Recognition and Management of Selective Serotonin/Noradrenaline Reuptake Inhibitor (SNRI) Overdoses

Abstract

Serotonin–noradrenaline reuptake inhibitors (SNRIs) — venlafaxine, desvenlafaxine, duloxetine, milnacipran and levomilnacipran — are among the most widely prescribed agents for major depressive disorder, generalized anxiety disorder and several chronic pain syndromes. Their dual action on serotonergic and noradrenergic neurotransmission confers broad therapeutic utility but also produces a distinctive toxidrome in overdose that differs meaningfully from that of the selective serotonin reuptake inhibitors and the tricyclic antidepressants. As a class, SNRIs must be approached as a heterogeneous group: venlafaxine carries a substantially higher toxicological risk than the remaining agents, with dose-dependent seizures, QRS and QT prolongation, malignant ventricular arrhythmia and a fatal toxicity index appreciably above that of most modern antidepressants, whereas duloxetine, desvenlafaxine, milnacipran and levomilnacipran appear comparatively less cardiotoxic in overdose. This review synthesises the contemporary clinical-toxicology literature on the recognition, risk-stratification and management of SNRI poisoning for emergency physicians, intensivists, toxicologists and psychiatrists. Evidence was prioritised according to a predefined hierarchy, with meta-analyses, systematic reviews and large overdose cohorts weighted above case series and case reports. The review addresses the pharmacological basis of agent-specific toxicity, epidemiological patterns of exposure, the clinical spectrum of cardiovascular, neurological, serotonergic and metabolic manifestations, diagnostic evaluation, differential diagnosis, and an evidence-graded approach to decontamination, supportive care, antiarrhythmic therapy, seizure control and the management of serotonin toxicity. Specific considerations for pregnancy and paediatric exposure are outlined, and a Limitations section explicitly characterises the evidence quality underpinning key clinical thresholds. Although most SNRI exposures are managed successfully with supportive care, massive venlafaxine ingestions can produce refractory cardiogenic shock requiring extracorporeal life support, underscoring the importance of early agent-specific risk stratification.