Differences in Demographic and Clinical Characteristics at Pre-treatment
At pre-treatment evaluation (), PTSD subjects who would subsequently not respond to therapy (non-responders) were significantly older and had a higher BMI than those who would demonstrate a criterion treatment response (responders), but there were no differences in gender or prior trauma exposure. However, after controlling for age, the two groups no longer differed significantly on BMI (F=3.14, df=1,25, ns). For the majority of participants in either group, 9/11 was deemed their worst lifetime traumatic event. There were also no differences in rates of current depression diagnoses, other anxiety disorders, or past substance abuse. Total PTSD and depression severity scores as assessed by clinician ratings were similarly comparable for responders and non-responders at pre-treatment.
Demographics, clinical characteristics, and biological measures at pre-treatment
At the time of post treatment evaluation, however, there were significant group differences between responders and non-responders in clinician ratings for both PTSD and depression (for PTSD: F=17.69, df=1,26, p<.0005; for HDRS scores: F=7.98, df=1,26, p=.010) that were sustained at follow-up (for PTSD: F=37.96, df=1,36, p<.0005; for HDRS scores: F=8.56, df=1,26, p=007). demonstrates significant effects of time, indicating that improvement occurred in both the responder and non-responder groups; the significant group × time interactions indicate that the responders showed significantly greater improvements than did the non-responders (by definition); with the significant group effects for PTSD and depression ratings indicating that, averaged across the three time points, these differences were substantial.
Comparison of clinical characteristics and biological measures for responders and non-responders.
Treatment effects on biological measures
Repeated measures ANCOVA showed significant group effects for 5α-THF and for total glucocorticoids, which reflects primarily the contribution of 5α-THF. To illustrate the significant contribution of 5α-THF to the level of total glucocorticoids, urinary levels of these metabolites are highly correlated at pre-treatment (partial r=.904, df=23, p<.0005), and almost as highly correlated at post-treatment and follow-up (at both time points, partial r=.873, df=23, p<.0005). These findings indicate a persistent effect of diminished 5α-reduction in the non-responders. Similar, but weaker results were found for 5β-THF and THE, indicating lower 5β-reduction among the non-responders, but these results did not meet Bonferroni criteria. The findings pertaining to diminished 5α-reduction among non-responders is borne out entirely by repeated measures analyses of the enzyme indices. A significant group effect is noted for 5α-reductase, indicating reduced activity in the non-responders that satisfies Bonferroni considerations, whereas a similar but weaker finding for the 5β-reductase index does not. Neither of the 11β-HSD enzymes (total or 11β-HSD-2) appeared to be altered by trauma focused treatment. Among the glucocorticoids, metabolites and enzyme indices derived from GCMS determinations, there were no significant effects of time, and no significant group × time interactions. These findings were not substantially altered by re-analysis with additional covariation for depression and/or medication status.
Differences in biological measures at pre-treatment
In order to identify predictors of recovery, we next employed univariate ANCOVA to compare pre-treatment values for responders and non-responders for the three biological measures for which a significant effect was found in the repeated measures analyses. Thus, Bonferroni corrections were applied to two metabolite measures (5α-THF and total glucocorticoids, each at α<.025) and to one enzyme index (5α-reductase, α<.05). 5α-reductase activity was identified as a predictor of treatment response. Non-responders demonstrated significantly reduced 5α-reductase activity (F=6.43, df=23, p=.019) in comparison to responders (there was greater than 70% lower pre-treatment 5α-reductase activity among non-responders). However, neither pre-treatment levels of 5α-THF (F=0.15, df=23, ns) or total glucocorticoids (F=1.01, df=23, ns) distinguished responders from non-responders.
For descriptive purposes, pre-treatment levels of F, glucocorticoid metabolites other than 5α-THF and enzymes other than 5α-reductase were compared for non-responders and responders, controlling for age, gender and BMI. There were no significant differences between the treatment responder groups in any of these measures, or in pre-treatment level of RIA-cortisol. .These findings, like those of the repeated measures ANCOVAs, were not substantively altered by additional covariation for depression or medication status.
Findings for RIA Cortisol
The primary outcomes of the present study were F, its metabolites, and glucocorticoid metabolic enzyme indices, as determined by estimating ratios of metabolites assessed by GCMS. Cortisol levels were also assessed by RIA, principally to facilitate comparison of the present results to previous findings pertaining to glucocorticoids in PTSD. At pre-treatment, urinary cortisol measured by RIA was significantly correlated with F (r=.694, df=23, p<.0005) and total glucocorticoids (r=.697, df=23, p<.0005), as well as each of the other glucocorticoid metabolites; for instance, RIA-cortisol was almost as strongly correlated with 5α-THF (r=.637, df=23, p=.001), and similarly correlated with 5β-THF (r=.691, df=23, p<.0005), as with F.
Repeated measures ANCOVA indicated a significant group × time interaction for urinary RIA cortisol (F=11.6, df=1,26, p=.002) in the absence of a main effect of group or time. Though not different at pre-treatment (mean± SE, non-responders: 51.9 ± 5.5; responders: 49.1 ± 5.5), RIA cortisol levels declined appreciably over time in the non-responder group and increased (less dramatically) in the responder group, such that by the follow-up assessment, the two groups were significantly distinguishable (mean± SE, non-responders: 37.5 ± 5.3; responders: 55.0 ± 5.3).
Relationship of glucocorticoid production to treatment response
Examination of the descriptive data provided in reveals a consistent overall pattern: glucocorticoid metabolites trend downward among non-responders from pre-treatment to post-treatment, and appear to stabilize or continue to decline from post-treatment to follow-up. This treatment effect is not observed in the enzyme data, where, fundamentally, stable indices are observed overtime, and group differences do not emerge, but are generally apparent at pre-treatment and persist across the three assessments.
The pattern observed for the metabolite data is summarized graphically in , which illustrates that the predominant effect overtime for the non-responder group was to show a decline in the production of cortisol and its metabolites, while those who responded to treatment tended to increase production. The figure depicts percent change of group means from pre-treatment to follow-up in F, E, 5α–THF, 5β-THF and THE, for the non-responders and responders, respectively. Calculated individually, percent change was negative for the non-responders and positive for the responders in F and every metabolite other than 5α–THF in which the percent increase among non-responders (35.0%) was only half as great as that for the responders (97.1%), but this difference was not significant (F=.83, df=22, ns), controlling for age, gender, BMI, and pre-treatment 5α–THF level. Percent change in total glucocorticoids, however, differed significantly between non-responders (−17.0%) and responders (64.2%) (F=5.05, df=22, p=.035), controlling for age, gender, BMI, and the level of total glucocorticoids at pre-treatment.
Percent change in means of free cortisol (F) and metabolites from pre-treatment to follow-up for treatment non-responders and responders
Associations between biological and symptom measures at pre-treatment and over time
Only 5α–THF, and total glucocorticoids, which is highly reflective of the contribution of 5α–THF, were shown to differentiate treatment responders from non-responders significantly in the repeated measures analyses. Of the enzyme indices, only 5α-reductase significantly differentiated these groups, but unlike the metabolites, the enzyme activity was significantly reduced among the non-responders at pre-treatment. Each of these three biological measures was evaluated for their association with PTSD symptom ratings at pre-treatment, and at follow-up as indicated in . Prior to treatment, urinary 5α–THF was significantly negatively associated with self-ratings for avoidance, as was total glucocorticoids, though somewhat less so. Negative correlations for 5α–reductase measures with avoidance scores were of similar magnitude prior to and following treatment. At follow-up, when a greater range was apparent for behavioral as well as biological measures as a result of clinical improvements among responders, significant correlations are evident for all three indices of 5α–reduction (5α–THF, total glucocorticoids, and 5α–reductase) across the three behavioral dimensions of PTSD and PTSD total score. All significant partial correlation results shown in at pre-treatment and at follow-up for measures of 5α–reduction meet Bonferroni criteria.
Relationships of 5α-reductase and related glucocorticoid metabolites to self-rated PTSD symptoms at pre-treatment and follow-up
There were only few pre-treatment biological predictors of PTSD symptom severity at follow-up, and all pertained to lower pre-treatment estimated 5α-reductase activity predicting greater follow-up PTSD symptom severity (i.e., pre-treatment 5α-reductase activity with follow-up self-rated intrusive symptoms, r=−.479, df=23, p=.018, and PTSD total score, r=−.407, df=23, p=.044). Lower pre-treatment self-rated avoidance symptoms correlated negatively with RIA cortisol at pre-treatment (r=−.500, df=23, p=.007) and at follow-up (r=−.550, df=23, p=.041).
For descriptive purposes, similar correlational analyses were evaluated for pre-treatment F, metabolites other than 5α–THF, and enzymes other than 5α–reductase. None of these glucocorticoids, metabolites, or enzyme indices was significantly associated with self- or clinician rated PTSD symptom subscales or total score at pre-treatment or follow-up.