Iloperidone

Indications

• Schizophrenia in adults, for acute treatment and for maintenance, with efficacy comparable to other second-generation agents at adequate doses.
• Acute manic or mixed episodes associated with bipolar I disorder in adults, an indication added to the label in 2024.
• Often selected for patients who cannot tolerate akathisia or parkinsonism on aripiprazole, risperidone, or lurasidone.
• Useful when prolactin elevation has been the limiting problem, since iloperidone raises prolactin only modestly.
• Off-label use is limited, largely to patients whose main constraint is movement side effects rather than efficacy.

Mechanism of action

• Antagonist at dopamine D2 and D3 receptors with high 5-HT2A affinity, giving a favorable ratio that limits extrapyramidal effects.
• Very potent alpha-1 adrenergic blockade is the source of the orthostatic hypotension and dizziness that dictate the titration schedule.
• Low histamine H1 and negligible muscarinic affinity mean modest sedation and no anticholinergic burden.
• Blockade of cardiac potassium channels underlies a dose-related QTc prolongation of roughly 9 ms at the higher end of dosing.
• Low striatal D2 occupancy at therapeutic doses accounts for the notably low rates of akathisia and parkinsonism seen in trials.

Pharmacokinetics

• Oral absorption is unaffected by food and peak concentrations occur 2-4 hours after dosing, with twice-daily administration required.
• Metabolized by CYP2D6 and CYP3A4 to two active metabolites, P88 and P95, which contribute meaningfully to overall effect.
• Half-life is about 18 hours in CYP2D6 extensive metabolizers and about 33 hours in poor metabolizers, who need half the usual dose.
• Steady state takes 3-4 days after each dose step, which is why the labeled titration is spread across a full week.
• Renal clearance of unchanged drug is minimal, but severe hepatic impairment is a reason to avoid the drug altogether.

Dosing

• Start 1 mg twice daily and double the twice-daily dose on each of days 2 through 4, reaching 6 mg twice daily by day 4.
• Continue to 8 mg twice daily on day 5, 10 mg twice daily on day 6, and 12 mg twice daily on day 7 if tolerated.
• The effective range is 12-24 mg/day given in two divided doses, and the labeled maximum is 24 mg/day.
• Halve the dose with strong CYP2D6 inhibitors such as fluoxetine or paroxetine, with strong CYP3A4 inhibitors, and in known poor metabolizers.
• Restart the full titration from 1 mg twice daily whenever the drug has been stopped for more than 3 days.
• Avoid in severe hepatic impairment, and taper gradually on discontinuation to avoid rebound symptoms.

Adverse effects

• Dizziness and orthostatic hypotension are the leading effects and are the entire reason for the slow, stepwise titration.
• Tachycardia, somnolence, dry mouth, nasal congestion, and fatigue are common, with nasal congestion reflecting alpha-1 blockade.
• QTc prolongation is dose related, averaging about 9 ms at 12 mg twice daily, and rises further with metabolic inhibitors.
• Weight gain is intermediate, averaging 2-3 kg, with modest effects on lipids and fasting glucose.
• Akathisia and extrapyramidal symptoms are among the lowest in the class, and prolactin elevation is small.
• Neuroleptic malignant syndrome, tardive dyskinesia, and priapism are rare but serious labeled risks.

Monitoring

• Baseline and follow-up ECG when there is cardiac disease, bradycardia, electrolyte disturbance, or concurrent QT-prolonging medication.
• Correct hypokalemia and hypomagnesemia before starting, and recheck electrolytes when diuretics or vomiting enter the picture.
• Orthostatic blood pressure and pulse at each step of the titration and after any interruption that requires restarting.
• Weight, BMI, fasting glucose or A1c, and lipids at baseline, 12 weeks, and annually, as for all antipsychotics.
• Ask about CYP2D6 inhibitor use at every visit, since adding fluoxetine or paroxetine effectively doubles the dose.

Interactions

• Strong CYP2D6 inhibitors including fluoxetine, paroxetine, and bupropion roughly double exposure and require halving the dose.
• Strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, and ritonavir likewise call for a 50 percent dose reduction.
• Strong inducers such as rifampin and carbamazepine markedly reduce exposure and combination is not recommended.
• Avoid combining with other QT-prolonging drugs including Class IA and III antiarrhythmics, methadone, and moxifloxacin.
• Additive orthostasis with antihypertensives and additive sedation with opioids, benzodiazepines, and alcohol.

Special populations

• Third-trimester exposure carries the class risk of neonatal extrapyramidal and withdrawal signs; human pregnancy data are limited.
• Lactation data are essentially absent, so prefer better-characterized agents or monitor the infant closely for sedation.
• Safety and effectiveness have not been established in pediatric patients, so use is confined to adults.
• In older adults the orthostatic burden and fall risk are substantial, and the dementia mortality warning applies.
• No renal adjustment is specified, but the drug is not recommended in severe hepatic impairment.

Clinical pearls

• The week-long titration is not optional; skipping it produces syncope, not faster response.
• Off the drug more than 3 days means restarting at 1 mg twice daily and titrating again.
• Consider it when akathisia has repeatedly ended treatment with other agents.