From the Guidelines
Clozapine has the least risk for extrapyramidal side effects (EPSE) among all antipsychotics. This second-generation (atypical) antipsychotic has a unique receptor binding profile with relatively weak dopamine D2 receptor antagonism and strong affinity for serotonin receptors, particularly 5-HT2A. This pharmacological profile explains why clozapine rarely causes EPSE such as parkinsonism, akathisia, dystonia, or tardive dyskinesia 1. Other atypical antipsychotics like quetiapine and olanzapine also have relatively low EPSE risk, but not as low as clozapine. Despite its favorable EPSE profile, clozapine use is limited by other serious side effects including agranulocytosis (requiring regular blood monitoring), myocarditis, seizures, metabolic syndrome, and severe constipation. It is typically reserved for treatment-resistant schizophrenia. When considering antipsychotic selection to minimize EPSE risk, the clinician must balance this benefit against other potential adverse effects and the specific needs of the patient.
Some key points to consider when selecting an antipsychotic to minimize EPSE risk include:
- The risk of EPSE is lower with atypical antipsychotics compared to traditional antipsychotics 1
- Clozapine has the lowest risk of EPSE among all antipsychotics, but its use is limited by other serious side effects 1
- Quetiapine and olanzapine are alternative options with relatively low EPSE risk, but may have other side effects such as sedation and weight gain 1
- Aripiprazole is another option with a low risk of EPSE, but may have other side effects such as akathisia and restlessness 1
In terms of specific recommendations, olanzapine, quetiapine, and aripiprazole appear less likely to be associated with EPSEs than first-generation antipsychotics 1. However, the choice of antipsychotic should be individualized based on the patient's specific needs and medical history. It is also important to use the lowest effective dose and to monitor patients regularly for potential side effects.
From the Research
Antipsychotic Medications and EPSE Risk
The risk of extrapyramidal side effects (EPSE) varies among antipsychotic medications. According to a study published in 2002 2, the atypical antipsychotics can be ranked by EPSE risk in the following order:
- clozapine
- quetiapine
- olanzapine = ziprasidone
- risperidone (with higher doses having a higher EPSE risk)
Factors Influencing EPSE Risk
The ranking of EPSE risk is inversely related to antidopaminergic (D2 receptor) potency. Additionally, the high antiserotonergic (5-HT2A receptor) potency of certain antipsychotics, such as risperidone, clozapine, ziprasidone, and olanzapine, may also limit EPSE risk. The antimuscarinic activity of olanzapine and clozapine may further contribute to their lower EPSE risk.
Clozapine and EPSE Risk
Clozapine is considered to have a low risk of EPSE, making it a suitable option for patients with psychotic reactions to dopamine agonist therapy in Parkinson's disease. However, it is essential to monitor patients taking clozapine due to the risk of agranulocytosis, as reported in studies published in 1992 3, 2022 4, 2023 5, and 2020 6.