First, the development of bipolar disorder after the onset of GERD may be the result of an inflammatory process activated by GERD. In patients with GERD, the esophageal mucosa produces higher amounts of various cytokines including IL-6, IL-8, IL1 beta, IFN-gamma, TNF-alpha. Even in non-erosive reflux disease, which the role of Monoammoniumglycyrrhizinate inflammation may be considered less obvious, enhanced expression of IL-8 and IL1 beta has been found. The chronic peripheral inflammatory process activated by GERD may Mechlorethamine hydrochloride increase the risk of subsequent bipolar disorder by upregulating CNS inflammation. Studies have revealed that chronic, mild inflammation in the periphery and in the brain occurs in bipolar disorder. Cytokines have been shown to access the brain and interact with pathophysiological domains relevant to bipolar disorder. Using animal models, it is shown that peripheral cytokines reach the brain through various mechanisms, including a leaky brain barrier, active transport, the activation of endothelial cells, and binding to cytokine receptors. Levels of proinflammatory cytokines such as IL-2, IL-4, and IL-6 are elevated during mania, whereas IL-6 is elevated during depression. Second, GERD and bipolar disorder share common risk factors, such as stress. Laboratory stress has been found to increase the perception of intraluminal acid stimuli and induced stress, anxiety, anger in GERD patients rather than normal control. Stressful psychosocial factors can induce GERD, and stress may also induce bipolar disorder in patients genetically prone to developing bipolar disorder. 
Psychological stress also may activate inflammatory responses in the brain.. When stratifying according to follow-up duration, the risk of bipolar disorder among GERD patients was significantly higher after the first year following the GERD diagnosis, which is consistent with our hypothesis that inflammation is responsible for the association between GERD and bipolar disorder. We hypothesize that long periods of time are required for the chronic inflammatory process. Based on our results, detection bias was unlikely. In our study, we observed that younger age was an independent risk factor for developing subsequent bipolar disorder among GERD patients. The incidence of bipolar disorder is determined to be relatively rare in people aged more than 60 years. Our study confirmed this finding. Epidemiological studies have shown that bipolar disorder is equally prevalent among men and women. However, in this study, we observed that women with GERD had a greater risk of developing a bipolar disorder than men did. One possible explanation is that women in our study group, with a median age of 52 years, were vulnerable to fluctuating estrogen levels, thereby increasing their risk of developing bipolar disorder.. In our analysis of the risk factors associated with subsequent bipolar disorder in GERD patients, alcohol use disorder was an independent risk. Evidence has shown that alcohol use disorder and bipolar disorder share certain common genetic characteristics, neuroimaging findings, and biochemical findings.. This is the first retrospective study to examine GERD as a risk factor for the development of bipolar disorder. This study’s strengths were its matched case-control design using a populationbased cohort of GERD patients, and adequate controls for comorbidity. However, several limitations inherent to the use of claims databases must be considered. First, the results of endoscopies and patient’s symptoms could not be obtained from the database.