The causal role of gastroesophageal reflux disease in anxiety disorders and depression: A bidirectional Mendelian randomization study

Abstract

BackgroundObservational studies have shown an association between gastroesophageal reflux disease (GERD) and anxiety disorders/depression. However, these evidences may be influenced by confounding factors. Therefore, our study aimed to determine the causal relationship between GERD and anxiety disorders/depression by conducting a bidirectional Mendelian randomization (MR) study.MethodsWe performed a bidirectional MR analysis using summary statistics from genome-wide association studies (GWAS) in European individuals. The inverse-variance weighted (IVW) method was used as the primary analytical method to assess causality. In addition, five additional MR methods [maximum likelihood, MR-Egger, weighted median, robust adjusted profile score (MR-RAPS), and mode-based estimate (MR-MBE)] were performed to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Finally, a multivariable MR (MVMR) analysis was performed to determine the causal relationship by adjusting for potential confounders.ResultsMR results of the IVW method indicated that GERD significantly increases the risk of anxiety disorders [odds ratio (OR) = 1.35, 95% confidence interval (CI) 1.15–1.59, P = 2.25 × 10–4] and depression (OR = 1.32, 95% CI: 1.15–1.52, P = 1.26 × 10–4). In addition, the MR results of maximum likelihood, MR-Egger, weighted median, MR-RAPS, and MR-MBE remained parallel to the IVW results. Furthermore, sensitivity analysis suggested that the results were robust, with no pleiotropy or heterogeneity detected. Nevertheless, reverse MR analysis showed that anxiety or depression did not increase GERD risk. Finally, MVMR analysis showed that the effect of GERD on increasing the risk of anxiety disorders/depression was independent of confounders.ConclusionThis MR study supports a causal association between GERD and an increased risk of anxiety disorders and depression. Therefore, complementing symptomatic treatment of GERD with psychological assessment and necessary psychological support therapy may help reduce the risk of future anxiety disorders and depression.

Association Between Anxiety/Depression and Gastroesophageal Reflux: A Systematic Review and Meta-Analysis

“…In relation to the sensitivity analyses, the meta-analysis findings based on the weighted median (OR = 1.33 [95% CI 1.17–1.48]; I 2 = 0.0%, P = 0.811) and MR-Egger regression (OR = 1.28 [95% CI 0.01–2.65]; I 2 = 4.8%, P = 0.305) methods were compatible with the primary results obtained from the IVW method. There was also a study by Zeng et al (17) that reported a direct causal effect of GERD on the risk of anxiety (OR = 1.35 [95% CI 1.15–1.59]).…”

“…A total of 4,537 publications were initially recovered by database searching, of which 4,501 were excluded because of duplication or unsuitability. Finally, 36 eligible studies were included in this systematic review and meta-analysis (7–11,13,14,17,18,22–48). The workflow of the search strategy and study selection have been illustrated in Figure 1.…”

“…adjusted for potential confounders with corresponding 95% confidence intervals (CI). Finally, concerning the third study outcome, we included studies that evaluated the association of genetic liability to exposure with the risk of the outcome of interest using the Mendelian randomization (MR) approach (14,17,18). The MR study is an innovative research method that explores the causal link between exposure and outcome using specific genetic markers (single-nucleotide polymorphisms) strongly correlated with exposure as instrumental variables (IV).…”

“…There were 3 large-scale MR studies that appraised the cause-andeffect relationship between anxiety/depression and GERD (see Supplementary Tables 6 and 7, Supplementary Digital Content 1, http://links.lww.com/AJG/C1000) (14,17,49). According to the meta-analysis of IVW estimates, genetic liability to depression was associated with an increased risk of GERD development (OR 5 1.36 [95% CI 1.27-1.45]; I 2 5 14.8%, P 5 0.279) (Figure 5a).…”

FDA approval of Zurzuvae (zuranolone) to combat postpartum depression

“…The majority of individuals with PPD typically experience recovery within a few months, although around 25-30% may still grapple with PPD a year following childbirth. 3 Suicide contributes to about 20% of postpartum fatalities, with 5-14% of pregnant and postpartum women reporting thoughts of suicide. 4…”