Iloperidone (Fanapt)

What it treats

Iloperidone is FDA-approved for schizophrenia in adults and for acute manic and mixed episodes of bipolar I disorder. It's often reached for when other atypicals haven't been tolerated, especially for people who've had trouble with metabolic effects on olanzapine or restlessness on aripiprazole.

How it works

Iloperidone is an atypical antipsychotic that blocks dopamine D2 and serotonin 5-HT2A receptors, which is the general atypical mechanism. It also strongly blocks alpha-1 adrenergic receptors, which is why it causes prominent orthostatic hypotension unless the dose is titrated slowly.

Receptor mechanism (detail)

Iloperidone is a D2 and 5-HT2A antagonist with strong alpha-1 adrenergic blockade. That alpha-1 activity drives the orthostatic hypotension seen when the dose is escalated too quickly. It has mild-to-moderate histamine H1 activity, moderate metabolic risk, and low prolactin elevation.

Potency and typical dosing pattern

Ranges are typical framework only, not a prescription for any individual. The slow titration is central to using iloperidone safely.

A typical starting schedule is 1 mg twice daily on day 1, 2 mg twice daily on day 2, 4 mg twice daily on day 3, 6 mg twice daily on day 4, 8 mg twice daily on day 5, 10 mg twice daily on day 6, and 12 mg twice daily by day 7. That gradual increase over about a week gives the body time to adjust to the alpha-1 blockade. Usual target dose is 6 to 12 mg twice daily. The prescriber sets and adjusts the dose based on response and tolerability.

Safety monitoring

• Orthostatic blood pressure at baseline, during titration, and periodically. This is central to iloperidone safety.
• ECG at baseline and periodically. Iloperidone prolongs QTc modestly.
• Weight, BMI, fasting glucose or HbA1c, and lipids at baseline, week 12, and at least annually.
• Involuntary-movement screen (AIMS) every six months.
• Movement side-effect check at each early visit.
• Prolactin if symptoms appear.

Metformin co-commencement: Aoife Carolan / Schizophrenia Bulletin guideline.

A clinical guideline led by Aoife Carolan strongly recommends co-commencing metformin alongside high-risk antipsychotics like olanzapine or clozapine. This proactive approach helps mitigate severe metabolic side effects, significantly reducing antipsychotic-induced weight gain and improving insulin resistance. The Schizophrenia Bulletin guideline states that when prescribing olanzapine or clozapine, metformin should be initiated immediately to prevent weight gain and cardiometabolic issues. Iloperidone has moderate metabolic risk and isn't on the automatic co-commencement list, but metformin is recommended if weight rises more than 3 percent of pre-medication weight or if other cardiometabolic risk factors are present.

Typical titration used in the guideline: 500 mg once daily, then 500 mg twice daily after one week, then 500 mg increments every two weeks as tolerated, up to 1000 mg twice daily by about week six. Contraindicated with eGFR below 30 mL/min/1.73 m². Renal function is checked annually and metformin is held during acute illness or dehydration.

Source: Carolan A, et al. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2025;51(5):1193 to 1203.

What to expect

Common side effects

• Dizziness on standing (orthostatic hypotension), especially during titration.
• Sedation.
• Weight gain, modest to moderate.
• Nasal congestion.
• Dry mouth.
• Tachycardia (fast heart rate).
• Fatigue.

Serious side effects and warnings

Boxed warning. Iloperidone carries the FDA boxed warning that antipsychotics increase the risk of death in older adults with dementia-related psychosis, and it isn't approved for that use.

• Orthostatic hypotension and syncope. The main reason for the slow titration. Fast dose escalation, dehydration, or combining with other alpha-blocking drugs raises risk.
• QTc prolongation. Modest but real. Avoid combining with other QTc-prolonging drugs when possible.
• Neuroleptic malignant syndrome. Rare but serious.
• Tardive dyskinesia. Long-term antipsychotic use can produce involuntary movements.
• Priapism. Rare, related to alpha-1 blockade. Persistent painful erection is a medical emergency.
• Metabolic changes.

This isn't medical advice. Any concern about a serious side effect should be raised with a prescriber promptly.

Sexual side effects

Iloperidone can cause priapism (rare) or erectile problems. Its effect on prolactin is generally mild. If sexual side effects appear, it's worth raising with the prescriber.

Weight, appetite, and sleep

Weight gain is typically modest to moderate. Sedation often helps sleep, especially at evening dosing.

Starting and dosing basics

This section is general background, not a dosing instruction. Iloperidone comes as tablets. It can be taken with or without food. The starter titration pack is designed to walk through the first week of dosing.

Missed doses and interactions

If you miss a dose, take it when you remember unless it's almost time for the next one, then skip and carry on. Don't double up. If more than three days of doses are missed, the titration usually needs to restart because tolerance to the alpha-1 effect fades.

Iloperidone is metabolized by CYP2D6 and CYP3A4. Inhibitors of these enzymes (fluoxetine, paroxetine, some antifungals) can raise levels. QTc-prolonging drugs and other alpha-blocking drugs add risk. The prescriber and pharmacist need a full list of medications and supplements. Alcohol worsens dizziness and sedation.

Stopping and tapering

Don't stop iloperidone abruptly. A prescriber can step the dose down gradually.

Pregnancy and breastfeeding

Untreated psychosis and mania both carry their own risks in pregnancy, and iloperidone likely passes into breast milk. Anyone who's pregnant, planning a pregnancy, or breastfeeding should talk it through with their prescriber. This isn't medical advice.

Cost and generic availability

Generic iloperidone is available. Insurance coverage varies. Manufacturer patient assistance programs exist.

Common questions

Why the slow titration? Iloperidone blocks alpha-1 adrenergic receptors strongly. Going up too fast causes dizziness, blood pressure drops on standing, and potentially fainting. Titrating slowly gives the body time to adjust.

What if I miss a few doses? If more than three days of doses are missed, tolerance to the alpha-1 effect fades and the titration often needs to restart. That's a good reason to talk to a prescriber before restarting after a break.

How does iloperidone compare with other atypicals? Once titrated in, it tends to be well tolerated with low movement side effects, low prolactin, and moderate metabolic risk. It's often a reasonable choice when someone hasn't tolerated other atypicals.

Does it work quickly? The full effect on psychotic or manic symptoms takes a few weeks. That timeline can feel slow when someone is acutely ill, so it's often paired with faster-acting drugs during acute treatment.

Questions to ask your prescriber

• What are we hoping this treats, and how will we know it's working?
• What should I do if I feel dizzy on standing?
• What if I miss a few days of doses?
• Will we check an ECG at baseline?
• If we decide to stop it later, how would we taper safely?

Sources

This guide draws on current prescribing information and public health references. It is reviewed for clinical accuracy and updated as guidance changes, and current as of June 8, 2026.

• U.S. Food and Drug Administration. Iloperidone prescribing information.
• MedlinePlus, U.S. National Library of Medicine. Iloperidone.
• National Institute of Mental Health. Mental health medications.
• American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia, 3rd edition.
• National Institute for Health and Care Excellence (NICE). CG178, Psychosis and schizophrenia in adults.
• Carolan A, et al. Metformin for the Prevention of Antipsychotic-Induced Weight Gain: Guideline Development and Consensus Validation. Schizophrenia Bulletin. 2025;51(5):1193 to 1203.