A Role of Alcohol and Adiposity in Low-grade Inflammation of Depression

Objective: Depression is one of the leading causes of disability, with a global estimate surpassing 15 % in lifetime prevalence. The same observation can be made in Finland, where depression has exceeded musculoskeletal diseases as the most common reason for seeking disability pension. The etiology of depression is still widely unknown, although associations with childhood maltreatment, personality factors and stressful life-events have been reported. Increased understanding of potential biological factors in the etiology of depression has evoked interest in developing novel treatments, as well as discussions of classifying depressive states to subgroups using biological measurements.

Alcohol use disorder has been reported in one fifth of depressed patients, and one third of patients diagnosed with alcohol use disorder suffer from concurrent depression. Obesity is also frequently observed in depressed patients, with reports of both obesity induced depression and obesity due to depressive state. However, depression seems to be associated with unfavorable life-style factors such as substance abuse, high-fat diet, and lack of physical exercise, which in turn increase the risk of obesity.

Depression, alcohol use and obesity have been linked with low-grade inflammation, yet earlier reports of possible interface are contradictory, with studies focusing similarly in only one or two of aforementioned factors. This study investigated low-grade inflammation in depressed patients at baseline and after six- months of follow-up and evaluated a possible effect of alcohol use and obesity to inflammatory status or the severity of depression. This study aimed to respond to a clinical request on finding biomarkers to assist in recognizing depression, treatment response and potential alcohol use disorder already in its early stage.

Materials and methods: This study is based on a six- months follow-up database of 242 patients with depression, during their treatment period in psychiatric specialty care units in Southern Ostrobothnia district of Finland. The clinical evaluation was performed at baseline and at six-months follow-up point, whether by a psychiatrist or by a research nurse. The severity of depression was assessed using MADRS score, and the clinical diagnosis was confirmed with M.I.N.I. interview. Low-grade

inflammation was assessed with serum measurements of inflammatory biomarker hs-CRP, cytokines IL-1Ra, IL-6, IL-8, YKL-40, MCP-1, and adipokines adiponectin, leptin, resistin and progranulin. Alcohol use was assessed with ALT, AST, AP, GT and CDT from serum and MCV from erythrocytes. Additionally, self-reported weekly alcohol consumption data was gathered, and patients supplied information with AUDIT and AUDIT-C questionnaires. Patients were measured for waist circumference, height and weight, and Body Mass Index (BMI) was calculated for assessment of possible obesity. Patients were divided into groups based on gender and reported alcohol consumption at baseline.

Results: The depressive symptoms diminished, alcohol use decreased, and BMI increased during the treatment period. Inflammatory biomarkers did not correlate with cumulative dose of medication, therefore, increase in body adiposity could not be explained with factors included in this study. Alcohol use affected treatment adherence, and the proportion of patients discontinuing the study was significantly higher in the patients with alcohol use disorder. The levels of cytokines, and especially adipokines, showed alterations in a gender-dependent manner. The levels of IL-6 were elevated in correlation with alcohol use, and the levels of YKL-40 decreased during the study period in concordance with traditional biomarkers of alcohol use. The levels of IL-8 decreased in all study groups during six-month follow- up. The levels of leptin were in significant correlation with obesity, but also with the levels of IL-6, indicating a potentially increased level of inflammation in obese patients. The levels of IL-6, calculation of GT-CDT ratio and results in AUDIT and AUDIT-C questionnaires proved reliable also when distinguishing moderate and high-risk consumption of alcohol.

Conclusion: Alcohol use and obesity are associated with alterations in the levels of cytokines and adipokines in a gender dependent manner. Alcohol use increases the levels of IL-6 and obesity the levels of leptin. The levels of YKL-40 seem to reflect alcohol use, but potential benefits in clinical practice would need to be studied further in a larger patient sample. The levels of serum IL-1Ra do not seem to have a significant role in the diagnosis of depression, therefore, the findings of this study do not support the hypothesis of using IL-1Ra recombinant in the treatment of depression. The levels of IL-1Ra did, however, decrease during the follow-up, potentially indicating a decrease in the overall status of inflammation. Also, the levels of IL-8 lowered during follow-up, independent of gender or alcohol use, possibly reflecting a relation of inflammatory status and alleviation of depressive symptoms.

The current methods of detecting alcohol use could be supplemented by calculation of GT-CDT ratio. Also, AUDIT and AUDIT-C questionnaires proved reliable in identifying alcohol use in patients seeking help for their psychiatric symptoms.

Screening of alcohol use should be a routine part of diagnosis of depression and in evaluating the treatment response. Life-style guidance should be incorporated in depression treatment to avoid increase of obesity related low-grade inflammation.