Mechanisms of high-dose citalopram-induced death in a rat model

Citalopram, a selective serotonin reuptake inhibitor, is generally considered to be of low toxicity. However, serotonin syndrome, seizures, electrocardiographic abnormalities as well as respiratory failure and death have been described in patients with citalopram overdose. The mechanisms of severe toxicity remain unclear. Our objective was to study the mechanisms of death following high-dose citalopram administration in Sprague Dawley rats. The median lethal dose (MLD) of intraperitoneal (i.p.) citalopram was measured using Dixon & Bruce's up-and-down method at 102 mg/kg. Dose-effect relationships of citalopram-induced clinical features, alterations in arterial blood gas and plethysmography, and disturbances in blood lactate, plasma and platelet serotonin concentrations were studied. Seizures were significantly increased in rats receiving 80% and 120% of citalopram MLD versus controls (p<0.05 and p<0.01, respectively). A significant decrease in body temperature was observed after 90 min in rats treated with doses >60% MLD in comparison to controls (p<0.05). The occurrence of serotonin behavioural syndrome was comparable in all groups. Citalopram administration did not result in significant hypoxemia, hypercapnia and lactate elevation. However, a significant moderate increase in the inspiratory time (p<0.05) accompanied with an expiratory braking was observed. A significant dose-related linear decrease in platelet serotonin and increase in plasma serotonin concentrations were measured (p<0.05). Pre-treatments of rats receiving 120% of citalopram MLD with diazepam (1.77 mg/kg) and cyproheptadine (17.1mg/kg) prevented seizures and death, but propranolol pre-treatment was ineffective. Neuroprotection with diazepam and cyproheptadine was not associated with decreased serotonin plasma concentrations. In conclusion, citalopram-induced deaths resulted from seizures in relation to serotonin release, whilst respiratory and metabolic toxicity was mild. Our observations support the role of serotonin-induced neurotoxicity in citalopram overdose and suggest that cyproheptadine and benzodiazepines, but not beta-blockers, may have a role in the management of citalopram toxicity.