Higher S100B Levels Predict Persistently Elevated Anhedonia with Escitalopram Monotherapy Versus Antidepressant Combinations: Findings from CO-MED Trial

Abstract

Background: Elevated S100 calcium binding protein B (S100B) levels in systemic circulation may induce neuroinflammation and reflect greater blood–brain barrier (BBB) dysfunction. Neuroinflammation in patients with major depressive disorder (MDD), in turn, may reduce likelihood of improvement with serotonergic antidepressants. Methods: Levels of S100B were measured in plasma samples obtained prior to initiation of treatment with bupropion-plus-escitalopram, escitalopram-plus-placebo, or venlafaxine-plus-mirtazapine in participants of Combining Medications to Enhance Depression Outcomes trial (n = 153). Depression severity was measured with 16-item Quick Inventory of Depressive Symptomatology Self-Report and anhedonia was measured with 3 items of 30-item Inventory of Depressive Symptomatology. Differential changes in depression severity and anhedonia over acute-phase (baseline, weeks 1, 2, 4, 6, 8, 10, and 12) in the three treatment arms were tested with logS100B-by-treatment-arm interaction in mixed model analyses after controlling for age, gender, and body mass index. Results: There was a significant logS100B-by-treatment-arm interaction for anhedonia (F = 3.21; df = 2, 142; p = 0.04) but not for overall depression severity (F = 1.99; df = 2, 142; p = 0.14). Higher logS100B levels were associated with smaller reductions in anhedonia (effect size = 0.67, p = 0.047) in escitalopram monotherapy but not in the other two arms. Correlation coefficients of anhedonia severity averaged over acute-phase (including baseline) with baseline S100B levels were 0.57, −0.19, and 0.22 for escitalopram monotherapy, bupropion-plus-escitalopram and venlafaxine-plus-mirtazapine arms respectively. Conclusion: Higher baseline S100B levels in depressed patients resulted in poorer response to escitalopram monotherapy. Addition of bupropion, a dopaminergic antidepressant, partially mitigated this effect.

High S100B Levels Predict Antidepressant Response in Patients With Major Depression Even When Considering Inflammatory and Metabolic Markers

“…Regarding inflammatory markers and their association with the antidepressant response, we found an inverse significant correlation between basal CRP levels and treatment response at week 4 but not at week 8. This is consistent with reports suggesting that elevated inflammatory markers, such as CRP, IL-1β, IL-6, IL-17, and TNF-α, predict poor antidepressant outcomes ( Baune et al, 2010 ; Jha et al, 2017 , 2018 ; Miller et al, 2017 ; Benedetti et al, 2021 ). However, baseline CRP levels did not predict treatment response at either week 4 or 8 by simple or multiple linear regression analysis.…”

“…Nevertheless, serum S100B levels are indicative of CSF concentrations even though extracranial sources secreted S100B (e.g., adipocytes) might interfere with the accurate interpretation of serum levels ( Reiber et al, 2001 ; Ambrée et al, 2016 ). As it was shown in a previous work, S100B levels displayed important value dispersion, generating a non-normal statistical distribution ( Jha et al, 2019 ). Results from the present study are compatible with this previous observation, being in the same range of values although with less data dispersion.…”

“…Supporting our results, previous studies have reported that high baseline S100B levels predict treatment response. Using different patient groups (i.e., melancholic/non-melancholic MDD), type of antidepressant treatments (serotoninergic, noradrenergic, dopaminergic) and assessment instruments (i.e., Hamilton Depression rating Scale), and endpoints (from 4 weeks to 6 months), 3 of 4 studies plead for a predictive effect of baseline S100B for antidepressant response ( Arolt et al, 2003 ; Jang et al, 2008 ; Ambrée et al, 2016 ; Jha et al, 2019 ). A recent meta-analysis of the 3 first studies that included 51 responders and 73 non-responders found that S100B levels at baseline were significantly elevated in responders ( Shi et al, 2020 ).…”

IL-33 in Mental Disorders

“…Emerging evidence highlights the role of immune response as a key factor in MDs. Immunological biomarkers seem to be related to illness progression and to treatment effectiveness; several studies suggest strong associations among IL-6, TNFa, S100b, IL 1b, and PCR with affective or schizophrenic disorders [ 6 , 7 , 8 , 9 , 10 , 11 ]. Yuan et al (2019) evaluated the meta-analysis considering inflammatory markers in mental disorders.…”

Sex Differences in the Brain-Blood Barrier in Rats Exposed to Early life Stress and the Treatment with Antidepressants and Psychobiotic

“…As far as we know, this was the rst study that investigated the effect of escitalopram on BBB integrity. On the other hand, there is a study that evidenced that BBB dysfunction results in poorer less response to escitalopram treatment (Jha et al 2019). It is worth mentioning that escitalopram was able to reverse the depressive-like behavior and the gut in ammation induced by a colitis protocol in ovariectomized rats, suggesting a potential anti-in ammatory effect of escitalopram (Abdo et al 2019).…”