Serotonergic Toxicity and Hyponatremia Associated with Antidepressant Therapy: The Pivotal Role of SIADH.

Serotonin syndrome (SS) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are well-recognized adverse drug reactions (ADRs) associated with serotonergic agents, particularly antidepressants. Although traditionally regarded as distinct clinical entities, accumulating evidence suggests that SIADH may represent a key pathophysiological link between serotonergic toxicity and acute hyponatremia, thereby explaining their frequent clinical overlap and, in some cases, severe or fatal outcomes. Excessive serotonergic activity can stimulate hypothalamic pathways regulating arginine vasopressin secretion, resulting in euvolemic hyponatremia and hyponatremic encephalopathy while simultaneously producing the characteristic neuromuscular, autonomic, and mental status abnormalities of SS. This narrative review examines the shared pathophysiological mechanisms, clinical manifestations, diagnostic challenges, and therapeutic implications of SS and SIADH-associated hyponatremia. A comprehensive literature search was conducted, including reviews, pharmacological studies, and case reports involving antidepressants, opioids, antihistamines, nutraceuticals, and emerging serotonergic agents such as ketamine, esketamine, and psilocybin. Particular attention is given to medication combinations, over-the-counter medications, and dietary supplements that may increase serotonergic burden through pharmacodynamic and pharmacokinetic interactions. The review highlights SIADH as the "thin red line" connecting serotonergic excess with rapid-onset hyponatremia and emphasizes the diagnostic complexity arising from the overlap between neurological manifestations of SS and metabolic encephalopathy secondary to hyponatremia. It also underscores the importance of a systematic diagnostic evaluation of suspected SIADH, including assessment of serum and urinary osmolality and urinary sodium concentration. In published case reports, the absence of urinary osmolality measurements frequently precludes confirmation of SIADH according to established diagnostic criteria, limiting the diagnosis to a possible or probable form rather than a definitive one. Greater awareness of this pathophysiological interplay is essential for early recognition, accurate differential diagnosis, risk stratification, and prevention of severe outcomes through careful medication review, appropriate laboratory evaluation, electrolyte monitoring, and prompt discontinuation of offending agents.