19th May 2025

Second generation anti-psychotic drugs

Mechanism of action

The main mechanism of action of SGAs is via serotonin 5HT2A receptor binding and dopaminergic D2/D3 binding. 

Examples 

• Aripiprazole
• Clozapine 
• Olanzapine
• Paliperidone 
• Quetiapine
• Risperidone

Adverse effects 

• Metabolic syndrome – risk appears highest with clozapine and olanzapine. 
• EPSEs – although the risk is reduced with SGAs as compared with FGAs generally, among SGAs risperidone carries the highest risk of EPSEs. This is more commonly seen at higher doses. 
• Tardive dyskinesias – this is substantially less likely to occur with SGAs than with FGAs. Of the SGAs, risperidone and aripiprazole carry relatively higher risk, while quetiapine carries a lower risk, and clozapine use is not associated with tardive dyskinesias. 
• QT prolongation / sudden cardiac death – may be seen with quetiapine, risperidone and olanzapine 
• Myocarditis / cardiomyopathy – such cardiac complications have been reported with clozapine use and are thought to result from a hypersensitivity reaction. 
• Postural hypotension – this is believed to occur secondary to alpha-adrenergic receptor antagonism and is seen across the SGAs with varying frequencies. 
• Hyperprolactinaemia – risperidone is one of the SGAs most strongly linked to hyperprolactinaemia; in contrast, this is rarely seen with clozapine, aripiprazole or quetiapine.  
• Neuroleptic malignant syndrome – while most strongly linked to FGAs, neuroleptic malignant syndrome has also been demonstrated with SGA use.
• Agranulocytosis – this is a well-recognised side effect of clozapine. Following initiation of clozapine, weekly monitoring of the differentiated white cell count should be performed for 18 weeks; two-weekly for up to 12 months after initiation; then monthly thereafter. 
• Hypersensitivity syndrome – drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with SGA use.
• Anticholinergic side effects – most commonly seen with clozapine, although note that clozapine may more commonly cause sialorrhoea than dry mouth.

Other side effects include cataract, seizures, sedation, sexual dysfunction, falls, increased mortality, and hypothyroidism.

The National Institute for Health and Care Excellence (NICE) recommends monitoring of multiple parameters during antipsychotic therapy, including:  

• Weight
• Waist circumference
• Pulse
• Blood pressure
• Serum lipid levels
• Fasting glucose levels or HbA1c
• Adherence
• Development of movement disorders
• Symptomatic or behavioural changes
• Other reported side effects.