Elevated skin advanced glycation end products in acute bipolar mania: interim pilot findings

Introduction

Advanced glycation end products (AGEs) result from the non-enzymatic glycation and oxidation of proteins and lipids, and are implicated in pro-inflammatory and oxidative stress pathways. Skin autofluorescence provides a non-invasive composite estimate of long-term tissue AGE accumulation, reflecting cumulative glycoxidative burden. Elevated skin autofluorescence-derived AGE levels have previously been reported in schizophrenia-spectrum disorders and recent-onset psychosis, supporting the relevance of carbonyl stress and accelerated biological ageing in severe psychiatric conditions [1,2]. Whether a similar pattern of elevated skin AGE levels is observed in bipolar disorder, particularly during acute manic episodes, remains poorly characterised.

Aims

This ongoing study aimed to determine whether skin autofluorescence-derived AGE levels are elevated in patients hospitalised for acute bipolar mania compared with healthy controls, and to explore whether these levels are associated with Young Mania Rating Scale (YMRS) scores after adjustment for major demographic and metabolic confounders.

Methods

This interim pilot study used a case-control design with short-term longitudinal follow-up. It included 39 participants at baseline: 12 patients hospitalised for acute bipolar mania and 27 healthy controls. Skin autofluorescence-derived AGE levels were assessed at admission/baseline (T0) and follow-up (T1), with T1 AGE data available for 35 participants, including 9 patients and 26 controls. Covariates included age, sex, body mass index (BMI), smoking status and manic episode status. Given the significant deviation of AGE values from normality and the small patient sample size, between-group comparisons used Wilcoxon-Mann-Whitney tests. Exploratory Spearman correlations examined the relationship between baseline AGE levels and YMRS scores. Robust regression using rank-based estimation assessed whether manic episode status remained associated with AGE levels after controlling for age, sex, BMI and smoking, with bootstrapping used as a sensitivity analysis for the adjusted group effect.

Results

Groups were comparable for sex, age and BMI, while smoking was more prevalent among patients. AGE levels were significantly higher in patients at T0 (mean±SD: 2.28±0.61 vs. 1.65±0.30; median: 2.15 vs. 1.60; W=282.5; p<0.001) and at T1 (2.18±0.54 vs. 1.69±0.33; median: 1.90 vs. 1.62; W=189.0; p=0.0068). In the baseline complete-case adjusted model, manic episode status remained associated with higher AGE levels after adjustment for age, sex, BMI and smoking, with controls showing lower AGE levels than patients (β=−0.53; p=0.0015), while age was a significant positive predictor (β=0.018; p<0.001). A bootstrapped sensitivity analysis supported the adjusted group effect, with a 95% bootstrap confidence interval excluding zero. An exploratory inverse association was observed between baseline AGE levels and YMRS scores within the patient group, but it did not reach statistical significance in the expanded interim sample (rho=−0.53; p=0.076).

Conclusions

These interim findings indicate elevated skin autofluorescence-derived AGE levels in patients hospitalised for acute bipolar mania, persisting across two assessment points and remaining detectable after adjustment for major confounders. These results may extend prior observations from schizophrenia-spectrum disorders to bipolar mania, suggesting that carbonyl stress and cumulative glycoxidative burden could represent transdiagnostic biological processes in severe psychiatric disorders. Given the interim nature of the analysis and ongoing recruitment, the exploratory association with manic severity should be considered hypothesis-generating and requires confirmation in the expanded cohort.

References

Kouidrat Y, Amad A, Desailloud R, Diouf M, Fertout E, Scoury D, Lalau JD, Loas G. Increased advanced glycation end-products (AGEs) assessed by skin autofluorescence in schizophrenia. Journal of Psychiatric Research. 2013;47(8):1044–1048.
Hagen JM, Sutterland AL, Edrisy S, Tan HL, de Haan L. Accumulation rate of advanced glycation end products in recent onset psychosis: A longitudinal study. Psychiatry Research. 2020;291:113192.