Incidence rates and risk factors

Incidence rates of PDSS with olanzapine LAI reported in international literature vary, ranging from 0.04–0.08% per injection to 1.2–1.4% per patient.5 6 8–10 Patients reported in the literature are mainly male (59–89%) with a median age of 41–49 years.10 11 This can partly be explained by the fact that olanzapine LAI is mostly used by male patients, for example, 75% of the users in the Netherlands in 2020 are men, of whom 94% are aged between 20 and 65 years.3 Diagnosis of the syndrome is usually straightforward, but there is a list of clinical criteria available, as shown in figure 1.8

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Figure 1

Most common symptoms and clinical criteria for the diagnosis of postinjection delirium/sedation syndrome (PDSS) following olanzapine LAI.8

Orally administrated olanzapine undergoes first-pass metabolism (40%) by the capacity-limited isozyme cytochrome P450 2D6 (CYP2D6), and olanzapine is further metabolised by UGT, CYP1A2 and CYP2D6. In case of PDSS, olanzapine enters the bloodstream, bypassing first-pass metabolism in the liver, resulting in high serum levels. A large overdose of olanzapine, such as PDSS, results in non-linear pharmacokinetic behaviour, with disproportionate increases in the serum concentration relative to dose and potentially severe adverse effects. Instead of linear and dose-proportionate pharmacokinetics as described in therapeutic range, in overdose, a two-phase elimination is observed.

Although no clear risk factors for PDSS have been described in clinical trials, weak evidence suggests that low body mass index and advanced age may be risk factors, as both can result in a higher risk of vascular injury.8 10 A higher dose of olanzapine LAI was marginally associated with an increased risk of PDSS in clinical trials in one study.8 Another study described an association between a dose of >350 mg (eg, 405 mg) and an almost fourfold higher chance of PDSS compared with a lower dose (eg, 210 mg), and twofold higher chance compared with a medium dose (eg, 300 mg).10 However, another study suggested that the dose of olanzapine entering the systemic circulation determines the serum concentration of olanzapine and not the total injected dose.5 Finally, other potential risk factors mentioned include chronic salicylate usage, diabetes and alcoholism, as they create a predisposition towards excessive bleeding or vessel injury and therefore might theoretically increase the risk of accidental drug spillage into the bloodstream.8 No studies have been performed to describe the association between these factors and PDSS.

Clinical features and management

PDSS has been reported to occur within minutes to hours after the injection, but 90% of cases occur within the first hour of injection. Very rarely PDSS develops more than 3 hours after injection.8–10 A distinctive feature of PDSS is that both sedation and agitation can occur, and can alternate in the same patient during the episode. Sedation or even somnolence has been reported in 40–61%, agitation in 7–30% and delirium in 20–47% of patients.8–10 Other symptoms reported in the literature are altered mental state, anticholinergic symptoms, extrapyramidal symptoms, haemodynamic changes and potentially QTc prolongation.8 9 12–15

If PDSS is suspected, hospitalisation is indicated to monitor the patient until all symptoms have resolved. Symptoms typically resolve fully within 24–72 hours.8–10

Treatment is usually supportive. There is no antidote available and accelerating olanzapine excretion with dialysis is not possible.8 Patients should be observed and monitored for respiration, oxygen saturation, cardiac function and behaviour. Olanzapine serum levels are usually not measured due to lack of therapeutic consequences.

While in most cases, first-line therapy is observation, correction of electrolyte disturbances and perhaps treatment with benzodiazepines, in some situations there is a role for additional medication. Table 1 summarises treatment strategies which we discuss next.

Altered mental state

Olanzapine has an antagonising effect on serotonergic (5-HT_2A), alpha-1 and histaminergic (H₁) receptors; therefore, patients may present with central nervous system depression or coma.16 Intubation may be required in case of severely diminished ventilatory drive or to adequately protect the airway and reduce risk of aspiration.9 In our own experience, a nasopharyngeal airway was required once in a case of PDSS due to a potentially endangered airway. In most cases, observation alone is sufficient and supportive oxygen can be added if necessary.

On the other end of the spectrum, patients can show agitation and/or aggression due to interaction of olanzapine with the serotonergic (5-HT_1A) and muscarine (M₂) receptors (see the Anticholinergic syndrome section). Agitated delirium is seen in approximately 20% of patients with PDSS.10 In most cases, observation alone is sufficient. The treatment for agitated delirium is a sedative such as benzodiazepine. Propofol can be prescribed in case of severe agitation/aggression under close monitoring of respiration, as all can cause respiratory depression and sedation as a side effect.9 Delirium and agitation requiring propofol and intubation have been described in previous PDSS case series.9 11 Seeing as olanzapine LAI can only be administered by a healthcare professional, in most cases there will be documentation of a recent injection. However, in cases where this is unclear, the alternating mental state changes and/or anticholinergic symptoms can be used to differentiate between olanzapine overdose and, for instance, benzodiazepine overdose.

Anticholinergic syndrome

Olanzapine has a strong antagonising effect on muscarinic (M₁, M₂, M₃) receptors, causing anticholinergic side effects such as dry mouth, constipation, tachycardia and confusion.16 In patients with delirium, agitation and a clear anticholinergic syndrome, physostigmine, a cholinesterase inhibitor, can be used as an alternative first-line treatment instead of sedatives. Physostigmine has been shown to be superior to lorazepam in reversing anticholinergic agitation and delirium without serious side effects such as further sedation.17 Physostigmine has long been overlooked as a treatment for anticholinergic syndrome due to safety concerns. In the 1980s, it was associated with several reports of deaths in patients with tricyclic antidepressant (TCA) overdose following the development of asystole.18 Physostigmine as the causative agent in these deaths has however been debated, and recent studies have shown that physostigmine is generally safe and effective as first-line therapy in the treatment of anticholinergic toxicity; after an initial dose, reversal or improvement of anticholinergic delirium was described in 74–80% of patients.19 20 Most clinical experts now recommend using physostigmine for a clear anticholinergic syndrome, where mydriasis, urinary retention and dry skin are the main symptoms besides agitation. However, there are many differences in the use of physostigmine worldwide. In the Netherlands, for example, its use is fairly uncommon, while Rasimas and colleagues (USA) advocate more extensive use of physostigmine in emergency medicine as the only antidote for an anticholinergic syndrome.21

Therefore, the first-line treatment of agitated delirium consists of sedatives; in case of a clear anticholinergic syndrome, physostigmine can be used as an alternative. Physostigmine should be dosed carefully to avoid the risk of developing a cholinergic syndrome. The recommended dose is either repeated intravenous boluses of 0.5–1 mg every 20–30 min, or a bolus followed by an infusion of 0.02 mg/kg/hour (max 2 mg/hour) because physostigmine has a very short half life (22 min).19–21 However, clinical experts recommend the use of (multiple) single boluses, not followed by a continuous infusion. Practice shows that the effect of a bolus lasts longer than expected based on half life.

In some settings, rivastigmine may be more available and can be used as alternative antidote for anticholinergic toxicity. The recommended oral dose of rivastigmine is at least 6 mg, which can be repeated as a second dose. An oral maintenance dose of rivastigmine 1.5–6 mg two to three times a day or a transdermal variant may be considered.11 22

Extrapyramidal symptoms

Extrapyramidal symptoms such as akathisia, muscle cramps, stiffness and rigidity are found to occur in 9–12% of patients.8 9 These symptoms are caused by antagonism of the dopamine (D₂) receptor.16 Extreme cases can manifest as neuroleptic malignant syndrome (NMS). The first-line treatment is observation. In case of severe extrapyramidal symptoms, anticholinergic drugs, such as biperiden 2.5–5 mg intravenously or benztropine 1–2 mg intravenously, can be used, depending on local availability.11 12 Anticholinergic drugs are contraindicated if tardive dyskinesia is present.

NMS is a rare but potentially life-threatening side effect of antipsychotic drugs such as olanzapine, although it is only reported in the literature after an overdose of oral olanzapine and not following PDSS.23 It is characterised by high fever, muscle rigidity, dysautonomia and mental status changes.24 In PDSS, hyperthermia has been described with temperatures of up to 38.2℃ (without other explanation), but never higher.14 Hyperthermia in PDSS can exist without the presence of extrapyramidal symptoms, possibly due to the increase in the thermoregulatory set point in the hypothalamus and to a lesser extent to the inhibition of serotonin activity associated with heat production. Olanzapine may additionally act as an exogenous pyrogen by triggering endogenous pyrogens.25 External cooling can be considered. Distinguishing between PDSS with hyperthermia and NMS can be difficult, but NMS should always be considered when hyperthermia and clear extrapyramidal symptoms are present.

Haemodynamic changes

A study summarising safety data of olanzapine LAI trials reported no clinically significant change in BP and HR during PDSS.8 However, tachycardia, probably caused by antagonism of the muscarinic (M₂) receptor in the central nervous system and to a lesser extent by alpha-2 receptors on cardiac tissue, is often described in previous literature.11 12 14 The first-line treatment is observation. Furthermore, hypotension has also been reported in real-world data, probably as a result of antagonism of alpha receptors on vascular tissue.9 12 Hypotension should be treated with intravenous fluid resuscitation and/or, in extreme cases, with vasopressors. Since olanzapine exerts its hypotensive effects by blocking adrenergic alpha-1 receptors, the use of norepinephrine has been proposed. Vasopressors that have beta-adrenergic activity, such as epinephrine or dopamine, should be avoided since olanzapine alpha blockade may lead to an increase in hypotension.26 To our knowledge, no cases of PDSS with severe hypotension requiring vasopressors, such as in oral olanzapine overdose, have been described. Lastly, hypertension has been mentioned in a few case series as well and can be treated with antihypertensive drugs or a wait-and-see policy.8 9

QT interval and arrhythmias

Antipsychotics in general have the ability to prolong the QTc interval by blocking potassium channels and therefore prolonging the repolarisation phase of cardiac cells.27 A prolonged QT interval is an important diagnostic tool for assessing the risk of developing life-threatening ventricular arrhythmias. A prolonged QT interval is defined as QTc longer than 450 ms for adult men and 470 ms for adult women.28

Olanzapine does not have an effect on the potassium channels and therefore has a low QTc prolonging potential. However, a significant prolongation (13%) of cardiac repolarisation induced by olanzapine has been shown in vitro.13 In PDSS, one study described a case with QTc prolongation (QTc interval of 500 ms).12 Several other clinical studies have found no QTc prolongation in PDSS and there are no reported cases of olanzapine-induced torsades de pointes.15 29–31 Olanzapine is a drug that, in overdose (and even therapeutic dosing), causes tachycardia. Due to this tachycardia, correction with Bazett’s formula will overestimate the QT interval and therefore identify patients with sinus tachycardia with a prolonged QTc.30

A better option may be to not use the QTc interval at all but to plot the uncorrected QT together with the HR on the QT nomogram, for then overcorrection cannot occur. An ECG in the ED is indicated for patients with PDSS. Furthermore, ECG changes can help differentiate between PDSS and other intoxications known to cause different ECG changes, such as QRS widening in TCA toxicity. In case of QTc prolongation or a QT interval above the line in the nomogram, consider repeat ECG monitoring until the QTc interval shows a decreasing trend. In addition to cardiac monitoring, correction of metabolic and electrolyte disturbances, in particular hypomagnesaemia, hypokalaemia and hypocalcaemia, is indicated.27