Expression of Interleukin-6 may contribute to treatment resistance and outcome in bipolar depression

Abstract

Background

Immune system activation has been implicated in the pathophysiology of psychiatric disorders. Pro-inflammatory cytokine elevations, including interleukin-6 (IL-6), have been reported in bipolar disorder (BD), although results are mixed. Elevated IL-6 has been associated with symptom severity, poor treatment response, and may be influenced by single nucleotide polymorphisms (SNPs). This ancillary study examined IL-6 SNPs in treatment-resistant bipolar depression (TRBDD) to assess their relationship with inflammatory modulation and treatment outcomes.

Methods

This secondary analysis was derived from a 10-week, double-blind, randomized, placebo-controlled trial of escitalopram (ESC) plus celecoxib (CBX) versus ESC plus placebo (PBO) in 43 patients with TRBDD. Plasma IL-6 was measured at baseline and week 8 by ELISA. Genome-wide genotyping identified two SNPs on the IL-6 promoter (rs1800795, rs1800796). Associations between genotype, IL-6 expression, and treatment response were assessed using multiple regression and ANCOVA.

Results

At baseline, mean IL-6 levels were elevated in TRBDD compared to healthy controls (p = 0.007). No significant correlation was observed between baseline IL-6 and either SNP. For rs1800795, IL-6 levels differed across genotypes (CC: 1.21, GC: 1.99, GG: 1.48 ng/ml). Patients with the G allele showed lower Hamilton Depression Rating Scale (HAMD) scores in the CBX arm, suggesting greater treatment response. For rs1800796, the sample was skewed toward the CC genotype, limiting interpretation; however, higher IL-6 levels and improved outcomes with CBX were observed in CC carriers.

Conclusions

Although limited by sample size, these findings suggest IL-6 polymorphisms may influence inflammatory profiles and antidepressant response in TRBDD, with CBX augmentation showing potential benefit.