Pharmacodynamics of venlafaxine in overdose

Background: Venlafaxine, a serotonin-noradrenalin reuptake inhibitor, appears to be more toxic in overdose than other newer antidepressants. Various studies have shown that there is an increased risk of seizures [1], a potential for cardiac toxicity [2] and a higher rate of fatalities [3] with venlafaxine overdose when compared to other antidepressants. A population pharmacokinetic (PK) analysis of venlafaxine in overdose and effect of decontamination procedures was previously reported [4]. In the PK analysis it was shown that single dose activated charcoal (SDAC) increases the clearance of venlafaxine by 35% and combination of SDAC and whole bowel lavage (WBL) decreases bioavailability by 29%.

Aims: 1. To investigate the relationship between decontamination procedures and combination of both and seizure events. 2. To determine the time at which 90% (T90) of patients would have had their first seizure in the presence and absence of decontamination.

Methods: Data included 319 patients who consumed an overdose of venlafaxine on 436 occasions. 5% of these patients had seizures. SDAC, WBL, a combination of either (SWBL) or no decontamination were administered to patients according to the treating clinician. Data were modelled using WinBUGS 1.4.3. Logistic regression was used to investigate the influence of dose and decontamination procedures on the probability of seizures after various venlafaxine overdoses. Time to event analysis was performed to estimate the time to 90% of seizure occurrence based on dose size and decontamination procedure.

Results: A linear logistic regression model without random effects described the data well. Simulation from the logistic regression model showed that the probability of seizure was 0.05 (0.03-0.08) at 1000 mg, 0.19 (0.09-0.35) at 5000 mg and 0.75 (0.30-0.96) at 10000 mg (data are shown as median and 95% credible interval). At a dose of 2100 mg (the mean dose in the data set) the odds ratio in presence of SDAC was 0.48 (0.25-0.89) and in presence of WBL was 0.71 (0.35-1.22) and in presence of SWBL was 0.25 (0.08-0.62). A modified Gompertz model provided the best description of the time to seizures. Simulations from the time to event model showed that the T90 values for first seizure was 26 h at and was not affected by dose or decontamination procedure.

Conclusion: SWBL provided greater benefits than the sum of the independent effects of SDAC and WBL. The results of logistic regression analysis concur with the results from pharmacokinetic study previously performed on venlafaxine overdose. Patients should be monitored for 24 hours for the occurrence of seizure after doses in excess of 1000 mg.


  1. Whyte, I.M., A.H. Dawson, and N.A. Buckley, Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Qjm, 2003. 96(5): p. 369-74.
  2. Isbister, G.K., Electrocardiogram changes and arrhythmias in venlafaxine overdose. Br J Clin Pharmacol, 2008.
  3. Buckley, N.A. and P.R. McManus, Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. Bmj, 2002. 325(7376): p. 1332-3.
  4. Kumar, V.V., et al., The effect of decontamination procedures on the pharmacokinetics of venlafaxine in overdose. Clin Pharmacol Ther, 2009. 86(4): p. 403-10.