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Iloperidone

Antipsychotics

Drug Overview

Iloperidone is an atypical antipsychotic medication marketed under the brand name Fanapt. It is approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in adults.

This drug is primarily used to manage the symptoms of schizophrenia, including hallucinations, delusions and disorganized thinking. By modulating neurotransmitter pathways in the brain, iloperidone helps restore chemical balance and improve thought processes and behavior.

Iloperidone works by blocking dopamine D2 and serotonin 5-HT2A receptors, as well as inhibiting α1-adrenergic receptors. This mechanism reduces excessive dopaminergic activity and stabilizes mood, contributing to its antipsychotic effects.

Relevant Genes and Their Roles

The primary gene involved in iloperidone metabolism is CYP2D6. CYP2D6 is an enzyme in the liver that helps break down many medications, including iloperidone. It converts the drug into inactive or less active compounds that can be eliminated from the body.

Variations in the CYP2D6 gene can alter how quickly or slowly iloperidone is metabolized. Poor metabolizers have reduced enzyme function leading to higher drug levels, while ultrarapid metabolizers clear the drug more quickly, potentially lowering its effectiveness.

Impact of Genetics on Drug Response

Genetic differences in CYP2D6 activity group patients into phenotypes—ultrarapid, normal, intermediate, and poor metabolizers. These groups influence iloperidone blood levels, therapeutic efficacy, and the risk of side effects such as QT prolongation. Clinicians may adjust dosing based on phenotype to optimize treatment.

Expected Clinical Effects of Genetic Variation

Ultrarapid Metabolizer

  • Effect on drug levels: Decreased systemic exposure to iloperidone
  • Clinical consequence: Possible subtherapeutic response and insufficient symptom control
  • Side effects: Fewer adverse effects but risk of persistent psychotic symptoms

Normal Metabolizer

  • Effect on drug levels: Expected therapeutic levels
  • Clinical consequence: Standard efficacy and tolerability profile
  • Side effects: Typical side effect risk including dizziness and orthostatic hypotension

Intermediate Metabolizer

  • Effect on drug levels: Mildly increased blood concentrations
  • Clinical consequence: Slightly higher risk of dose-related side effects
  • Side effects: Possible mild sedation or hypotension more frequently

Poor Metabolizer

  • Effect on drug levels: Significantly increased systemic concentrations
  • Clinical consequence: Elevated risk of QT prolongation and cardiac arrhythmias
  • Side effects: Higher likelihood of dizziness, orthostatic hypotension, and serious cardiac events

Indeterminate / Not Available

  • Effect on drug levels: Unknown
  • Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring
  • Side effects: Typical risk profile; monitor for usual adverse reactions

Dosing Guidelines

The following dosing guidelines are based on FDA pharmacogenetic associations for iloperidone and CYP2D6 metabolism.

CYP2D6 Dosing Guidelines

Phenotype Clinical Consequence Guideline Recommendation
Ultrarapid Metabolizer No FDA guidance for this phenotype; potential subtherapeutic levels Use standard dosing; monitor symptoms and adjust if needed
Normal Metabolizer No FDA guidance for this phenotype; expected therapeutic exposure Use standard dosing
Intermediate Metabolizer No FDA guidance for this phenotype; mildly increased exposure Use standard dosing; monitor for side effects
Poor Metabolizer Higher systemic concentrations; increased QT prolongation risk Reduce dosage by 50%
Indeterminate / Not available Unknown impact Initiate therapy with recommended starting dose; monitor clinically

Alternative Treatment Options

The FDA guidelines do not specify alternate drugs for CYP2D6 poor metabolizers of iloperidone. Clinicians may consider other atypical antipsychotics without strong CYP2D6 dependence, such as risperidone or quetiapine, based on individual patient needs and tolerability.

Sources and References

Disclaimer: This document is for informational purposes only and is not a substitute for medical advice. Clinical decisions should be made by a qualified healthcare professional.

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