1. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose Ian Whyte Andrew Dawson

2. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Introduction  Venlafaxine –approved for use in Australia on 16th November, 1994 –serotonin and noradrenaline reuptake inhibitor (SNRI) –case reports of seizures in overdose –ADRAC reports of seizures in therapeutic use –increasing use

3. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Objective  To assess the toxicity in overdose of venlafaxine compared with –serotonin specific reuptake inhibitors (SSRIs) –tricyclic antidepressants (TCAs)

4. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Design  Cohort study –consecutive patients admitted with antidepressant poisoning  Hunter Area Toxicology Service (HATS)

5. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Study factors  Age  Gender  Coingested proconvulsant drugs  History of epilepsy and/or anticonvulsant therapy  Amount taken –Defined Daily Dose  Time to presentation

6. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Main outcome measures  Seizures  Arrhythmias  QRS duration  Conscious level –Glasgow Coma Score –Coma scale  Intensive care unit admission  Serotonin syndrome

7. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Methods  HATS database  Admissions with antidepressant deliberate self-poisoning (DSP)  Excluded coingestion –thioridazine  Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more common in thioridazine overdose than with other neuroleptics. Journal of Toxicology - Clinical Toxicology 1995;33(3):199–204

8. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cohort  3438 DSP admissions between 16/11/1994 and 4/4/2000  889 antidepressant DSPs

9. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Subjects  Excluded –moclobemide, nefazodone, mianserin –second and subsequent admissions –coingested antidepressants –82 dothiepin  456 first admissions of a single antidepressant –172 TCA (excluding dothiepin) –233 SSRI –51 venlafaxine

10. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Dothiepin  9 of 82 (11%) dothiepin overdoses had a seizure  6 of 172 (3.5%) other TCA overdoses seized  Odds ratio (95% CI) –3.4 (1.2 – 9.9)  Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater toxicity in overdose of dothiepin than of other tricyclic antidepressants. Lancet 1994;343:159–162

11. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Market share

12. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Study factors

13. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Outcomes (1)

14. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Outcomes (2)

15. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Venlafaxine vs TCAs

16. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital SSRIs vs TCAs

17. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Seizures

18. Conclusions  Dothiepin in overdose –compared to other TCAs l is proconvulsant  Venlafaxine in overdose –compared to other TCAs l is proconvulsant l more likely to cause serotonin toxicity l less likely to cause coma

19. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Conclusions  SSRIs in overdose –compared to other TCAs l less likely to cause coma l less likely to require ICU admission l less likely to prolong the QRS l more likely to cause serotonin toxicity  Antidepressants other than dothiepin or venlafaxine should be considered in patients at risk of seizures or suicide