1. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Poisoning with newer antidepressants, diagnosis and management. AH Dawson, IM Whyte, GK Isbister Department of Clinical Toxicology, Newcastle Mater Hospital, Australia

2. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital The new antidepressants  Classes –SSRI –Selective MAOI –NSSRI –Nefazodone  Patterns of Use

3. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Toxicity  Direct extension of therapeutic effect –Serotonin Toxicity  Non-therapeutic effects –CNS, Cardiac, other  Differences –between drug class –within drug class

4. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital ADR

5. Pharmacology  High lipid solubility  P450 drug metabolism –Saturable metabolism –Drug interactions  High volume of distribution

6. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae HospitalMechanism  ©Jacob L. Driesen, Ph.D., 2000, 2001 http://www.driesen.com/index.html

7. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotinergic Toxicity: 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 l Correlation with concentration

8. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotinergic Toxicity: an extension of therapeutic effect.  Diagnosis  Prediction  Treatment

9. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotonin Syndrome: Sternbach criteria  Mental status changes (confusion, hypomania)  Agitation  Myoclonus  Hyperreflexia  Diaphoresis  Shivering  Tremor  Diarrhoea  Incoordination  Fever

10. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Redefining the Clinical Syndrome of Serotonin Toxicity  Incidence of signs in serotinergic drug poisoning vs other drugs –diagnostically useful  Examination of signs may assist in deciding who we treat

11. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Sternbach criteria in HATS

12. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Other clinical features

13. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Major Features Odds Ratio of signs: SSRI vs nonSSRI

14. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Minor Features Odds Ratio of signs: SSRI vs nonSSRI

15. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Non-features Odds Ratio of signs: SSRI vs nonSSRI

16. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Who 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

17. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Odds of Clinical Sign being present in treated patients

18. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Serotinergic Symptom Score  3 – Clonus l Inducible/spontaneous/ocular  2 – Flushing  2 – Tremor/shivering  1 – Nystagmus  1 – Fever

19. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Application of Score to Serotinergic Poisonings 61%

20. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Predicting Serotonin Toxicity

21. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Rate of SS slide  Single ingestions  Synergistic combinations –MAOI l serotinergic drugs

22. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Synergistic Effects  Coingestion  Inadequate washout  Serotinergic nonpharmaceuticals

23. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Poor Prognosis  SS due to combination therapy  Fever  Respiratory Failure  Spontaneous clonus.

24. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Treatment of Serotonin Toxicity  Supportive Care  Specific Antagonists? –Theory –Animal models –Case Reports –Absence of Clinical Trials

25. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Benzodiazepines lorazepam diazepam clonazepam Drugs used for NMS dantrolene bromocriptine Neuroleptics chlorprothixene chlorpromazine haloperidol Non–specific blocking agents methysergide cyproheptadine  –blockers propranolol pindolol Miscellaneous chlormethiazole nitroglycerine Drugs used to treat serotonin syndrome

26. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Which 5–HT receptor?  Originally thought to be 5–HT 1A mediated  Evidence implicating 5-HT 2 –failure of propranolol (5-HT 1A blocker) –5-HT 2 antagonists apparent efficacy –5-HT 2 agonists produce hyperthermia

27. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital  Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist.American Journal of Psychiatry, 154, 884 Affinity=10 -7 x 1/Kd. Cyproheptadine  Case reports  Oral preparation  Safe  20-30mg required to achieve 90% blockade of brain 5-HT 2 receptors (Kapur et al., 1997).

28. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Chlorpromazine  5-HT 2 antagonist  PET scans avid 5-HT 2 binding  Case reports (mostly old)  Oral or parenteral medication  Sedating and a potent vasodilator.

29. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Rat model: Nisijima K et al. Brain research 890 (2001) 23-31. Nisijima K et al. Psychopharmacology (2000) 150:9-14 Rat model: Nisijima K et al. Brain research 890 (2001) 23-31. Nisijima K et al. Psychopharmacology (2000) 150:9-14  Clorgyline & 5-HTP ( 5-hydroxy-L-tryptophan)  Outcomes –Rectal Temperature –hypothalamic [NA] –mortality

30. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Risperidone

31. Therapy  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 > 39 o C –barbiturate anaesthesia, muscle relaxation ± active cooling

32. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Conclusion  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.

33. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Defining Other Toxicity  Citalopram –? Death –Reports of QT prolongation  Venlafaxine –QRS widening –Reports of arrythmia –Seizures

34. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Citalopram Controversy Background  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

35. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Cardiac toxicity of citalopram & other selective serotonin reuptake inhibitors in overdose GK Isbister 1,2, IM Whyte 1,3, AH Dawson 1,3 1 Department of Clinical Toxicology, Newcastle Mater Hospital, 2 Emergency Department, Royal Prince Alfred Hospital, Sydney 3 Discipline of Clinical Pharmacology, University of Newcastle

36. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Methods  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

37. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae HospitalAnalysis  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 = QT 37 QTc = (RR) 0.5 QT QT 37 = (RR) 0.37 QT  Statistical analysis : –Comparisons were made of QT, QTc, QT 37 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

38. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Admission 6 hours after overdose Discharge 38 hours after overdose

39. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae HospitalResults

40. QT 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

41. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital QTc 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

42. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital QTc > 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 QT 37 Interval ANOVA comparison of SSRIs and control –5 SSRIs + control (6 groups) p = 0.004 : Citalopram significantly different to paroxetine, sertraline and controls QRS Interval

43. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital Discussion This study has demonstrated a significant increase in QT, QTc and QT 37 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.

44. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae HospitalLimitations The 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. 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 patients with bradycardia or known long QT syndrome.

45. Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital

46. Takehome  Be aware of synergistic combinations  Increased seizure rate of venlaxine  Potential cardiotoxicity of cipramil