Pimozide

Pimozide (brand name Orap) is a typical antipsychotic medication used primarily to manage the symptoms of Tourette’s disorder and to treat chronic psychoses, including schizophrenia. It belongs to the diphenylbutylpiperidine class of antipsychotics.

Pimozide is approved for controlling motor and vocal tics in Tourette’s syndrome and may be used off-label for other psychotic disorders. Its effectiveness in these conditions is linked to its potent antagonism of dopamine D2 receptors in the brain.

By blocking dopamine D2 receptors in the mesolimbic pathway, pimozide helps reduce excessive neurotransmission that contributes to tic behaviors and psychotic symptoms. It may also have minor effects on other neurotransmitter systems, but its primary action is on dopamine signaling.

The primary gene involved in pimozide metabolism is CYP2D6, which encodes an enzyme in the liver responsible for oxidizing and clearing many psychotropic medications. CYP2D6 is part of the cytochrome P450 family of enzymes, which are essential for drug metabolism.

Genetic variations in CYP2D6 can lead to differences in enzyme activity, influencing how quickly pimozide is broken down. Individuals may be classified as ultrarapid, normal, intermediate, or poor metabolizers based on these variants, affecting drug exposure and response.

CYP2D6 phenotype groups determine pimozide plasma levels: ultrarapid metabolizers may have lower drug concentrations and reduced efficacy, while poor metabolizers exhibit higher systemic levels, increasing the risk of adverse effects such as QT prolongation and arrhythmias. Intermediate and normal metabolizers generally have exposures within the expected range.

Ultrarapid Metabolizer

• Effect: Lower than expected pimozide levels
• Clinical consequence: Potential subtherapeutic response
• Side effects: Fewer adverse effects; reduced risk of sedation or extrapyramidal symptoms

Normal Metabolizer

• Effect: Expected, therapeutic pimozide levels
• Clinical consequence: Standard efficacy and safety profile
• Side effects: Typical risk of sedation, extrapyramidal symptoms; frequency as in general population

Intermediate Metabolizer

• Effect: Slightly increased pimozide levels
• Clinical consequence: Generally therapeutic, but monitor for mild increased exposure
• Side effects: Possible mild increase in risk of QT prolongation; monitor ECG

Poor Metabolizer

• Effect: Higher systemic pimozide concentrations
• Clinical consequence: Increased risk of QT interval prolongation and arrhythmias
• Side effects: Potential torsades de pointes, severe but rare; requires ECG monitoring

Indeterminate/Not Available

• Effect: Unknown
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring

CYP2D6 Dosing Guideline

No alternate medications or dosing strategies were specified in the FDA guideline. Clinicians may consider other antipsychotics with less CYP2D6 dependence, such as risperidone or haloperidol, based on individual patient needs and professional judgment.

• FDA – Table of Pharmacogenetic Associations