Comprehensive evaluation of the association between common drugs and psychiatric disorders using Mendelian randomisation and the real-world pharmacovigilance database

Chronic diseases, such as diabetes, cardiovascular disease and lung disease, require prolonged medication. Many of the drugs used for these diseases have varying degrees of neurological side-effects, while some drugs may have potential protective effects for neuropsychiatric disorders.

Pre-marketing clinical trials of drugs often only assess short-term neuropsychiatric symptoms, leaving the long-term effects of drugs on brain structures and associated psychiatric conditions unrecognised.

How can oral drugs affect brain structures and disease? In addition to direct means such as crossing the blood-brain barrier, influencing target gene expression and activating signalling pathways in neurons, the gut microbiota may serve as a key mediator linking oral drug use to brain structure and disease. Pharmacomicrobiomics has revealed that drugs can have an impact on the composition of the gut microbiota by directly killing microbes, modulating the host immune response and altering gut pH. The gut microbiota can also influence brain function via the microbiota-gut-brain axis, producing tryptophan metabolites and other neurotransmitters.

The authors comprehensively analysed the FDA Adverse Event Reporting System database and conducted Mendelian randomisation (MR) studies on six common drug classes, 477 brain imaging-derived phenotypes (BIPs) and eight psychiatric disorders.