A fatal case report in a Parkinson's patient links sequential SSRI exposure while on rasagiline to severe serotonin syndrome, with a homozygous CYP2D6*10/*10 pharmacogenotype implicated in drug accumulation and extreme toxicity.

Clinically actionable finding: supports pre-emptive pharmacogenomic screening and stricter management of serotonergic polypharmacy (including MAO-B inhibitors) in PD to improve safety and personalize therapeutic choices.

Serotonin syndrome (SS) is a potentially life-threatening condition resulting from excessive serotonergic activity in the central nervous system. We present a fatal case of SS complicated by multiple organ failure in a 72-year-old patient with Parkinson's disease following the sequential administration of two selective serotonin reuptake inhibitors (sertraline and escitalopram) while on a stable regimen of the monoamine oxidase-B inhibitor rasagiline. Pharmacogenomic testing revealed a homozygous CYP2D6*10/*10 genotype, conferring an intermediate metabolizer phenotype, which is postulated to have contributed to serotonergic drug accumulation and resultant toxicity in combination with other significant pharmacodynamic and pharmacokinetic interactions. This case was distinguished by three key features: first, the sequential serotonergic challenge from two different SSRIs in combination with rasagiline; second, the unprecedented severity of clinical manifestations, including rhabdomyolysis, acute hepatic and renal injury, and a disseminated intravascular coagulation-like state; and finally, the pharmacogenetic findings that provide a partial mechanistic explanation for the extreme drug sensitivity. This report underscores the critical importance of pre-emptive pharmacogenomic screening in patients receiving complex polypharmacy, particularly when combining drugs with serotonergic properties. It also serves as a critical warning that even selective MAO-B inhibitors can precipitate life-threatening interactions with SSRIs in genetically susceptible individuals, thereby informing more stringent personalized therapeutic strategies.