Exploring Associations Between C-Reactive Protein And Self-Reported Interoception in Major Depressive Disorder: A Bayesian Analysis Part 2

3.2. Zero-Order Correlations between CRP and Self-Rating Scales

The main findings of the Bayesian correlation analyses are shown in Table 2. Considering the MAIA-2 scales, our data support moderate evidence for H0, assuming null correlations with peripheral CRP except for the Not-Distracting scale, suggesting no clear conclusions based on our data (absence of evidence). There was moderate evidence for a positive correlation between log-normalized CRP and both depression severity (Figure 1A) and reduced activity (Figure 1B). We found strong evidence for a positive correlation between CRP and physical fatigue (Figure 1C).3

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The sensitivity analysis (Table 2) showed consistent BFs and qualitatively similar results over a broad range of changing priors. Effect directions were stable, which was also the case under the uniform prior (γ4=1), representing an extreme assumption. These findings support the robustness of the bivariate analysis.

3.3. Adjusted Associations between CRP and Self-Rating Scales

We estimated the effects of log-normalized CRP on multidimensional self-reported interoception, fatigue, and overall depression severity, after adjusting for relevant covariates (Table 3). In a sensitivity analysis, we repeated the computations after the exclusion of patients with acute inflammation (CRP >10.0 mg/L). The multivariate models were not affected by autocorrelation (ESS>1000), showed chain convergence for all predictors ( ˆR =1.00), and an adequate model fit.

The main findings from the bivariate analyses regarding self-reported interoception could be replicated, except for the Not-Worrying scale. The sensitivity analysis identified low-grade inflammation as a predictor of higher scores on the Not-Worrying scale (Figure 2). These results suggest that the effects of third variables are involved that were not controlled for in the bivariate analysis and likely obscured the association. In a post-hoc analysis, we screened for potential influential covariates. The significant effect of low-grade inflammation on Not-Worrying subsided after excluding BMI from the analysis (βMedian=0.19 [95% HDI −0.04, 0.42], bMedian=0.55 [95% HDI −0.12, 1.24], BF=1.12) but remained after omitting other covariates. Therefore, we conducted another sensitivity analysis for the Not-Worrying scale by excluding obese patients (BMI≥30.00), to rule out influential effects of extreme values: the regression coefficients were consistent for both overall inflammation (βMedian=0.35 [95% HDI 0.09, 0.60], bMedian=1.03 [95% HDI 0.27, 1.80], BF=2.69) and low-grade inflammation (βMedian=0.37 [95% HDI 0.11, 0.63], bMedian=1.14 [95% HDI 0.35, 1.94], BF=3.97). Evidence against an inflammatory involvement in self-reported interoception (except for not worrying) was demonstrated for the Attention Regulation, Emotional Awareness, Self-Regulation, Body Listening, and Trusting scales. These findings were also consistent after excluding subjects with acute inflammation.

There was moderate evidence that both physical fatigue and reduced activity were positively associated with CRP (Table 3). However, the sensitivity analysis showed that only reduced activity was significantly predicted by low-grade inflammation (moderate evidence), whereas anecdotal evidence indicated an association between log10 CRP and physical fatigue. There was further evidence against an association between log10 CRP and general fatigue. The analysis did not support reliable conclusions about the associations with mental fatigue, reduced motivation, and overall depression severity,  suggesting the absence of evidence.

4. Discussions 

In the present study, we found preliminary evidence that systemic inflammation measured by peripheral CRP is not associated with dysfunctional self-reported interoception. The validity of our analysis was substantiated by replicating previous findings that showed associations between CRP and depression/fatigue severity [9,12,57]. These results are relevant because abnormal interoception is a core characteristic of depression [29,58,59], with a significant impact on its treatment [26–28].

The evidence found against an effect of pro-inflammatory activation on dysfunctional self-reported interoception was contrary to our expectations, for several reasons. First, functional brain imaging findings have suggested an involvement of the insula, a primary region for interoceptive processing [18], in the processing of inflammatory states [32]. Second, it has been shown that peripheral CRP is associated with a somatic symptom and energy-related phenotype of atypical depression [11], which in turn is associated with dysfunctional self-reported interoception [28]. Third, sickness behavior in response to inflammation is, inter alia, mediated by the vagus nerve, which is part of the interoceptive nervous system [8,58]. However, our findings can also be discussed in light of the active inference theory of interoception [60]. Predictive coding models of MDD suggest an insensitivity to somatic signals, due to noisy afferent inputs and unresolved prediction errors (conceptualized as mismatches between top-down predictions and bottom-up sensations), leading to a “locked-in” state of the brain [60]. The resulting sense of disturbed embodiment has also been reported in phenomenological psychopathology, including a ‘corporealization’ of the lived body, i.e., the detachment from vibrant bodily feelings [1]. Abnormal awareness of somatic signals in MDD has also been reported for a subgroup of patients showing reduced heartbeat perception accuracy [22]. Therefore, the insensitivity to vague somatic signals in MDD could lead to a potential uncoupling of bodily feelings from interoceptive signaling of inflammation at the level of consciousness. Given that inflammatory states (a) involve interoceptive pathways [31], (b) are linked to the somatic symptom profile of atypical depression (e.g., leaden paralysis, hypersomnia) [14], but (c) are uncorrelated with dysfunctional self-reported interoception (as shown here for CRP),  our findings contribute to a growing body of research that conceptualizes interoception as independent across submodalities at the perceptual level [24,61]. Therefore, the evidence against the involvement of CRP in the pathophysiology of dysfunctional self-reported interoception may not be generalized to other dimensions of interoception. Future research should further clarify the cause of maladaptive self-reported interoception, by considering other pro-inflammatory markers and non-immunologic processes beyond neuroscience,  such as childhood trauma [62], attachment styles [63], or stress regulation [64].

In the multivariate analysis, moderate evidence of a positive association between systemic low-grade inflammation and self-reported interoception was found for the MAIA-2 Not-Worrying scale, indicating reduced catastrophizing cognitions and emotional distress in response to pain or physical discomfort. The association was obscured in the bivariate analysis, suggesting a statistical suppression effect that was controlled for after the inclusion of BMI. It may be counterintuitive that elevated CRP levels correlate with the tendency not to worry when experiencing pain or discomfort. For example, higher levels of CRP have been associated with lower pain thresholds and more physical pain, indicating altered pain processing in suicidal patients [65]. A meta-analysis also found decreased pain thresholds and lower tolerance for interoceptive noxious stimuli in individuals suffering from MDD compared to healthy controls [66]. However, consistent with our findings, Milaneschi et al. reported a protective effect of CRP on psychological symptom dimensions of depression, which was confirmed in a Mendelian randomization study linking genetically elevated CRP to a reduced risk of symptoms, such as suicidal ideation, feelings of inadequacy, anhedonia, cognitive problems, and anxiety [57]. Although statistical significance was not reached, the authors also found a CRP-predicted trend toward less worrying and better worry control [57]. Accordingly, the MAIA-2 Not-Worrying scale assesses psychological responses to pain and unpleasant bodily sensations rather than vulnerability to body sensations. Our findings contribute to a growing body of research that contradicts the notion that inflammatory activation is a general risk factor for mental health. For example, cumulative evidence suggests that higher serum levels of CRP protect individuals from developing schizophrenia, even though elevated CRP is correlated with disease activity after the onset of schizophrenia [67,68]. With the recent advent of Mendelian randomization studies, further discrepancies have become apparent in depression research, where have challenges arisen in disentangling the protective effects of CRP from its risks [57].

The replication part of this study showed positive associations between serum levels of CRP and facets of multidimensional fatigue, which were in the expected directions [57]. Peripheral CRP specifically predicted both physical fatigue and reduced activity. These symptoms refer to the inflammatory phenotype of atypical depression, including physical exhaustion and leaden paralysis [12,14]. However, it has to be noted that recent findings from genetic Mendelian randomization studies suggest a causal involvement of IL-6 rather than CRP in the pathophysiology of fatigue [57,69]. Moreover, we found a positive association between peripheral CRP and the overall severity of depression, which was consistent with meta-analytic evidence [70]. Congruent with past research, statistical adjustment for BMI  in the multivariate analysis affected the strength of associations between the inflammatory marker and symptom dimensions of MDD [9,57,70], probably due to the confounding effect of obesity, which is moderately correlated with CRP [71].

The prevalence of overall inflammation (CRP > 3.0 mg/L: 37.12%) or acute inflammation (CRP > 10.0 mg/L: 8.25%) in our inpatient sample was consistent with findings from a meta-analysis reporting similar proportions [10]. These findings emphasized the significance of low-grade inflammation in a considerable subgroup of affected individuals who are at risk for treatment-resistant depression [15]. Elevated blood concentrations of CRP have been linked to subsequent risk of coronary heart disease, stroke, and vascular mortality [72]. However, there is still an ongoing debate about the source of inflammation in depression [73]. It has been suggested that MDD and chronic inflammatory conditions share common risk factors in their pathogenesis [31]. For example, a meta-analysis reported longitudinal associations between parental absence during early development and elevated CRP in adults suggesting a mechanism that may mediate the susceptibility to depression [74]. Additionally, an inflammatory mechanism has been proposed that links sleep disturbances to MDD [75].

From a methodological perspective, the replication of past research results supports the validity of our analysis, which applied modern Bayesian statistical methods. The Bayesian framework regularly faces major criticism considering the arbitrary selections of priors, which may reflect subjective assumptions of the researcher rather than objective criteria [53]. We faced these concerns by conducting a sensitivity analysis, which showed the robustness of our results, even after considering extreme priors. Fluctuations of the BFs were only marginal, without substantially influencing the main findings. Against the background of the key findings of this study, we could demonstrate a major strength of the Bayesian statistical framework by quantifying evidence not only against, but also for the H0, which is not possible in conventional frequentist statistics, for epistemological reasons [41,45]. The application of Bayesian methods in future clinical research is strongly encouraged as computational power continues to increase.

The present study is subject to several limitations, as it is based on a cross-sectional analysis of secondary data, which precluded causal conclusions. The MAIA-2 Noticing, Not-Distracting, and Not-Worrying scales showed relatively low internal consistency reliability (ω < 0.70), which might have affected the validity of the results. Our findings may not be generalizable to proximal (e.g., IL-6, TNF-α) or other distal inflammatory markers. For example, certain symptoms of MDD are associated with a specific signature of inflammatory dysregulation [8]; a similar pattern can be observed in the long-term immunological sequelae of various types of childhood trauma [74]. Future research should therefore investigate the associations of other inflammatory mediators with facets of interoception and distinguish between central/peripheral inflammation. Our findings may also be replicated by including high-sensitivity CRP, which is more sensitive at lower concentrations [39]. Furthermore, we could not control for relevant confounding factors such as smoking status, alcohol consumption, cardiovascular fitness, and stress reactivity [54], because these variables were not available in the dataset. In addition, healthy controls were not recruited, limiting conclusions about the discriminative ability of CRP to predict dysfunctional vs. functional self-reported interoception. As we relied on sampling in an inpatient setting, the results of the study may not be generalizable to community samples with mild depression. Due to the limited sample size, we were unable to investigate sex as a potential moderator variable affecting the strength or direction of the associations examined, while sex-specific effects have been discussed for both CRP and interoception in MDD [9,28,76,77]. Our study was not sufficiently powered to derive conclusive evidence for all individual analyses. Future studies could use a sequential Bayes factor design that would allow researchers to stop collecting data once clear evidence for or against the H0 was obtained [78].

Over a third of the included patients demonstrated low-grade or acute inflammation, as indicated by elevated CRP blood levels, but inflammatory responses were not associated with dysfunctional self-reported interoception. In contrast, systemic low-grade inflammation could potentially exert a protective effect against worries about unpleasant body sensations; a finding which merits future investigation. Preliminary evidence from our study suggests that anti-inflammatory treatment may not be appropriate to address deficits in self-reported interoception. However, an immunologic contribution to maladaptive interoception cannot be ruled out until future studies replicate our findings considering other inflammatory markers.

Author Contributions: Conceptualization, J.V.-S. and M.E.; methodology, M.E.; software, M.E.; validation, M.E.; formal analysis, M.E.; investigation, M.E.; data curation, M.E.; writing—original draft preparation, M.E.; writing—review and editing, M.H., J.V.-S., B.M.-O. and M.E.; visualization, M.E.; supervision, M.H., J.V.-S. and B.M.-O.; project administration, M.E. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. 

Institutional Review Board Statement: The study was conducted by the Declaration of Helsinki, and approved by the Ethics Committee of Ulm University (protocol code 13/17, 08 March 2017).

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study

Data Availability Statement: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgments: We thank all patients who participated in the study and would like to express our gratitude to the team of the hospital ward 2011 (Center for Psychiatry Südwürttemberg, Weißenau, Germany). We also sincerely thank Alexandre Alvarez and his staff from the Laboratory of the Department of Psychiatry and Psychotherapy I (Center for Psychiatry Südwürttemberg, Weißenau, Germany), who performed the blood analyses and supported us with valuable information.

Conflicts of Interest: The authors declare no conflict of interest. 

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