If HPA-axis hyperactivity accounts, at least in part, for the association between depressive disorder and an increased likelihood for CV death, and if a cortisolemia dose-effect operates in this mediation, then the association should be more apparent among patients who have depressive disorder with psychotic features. Not all patients with psychotic depressive disorder manifest HPA-axis hyperactivity but they are more likely to do so than depressed patients without psychotic features (Nelson and Davis, 1997
), and many of those that do have particularly high post-dexamethasone cortisol concentrations (Brown et al., 1988
; Coryell et al., 1984
; Evans and Nemeroff, 1987
; Rothschild et al., 1982
). Moreover, in comparison to patients with non-psychotic MDD, those with psychotic MDD have longer episode durations and shorter intervals between episodes (Coryell et al., 1990
). They would therefore have greater within-episode exposure to high cortisol concentrations.
While our findings that patients with psychotic depressive disorder who died from cardiovascular disease had significantly higher post-dexamethasone cortisol concentrations lend support to these suppositions, several important caveats apply. Because the data included only four deaths from CV disease, and high post-dexamethasone cortisol concentrations predicted these deaths with very wide confidence intervals, the possibility that this is a chance finding is substantial. In addition, the current results do not concur with two earlier studies of DST results and mortality. Vythilingam et al (Vythilingam et al., 2003
) followed an older MDD group with psychotic MDD and found that they had elevated all-cause mortality compared to a group with non-psychotic MDD, but also that DST results were not predictive of mortality. They included a separate analysis of suicides but not of CV deaths.
Coryell et al (Coryell et al., 2006
) followed a mixed sample of inpatients and outpatients with MDD. This was a substantially larger sample of 334 of whom 32 (9.6%) died of CV disease; 7 (21.9%) of these patients had had 4:00 p.m. post-dexamethasone cortisol concentrations >10 μg/dl while 41 (12.5%) of the other patients had values in this range. Thus, the increase in risk for CV death associated with a value above 10 μg/dl was 1.6, lower than the increase in risk of 2.4 reported in the current sample. The analyses did not separate those who had psychotic features and, not surprisingly, the proportion with values >10 μg/dl (48 of 334 or 14.4%) was substantially lower than the 19 of 55 (34.5%) in the current series (t = 13.4, 1 df, p< .001). It is thus possible that the values exceeding 10 μg/dl did so by a narrower margin.
A post-dexamethasone cortisol threshold of 10 μg/dl was also more predictive of suicide than was one of 5 μg/dl. Notably, though, the conventional threshold of 5ug/dl yielded a hazard ratio of 3.8, a value approaching the four-fold risk described in a recent meta-analysis of the DST and completed suicide (Mann et al., 2006
The above study also described a relationship between DST nonsuppression and eventual suicide but this applied only to those with recent suicidal ideation or behaviors. Ratings of suicidality were obtained for subjects in the current study but these data are, unfortunately, no longer available and it is not possible to test whether an interaction between suicidality and DST results on eventual suicide existed in this cohort as well.
To our knowledge only two of the previous studies concerning DST results and suicide tested 8 a.m., 4 p.m. and 11 p.m. post-dexamethasone results separately (Coryell et al., 2006
; Jokinen et al., 2008
). Those two found that 4 p.m. results were the most predictive of suicide while, in the current study, 11 p.m. sample values produced the only significant results in logistic regression analyses. On the other hand, the relationship between post-dexamethasone cortisol values and cardiovascular death was strongest for the 4 p.m. sample. Reasons for differences by sampling time are not obvious.
In summary, HPA axis hyperactivity predicted mortality from cardiovascular causes and, to a limited extent, from suicide. Though negative studies of DST results and suicide exists (Black et al., 2002
), it can be argued that the current number of positive studies justify the use of DST results as a tool for estimating suicide risk in conjunction with other clinical measures. The findings regarding risks for cardiovascular death should be considered preliminary given the small numbers available for analysis. As noted earlier, though, there are numerous reasons to expect such a relationship. The prevalence of MDD, and its recurrent nature, gives considerable public health importance to further investigation into the physiological links between it and cardiovascular morbidity.