Neuroleptic malignant syndrome in the context of venlafaxine and tamoxifen: a case report

Background Neuroleptic malignant syndrome (NMS) is classically associated with potent dopamine D2 receptor blockade from antipsychotic medications. Emerging evidence, however, suggests that non-neuroleptic agents may also precipitate NMS by destabilizing dopaminergic pathways. We report a case highlighting the potential role of tamoxifen and venlafaxine in lowering the threshold for NMS through convergent neuroendocrine and monoaminergic effects. Case presentation We describe a 68-year-old white American female who developed NMS in the setting of polypharmacy, including tamoxifen and venlafaxine, and pair this with a mechanistic analysis of how these medications may meaningfully lower the threshold for NMS. We propose that endocrine disruption, serotonergic-noradrenergic modulation, and cumulative dopaminergic burden converge to produce a state of dopaminergic instability that predisposes susceptible patients to NMS, even in the absence of high-potency dopamine antagonists. Conclusions Recognition of tamoxifen and venlafaxine as potential contributors to dopaminergic instability expands the conceptual framework of NMS beyond traditional high-potency neuroleptic-centric models. Increased awareness of these underappreciated pharmacologic risk factors may improve diagnostic clarity, facilitate earlier recognition of atypical NMS presentations, and inform safer prescribing and monitoring strategies for high-risk individuals.