1. RELATIVE TOXICITY OF CITALOPRAM AND OTHER SSRIs IN OVERDOSE GK Isbister 1,2, IM Whyte 1,2, AH Dawson 1,2 1 Department of Clinical Toxicology, Newcastle Mater Hospital, 2 Discipline of Clinical Pharmacology, University of Newcastle

2. Background Concern regarding citalopram overdose: –reports of fatal cases –cardiotoxicity and seizures with massive OD Case series (Sweden) suggested: –prolonged QTc if > 600 mg –seizures –no deaths CLASS OR INDIVIDUAL DRUG EFFECT ?

3. Aim To define : spectrum of toxicity of SSRI overdose relative toxicity of individual SSRIs –to investigate the cardiac toxicity of the SSRIs in overdose –to investigate the serotonergic effects of SSRIs in overdose

4. Methods Cohort of inpatient overdose admissions –Prospective data collection Inclusions : –All SSRI overdoses presenting to Hunter Area Toxicology Service (HATS) Exclusions : –more than one SSRI ingested –coingestion of TCA, venlafaxine, nefazodone

5. Methods Cases included were: –SSRI dose > maximum daily dose –SSRI alone OR –coingestant with no known effect on QT Only one ECG/admission per patient included: –ECG with longest QT used to select cases

6. Methods Control group Overdoses of medications with no known cardiotoxicity, or affect the QT or QRS interval –paracetamol –paracetamol/codeine –diazepam –temazepam

7. Methods Electrocardiograph: –QT –QTc –QRS Clinical Features: –Incidence of arrhythmia –Bradycardia (HR < 60 bpm) –Tachycardia (HR > 100 bpm) –Hypotension (systolic BP < 90 mmHg)

8. Electrocardiographic Analysis RR, QT and QRS measured manually on ECGs QTc from Bazett’s formula QTc > 440 msec was defined as ABNORMAL

9. Analysis Statistical analysis : –Comparison of proportion QTc > 440 msec –Comparison of mean/median QTc (ANOVA) Logistic regression –Dependent variable QTc>440 msec –Independent variable : age, sex, DDD, time to ingestion, SSRI type –Forward stepwise logistic regression modelling

10. Results Poisoning admissions to HATS: 8909 cases 413 single SSRI admissions: –118 coingested cardiotoxic drugs –30 had no ECG done (10%) 265 admissions with 312 ECGs 236 ECG/patients were included 318 Control patients

11. Results 236 ECG/patients were included: Citalopram 32 Sertraline 82 Paroxetine 70 Fluoxetine 39 Fluvoxamine13

12. Median ECG parameters * ANOVA of medians (5 SSRIs and controls); Control Group Citalopram P value * FluoxFluvoxParoxSert

13. QTc > 440 msec 66% of citalopram overdoses with QTc > 440 msec Calculated the odds ratio of QTc > 440 msec compared to control overdoses THEN did logistic regression

15. Drug Ingested Controls1.00 Fluoxetine1.000.482 - 2.0900.993 Fluvoxamine0.380.080 - 1.7870.220 Paroxetine1.100.625 - 1.9450.736 Citalopram3.791.672 - 8.5910.001 Sertraline1.170.657 – 2.0720.599 Age1.021.004 – 1.0280.011 DDD1.010.996 - 1.0220.168 Gender Males1.00 Females2.481.643 – 3.730<0.001

16. Clinical Effects ControlFluoxFluvoxParoxCitalSertP value Cardiovascular Effects Arrhythmia-3%0% 3%0%0.504 * Bradycardia7%10%8%9%13%6%0.821 Tachycardia17%15%0%10%13%22%0.224 Hypotension-0% 1%0%0.191 *

17. Citalopram overdose : Admission 6 hours after overdose

18. Discharge 38 hours after overdose

19. Summary of Cardiac Toxicity Citalopram has significant cardiotoxicity: –Median QTc significantly longer –Median QT significantly longer –Proportion of QTc>440 msec significantly greater –Almost 4 times the risk of QTc prolongation compared to control –Potential for arrhythmias/bundle branch block Other SSRIs –Appears to be much less risk

20. Limitations One ECG for each patient, but: –Compared to controls (overdose controls) –Adjusted for baseline; female significant QTc is marker of cardiotoxicity only, but: –Poison Severity Score : moderate –FDA : uses median QTc and proportion of abnormal QTc in evaluation

21. Recommendations All patients with citalopram overdoses > 60 mg should have serial 12 lead ECGs and be monitored until the QTc < 440 msec. Citalopram should be used with care in patients with a history of cardiac disease or arrhythmias, in particular bradycardia or known long QT syndrome

22. Acknowledgements Steve Bowe : statistical analysis Toni Nash and Debbie Whyte for data entry Stuart Allen for data extraction