Angiogenic Vascular Endothelial Growth Factor (VEGF) Levels Significantly Correlate to Systemic Inflammatory Response Index (SIRI) Measures in Patients with Treatment-Resistant Bipolar Depression Disorder (TRBDD)

Background: VEGF is a known angiogenic biomarker that is involved in both physiologic and pathologic processes. It has recently been implicated in the stress response and thus, garnered more attention for its role in affective disorders. Its more prominent role in endothelial function may offer insight into the increased risk of cardiovascular pathologies in patients with affective disorders, as it has been well-established that this patient population is at higher risk of developing cardiovascular disease (CVD). Increased inflammation has also been investigated as potential mechanism of the increased risk of CVD in this patient population. In a randomized, double-blind, placebo-controlled trial we demonstrated efficacy of escitalopram (ESC) + Celecoxib (CBX) compared to ESC + placebo (PBO) in patients with TRBDD. In this secondary analysis, we aimed to investigate the relationship between inflammation and endothelial function in TRBDD subjects by utilizing SIRI (monocytes x neutrophils/lymphocytes) as a measure of inflammation and VEGF as a measure of endothelial function. We hypothesized that increased measures of SIRI would be associated with increased levels of VEGF in patients with TRBDD.

Methods: The original sample (N=79) included healthy controls (n=32) and TRBDD subjects (n=47). The TRBDD cohort included an ESC+CBX arm (n=26) and ESC+PBO arm (n=21). Of the TRBDD subjects, 10 patients had a complete set of data that included measures of SIRI and VEGF at baseline. SIRI was calculated from complete blood count (CBC) drawn at baseline and end of treatment (8 weeks). ELISA assays were used to measure VEGF levels. Depression severity was measured using HAMD17 scores. Statistical analysis was conducted using R-3.6.3. Student's t-test for independent groups was used for the group comparison of SIRI at baseline between the various cohorts and the Pearson correlation coefficient was used to study the correlations.

Results: A statistically significant, strong positive correlation was observed between SIRI at baseline and VEGF at baseline in TRBDD subjects regardless of treatment arm (p=0.024; Pearson's r=0.702). Group comparison revealed no significant differences in pre- or post- treatment SIRI levels, according to patient status at baseline or at week 8. VEGF did not demonstrate any significant changes post-treatment in either treatment arm, but levels of VEGF were significantly higher in TRBDD patients at baseline compared to healthy controls (p=0.01). Post-treatment depression scores were significantly decreased in the ESC+CBX treatment arm group (p<0.002).

Conclusion: Significant, strong positive correlations were observed between measures of inflammation (SIRI) and angiogenesis (VEGF) in TRBDD subjects. Moreover, levels of VEGF were found to be significantly higher in TRBDD patients compared to healthy controls. This data underscores the role that inflammation and endothelial dysfunction may play in the pathogenesis affective disorders. Such results may suggest the underlying mechanisms that place patients with affective disorders at higher risk of CVD, thus offering potential targets of prophylactic CVD therapies. These observations are also suggestive of the role of blood and endothelial cells in mediating the vascular complications observed in patients with affective disorders. Adjunct treatment of these patients resulting in improved outcomes may be related to modulation of other mediators of inflammation. Future studies on SIRI and VEGF are warranted and should clarify their potential roles as predictive biomarkers of CVD risk in affective disorders.

No relevant conflicts of interest to declare.

Investigating adjunctive non-steroidal anti-inflammatory drug use in bipolar depression.