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.