Potential Use of Pharmacogenetics to Reduce Drug-Induced Syndrome of Inappropriate Antidiuretic Hormone (SIADH)

Syndrome of inappropriate antidiuretic hormone (SIADH) is a common cause of hyponatremia, and many cases represent adverse reactions to drugs that alter ion channel conductance within the peptidergic nerve terminals of the posterior pituitary. The frequency of drug-induced SIADH increases with age; as many as 20% of patients residing in nursing homes have serum sodium levels below 135 mEq/L. Mild hyponatremia is associated with cognitive changes, gait instability, and falls. Severe hyponatremia is associated with cerebral edema, seizures, permanent disability, and/or death. Although pharmacogenetic tests are now being deployed for some drugs capable of causing SIADH (e.g., antidepressants, antipsychotics, and opioid analgesics), the implementation of these tests has been based upon the prior known association of these drugs with other serious adverse drug reactions (e.g., electrocardiographic abnormalities). Work is needed in large observational cohorts to quantify the strength of association between pharmacogene variants and drug-induced SIADH so that decision support can be developed to identify patients at high risk.