Prolonged Tricyclic Antidepressant Toxicity in a Pediatric Patient: The Importance of Understanding the Multifactorial Nature of Amitriptyline Metabolism.

Tricyclic antidepressant (TCA) overdose is a potentially life-threatening condition characterized by anticholinergic, cardiotoxic, and neurotoxic effects. Amitriptyline is a highly lipophilic TCA metabolized by cytochrome (CYP)2C19, CYP3A4, and CYP2D6 and may be associated with altered metabolism with concurrent use of cannabinoids, mutations of the CYP enzymes, and elevated body mass index (BMI). With higher levels of adipose tissue, elevated BMI can lead to a larger volume of distribution for lipophilic drugs. Deviations from expected drug clearance may prolong toxicity and complicate management. We describe a 15-year-old female with obesity (BMI of 36 kg/m²) and a complex psychiatric history who presented after an intentional overdose of approximately 750 mg of amitriptyline. On arrival, she was unresponsive with a Glasgow Coma Scale (GCS) score of 3, tachycardia, respiratory distress, and electrocardiographic evidence of TCA cardiotoxicity, including a wide complex tachycardia and QRS prolongation. She required emergent intubation, sodium bicarbonate therapy, seizure prophylaxis, serial electrocardiograms, laboratory monitoring, and intensive care monitoring. Despite appropriate supportive management and based on typical half-life estimates under therapeutic conditions, QRS prolongation persisted, and serum amitriptyline/nortriptyline levels remained markedly elevated on day seven (combined level 612 ng/mL) and detectable on day ten (combined level 131 ng/mL). The prolonged elimination observed in this case was likely multifactorial, with cannabinoid use potentially contributing to prolonged toxicity through interactions with CYP enzymes. Additional contributing factors may have included elevated BMI or CYP enzyme polymorphisms. Although CYP testing was not performed in this case, consideration of testing in similar presentations in the future may aid in clinical management if a mutation is identified. The contribution of elevated BMI in this case remains speculative, as current evidence regarding its effects on the pharmacokinetics of lipophilic drugs is inconsistent, highlighting the importance of further studies on this topic. This case illustrates the impact of cannabinoid use and other factors on the pharmacokinetics of amitriptyline and underscores the need for prolonged monitoring, serial electrocardiograms, and consideration of extended drug clearance in cases of pediatric patients with TCA overdose. Clinicians should be aware that standard half-life estimates may underestimate the duration of toxicity in populations that have factors influencing metabolism.