4.0 Discussion:
Overall, the current results suggest that despite their common actions
in the inflammatory response, the pro-inflammatory cytokines are
differentially associated with psychological symptoms related to MDD,
with some interesting sex-specific effects. The pro-inflammatory
cytokines IL-1α and IL-6 were significantly higher in those with MDD
than healthy controls; however, a group by sex interaction for IL-6 and
post-hoc analysis revealed that IL-6 was significantly higher in MDD
versus control only for females. Both IL-1α and IL-6 were associated
with all psychological symptoms measured. In contrast, TNF-α did not
differ between those with versus without MDD and was correlated with
anxiety and hostility only. Despite none of the inflammatory cytokines
being different between sexes, there was a sex difference in their
associations with psychological symptoms; these were associated with
IL-6 and TNF-α, but not IL-1α in females, and with IL-1α but neither
IL-6 nor TNF-1α in males. In contrast to hypotheses, the
pro-inflammatory cytokines were not significantly associated with
adiposity or cardiac health measures.
The current finding of significantly higher plasma IL-1α with MDD is
consistent with a previous study (Simon et al. 2008) and add to the
limited reports on examination of IL-1α in MDD. Interestingly, in the
current study, although IL-6 was similarly higher in the MDD group, this
was with a sex interaction and IL-6 was only higher in females with MDD
versus without MDD with no difference between MDD males and control
males. While previous studies also reported that individuals with MDD
had higher IL-6 than controls, they did not examine any sex differences
(Al-Hakeim et al. 2015; Munjiza et al. 2018). This gives the assumption
of a difference between groups for both males and females, which may be
incorrect. The current results highlight how important it is to test for
the sex effect. Given females are more prone to MDD (Kessler et al.
2005), show more pronounced inflammatory responses (Wegner et al. 2017)
and have higher CVD-related mortality rate than males (Gao et al. 2019),
and the female-specific association of IL-6 with depression here, it is
worth further investigating a potential role for IL-6 in mediating these
relationships.
Both IL1-α and IL-6 were significantly correlated with the GSI score as
well as scores of depression, anxiety, hostility and stress, and
accounted for unique variance in each of these psychometric measures,
when included alongside TNF-α and sex in multiple linear regression
analyses. Interestingly, they both were independent predictors of
depression and hostility, while only IL1-α was predictive of stress and
only IL-6 was predictive of anxiety. Similarly, previous studies in
non-depressed cohorts reported associations of IL-1α with depressive
symptom severity (Suarez et al. 2003) and with hostility (Suarez et al.
2004), and associations of IL-6 with depressive symptoms, anxiety
(Reichenberg
et al. 2001) and hostility (Suarez et al. 2003; Suarez et al. 2004). The
positive associations of IL-1α and IL-6 with stress in the current study
is expected, since stress stimulates the release of glucocorticoids and
catecholamines which themselves promote inflammation, and the
pro-inflammatory cytokines are also involved in the adaptation to
stressors (McEwen, 2008). The current results are important since they
extend beyond the previous studies in non-depressed individuals to
report on the association of pro-inflammatory cytokines with specific
psychopathology symptoms in participants with MDD.
In the current study, TNF-α concentration did not differ between
diagnostic groups or between females and males and was only correlated
with the psychological measures of anxiety and hostility, and not with
the GSI, depression severity or stress. Although this result agrees with
previous research (Cilan et al. 2012; Karlović et al. 2012; Cassano et
al. 2017; Obermanns et al. 2021; Bürhan-Çavuşoğlu et al. 2021), others
have reported that TNF-α was significantly higher in MDD than healthy
controls (Tulgu et al. 2003; Liu et al. 2012; Al-Hakeim et al. 2015;
Köhler et al. 2017). However, two of these latter studies had small
sample size (N = 43) (Tulgu et al. 2003) and (N = 60) (Al-Hakeim et al.
2015), included depressed patients who were using anti-depressed
treatment (Al-Hakeim et al. 2015), and they were not age and sex matched
with the control participants (Tulgu et al. 2003); all these factors may
have confounded the findings.
TNF-α had a more discriminatory profile than IL-1α and IL-6 in terms of
associations with psychological symptoms, being correlated only with
anxiety and hostility. This agrees with previous research that reported
an association of TNF-α with anxiety
(Reichenberg
et al. 2001; Postal et al. 2016) and hostility (Suarez et al. 2004;
Takahashi et al. 2018), albeit among healthy participants. Of note is
that there is a well-established relationship between hostility and CMD
risk: hostility is linked with high blood pressure (Spicer and
Chamberlain, 1996), elevated levels of low-density lipoproteins (Suarez
et al. 1998) and greater risk of coronary heart disease (Wong et al.,
2013), all associated with inflammatory processes (Goldbacher and
Matthews, 2007; Nabi et al. 2010). Given these pieces of evidence, TNF-α
could be associated with the risk of CMD directly by its
pro-inflammatory nature and indirectly through its link with hostility.
Although TNF-α correlated significantly with hostility and anxiety, when
it was entered in regression analyses alongside the other
pro-inflammatory cytokines in the current study, it did not
significantly account for unique variance in psychological symptoms.
This is perhaps due to the positive correlation between IL-6 and TNF-α,
and since IL-6 was a stronger predictor of psychological symptoms than
TNF-α, IL-6 accounted for unique variance in most types of psychological
symptoms.
Investigating the sex effect on the association of pro-inflammatory
cytokines with psychological symptoms showed compelling results in the
current study. IL-1α was correlated with all psychological symptoms in
males but none in females, while IL-6 and TNF-α were correlated with all
psychological symptoms, except not TNF-α with depression severity, in
females, but none in males. IL-1α may be a risk factor for depression,
hostility and stress in males, and IL-6 and TNF-α could be risk factors
to being anxious, hostile and stressed in females. These novel findings
of sex-specific relationships between pro-inflammatory cytokines and
psychopathology symptoms in a clinical cohort with MDD may be related to
sex differences in MDD prevalence, symptoms and treatment response
(Seney et al. 2021).
In the current study, none of the pro-inflammatory cytokines were
correlated with CMD risk indices of waist circumference, BMI, blood
pressure or heart rate. Although one study presented an association
between pro-inflammatory cytokines (IL-1α) and obesity (Um et al. 2011),
this was in non-depressed participants. A previous study among people
with MDD reported that IL-6 and TNF-α were both correlated with BMI
(Shelton et al. 2015); however, these individuals were obese or severely
obese with BMI greater than 30 Kg/m2. The lower mean
BMI of participants in the current study, in the overweight rather than
the obese range, may have contributed to the lack of significant
association between the inflammatory cytokines and BMI or waist
circumference. Similarly, participants in the current study were in the
normotensive range on average, and the lack of correlation between any
of the pro-inflammatory cytokines and blood pressure likely indicates
that pro-inflammatory cytokines are more relevant to high blood
pressure.
There were several limitations to the current study. Firstly, the cohort
was normotensive, and most participants were non-obese. This likely
affected the non-significant association between pro-inflammatory
cytokines with blood pressure and BMI. Being a cross-sectional study
allowed only for associations to be assessed rather than examination of
any causative effects as per a longitudinal study design. Further, since
research supports a role of IL-1β in the development of adipose tissue
inflammation, insulin resistance and metabolic syndrome (Ballak et al.
2015), it would be important to assess IL-1β alongside IL-1α in a cohort
with MDD who have physical and physiological CMD risk indices such as
high blood pressure and BMI.
In conclusion, of the plasma pro-inflammatory cytokines, only IL-1α was
elevated in MDD versus control, IL-6 was higher in MDD versus control
among females, and TNF-α did not differ between groups. The latter
finding and the lack of a main effect of sex on IL-1-α and TNF-α were
contrary to our hypothesis. The
group by sex interaction for IL-6 and sex specific associations between
pro-inflammatory cytokines and psychometrics suggests potentially
differential roles of these cytokines and mental health between males
and females. These results of sex differences in inflammatory processes
linked to depressive symptoms are compelling and could be aetiologically
important in depression interventions and treatments.