The role of acid-sensitive ion channels in panic disorder: a systematic review of animal studies and meta-analysis of human studies

Acid-sensitive ion channels, such as amiloride-sensitive cation channel (ACCN), transient receptor potential vanilloid-1 (TRPV1), and T-cell death-associated gene 8 (TDAG8) are highly related to the expression of fear and are expressed in several regions of the brain. These molecules can detect acidosis and maintain brain homeostasis. An important role of pH homeostasis has been suggested in the physiology of panic disorder (PD), with acidosis as an interoceptive trigger for panic attacks. To examine the effect of acid-sensitive channels on PD symptoms, we conducted a systematic review and meta-analysis of these chemosensors in rodents and humans. Following PRISMA guidelines, we systematically searched the Web of Science, Medline/Pubmed, Scopus, Science Direct, and SciELO databases. The review included original research in PD patients and animal models of PD that investigated acid-sensitive channels and PD symptoms. Studies without a control group, studies involving patients with a comorbid psychiatric diagnosis, and in vitro studies were excluded. Eleven articles met the inclusion criteria for the systematic review. The majority of the studies showed an association between panic symptoms and acid-sensitive channels. PD patients appear to display polymorphisms in the ACCN gene and elevated levels of TDAG8 mRNA. The results showed a decrease in panic-like symptoms after acid channel blockade in animal models. Despite the relatively limited data on this topic in the literature, our review identified evidence linking acid-sensitive channels to PD in humans and preclinical models. Future research should explore possible underlying mechanisms of this association, attempt to replicate the existing findings in larger populations, and develop new therapeutic strategies based on these biological features.