). Examination of high-risk probands with a positive family history for depression have demonstrated alterations in cortisol negative feedback inhibition only when the high-risk subjects became affected, and persisted even after successful treatment (12). Thus, there may be an acquired component to the dexamethasone suppression test response that depends on an interaction of specific risk factors and environmental events.

Indeed, there is ample reason to suspect a role for environmental events in modulating the effects of parental PTSD, since offspring of parents with PTSD report significantly more emotional abuse and neglect than offspring of parents without PTSD and demographically comparable healthy subjects (5). Nonetheless, in the current study, the association between cortisol suppression and parental PTSD persisted after we controlled for childhood trauma and offspring’s own PTSD. Alternatively, alterations in glucocorticoid receptor sensitivity occurring very early in development, possibly even related to in utero factors, may be responsible for the findings. It is now well established that the activity of genes regulating HPA activity can be programmed by pre- and postnatal early life events, and even by differences in maternal care (13). Such influences in rat pups have been demonstrated to result in permanent changes in hippocampal glucocorticoid receptor expression and HPA function that are transmitted intergenerationally (14) and provide a clear molecular link between early environment and gene expression and function. It is interesting that the alterations observed are in the same direction as those described in PTSD (i.e., increased glucocorticoid receptor sensitivity, enhanced cortisol response to dexamethasone, lower ambient cortisol levels), offering proof of the principle that environmental exposures can result in the kind of changes that alter glucocorticoid receptor expression, and form the basis for individual differences in endocrine function including, perhaps, vulnerability to PTSD. One of the major limitations of studying endocrine aspects of PTSD has been the inability to know for certain whether what is being measured constitutes a change associated with PTSD pathophysiology, the trauma that produced it, or an earlier risk factor. To the extent that neuroendocrine measures associated with PTSD, or risk for PTSD, are somewhat stable, it is possible that they reflect even more enduring patterns (e.g., changes in patterns of DNA methylation) that reflect earlier life events, rather than cumulative effects of stress, and result in an increased cortisol signaling capacity so that lower levels of cortisol efficiently suppress HPA function. Under certain environmental conditions, such as in response to a traumatic event, increased cortisol signaling might alter or interact with psychological and biologic risk factors to result in the PTSD clinical phenotype. The current findings constitute support for employing a transgenerational approach to the study of biologic risk factors in PTSD.

Received March 16, 2006; revision received May 24, 2006; accepted June 5, 2006. From the Traumatic Stress Studies Program, Department of Psychiatry, Mount Sinai School of Medicine and Bronx Veterans Affairs. Address correspondence and reprint requests to Dr. Yehuda, Psychiatry 116A, Bronx Veterans Affairs, 130 West Kingsbridge Rd., Bronx, NY 10468; [email protected] (e-mail). Dr. Yehuda reports having served on advisory boards for Acetelion Pharmaceuticals and Lundbeck Research. The other authors report no competing interests. Supported by NIMH grant R01-MH-64675-01 (“Biology of Risk and PTSD in Holocaust Survivor Offspring”) and NIH grant 5-M01-RR-00071 for the Mount Sinai General Clinical Research Center.The authors acknowledge Sarah Brand for her assistance with data analysis and manuscript preparation, Drs. Lisa Tischler and Alicia Hirsch for assisting with diagnostic evaluations and consensus conferencing, Dr. Robert Grossman for assisting with medical clearance, and Dr. Ling Song Guo for cortisol and dexamethasone determination.