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Iloperidone

Iloperidone: A Comprehensive Guide to the Atypical Antipsychotic

Introduction

Iloperidone is a second-generation (atypical) antipsychotic medication used primarily in the treatment of schizophrenia. It is a relatively newer addition to the arsenal of drugs available for managing psychotic disorders. Approved by the U.S. Food and Drug Administration (FDA) in 2009 under the brand name Fanapt, Iloperidone was developed with the goal of providing effective symptom control while minimizing some of the severe side effects seen in older antipsychotic medications.

Understanding Schizophrenia

Before diving into the specifics of Iloperidone, it's important to understand the condition it primarily treats: schizophrenia.

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. Symptoms often include:

  • Positive symptoms: hallucinations, delusions, disorganized thinking

  • Negative symptoms: lack of emotion, reduced social engagement, anhedonia

  • Cognitive symptoms: impaired memory, attention deficits, executive dysfunction

Antipsychotics like Iloperidone aim to reduce the severity of positive symptoms and improve quality of life, although effects on negative and cognitive symptoms are more limited.

Iloperidone: An Overview

Drug Class and Brand Name

  • Class: Atypical antipsychotic

  • Brand name: Fanapt

  • FDA approval: 2009

  • Available forms: Oral tablets (1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg)

Indication

  • Treatment of schizophrenia in adults

  • Off-label uses may include bipolar disorder, but it is not FDA-approved for that indication

Mechanism of Action

Iloperidone functions primarily as a dopamine D2 receptor antagonist and serotonin 5-HT2A receptor antagonist, which is a hallmark of atypical antipsychotics.

Receptor Activity

Receptor Type Action Clinical Relevance
D2 (Dopamine) Antagonist Reduces psychosis (positive symptoms)
5-HT2A (Serotonin) Antagonist Enhances antipsychotic efficacy, reduces EPS risk
α1-adrenergic Antagonist Can cause orthostatic hypotension
D3, D4 Antagonist Potential role in mood and cognition
H1 (Histamine) Low affinity Less sedation compared to some other antipsychotics
M1 (Muscarinic) Low affinity Fewer anticholinergic side effects

Its receptor profile makes it effective while offering a relatively favorable side effect profile for extrapyramidal symptoms (EPS), though orthostatic hypotension is a concern due to α1 blockade.

Pharmacokinetics

  • Absorption: Well absorbed orally

  • Peak plasma levels: 2–4 hours after ingestion

  • Bioavailability: ~96%

  • Half-life: 13–14 hours

  • Metabolism: Primarily by CYP2D6 and CYP3A4 enzymes

  • Excretion: Urine (via metabolites) and feces

Due to metabolism by CYP450 enzymes, there is potential for drug interactions, especially with inhibitors or inducers of CYP2D6 and CYP3A4.

Dosing and Administration

Iloperidone requires gradual titration to minimize the risk of orthostatic hypotension. The typical dosing regimen is:

  • Day 1: 1 mg twice daily

  • Day 2: 2 mg twice daily

  • Day 3: 4 mg twice daily

  • Day 4: 6 mg twice daily

  • Target dose: 12–24 mg/day (given in two divided doses)

If the patient discontinues treatment for more than 3 days, re-titration is required starting from 1 mg twice daily.

Efficacy in Clinical Trials

Several double-blind, placebo-controlled trials have demonstrated the efficacy of Iloperidone in managing symptoms of schizophrenia.

Key Findings

  • Iloperidone showed significant improvements in Positive and Negative Syndrome Scale (PANSS) scores compared to placebo.

  • Comparable efficacy to ziprasidone and risperidone, with potentially fewer extrapyramidal side effects.

  • Some studies noted superior patient tolerability due to low rates of akathisia and dystonia.

Side Effects and Safety Profile

While Iloperidone has a favorable EPS profile, it is not without adverse effects.

Common Side Effects

  • Dizziness

  • Somnolence

  • Orthostatic hypotension

  • Dry mouth

  • Nasal congestion

  • Weight gain (modest compared to olanzapine)

  • Tachycardia

Serious Side Effects

  • QT Prolongation: Can increase risk of arrhythmia; avoid with other QT-prolonging drugs

  • Neuroleptic Malignant Syndrome (NMS): Rare but potentially fatal

  • Tardive Dyskinesia: Risk exists with prolonged use

  • Seizures: Use caution in patients with seizure disorders

Weight and Metabolic Effects

Iloperidone has a moderate risk for weight gain and metabolic side effects, typically less than clozapine or olanzapine but more than ziprasidone or aripiprazole.

Contraindications and Precautions

  • Hypersensitivity to Iloperidone or its components

  • QT prolongation or known cardiac arrhythmias

  • Concomitant use with strong CYP2D6 or CYP3A4 inhibitors may require dose adjustment

Special Populations

  • Pregnancy Category C: Use only if the potential benefit justifies the potential risk

  • Elderly with Dementia-Related Psychosis: Increased risk of death; not approved for this population

  • Renal or Hepatic Impairment: Caution due to altered metabolism and clearance

Drug Interactions

Iloperidone is a substrate of both CYP2D6 and CYP3A4 enzymes, making it vulnerable to interactions with various drugs.

CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine)

  • May increase Iloperidone plasma levels

  • Consider reducing the dose by 50%

CYP3A4 Inhibitors (e.g., ketoconazole)

  • Can significantly elevate Iloperidone levels

  • Dose adjustment required

Other QT-Prolonging Drugs

  • Avoid combination with drugs such as amiodarone, quinidine, and certain antibiotics (e.g., erythromycin)

Comparison with Other Antipsychotics

Drug EPS Risk Weight Gain QT Prolongation Sedation Notes
Iloperidone Low Moderate High Moderate Favorable EPS profile
Risperidone Moderate Moderate Low Moderate Higher prolactin elevation
Olanzapine Low High Low High Potent but significant weight gain
Aripiprazole Low Low Low Low Partial D2 agonist
Ziprasidone Low Low High Low QTc prolongation a concern
Clozapine Very low Very high Low Very high Last-line due to side effects

Iloperidone is often selected for patients needing a balance between efficacy and tolerability, especially those sensitive to extrapyramidal symptoms or prolactin elevation.

Patient Monitoring

  • EKG at baseline and periodically (especially if on QT-prolonging drugs)

  • Weight, lipid profile, glucose levels at baseline and during therapy

  • Vital signs, particularly orthostatic blood pressure

  • Liver function tests if clinically indicated

Patient Counseling and Education

When prescribing Iloperidone, patient education is crucial:

  • Take as prescribed and do not skip doses

  • Avoid alcohol or sedatives unless approved by the physician

  • Stand up slowly to avoid dizziness or fainting

  • Report symptoms of irregular heartbeat, severe dizziness, or mental changes

  • Inform providers of all medications being taken to avoid interactions

Future Directions and Research

While Iloperidone is approved only for schizophrenia at present, studies are underway to explore its potential in treating:

  • Bipolar Disorder

  • Post-Traumatic Stress Disorder (PTSD)

  • Psychosis associated with Parkinson’s disease

Researchers are also evaluating long-acting injectable formulations and pharmacogenomic testing to tailor dosing based on CYP2D6 genotype.

Conclusion

Iloperidone (Fanapt) is a second-generation antipsychotic that offers a favorable profile for patients with schizophrenia, particularly those prone to extrapyramidal side effects. It requires slow titration, and although its metabolic side effect profile is modest, careful monitoring is essential. With ongoing research and a growing understanding of its role in psychiatric care, Iloperidone remains a valuable option in the treatment landscape for schizophrenia. As always, treatment decisions should be individualized based on the patient’s symptoms, medical history, and response to therapy. Collaboration between patient and healthcare provider ensures optimal outcomes and minimal adverse effects.