2024-09-03
Comprehensive evaluation of the association between common drugs and psychiatric disorders using Mendelian randomisation and the real-world pharmacovigilance database
Neurology
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.
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.
Results: Among the 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. The authors identified ten drug-psychiatric disorder associations, 202 drug-brain imaging associations, 16 drug-microbiota associations and four drug-microbiota-medical imaging causal links.
Statins were associated with higher risks of ‘reduced self-esteem’ (OR = 18.92 [14.09, 25.42]), ‘agitated depression’ (OR = 9.76 [4.54, 20.99]) compared with other drugs, and significant changes in various brain structures.
GLP-1R agonists, a class of hypoglycaemic agents highly recommended for the treatment of type 2 diabetes, have been shown to improve cognitive functions such as episodic memory. A recent study found that they exert anti-inflammatory effects in relation to central neuronal GLP-1R, further indicating the importance of the CNS effects of this class of drugs. A 16-week randomised controlled trial showed that liraglutide improved cognitive function in delayed memory, attention and executive function, partly through a direct effect on activation of the left hippocampus.
For thiazolidinediones, a class of hypoglycaemic agents, the authors identified that they were significantly associated with a higher risk of type II bipolarity.
Common medications can affect the structure of the brain and the risk of psychiatric disorders. Oral medicines in particular can exert some of these effects by influencing the intestinal microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages the reallocation of drugs.
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