Atypical antipsychotics

Abaperidone, Amisulpride, Amperozide¹ , Aripiprazole, Asenapine, Bifeprunox, Clozapine, Fluperlapine² , Iloperidone, Lurasidone, Melperone, Nemonapride, Olanzapine, Paliperidone³ (metabolite of risperidone), Perospirone, Quetiapine³ , Remoxipride² , Risperidone, Sertindole, Sulpiride, Sultopride, Tiospirone, Ziprasidone, Zotepine

There is also a combination product with an SSRI:

Fluoxetine plus olanzapine

1 Used in veterinary medicine
2 Discontinued
3 Modified release formulation available

Atypical antipsychotics are an increasingly common cause of poisoning. Most are drugs introduced in recent years with the aim of reducing the problem of extrapyrmidal adverse effects. Many are also potent serotonin antagonists (5HT2A), but they are a diverse group many of whose toxicity profile is still being recognized. Their toxicity in overdose varies widely between the different drugs with some producing life-threatening arrhythmias and others being predominately sedating.

Antipsychotic effects are attributable primarily to blockade of dopamine (D2, D4) and serotonin (5HT2) receptors. The dopamine blockade contributes significantly to adverse effects in therapeutic use. However, the major effects in overdose with any of these agents are mainly due to other effects. Thus they can only loosely be considered a “toxicological class”. The toxicity of each individual agent in overdose varies considerably (see below) although the general effects in overdose are qualitatively similar comprising sedation, hypotension, tachycardia and other anticholinergic effects, and in the most severe cases arrhythmias and seizures.

Blockade of histamine receptors leads to sedation, alpha receptor blockade leads to vasodilatation and hypotension, GABA-A blockade may contribute to seizures and anticholinergic effects including delirium result from muscarinic receptor blockade. In addition, some of these drugs (amisulpride in particular) appear to block potassium membrane ion channels leading to QT prolongation and torsades de pointes.

There are also substantial differences in their adverse effect profiles. Most importantly this affects severe adverse idiosyncratic reactions, where clozapine is more frequently implicated in agranulocytosis, seizures, myocarditis and cardiomyopathy in therapeutic dose (not reported in overdose). It is also apparent in different propensities to cause QT prolongation, arrhythmias and sudden death, with amisulpride more frequently implicated. Olanzapine, clozapine and quetiapine appear to cause significantly more weight gain, glucose intolerance and hyperlipidemia.

These drugs are generally lipid soluble weak bases that are rapidly absorbed, have high protein binding to alpha-1-acid glycoprotein and large volumes of distribution. Generally, peak concentrations occur within a few hours. Anticholinergic effects associated with many of these drugs may delay absorption and cause delayed peak concentrations.

The large volume of distribution reflects high intracellular concentrations in the brain, heart and other tissues. To some extent their effects in overdose may be more pronounced due to the initial high concentrations they achieve in plasma before they redistribute extensively into the tissues. The initial fall in serum concentrations after overdose would be primarily due to distribution rather than clearance. These drugs are highly bound to protein. It is not known whether this protein binding is sensitive to changes in the pH (c.f. TCAs).

These drugs are generally metabolised by the hepatic microsomal enzyme system. The main enzymes involved in metabolism are cytochrome P450 (CYP) enzymes; CYP1A2 , CYP2D6 and CYP3A4 are the major enzymes involved. In cases where the major pathway is one of these enzymes, significant differences in effect may be found. For example, risperidone is largely metabolised by CYP2D6. “Poor metabolisers” and those on drugs that inhibit this enzyme may have risperidone drug concentrations that are up to ten-fold higher than those of other individuals. In overdose, atypical antipsychotic clearance mechanisms may be overwhelmed and so the half-life of the drug becomes prolonged. Many have active metabolites. Both the parent drug and the active metabolites may undergo enterohepatic circulation. Renal excretion of the parent drugs is low (3% - 10%).

In atypical antipsychotic overdose there a four possible toxic scenarios. These are:

Dopamine blocking effects
Anticholinergic effects
Cardiac toxicity
CNS toxicity (sedation and seizures)

Death in atypical antipsychotic overdose is usually due to CNS and cardiotoxic effects.

These are usually minimal, perhaps due to competing anticholinergic effect. However, patients may, rarely, develop dystonias, dyskinesia or akathisia.

The anticholinergic syndrome seen in tricyclic antidepressant, neuroleptic (typical and atypical) and antihistamine poisonings is often less florid than that seen in the classic anticholinergic syndromes from antimuscarinic plants (Datura) and anticholinergic drugs such as benztropine. These pure anticholinergic poisonings often have an agitated delirium with associated management problems. This may be due to the lack of any other sedating drug effects in those poisonings.

The atypical antipsychotics with both antihistamine (sedating) and anticholinergic effects (clozapine, olanzapine, quetiapine) can have an unusual but quite striking combination of marked sedation from which the patient can be roused to an agitated delirium which settles when the patient is left alone. This has the potential for the patients to be deliberately left alone and develop significant respiratory depression.

The pupils may be dilated, but are often found to be mid range or small. Paralysis of accommodation may lead to some blurring of vision. The pupils react relatively poorly to light. The other anticholinergic effects will lead to a dry mouth (except clozapine and occasionally olanzapine where hypersalivation is the rule), dry skin and a tachycardia, occasionally urinary retention. Bowel sounds may be absent; this may be associated with an ileus. These symptoms or signs are poor predictors for life threatening toxicity.

Severely poisoned patients (who are generally unconscious on presentation) very commonly develop an anticholinergic delirium late in the course of their illness and this may persist for some days. The patient may have visual and auditory hallucinations or patients with relatively mild delirium may just appear to be hypervigilant and suspicious. Thus, it is often useful to ask patients when they regain consciousness whether they're hearing or seeing anything strange and reassure them that this is a drug effect.

A severe delirium may make it difficult to communicate with the patient at all and may interfere with their psychiatric assessment.

There is a wide spectrum of toxic effects ranging from trivial to life threatening.

Minor ECG changes
There may be an increase in the PR interval and dimpling of the T-waves.

Narrow complex tachycardia
Many patients with significant neuroleptic poisonings have a sinus tachycardia which is due to the anticholinergic effects of these drugs. Persistent tachycardia after regaining consciousness is most frequently due to persisting anticholinergic effect or volume depletion (exacerbated by osmotic faecuretics). Other possibilities include anxiety, catecholamine excess and drug withdrawal.

Broad complex tachycardia
The atypical antipsychotic most associated with broad complex tachycardias is amisulpride. Although clinical trials of the antipsychotic amisulpride revealed no cardiac adverse effects, four patients with severe cardiac toxicity after overdose were reported to Australian poisons information centres in 2004-2005. All four had QT prolongation over 500 ms, two had rate-dependent bundle branch block, two developed torsades de pointes, and one died after cardiac arrest. Pending further studies, we recommend electrocardiogram assessment until at least 16 h after amisulpride overdose and, if QT interval is prolonged, cardiac monitoring until the patient is clinically well and conduction intervals are normal.

For more mechanistic detail and clinical evaluation see Cardiotoxic Drugs.

Hypotension
Hypotension may be due to a number of causes. In practice, the hypotension usually relates to relative volume depletion and alpha receptor blockade induced vasodilatation. Thus it usually responds rapidly to intravenous fluids. The use of inotropes is almost never necessary. Risperidone is the agent with the most hypotension in overdose.

Many patients with significant ingestions of atypical antipsychotics are likely to have a significantly impaired level of consciousness. Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug. Patients should be assessed on admission to see if they are hyperreflexic or have myoclonic jerks or any evidence of seizure activity. Some patients who are likely to have seizures may be noted to have relatively brisk reflexes compared to the normal hyporeflexia seen with coma from other causes. This can be a marker of high seizure risk. The mechanism for this general effect is not known and is probably multifactorial. However, a small number of these drugs are potent GABA antagonists. This includes clozapine, which has a much higher rate of drug-induced seizures (around 5%).

In a cohort study involved 176 patients presenting to a toxicology unit on 286 occasions with quetiapine overdose. The probability of intubation was 10% after 2 g, 22% after 5 g, 37% after 10 g and 55% after 20 g and SDAC resulted in a reduced probability of intubation of 7% for 2 g ingestion. Isbister GK, Duffull SB.

The following investigations are usually performed:

Electrolytes
Arterial blood gases (ABGs)
ECG

Biochemistry
Electrolytes are normally assessed but are rarely of much assistance with the exception of patients who are on other medications that may effect electrolytes and thus their risk for arrhythmia.

Blood gases
All unconscious patients require arterial blood gas to access adequacy of ventilation and to ensure they are not acidotic. In sedated patients with normal gas exchange, an oxygen saturation of less than 95% on room air indicates a pCO2 of 50 mmHg or more and is an indication to do arterial blood gases.

ECG
An ECG should be performed on admission and also at 6 hours after the self poisoning. Patients with abnormal ECGs require further monitoring. Reliance on ECG findings on presentation as the sole predictor of subsequent problems cannot be recommended.

The majority of complications occur within the first six hours and in patients who are sedated. An alert patient with a normal ECG six hours after overdose who has had gastrointestinal decontamination is extremely unlikely to develop major complications.

Blood concentrations
These are unhelpful in aiding management.

Atypical antipsychotics should be considered, along with other sedating drugs, in patients with CNS depression. A presentation with coma in the presence of anticholinergic signs make typical and atypical antipsychotics likely (after TCAs).

The atypical antipsychotics with both antihistamine (sedating) and anticholinergic effects (clozapine, olanzapine, quetiapine) can have an unusual but striking combination of marked sedation from which the patient can be roused to an agitated delirium which settles when the patient is left alone. Clozapine (and occasionally olanzapine) overdose often has hypersalivation as a feature. Risperidone is the agent with the most hypotension in overdose. Amisulpride has been associated with QT prolongation and torsades de pointes.

A worse outcome is associated with any of the following:

cardiac arrest
cardiac arrhythmias
seizures
prolonged QT

However the in-hospital mortality is low (<0.5% in most centres) and therefore patients even from these groups have a reasonable prognosis once they reach hospital.

All patients should have assessment of the adequacy of their airway protection and ventilation. Comatose patients require management in ICU and will need to be intubated in order to have gastrointestinal decontamination safely. All patients should have intravenous fluids (normal saline).The outcome with supportive care alone is generally favorable if there are no other more toxic drugs ingested. Gastric lavage should be considered in patients who require airway protection. Activated charcoal in a standard dose should be given to patients following the lavage or to alert and co-operative patients presenting within 2 hours. In patients with normal gas exchange, an oxygen saturation of less than 95% on room air indicates a pCO2 of 50 mmHg or more and is an indication to do arterial blood gases.

Seizures

Initially, diazepam 5-20 mg IV followed by phenobarbitone 15-18 mg/kg IV and elective intubation and ventilation. If neuromuscular blockade is required for management, EEG monitoring is mandatory.

Anticholinergic delirium

Mild delirium can often be managed with reassurance plus or minus oral benzodiazepines. Severe hallucinations may require large doses of parenteral benzodiazepines. Although physostigmine may be effective, the short half life of this drug and its occasional life threatening adverse effects limit its application.

Arrhythmias

The preferred treatment for polymorphic ventricular tachycardia (torsades de pointes) is usually magnesium sulfate.However, in the overdose setting the calcium channel blocking effects of magnesium may worsen hypotension and this should be used only after hypotension has been corrected. Overdrive pacing should be considered for polymorphic or refractory ventricular tachycardia. Most arrhythmias, especially if they are associated with low output are treated in a standard cardiac arrest protocol manner.

Hypotension

This usually responds to volume expansion. Refractory hypotension may require drugs with alpha agonist properties (e.g. adrenaline & noradrenaline) but these should be used cautiously.

Repeated doses of activated charcoal may increase the clearance of the drug, but there is no evidence of clinical benefit. If the patient is unconscious and develops increasing abdominal distension with absent bowel sounds, repeated doses of charcoal should be stopped. Haemoperfusion and haemodialysis are of no benefit.

Patients are medically fit for discharge if they have no symptoms or signs of toxicity and a normal ECG six hours following the overdose (especially if they have passed a charcoal stool). Patients who still have an isolated tachycardia generally should be kept in hospital and observed. As the usual cause is volume depletion, IV fluid to ensure adequate volume replacement should be given. Patients with a QT complex of greater than 440 milliseconds should be monitored until this has returned to normal.

Acri AA, Henretig FM. Effects of risperidone in overdose. Am J Emerg Med 1998; 16(5):498-501.
Buckley NA. Antipsychotic Drugs (Neuroleptics) In: Dart RC Medical Toxicology 3rd Edition. Lippincott Williams and Wilkins, Philadelphia 861-70.
Isbister GK, Duffull SB. Quetiapine overdose: predicting intubation, duration of ventilation, cardiac monitoring and the effect of activated charcoal. Int Clin Psychopharmacol. 2009 Jul;24(4):174-80.
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 2001; 39(1):1-14.
Campbell TJ. Proarrhythmic actions of antiarrhythmic drugs: a review. Aust NZ J Med 1990; 20(3): 275-82.
Capel MM, Colbridge MG, Henry JA. Overdose profiles of new antipsychotic agents. Int J Neuropsychopharmacol 2000; 3(1):51-54.
Faber TS. Zehender M. Just H. Drug-induced torsade de pointes. Incidence, management and prevention. Drug Safety 1994;11(6):463-76.
Keren A, Tzivoni D. Torsades de pointes: prevention and therapy. Cardiovasc Drugs Ther 1991; 5(2): 509-13.
Killian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet 1999; 354(9193):1841-1845.
Newcomer JW, Haupt DW. The metabolic effects of antipsychotic medications. Can J Psychiatry. 2006 Jul;51(8):480-91.
Parsons M, Buckley NA. Antipsychotic drugs in overdose: Practical Management Guidelines. CNS Drugs 1997;6(6):427-441
Tarsy D, Baldessarini RJ, Tarazi FI. Effects of newer antipsychotics on extrapyramidal function. CNS Drugs 2002; 16(1):23-45.
Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose of atypical antipsychotics. CNS Drugs 2003; 17(5):307-324
Yunis JJ, Corzo D, Salazar M, Lieberman JA, Howard A, Yunis EJ. HLA associations in clozapine-induced agranulocytosis. Blood 1995; 86(3):1177-1183.