RELATIVE TOXICITY OF CITALOPRAM AND OTHER

SSRIs IN OVERDOSE

GK Isbister 1,2, IM Whyte 1,2, AH Dawson 1,2

1Department of Clinical Toxicology, Newcastle Mater Hospital, 2Discipline of Clinical Pharmacology, University of Newcastle

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 ?

AimTo 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

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

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

Methods

• Control group

• Overdoses of medications with no known cardiotoxicity, or affect the QT or QRS interval– paracetamol– paracetamol/codeine– diazepam– temazepam

Methods• Electrocardiograph:

– QT– QTc– QRS

• Clinical Features:– Incidence of arrhythmia– Bradycardia (HR < 60 bpm)– Tachycardia (HR > 100 bpm)– Hypotension (systolic BP < 90 mmHg)

Electrocardiographic Analysis

• RR, QT and QRS measured manually on ECGs

• QTc from Bazett’s formula

• QTc > 440 msec was defined as ABNORMAL

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

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

Results

236 ECG/patients were included:

Citalopram 32

Sertraline 82

Paroxetine 70

Fluoxetine 39

Fluvoxamine 13

Median ECG parameters

* ANOVA of medians (5 SSRIs and controls);

Control Group CitalopramP value *

Fluox Fluvox Parox Sert

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

Drug Odds

Ratio

C.I. (95%) P

value

Fluoxetine 0.97 0.48 - 1.97 0.94

Fluvoxamine 0.35 0.08 – 1.62 0.18

Paroxetine 1.15 0.67 - 1.97 0.61

Citalopram 3.71 1.73 - 7.98 0.001

Sertraline 1.18 0.71 - 1.95 0.52

Drug Ingested

Controls 1.00

Fluoxetine 1.00 0.482 - 2.090 0.993

Fluvoxamine 0.38 0.080 - 1.787 0.220

Paroxetine 1.10 0.625 - 1.945 0.736

Citalopram 3.79 1.672 - 8.591 0.001

Sertraline 1.17 0.657 – 2.072 0.599

Age 1.02 1.004 – 1.028 0.011

DDD 1.01 0.996 - 1.022 0.168

Gender

Males 1.00

Females 2.48 1.643 – 3.730 <0.001

Clinical EffectsControl Fluox Fluvox Parox Cital Sert P value

Cardiovascular Effects

Arrhythmia - 3% 0% 0% 3% 0% 0.504*

Bradycardia 7% 10% 8% 9% 13% 6% 0.821

Tachycardia 17% 15% 0% 10% 13% 22% 0.224

Hypotension - 0% 0% 0% 1% 0% 0.191*

Citalopram overdose : Admission 6 hours after overdose

Discharge 38 hours after overdose

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

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

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

Acknowledgements

• Steve Bowe : statistical analysis

• Toni Nash and Debbie Whyte for data entry

• Stuart Allen for data extraction