Clinical Safety of Antipsychotics

Indications for Use

First-generation antipsychotics, also known as typical antipsychotics, are used in the following circumstances: 

• Rapid tranquillisation
• Schizophrenia
• Bipolar disorder
• Agitation
• Palliative care
• Nausea and vomiting

Additionally, levomepromazine is used for restlessness and pain in palliative care. 

Second-generation, or atypical antipsychotics, are used in:

• Schizophrenia
• Bipolar disorder (olanzapine, quetiapine and risperidone)
• Mania
• Generalised anxiety disorder (GAD)
• Nausea and vomiting

Risperidone can also be used for agitation and restlessness in the elderly. Furthermore chlorpromazine and haloperidol can be used in cases of intractable hiccups. 

Clozapine was the first second-generation antipsychotic developed and should only be used in patients who have experienced treatment failure with two or more antipsychotic drugs (including at least one second-generation antipsychotic). 

The table below lists antipsychotics under their respective class, alongside long-acting (depot) antipsychotic injections, which are used for maintenance treatment when adherence to oral medication is poor. They are typically administered at intervals of 1 to 4 weeks. 

Cautions and Adverse Effects

Impulse control disorders

Aripiprazole can cause impulse control disorders such as increased urges for gambling and compulsive shopping or eating.

Dysphagia

Dysphagia has been reported with the use of antipsychotics, therefore should be used with caution in patients at risk of aspiration pneumonia. 

Extrapyramidal Side Effects (EPSE) 

EPSE are due to blockade of D2 receptors in the nigrostriatal pathway. EPSE are more likely with first generation antipsychotics such as trifluoperazine and haloperidol, which have high affinity to D2 receptors.

Second-generation antipsychotics tend to bind more receptor types, such as muscarinic and serotonin, with lower affinity to the D2 receptor, making EPSE less likely. 

• Reduced risk of EPSE with amisulpride may be due to activity at the D3 receptor or weak partial agonism at the D2 receptor. 
• Quetiapine dissociates quickly from the D2 receptor
• Aripiprazole is a partial agonist at the D2 receptor 

EPSE include acute dystonias and tardive dyskinesias, a summary of signs and symptoms are described below:

Metabolic Effects

The metabolic side effects of second generation antipsychotics are often worse compared to first generation antipsychotics. Blockade of D2 receptors in the tuberoinfundibular pathway increases prolactin secretion which can lead to breast enlargement and lactation (galactorrhoea) in males and females. 

Hyperprolactinaemia is particularly pronounced with risperidone and amisulpride, and is less likely with quetiapine, aripiprazole, clozapine and olanzapine. Aripiprazole is a partial agonist at the D2 receptor, which reduces the risk, and reports of increased and decreased serum prolactin have been reported with aripiprazole therapy. 

Caution should be taken if prescribing amisulpride to patients with a history or family history of breast cancer due to the potential to increase prolactin levels. Furthermore, cases of benign pituitary tumours such as prolactinomas have been observed with amisulpride. If a patient develops a pituitary tumour, amisulpride should be discontinued. 

Antipsychotics are associated with metabolic effects such as:

• Weight gain
• Hyperglycaemia
• Dyslipidaemia

These increase the risk of diabetes and cardiovascular disease. The risk is higher with second generation antipsychotics, such as olanzapine, risperidone and clozapine, and this is likely due to activity at histamine, serotonin and muscarinic receptors. 

Blood disorders

Agranulocytosis, neutropenia and leucopenia can occur with antipsychotics, although rare (<1 in 10,000), except with clozapine where the risk is approximately 1%. If patients experience fever, sore throat or any infection they should inform their clinician and regular blood monitoring should be undertaken.

Cardiac Effects

Tachycardia and QT interval prolongation can occur with antipsychotic use; this increases the risk of arrhythmia and sudden death. 

• Haloperidol is recommended to be used intramuscularly over intravenous use, however if used intravenously, continuous ECG monitoring must be performed. 
• Quetiapine should only be prescribed cautiously in patients with a family history of QT prolongation or in patients with cardiovascular disease.
• Amisulpride induces dose dependent prolongation of the QT interval, therapy should be discontinued if QTc is >500ms

Furthermore, electrolyte disturbances such as hypomagnesaemia and hypokalaemia should be corrected prior to initiation of antipsychotics which carry risk of QT interval prolongation and arrhythmias. 

In addition to this, like clozapine, cardiomyopathy and myocarditis has been reported with quetiapine use. 

Neuroleptic malignant syndrome (NMS)

NMS is a rare idiosyncratic response that can occur with antipsychotic treatment. NMS is characterised by the following signs and symptoms:

• Pallor
• Blurred vision 
• Rhabdomyolysis 
• Hyperthermia
• Muscle rigidity 
• Autonomic instability 
• Reduced consciousness
• Increases creatinine phosphokinase 

Antimuscarinic Effects 

Muscarinic antagonism can lead to sedation, constipation, dry mouth and blurred vision. This is especially potent with chlorpromazine and clozapine. Patients with prostatic enlargement and narrow angle glaucoma should be monitored closely, chlorpromazine should be avoided in these conditions. The sedating effects of olanzapine are less than with clozapine. 

By TeachMeSeries Ltd (2026)

Fig 1: Antimuscarinic/Anticholinergic Adverse Effects

Other Effects

• Orthostatic hypotension (α-blockade) – commonly associated with clozapine, chlorpromazine, aripiprazole, quetiapine and risperidone. 
• Hypertension can occur with clozapine but also aripiprazole, olanzapine, quetiapine and risperidone. 
• Dose-related seizures (highest risk with clozapine)
• Hypersalivation
• Liver toxicity can occur with antipsychotic treatment – jaundice should be investigated and LFT monitoring should be undertaken.
• Erectile dysfunction 
• Abrupt withdrawal can cause onset of a psychotic episode and acute withdrawal symptoms such as nausea, vomiting and insomnia.  
• Pancreatitis with quetiapine, often associated with raised triglycerides, gallstones and alcohol intake. 
• Hyponatraemia can occur with antipsychotic use such as quetiapine and chlorpromazine
• Increased risk of stroke (e.g. olanzapine and risperidone) in patients with dementia.
• Increased risk of venous thromboembolism 
• Increased risk of suicide early in treatment or upon switching antipsychotic 
• Photosensitivity with chlorpromazine

Contraindications

The following contraindications should be noted for antipsychotics, this list is not exhaustive.

• QT prolongation/arrhythmia/Torsades de pointes/Parkinsons disease: Haloperidol
• Hypothyroidism/Myasthenia Gravis: Chlorpromazine
• Prolactin-dependent tumours: amisulpride

Monitoring 

The following monitoring requirements have been suggested (NICE), however may be indicated more frequently if patient is experiencing adverse effects:

• Weight (weekly for 6 weeks, then at 3 months, then yearly)
• Pulse and blood pressure (not required for amisulpride, aripiprazole, trifluoperazine, and sulpiride)
• Yearly full blood count to check for agranulocytosis, leucopenia, eosinophilia, thrombocytopenia
• Blood lipids (3 months then yearly)
• Plasma glucose or HbA1c (3 months then yearly). Also at 1 month for clozapine and olanzapine.
• Liver function tests (yearly)
• Prolactin (6 months, then yearly. Not required for aripiprazole, clozapine, quetiapine, or olanzapine (<20 mg daily), unless symptoms of hyperprolactinaemia are present.)
• ECG yearly and after dose changes; mandatory for haloperidol, pimozide, and sertindole or in patients with risk factors for arrhythmia such as taking medications that also increase risk of QTc prolongation

Monitoring for clozapine differs from the above and is detailed in the article on clozapine

Interactions

QT prolongation

Combining antipsychotics with other QT-prolonging drugs should be undertaken with caution and in some cases is contraindicated:

Haloperidol is contraindicated with drugs that also prolong QT interval such as the following:

• Amiodarone, sotalol, SSRIs, macrolides, quinolones, methadone 

Levomepromazine also is contraindicated with the following: 

• Citalopram, escitalopram, hydroxyzine, piperaquine, domperidone, and caution should be applied with any other drugs that also prolong the QT interval 

Chlorpromazine is contraindicated alongside citalopram and escitalopram 

Amisulpride is contraindicated with drugs that can cause torsade de pointes

Quetiapine, risperidone and aripiprazole should be used cautiously alongside other drugs that prolong the QT interval

Due to the effects described above, any drugs that cause hypokalaemia and hypomagnesemia should be used with caution alongside antipsychotics due to the increased risk of QT prolongation and arrhythmias. 

Lower Seizure Threshold 

Antipsychotics should be used with caution with drugs that also lower the seizure threshold, especially if the patient is at risk of seizures. The following medications can lower the seizure threshold: 

• Quinolones
• Theophylline 
• SSRIs
• Tramadol 
• Bupropion
• Chloroquine 

Dopaminergics

Antipsychotics will antagonise the action of dopaminergics, therefore caution needs to be applied if concurrent administration is required:

• Chlorpromazine is contraindicated with the use of dopaminergic agents such as cabergoline, and not recommended with dopaminergic antiparkinsonism agents such as bromocriptine and levodopa. 
• Haloperidol is contraindicated in Parkinson’s disease. 
• Amisulpride is contraindicated with levodopa. 

CNS depressant effects

When antipsychotics are used alongside other drugs that can cause CNS depression patient should be monitored closely, e.g. alcohol, hypnotics, sedatives, strong analgesics, methyldopa, due to the risk of CNS depression.

CYP mediated interactions

There are several CYP-medicated interactions to be aware of for antipsychotics, the list below is not exhaustive:

• Haloperidol is metabolised by CYP3A4 and CYP2D6, therefore caution should be applied for increased haloperidol levels with CYP inhibitors and reduced effectiveness with inducers. Fluoxetine and ritonavir inhibit both CYP3A4 and CYP2D6 therefore additional caution should be applied. 
• Haloperidol, chlorpromazine and levomepromazine inhibit CYP2D6, leading to increased TCA exposure if administered concomitantly 
• Chlorpromazine and olanzapine are metabolised by CYP1A2, therefore strong/moderate inhibitors of CYP1A2 may lead to increased exposure to chlorpromazine and olanzapine. 
• Quetiapine is extensively metabolised by CYP3A4, therefore concomitant administration with CYP3A4 inhibitors (azole antifungals, macrolides, HIV protease inhibitors, nefazodone) is contraindicated and caution should be applied with strong CYP3A4 inducers such as carbamazepine or phenytoin which may reduce quetiapine levels. 
• Aripiprazole is metabolised by CYP2D6 and CYP3A4. Strong inhibitors of either CYP enzyme have shown to lead to increased exposure of aripiprazole, which has led to a manufacturer recommendation of half the dose being used in this situation.  CYP inducers have shown to reduce aripiprazole exposure therefore higher doses may be required to elicit a pharmacological effect. 
• Risperidone is metabolised by CYP2D6 and to a lesser extent CYP3A4, furthermore risperidone and its active metabolite are P-gp substrates. The manufacturer makes the following recommendations:
  • Evaluate risperidone dose if given alongside OR therapy with one of the following is stopped: strong CYP2D6/CYP3A4 inhibitor or inducer, or P-gp inhibitor – risk of altered risperidone exposure

NMS

There is an increased risk of NMS when antipsychotics are used alongside lithium, which can be common practice in the treatment of bipolar disorder.

Absorption

Magnesium, aluminium and calcium containing agents reduce the gastrointestinal absorption of chlorpromazine and prochlorperazine – administration should be separated by 2 hours when possible

Serotonin syndrome 

Quetiapine and aripiprazole can cause serotonin syndrome when administered alongside other serotinergic agents such as SSRIs, MAOIs and TCAs. 

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Fig 2: Mechanism and symptoms of serotonin syndrome

Myelosuppression

There is risk of myelosuppression when antipsychotics with potential to cause this adverse effect are given alongside other drugs such as carbamazepine and azathioprine. There is an increased risk of neutropenia when olanzapine and valproate are given concomitantly. 

References

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