Abstract:
Olanzapine pamoate is an intramuscular depot injection for the treatment
of schizophrenia. Approximately 1.4% of patients develop a serious
adverse event called Post Injection Delirium/Sedation Syndrome (PDSS);
characterised by drowsiness, anticholinergic and extrapyramidal
symptoms.
The objective is to investigate olanzapine PDSS presentations including
clinical features and treatment approach.
This is a retrospective review of olanzapine PDSS patients from three
toxicology units and the NSW Poisons Information between 2017 and 2022.
Adult patients were included if they had intramuscular olanzapine then
developed PDSS criteria. Clinical symptoms, treatment, timing and length
of symptoms were extracted into a preformatted Excel database.
There were 18 patients included in the series, with a median age of 49
years (IQR: 38-58) and male predominance (89%). Median onset time post
injection was 30 minutes (IQR: 11-38). PDSS symptoms predominate with
drowsiness, confusion and dysarthria. Median length of symptoms was 24
hours (IQR: 20-54). Most common treatment included supportive care
without any pharmacological intervention (n=10), benzodiazepine (n=4)
and benztropine (n=3).
In one case, bromocriptine and physostigmine followed by oral
rivastigmine were given to manage anti-dopaminergic and anti-cholinergic
symptoms respectively. This proposed treatment combination could
alleviate some of the symptoms.
In conclusion, this case series supports the characterisation of PDSS
symptomology predominantly being anti-cholinergic with similar onset
(<1 hour) and duration (<72hours). A combination of
bromocriptine and physostigmine followed by rivastigmine is proposed to
manage PDSS if patients develop severe dopamine blockade or
anti-cholinergic delirium.
Introduction: Olanzapine is a new generation of
thienobenzodiazepine class antipsychotic that has antagonist effect on
serotonin (5-HT2A, 5-HT2C), dopamine
(D1, D2, D3, D4),
histamine (H1), α1-adrenergic and
muscarinic receptors. Olanzapine pamoate is a long-acting salt based
intra-muscular depot injection for the treatment of schizophrenia since
20091. From 2000-2008, It is observed that
Delirium/Sedation Syndrome (PDSS) occurred approximately in 0.07% of
injections or 1.4% of patients who underwent clinical trials to assess
the safety of olanzapine long-acting injection (LAI)2.
In this cohort, PDSS is characterised by excessive sedation, delirium,
anticholinergic symptoms, extrapyramidal symptoms, dysarthria or ataxia
within an hour of injection2. The theorised
pathophysiology is partial intravascular inoculation, with inappropriate
rapid dissolution of the salt-based formulation due to direct exposure
to the high solubility in blood rather than muscle
tissue3. This is supported by the fact that PDSS is
primarily reported amongst patients who received olanzapine palmoate
depot injection and not other long acting
injectables4. In addition, the syndrome’s presentation
with anticholinergic and anti-dopaminergic symptoms is similar to oral
olanzapine overdose and high serum olanzapine levels occur in those who
develop it5, 6. Current management for this condition
is limited and involves supportive care and benzodiazepines for
agitation7. We aimed to investigate characteristics of
olanzapine PDSS including onset, clinical features and treatment
approach.
Methods: This is a retrospective review of patients who were
diagnosed with olanzapine PDSS from South-eastern Sydney toxicology unit
in New South Wales, Calvary Mater Newcastle toxicology unit in New South
Wales, Princess Alexandra Hospital toxicology unit in Queensland and the
New South Wales Poisons Information Centre between January 2017 and
February 2022. Adult patients over 18 years old were included if they
had been given intramuscular olanzapine and then developed symptomology
whilst fulfilling PDSS criteria outlined by Detke2(Table 1).
Patient demographics, clinical symptoms, time to symptoms, length of
symptomology and treatment were extracted and entered in a preformatted
Excel database. Categorical variables are summarised in percentages,
with skewed numerical data in median and interquartile range (IQR) as
appropriate. All involved institutions have ethics approval from their
respective Human Research and Ethics Committees.
Results: There were 18 patients in the case series who met the
inclusion criteria, with a median age of 49 years (IQR: 38-58, range:
21-38) and male predominance of 89% (n=17). The most frequent dosage
given in patients with PDSS was 405mg with doses ranging from 210-405
mg. All but 2 patients had the olanzapine depot injection in the past.
The median onset time to PDSS symptoms was 30 minutes (IQR 11-38, range:
5-180). PDSS symptoms predominate with drowsiness, confusion, slurred
speech, agitation and ataxia as highlighted by Figure 1. However, the
most frequent symptoms on presentation were drowsiness (61%), dizziness
(22%) and confusion (11%). Median heart rate on arrival was 91 beats
per min (bpm) (IQR: 85-115, range: 73-150). Forty-one percent (41%) of
patients has tachycardia on arrival defined as heart rate greater than
100 beats per minute. Median Systolic blood pressure was 128 mm Hg (IQR
128-140, range: 70-160) and temperature 36°C (Range: 36-39). Median
Glasgow Coma Scale was 13 (IQR: 10-14, range 3-15) and muscles tones
were noted to be increased, some with rigidity in 4 patients. Two
patients were intubated, one following sedation with benzodiazepines.
Complications included aspiration pneumonia (n=1), buttock abscess (n=1)
and rhabdomyolysis (n=1). Patients in our study had a median length of
symptoms of 24 hours (IQR: 20-54; range: 1.5-70h). The treatments given
were supportive care (n=10), benzodiazepines for agitation (n=4),
benztropine (n=3), physostigmine (n=2), rivastigmine (n=2) and
bromocriptine (n=1).
One patient received both physostigmine and bromocriptine for pronounced
anticholinergic and antidopaminergic toxicity. This was a 48-year-old
male admitted with progressive weakness, confusion, dysarthria and
rigidity 15 minutes post first depot intramuscular injection of 210mg
Olanzapine, to which he received 2mg Benztropine in 1mg aliquots to
minimal avail. His heart rate was 90 bpm, BP 115/85 mm Hg, temp 37.1°C.
He developed anti-cholinergic toxicity with progressive agitated
delirium, sinus tachycardia and urinary retention in addition to
extrapyramidal signs of cogwheeling in all four limbs and tremor. This
was complicated by rhabdomyolysis (peak CK 25,331 IU/L) and a mild acute
kidney injury (Creatinine 117 µmol/L, baseline Creatinine 69 µmol/L). He
was managed supportively with intravenous fluids and urinary
catheterization. Intravenous physostigmine 2mg was administered and
effectively reversed his anti-cholinergic symptoms rapidly, in
particular the delirium. The patient then received oral rivastigmine 6mg
three times a day for 2 days. The anti-dopaminergic symptoms (cogwheel
rigidity) were then treated with bromocriptine 5mg three times a day for
6 doses. There was complete resolution of anti-dopaminergic and
anti-cholinergic symptoms within 70 hours. This patient subsequently
received increasing dosage of paliperidone with no adverse effects.
While it is possible that neuroleptic malignant syndrome may have
accounted for the rhabdomyolysis and renal
impairment,8 the rapid onset and resolution of
symptoms makes this differential less likely. Rather the time course is
more consistent with dopamine blockade secondary to olanzapine.