Prolonged toxicity after massive olanzapine overdose: two cases with confirmatory laboratory data.

Abstract

Olanzapine is a second-generation atypical antipsychotic that is increasingly used in preference to older antipsychotic agents. Limited data is available concerning the toxic effects of olanzapine after deliberate overdose. Two patients presented to our institution after massive olanzapine ingestion, and required prolonged ventilatory support due to the development of coma and respiratory depression. Serum olanzapine concentrations were orders of magnitude higher than those associated with therapeutic doses, and remained elevated for several days after ingestion. Both patients made a full recovery with only supportive care, despite having initial serum drug concentrations > 2500 microg/l. These reports indicate the potential for olanzapine ingestion to cause coma that may persist for several days after overdose.

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INTRODUCTION
Recently, there has been increased use of atypical
antipsychotics, whereas the role of older ‘typical’ antip-
sychotics has been declining. Atypical antipsychotics are
considered to be as effective as older agents, whereas
they confer a lower risk of extrapyramidal adverse effects
(Luft and Taylor, 2006). The changes in prescribing pat-
terns have been reflected by corresponding increases in
poisons centre enquiries related to atypical antipsychot-
ics, and larger numbers of patients presenting to hospital
after atypical antipsychotic overdose (Poon et al., 2007).
Olanzapine is a recently introduced atypical antipsychot-
ic that is capable of exerting effects at serotonin, mus-
carinic, histaminic, alpha-andrenergic, and dopaminergic
receptors in the central nervous system (Fulton and Goa,
1997). The typical therapeutic dose is 10 to 20 mg daily.
The effects of olanzapine overdose include central
nervous system depression, tachycardia, hyperthermia,
orthostatic hypotension, and miosis (O’Malley et al.,
1999; Palenzona et al., 2004; Morgan et al., 2007). How-
ever, earlier studies have failed to define a clear relation-
ship between the ingested dose and the extent of central
nervous system depression (Morgan et al., 2007). Inges-
tion of massive quantities of olanzapine may result in suf-
ficient respiratory depression to require invasive ventila-
Correspondence: W.S. Waring (E-mail: s.waring@ed.ac.uk)
tory support and, in severe cases, coma and death have
been reported.
MATERIALS AND METHODS
We report two cases of massive olanzapine overdose
associated with very high serum olanzapine concentra-
tions and, in contrast to existing data, both patients suf-
fered respiratory depression that persisted for several days
after ingestion.
Serum olanzapine concentrations
Serum olanzapine concentrations were determined
after extraction by methyl tertiary butyl ether using a
Spherisorb S5SCX HPLC column (Waters Ltd., Hert-
fordshire, United Kingdom) and ultraviolet detection at
260 nm. Olanzapine concentrations were considered with
respect to the interval between ingestion and determina-
tion.
RESULTS
Case 1.
A 50-year-old woman with longstanding bipolar disor-
der ingested olanzapine 600 to 700 mg, diazepam 20 mg,
and propanolol 960 mg in the presence of her communi-
Prolonged toxicity after massive olanzapine overdose:
two cases with confirmatory laboratory data
G.H. Tse1, M.H. Warner2 and W.S. Waring1
1Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, Scotland, UK
2Clinical Biochemistry Department, Royal Infirmary of Edinburgh, Scotland, UK
(Received January 30, 2008; Accepted February 8, 2008)

ABSTRACT — Olanzapine is a second-generation atypical antipsychotic agent that is increasingly
used in preference to older antipsychotic agents. Limited data is available concerning the toxic effects
of olanzapine after deliberate overdose. Two patients presented to our institution after massive olanzap-
ine ingestion, and required prolonged ventilatory support due to the development of coma and respiratory
depression. Serum olanzapine concentrations were orders of magnitude higher than those associated with
therapeutic doses, and remained elevated for several days after ingestion. Both patients made a full recov-
ery with only supportive care, despite having initial serum drug concentrations > 2500 µg/l. These reports
indicate the potential for olanzapine ingestion to cause coma that may persist for several days after over-
dose.
Key words: Coma, drug effect, olanzapine, overdose, toxicity

Letter
The Journal of Toxicological Sciences (J. Toxicol. Sci.)
Vol.33, No.3, *-*, 2008
Vol. 33 No. 3
1

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ty psychiatric nurse, who immediately arranged transfer
to hospital. The patient arrived in the Emergency Depart-
ment 40 min after ingestion. Her usual medications were
olanzapine 20 mg daily, propranolol 40 mg twice dai-
ly, and diazepam 2 mg hourly as required; there was no
excess ethanol consumption or recreational drug use. On
arrival, conscious level was reduced and the patient was
unresponsive to painful stimuli. Heart rate was 90 min-1,
blood pressure 130/90 mmHg, respiratory rate 24 min-1,
temperature 36.1ºC, pupils were 2 mm and responsive,
and gag reflex was absent. An endotracheal airway was
inserted and the patient was transferred to a critical care
area for ventilatory support and maintenance of hydration
status and electrolytes. Serum olanzapine concentration
on admission was 2800 µg/l. Serum creatine kinase activ-
ity increased from 41 U/l on admission to 1672 U/l at 27
hr post-ingestion, and temperature was 38.7ºC. These
findings were attributed to drug toxicity, and normalized
with supportive care only. Serial blood and urine samples
found no bacterial growth. At 36 hr post-ingestion, when
the serum olanzapine concentration was between 760 and
1120 µg/l, the gag reflex was restored and the patient was
extubated, but remained responsive only to painful stim-
uli for a further 48 hr. At 84 hr post-ingestion conscious
level significantly improved, and the patient was trans-
ferred to a psychiatric hospital for further evaluation.
Case 2
A 56-year-old woman with bipolar disorder present-
ed to hospital after ingestion of an unknown quantity of
olanzapine and lithium and up to 80 mg citalopram 80
mg in the presence of her husband. Her regular medica-
tions were citalopram 40 mg, olanzapine 15 mg and lith-
ium 600 mg. Within 40 min of drug ingestion, the patient
became unresponsive and required immediate intubation
and ventilatory support in the Emergency Department.
Heart rate was 90 min-1, blood pressure 125/95 mmHg,
temperature 35.5ºC, pupils were 4 mm and responsive.
Serum olanzapine concentration on arrival was 2586 µg/l,
consistent with massive olanzapine ingestion, whereas
serum lithium concentration was 0.31 mmol/l and lower
than the therapeutic reference range (0.6 to 1.0 mmol/l).
Pyrexia (38.8ºC) and tachycardia developed, and persist-
ed for up to 65 hr post-ingestion, and were attributed to
olanzapine toxicity. The patient was extubated at 60 hr
post-ingestion, but severely impaired conscious level per-
sisted up until 80 hr post-ingestion, at which time serum
olanzapine concentration had fallen to 633 µg/l. After
this, the patient underwent formal psychiatric assessment
and was discharged home.
DISCUSSION
The cases illustrate the potential for olanzapine over-
dose to cause prolonged sedation and respiratory depres-
sion. Fluctuating mental status is a recognized fea-
ture of olanzapine overdose, but an earlier series found
that patients usually recover within 48 hr of ingestion
(Palenzona et al., 2004). These findings are in contrast
to the comparatively short duration of effects associated
with therapeutic olanzapine doses (Fulton and Goa, 1997;
Biswasl et al., 2001). Olanzapine is associated with two-
phase elimination kinetics, and non-linear toxicokinet-
ics have been observed in patients that present to hospital
after olanzapine overdose (Lennestål et al., 2007). Fac-
tors contributing to altered toxicokinetics might include
delayed drug absorption, altered gut motility and satura-
tion of hepatic and renal elimination pathways, and are
recognized after overdose with other drugs; for exam-
ple phenytoin, antihistamines and ethanol (Roberts and
Buckley, 2007). In certain situations, prolonged coma
may be regarded as a sign of irreversible brain injury or
other underlying central nervous system pathology; for
example non-convulsive seizure activity. The present cas-
es indicate that olanzapine ingestion alone is sufficient
to cause persisting coma for more than 48 hr and long-
er than indicated in previous reports, such that prolonged
supportive care including ventilation may be needed in
these patients.
Drug ingestion was witnessed in both patients, allow-
100
1000
10000
024487296
Interval after ingestion (h)
Serum [olanzapine] (µg/L)
Case 1Case 2
Fig. 1. Serum olanzapine concentrations in two patients who
presented to hospital after massive olanzapine inges-
tion that had prolonged features of severe toxicity (the
therapeutic reference range is 20 to 50 µg/l).
Vol. 33 No. 3
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G.H. Tse et al.

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ing an unusual opportunity to confirm the dose and time
of ingestion. As expected, serum olanzapine concentra-
tions were substantially higher than those encountered
after therapeutic doses. The normal laboratory reference
range for serum concentrations is 20 to 50 µg/l, where-
as forensic blood concentrations vary between 3 and 390
µg/l (Robertson and McMullin, 2000). The relationship
between serum concentrations and toxicity is uncertain.
However, concentrations higher than 100 µg/l are like-
ly to be associated with significant toxicity (Lennestål
et al., 2007). The concentrations in the present cases are
higher than reported elsewhere after non-fatal olanzapine
overdose. For example, ingestion of olanzapine 800 mg
in an adult was associated with a serum concentration of
990 µg/l, and ingestion of 275 mg in a 14-year old boy
was associated with a serum concentration of 1503 µg/l
(Cohen et al., 1999; Thiesen et al., 1995). Fatal olanzap-
ine overdose has been associated with post-mortem blood
concentrations ranging between 237 µg/l and 5200 µg/l
(Gerber and Cawthon, 2000; Robertson and McMullin,
2000). Despite the very high serum olanzapine concen-
trations encountered in the present cases, neither patient
developed any clinical or laboratory evidence of hepatic,
renal or cardiac impairment. Transient elevation of serum
creatine kinase activity has previously been reported after
olanzapine overdose, but is rarely associated with a signif-
icant impact on the clinical course (Waring et al., 2006).
A limitation of these data is that co-ingested drugs
might have contributed to prolongation of toxicity in
these cases. Nonetheless, the dosages and types of co-
ingested drugs would not themselves be expected to cause
coma prolonged to this extent. A further possible limita-
tion is that peak olanzapine concentrations might not have
been determined due to the comparatively wide interval
between samples. Notwithstanding, the serum olanzapine
concentrations help to corroborate the drug ingestion and
the duration of clinical features.
In conclusion, massive olanzapine ingestion may result
in prolonged impairment of conscious level, accompanied
by exposure to very high drug concentrations. Supportive
care, including invasive ventilation, may be required for
up to several days in patients that present to hospital after
olanzapine overdose.
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Pronged toxicity after olanzapine ingestion