Transcript newantidepressants

Poisoning with newer
antidepressants, diagnosis
and management.
AH Dawson, IM Whyte, GK Isbister
Department of Clinical Toxicology,
Newcastle Mater Hospital, Australia
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
The new antidepressants

Classes
–
–
–
–

SSRI
Selective MAOI
NSSRI
Nefazodone
Patterns of Use
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
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ADR
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Pharmacology


High lipid solubility
P450 drug metabolism
– Saturable metabolism
– Drug interactions

High volume of distribution
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Mechanism

©Jacob L. Driesen, Ph.D., 2000, 2001 http://www.driesen.com/index.html
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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

Correlation with concentration
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Serotinergic Toxicity:
an extension of therapeutic effect.

Diagnosis

Prediction

Treatment
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Serotonin Syndrome: Sternbach criteria










Mental status changes (confusion, hypomania)
Agitation
Myoclonus
Hyperreflexia
Diaphoresis
Shivering
Tremor
Diarrhoea
Incoordination
Fever
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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
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Sternbach criteria in HATS
Hyperreflexia
Agitation
Tremor
Confusion/hypomania
Fever
Diaphoresis
Ataxia/incoordination
Shivering
Diarrhoea
Myoclonus
Treated
(n = 45)
Untreated
(n = 351)
Other drug
(n = 2033)
93.3 %
55.6 %
44.4 %
15.6 %
28.9 %
17.8 %
13.3 %
20.0 %
11.1 %
11.1 %
38.7 %
16.0 %
5.4 %
7.1 %
7.7 %
5.1 %
8.5 %
4.0 %
5.7 %
2.3 %
11.3 %
NR
NR
4.4 %
3.4 %
0.7 %
NR
NR
NR
0.2 %
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Other clinical features
Tachycardia
Mydriasis
Inducible clonus
Spontaneous clonus
Hypertonia/rigidity
Ocular clonus/oscillations
Coma
Nystagmus
Flushed
Seizures
Rhabdomyolysis
Akathisia
Lacrimation
Oculogyric crisis
Opisthotonus
55.6 %
35.6 %
55.6 %
64.4 %
31.1 %
44.4 %
15.6 %
28.9 %
20.0 %
13.3* (4.4) %
8.9 %
0
0
0
0
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Odds Ratio of signs:
SSRI vs nonSSRI
Ocular clonus/oscillations
Hyperreflexia
Spontaneous clonus
Inducible clonus
Tremor
Agitation/restlessness
Hypertonia/rigidity
Shivering
Myoclonus
Flushing
30.4 (11.6 – 82.7)
22.1 (6.8 – 113.1)
20.9 (9.6 – 46.0)
19.6 (8.8 – 43.6)
14.0 (6.1 – 31.5)
6.6 (3.2 – 13.4)
6.2 (2.6 – 13.8)
6.0 (2.1 – 16.1)
5.4 (1.3 – 19.5)
5.2 (1.9 – 13.6)
Major Features
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Odds Ratio of signs:
SSRI vs nonSSRI
Fever
Nystagmus
Diaphoresis
Minor
Coma
Tachycardia
4.9 (2.1 – 10.9)
4.5 (1.9 – 10.0)
4.0 (1.4 – 10.5)
Features
3.4 (1.1 – 9.2)
2.3 (1.2 – 4.5)
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Odds Ratio of signs:
SSRI vs nonSSRI
Rhabdomyolysis
Seizures
Confusion/hypomania
Diarrhoea
Ataxia/incoordination
Mydriasis
Akathisia
Lacrimation
Oculogyric crisis
Opisthotonus
4.2 (0.9 – 16.4)
4.0 (0.4 – 29.0)
2.4 (0.8 – 6.2)
2.1 (0.6 – 6.1)
1.6 (0.5 – 4.4)
1.4 (0.7 – 2.8)
–
–
–
–
Non-features
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
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Odds of Clinical Sign being
present in treated patients
Clonus (any)
Flushing
Tremor/shivering
Nystagmus
Fever
28.8 (10.5 – 78.7)
8.8 (2.4 – 32.9)
8.7 (3.5 – 21.6)
4.4 (1.5 – 12.6)
3.7 (1.3 – 10.8)
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Serotinergic Symptom
Score

3 – Clonus





Inducible/spontaneous/ocular
2 – Flushing
2 – Tremor/shivering
1 – Nystagmus
1 – Fever
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61%
Patients (%)
61%
Application of Score to
Serotinergic Poisonings
10
9
8
7
6
5
4
3
2
1
0
Untreated
0
1
2
3
4
5
6
7
Treated
8
Score
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9
Predicting Serotonin Toxicity
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Rate of SS slide


Single ingestions
Synergistic combinations
– MAOI

serotinergic drugs
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Synergistic Effects



Coingestion
Inadequate washout
Serotinergic nonpharmaceuticals
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Poor Prognosis




SS due to combination therapy
Fever
Respiratory Failure
Spontaneous clonus.
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Treatment of Serotonin
Toxicity


Supportive Care
Specific Antagonists?
–
–
–
–
Theory
Animal models
Case Reports
Absence of Clinical Trials
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Drugs used to treat
serotonin syndrome
Non–specific blocking
agents
methysergide
cyproheptadine
–blockers
propranolol
pindolol
Miscellaneous
chlormethiazole
nitroglycerine
Benzodiazepines
lorazepam
diazepam
clonazepam
Drugs used for NMS
dantrolene
bromocriptine
Neuroleptics
chlorprothixene
chlorpromazine
haloperidol
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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
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Cyproheptadine




Case reports
Oral preparation
Safe
20-30mg required to
achieve 90% blockade
of brain 5-HT2 receptors
(Kapur et al., 1997).
Sertindole
Chlorprothixene
Ketanserin
Risperidone
Cyproheptadine
Chlorpromazine
Clozapine
Olanzapine
Methysergide
Haloperidol
Affinity=10-7 x 1/Kd.
 Kapur, S et al. (1997). Cyproheptadine: a potent in vivo
serotonin antagonist.American Journal of Psychiatry, 154,
884
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260
233
178
170
100
71
62
25
14
2.8
Chlorpromazine





5-HT2 antagonist
PET scans avid 5-HT2 binding
Case reports (mostly old)
Oral or parenteral medication
Sedating and a potent vasodilator.
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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
Saline
WAY 100635
Propranolol
Ritanserin
Pipamperone
Chlorpromazine
Cyproheptadeine
Dantroline
Risperidone
Ketanserin
Haloperidol
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Dose Deaths/
mg/kg
Total
6/6
1
5/5
10
5/5
3
0/5
20
0/6
20
6/6
40
0/5
5
5/5
10
0/5
20
6/6
0.5
0/6
5
0/6
0.5
6/6
Risperidone
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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 > 39oC
– barbiturate anaesthesia, muscle relaxation ±
active cooling
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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.
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Defining Other Toxicity

Citalopram
– ? Death
– Reports of QT prolongation

Venlafaxine
– QRS widening
– Reports of arrythmia
– Seizures
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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
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Cardiac toxicity of citalopram &
other selective serotonin
reuptake inhibitors in overdose
GK 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
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
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Analysis

Electrocardiograph analysis :
– R-R, QT and QRS were measured manually on ECGs by
independent trained persons
QT
– QTc was calculated using Bazett’s formula
QTc =
0.5
(RR)
– QTc > 440 msec was defined as abnormal
– An alternate HR correction for QT was used 5 = QT37
QT
QT37 =
 Statistical analysis :
(RR)0.37
– 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
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Admission
6 hours after
overdose
Discharge
38 hours after
overdose
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Results
Mean (+/-SD)
Citalopram (22)
QT
QTc
QT37
QRS
(msec)
(msec)
(msec) (msec)
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
Fluvoxamine (8) 363  19 425  12
87  9
408  9
88  8
-
87  11
SSRI (169)
368  41 428  40
Control (317)
366  41 425  38 409  34 88  14
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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
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
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.
QT37 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
No significant different between all 5 SSRIs and controls
Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Discussion
This 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.
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Limitations
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.
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Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital
Takehome



Be aware of synergistic combinations
Increased seizure rate of venlaxine
Potential cardiotoxicity of cipramil
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