Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Poisoning with newer antidepressants, diagnosis and management. AH Dawson, IM.

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

Poisoning with newer Poisoning with newer antidepressants, diagnosis antidepressants, diagnosis

and management. and management. AH Dawson, IM Whyte, GK IsbisterDepartment of Clinical Toxicology, Newcastle Mater Hospital, Australia


The new antidepressantsThe new antidepressants

Classes– SSRI– Selective MAOI– NSSRI– Nefazodone

Patterns of Use


ToxicityToxicity

Direct extension of therapeutic effect– Serotonin Toxicity

Non-therapeutic effects – CNS, Cardiac, other

Differences– between drug class– within drug class


ADRADR


PharmacologyPharmacology

High lipid solubility P450 drug metabolism

– Saturable metabolism– Drug interactions

High volume of distribution


Mechanism Mechanism

©Jacob L. Driesen, Ph.D., 2000, 2001 http://www.driesen.com/index.html


Serotinergic Toxicity:Serotinergic Toxicity: an extension of therapeutic effect.an extension of therapeutic effect.

Dose studies in therapeutic trials Hergyl et al. The serotonin syndrome scale:

first results on validity. Eur Arch Psychiatry Clin Neurosci. 1998; 248:96-103

– Grouping of symptoms into 9 items– Auditory evoked potentials

Correlation with concentration


Serotinergic Toxicity:Serotinergic Toxicity: an extension of therapeutic effect.an extension of therapeutic effect.

Diagnosis

Prediction

Treatment


Serotonin Syndrome: Sternbach criteriaSerotonin Syndrome: Sternbach criteria Mental status changes (confusion, hypomania) Agitation Myoclonus Hyperreflexia Diaphoresis Shivering Tremor Diarrhoea Incoordination Fever


Redefining the Clinical Syndrome Redefining the Clinical Syndrome of Serotonin Toxicityof Serotonin Toxicity

Incidence of signs in serotinergic drug poisoning vs other drugs– diagnostically useful

Examination of signs may assist in deciding who we treat


Sternbach criteria in HATSSternbach criteria in HATSTreated(n = 45)

Untreated(n = 351)

Other drug(n = 2033)

Hyperreflexia 93.3 % 38.7 % 11.3 %Agitation 55.6 % 16.0 % NRTremor 44.4 % 5.4 % NRConfusion/hypomania 15.6 % 7.1 % 4.4 %Fever 28.9 % 7.7 % 3.4 %Diaphoresis 17.8 % 5.1 % 0.7 %Ataxia/incoordination 13.3 % 8.5 % NRShivering 20.0 % 4.0 % NRDiarrhoea 11.1 % 5.7 % NRMyoclonus 11.1 % 2.3 % 0.2 %


Other clinical featuresOther clinical featuresTachycardia 55.6 %Mydriasis 35.6 %Inducible clonus 55.6 %Spontaneous clonus 64.4 %Hypertonia/rigidity 31.1 %Ocular clonus/oscillations 44.4 %Coma 15.6 %Nystagmus 28.9 %Flushed 20.0 %Seizures 13.3* (4.4) %Rhabdomyolysis 8.9 %Akathisia 0Lacrimation 0Oculogyric crisis 0Opisthotonus 0


Major Features

Ocular clonus/oscillations 30.4 (11.6 – 82.7)Hyperreflexia 22.1 (6.8 – 113.1)Spontaneous clonus 20.9 (9.6 – 46.0)Inducible clonus 19.6 (8.8 – 43.6)Tremor 14.0 (6.1 – 31.5)Agitation/restlessness 6.6 (3.2 – 13.4)Hypertonia/rigidity 6.2 (2.6 – 13.8)Shivering 6.0 (2.1 – 16.1)Myoclonus 5.4 (1.3 – 19.5)Flushing 5.2 (1.9 – 13.6)

Odds Ratio of signs:Odds Ratio of signs:SSRI vs nonSSRISSRI vs nonSSRI


Minor Features


Fever 4.9 (2.1 – 10.9)Nystagmus 4.5 (1.9 – 10.0)Diaphoresis 4.0 (1.4 – 10.5)Coma 3.4 (1.1 – 9.2)Tachycardia 2.3 (1.2 – 4.5)


Non-features


Rhabdomyolysis 4.2 (0.9 – 16.4)Seizures 4.0 (0.4 – 29.0)Confusion/hypomania 2.4 (0.8 – 6.2)Diarrhoea 2.1 (0.6 – 6.1)Ataxia/incoordination 1.6 (0.5 – 4.4)Mydriasis 1.4 (0.7 – 2.8)Akathisia –Lacrimation –Oculogyric crisis –Opisthotonus –


Who do we treatWho do we treat

Hunter Area Toxicology Service (HATS)– over last 4 years (1995–1999)

2429 admissions 396 (16.3 %) primary serotinergic

drug overdose 45 (11.4 %) of those admissions were

treated with a serotonin blocker


Odds of Clinical Sign being Odds of Clinical Sign being present in treated patients present in treated patients

Clonus (any) 28.8 (10.5 – 78.7)Flushing 8.8 (2.4 – 32.9)Tremor/shivering 8.7 (3.5 – 21.6)Nystagmus 4.4 (1.5 – 12.6)Fever 3.7 (1.3 – 10.8)


Serotinergic Symptom Serotinergic Symptom ScoreScore

3 – Clonus Inducible/spontaneous/ocular

2 – Flushing 2 – Tremor/shivering 1 – Nystagmus 1 – Fever


0123456789

10

Pati

en

ts (

%)

0 1 2 3 4 5 6 7 8 9

Score

Untreated Treated

61%

Application of Score to Application of Score to Serotinergic PoisoningsSerotinergic Poisonings

61%


Predicting Serotonin ToxicityPredicting Serotonin Toxicity


Rate of SS slideRate of SS slide

Single ingestions Synergistic combinations

– MAOI serotinergic drugs


Synergistic EffectsSynergistic Effects

Coingestion Inadequate washout Serotinergic nonpharmaceuticals


Poor PrognosisPoor Prognosis

SS due to combination therapy Fever Respiratory Failure Spontaneous clonus.


Treatment of Serotonin Treatment of Serotonin ToxicityToxicity

Supportive Care Specific Antagonists?

– Theory– Animal models– Case Reports– Absence of Clinical Trials


Benzodiazepineslorazepamdiazepamclonazepam

Drugs used for NMSdantrolenebromocriptine

Neurolepticschlorprothixenechlorpromazinehaloperidol

Non–specific blocking agents

methysergidecyproheptadine

–blockerspropranololpindolol

Miscellaneouschlormethiazolenitroglycerine

Drugs used to treat Drugs used to treat serotonin syndromeserotonin syndrome


Which 5–HT receptor?Which 5–HT receptor?

Originally thought to be 5–HT1A mediated

Evidence implicating 5-HT2

– failure of propranolol (5-HT1A blocker)

– 5-HT2 antagonists apparent efficacy

– 5-HT2 agonists produce hyperthermia


Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist.American Journal of Psychiatry, 154, 884

Affinity=10-7 x 1/Kd.

CyproheptadineCyproheptadine

Case reports Oral preparation Safe 20-30mg required to

achieve 90% blockade of brain 5-HT2 receptors (Kapur et al., 1997).

Sertindole 260Chlorprothixene 233Ketanserin 178Risperidone 170Cyproheptadine 100Chlorpromazine 71Clozapine 62Olanzapine 25Methysergide 14Haloperidol 2.8


ChlorpromazineChlorpromazine

5-HT2 antagonist

PET scans avid 5-HT2 binding

Case reports (mostly old) Oral or parenteral medication Sedating and a potent vasodilator.


Rat model: Rat model: Nisijima K et al. Brain research 890 (2001) 23-31.Nisijima K et al. Brain research 890 (2001) 23-31.

Nisijima K et al. Psychopharmacology (2000) 150:9-14 Nisijima K et al. Psychopharmacology (2000) 150:9-14

Clorgyline & 5-HTP

(5-hydroxy-L-tryptophan)

Outcomes– Rectal Temperature

– hypothalamic [NA]

– mortality

Dose mg/kg

Deaths/Total

Saline 6/6WAY 100635 1 5/5Propranolol 10 5/5Ritanserin 3 0/5Pipamperone 20 0/6Chlorpromazine 20 6/6

40 0/5Cyproheptadeine 5 5/5

10 0/5Dantroline 20 6/6Risperidone 0.5 0/6Ketanserin 5 0/6Haloperidol 0.5 6/6


RisperidoneRisperidone


TherapyTherapy

when oral therapy suitable– cyproheptadine 8-12 mg stat & review

when oral therapy unsuitable or cyproheptadine fails– chlorpromazine 50-100 mg IVI stat & review

if respiratory failure or fever > 39oC– barbiturate anaesthesia, muscle relaxation ±

active cooling


ConclusionConclusion

Serotonin toxicity not the syndrome requires treatment

More rigorous case definition is required

The pharmacology and clinical evidence for a number of agents appears promising and should be subject to clinical trial.


Defining Other ToxicityDefining Other Toxicity

Citalopram– ? Death– Reports of QT prolongation

Venlafaxine– QRS widening– Reports of arrythmia– Seizures


Citalopram Controversy Citalopram Controversy BackgroundBackground

Reports of fatal cases and severe cases with survival

Grundemar L, Wohlfart B, Lagerstedt C, et al Symptoms and signs of severe citalopram overdose. Lancet 1997; 349:1602-1602

Case series suggesting reasonable safety in overdose, with no deaths in the study, but a risk of seizures & ECG abnormalities 1,4

Hale AS. Citalopram is safe. BMJ 1998; 316:1825-1825. Personne M, Sjöberg G, Persson H. Citalopram overdose - review of

cases treated in Swedish hospitals. J.Toxicol.Clin.Toxicol. 1997; 35:237-240


Cardiac toxicity of citalopram & Cardiac toxicity of citalopram & other selective serotonin other selective serotonin

reuptake inhibitors in overdosereuptake inhibitors in overdoseGK Isbister 1,2, IM Whyte 1,3, AH Dawson 1,3

1Department of Clinical Toxicology, Newcastle Mater Hospital, 2Emergency Department, Royal Prince Alfred Hospital, Sydney 3Discipline of Clinical Pharmacology, University of Newcastle


MethodsMethods Prospective data from the Hunter Area Toxicology Service

(HATS) was used.

Cases included were :– single SSRI overdoses (SSRI dose > max. daily dose)

– SSRI and co-ingestant with no known effect on the QT or QRS intervals

Control group :– overdoses with medications not known to cause cardiac

toxicity, or effect the QT or QRS interval

– paracetamol, paracetamol/codeine, diazepam and temazepam


AnalysisAnalysis Electrocardiograph analysis :

– R-R, QT and QRS were measured manually on ECGs by independent trained persons

– QTc was calculated using Bazett’s formula– QTc > 440 msec was defined as abnormal– An alternate HR correction for QT was used 5 = QT37

QTc =(RR)0.5

QT

QT37 = (RR)0.37

QT Statistical analysis :

– Comparisons were made of QT, QTc, QT37 and QRS– The means of the five groups of SSRIs and controls were

compared using ANOVA– Citalopram was compared to all other SSRIs using either

Welch’s t test or Mann-Whitney for non-parametric data.– Comparison of the proportion of abnormal measurements was

made using Fisher’s Exact Test


Admission 6 hours after overdose

Discharge 38 hours after overdose


Mean (+/-SD) QT(msec)

QTc(msec)

QT37

(msec)QRS

(msec)Citalopram (22) 396 49 455 31 439 32 89 17

Sertraline (69) 372 45 429 34 412 29 86 10

Paroxetine (57) 369 43 422 39 407 36 87 14

Fluoxetine (35) 366 40 435 54 418 48 87 9

Fluvoxamine (8) 363 19 425 12 408 9 88 8

SSRI (169) 368 41 428 40 - 87 11

Control (317) 366 41 425 38 409 34 88 14

ResultsResults


QT IntervalQT Interval The QT interval in citalopram overdoses was

396 msec (SD 49), significantly different to the 368 msec (SD 41) of all other SSRI overdoses (p=0.02), and to the 366 msec (SD 41) of controls (p= 0.001)

ANOVA comparison of SSRIs and control– 5 SSRIs + control (6 groups) p = 0.06– 3 SSRIs (C,P,S) p = 0.0144 with citalopram

significantly different to paroxetine and sertraline


QTc IntervalQTc Interval The QTc interval in citalopram overdoses was 455

msec (SD 31), significantly different to the 428 msec (SD 40) of all other SSRI overdoses (p=0.0008), and to the 425 msec (SD 38) of controls (p= 0.0002)

ANOVA comparison of SSRIs and control– 5 SSRIs + control (6 groups) p = 0.006 : C vs P; and C

vs. controls significantly different– 3 SSRIs (C,P,S) p = 0.003 with citalopram significantly

different to paroxetine, sertraline and controls


QTc > 440 msecQTc > 440 msec Proportion of overdoses with QTc > 440 msec was

significantly more for citalopram compared to controls, all other SSRIs, and each group of SSRIs individually.

No significant different between all 5 SSRIs and controls

QTQT3737 Interval IntervalANOVA comparison of SSRIs and control

– 5 SSRIs + control (6 groups) p = 0.004 : Citalopram significantly different to paroxetine, sertraline and controls

QRS IntervalQRS Interval


DiscussionDiscussionThis study has demonstrated a significant increase in QT, QTc and QT37 with citalopram overdose compared to overdose of other SSRIs as a group, paroxetine and sertraline overdoses individually, and control overdoses. This supports a previous cases series of citalopram overdoses 2,4 and shows the effect is for citalopram alone and not other SSRIs. There was no significant difference between controls and other SSRIs. There have been previous reports of severe symptomatic sinus bradycardia, with normal QT/QTc, in patients recently started on therapeutic doses of citalopram 6.


LimitationsLimitationsThe major limitation in this study was the size of the citalopram group which meant that ANOVA comparisons including controls and SSRIs were limited because nonparametric methods were required. Lengthening of the QT or corrected QT interval is only a surrogate measure for cardiac toxicity, and in some cases may be benign. However until larger data sets are available to demonstrate no cases of torsades de pointes, QT prolongation should be considered an indicator of cardiac toxicity.

RecommendationsRecommendationsAll 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 patients with bradycardia or known long QT syndrome.



TakehomeTakehome

Be aware of synergistic combinations Increased seizure rate of venlaxine Potential cardiotoxicity of cipramil

Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Poisoning with newer antidepressants, diagnosis and management. AH Dawson, IM.

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