We would like to thank Breidenstein and colleagues for writing a commentary on our
study titled “Sex Differences in the Peripheral Immune System in Patients with Depression”
and appreciate the positive comments (1). We agree that even though our study points
toward women showing higher levels of inflammation during depression, it is not possible
to draw inferences about causality from our results due to the cross-sectional nature
of the study. Therefore, a longitudinal study is warranted to determine the causal
relationship between inflammation and major depressive disorder (MDD) (2).
With regard to interleukin-6 (IL-6), Breidenstein et al. pointed out that we did not
identify elevated levels of IL-6 in depressed women compared with controls after controlling
for body mass index nor a positive correlation between IL-6 and depression severity.
However, our study did find elevated IL-6 in depressed females when compared with
depressed males after controlling for body mass index (2). To further support this,
one of our previous studies found higher circulating levels of IL-6 in MDD, which
was largely explained by obesity (3). Although numerous correlative studies have found
elevated IL-6 in depressed patients relative to controls, a recent meta-analysis using
longitudinal studies showed that the weighted-mean effect size for IL-6 was relatively
small (unadjusted r = 0.045, p = 0.007; adjusted r = 0.097, p = 0.06) (4). In addition,
elevated circulating IL-6 has been reported in several animal models of depression
in which chronic mild stress or learned helplessness was applied to establish depressive-like
symptoms (5). Taken together, studies in humans and animal models have provided strong
evidence that inflammation is altered and IL-6 may be elevated in a subset of depressed
patients or animals that are exposed to stress. However, the role of elevated IL-6
levels in depressed patients may need to be interpreted in a sex-specific manner as
well as to include other confounding factors such as obesity. Thus, more rigorous
and longitudinal studies in humans are needed to establish the sex–IL-6 relationship
in depressed patients.
Breidenstein et al. raise an important issue regarding the relationship between gonadal
hormones and inflammation that referred to a paper focusing on an immune system-related
disease, i.e., rheumatoid arthritis, instead of the observations in depression (6).
Indeed, recent studies indicate that the relationship between gonadal hormones and
cytokines is complicated and their relationship varies from disease to disease. For
example, several clinical and experimental studies have showed a gender dimorphism
of the immune and organ responsiveness in the susceptibility to and morbidity from
shock, trauma, and sepsis. Specifically, studies indicate that androgens are responsible
for the immunodepression after trauma hemorrhage in males. By contrast, female sex
steroids seem to exhibit immunoprotective properties after trauma (7). Furthermore,
postmenopausal women have higher basal levels of IL-6 and a larger IL-6 stress response
than age-matched men in response to acute stress (8). Although gonadal hormones are
not in the scope of our current study, we would like to include gonadal hormone measurements
in future studies to explore its complicated roles in depression and to determine
if those effects are sex and age dependent.
Another issue raised by Breidenstein et al. is the role of psychosocial stress as
a possible mediator in the relationship between inflammation and MDD, as well as the
hypothalamic–pituitary–adrenal (HPA) axis in the pathogenesis of MDD. Two other studies
from our group have suggested that childhood maltreatment is positively correlated
with elevated inflammatory markers (9, 10). Our observations were consistent with
Mondelli et al.’s reports (11) that psychosocial stress was one of the main factors
determining neuroinflammation. Stress is a major risk factor for depression and the
HPA axis mediates stress response. Altered HPA axis activity in depressed patients
has been associated with both childhood maltreatment and acute stress responses. One
of our prior studies suggests that individuals with childhood maltreatment showed
suppressed HPA axis activity measured by cortisol awakening curve; this effect was
independent of depression (9). Our observations were supported by other research groups
who found early life adverse experiences were associated with decreased salivary cortisol
responses to awakening (12). Both Holsboer et al. and Gold et al. reported that depressed
women with and without childhood trauma exhibited blunted adrenocorticotropic hormone
response to corticotropin-releasing factor (13, 14). By contrast, Heim et al. reported
that women with a history of childhood abuse with and without current major depression
exhibited increased adrenocorticotropic hormone but normal cortisol responses to stress
compared with controls (15). Taken together, an interconnected relationship between
inflammation, HPA axis, and depression might be present, which definitely warrants
further investigation in humans and in animal models.
To summarize, our study demonstrated that inflammation is related to depression; however,
the association is sex specific. Understanding the influence of inflammation on women’s
mental health may help enhance our understanding of the sex differences in depression
as well as help clinicians choose effective antidepressants in the future. More longitudinal
studies are needed to answer the causal relationship between inflammation and MDD.
Currently, more studies are ongoing in our department to understand the link between
sex, depression, inflammation, and the HPA axis. We thank Dr. Breidenstein and group
for the thoughtful comments, which focus our attention to be careful as we describe
and interpret our outcome measures, and helpful to design future studies.
Author Contributions
BB and LL wrote, edited, and approved the submission. RS and EA edited and approved
the submission.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.