Out Of The Pipeline

Iloperidone for schizophrenia

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New treatment option for patients who have not fully responded to or cannot tolerate other antipsychotics



Iloperidone is a second-generation (atypical) antipsychotic the FDA approved in May 2009 for treating acute schizophrenia in adults (Table 1). Iloperidone is not a derivative (metabolite, isomer, or different formulation) of any other antipsychotic. Clinical trials have shown that iloperidone is efficacious and suggest that for some patients its side-effect profile may be more favorable than that of other antipsychotics.

Table 1

Iloperidone: Fast facts

Brand name: Fanapt
Class: Atypical antipsychotic (serotonin/dopamine antagonist)
Indication: Acute schizophrenia in adults
Approval date: May 2009
Availability date: Late 2009
Manufacturer: Vanda Pharmaceuticals, Inc.
Dosing forms: 1-, 2-, 4-, 6-, 8-, 10-, and 12-mg tablets (nonscored); titration pack of 2×1-mg, 2×2-mg, 2×4-mg, and 2×6-mg tablets
Starting dose: 1 mg bid (2 mg total daily dose)
Target dose: 12 to 24 mg total daily dose

Clinical implications

Iloperidone’s binding profile is similar to that of other antipsychotics with relatively stronger affinity for serotonin (5-HT2A) than dopamine (D2) receptors, and its efficacy is roughly comparable to that of other non-clozapine antipsychotics.

Individual patients may respond differently to specific antipsychotics, even when those agents have shown equivalent efficacy in clinical trials. Therefore, a key therapeutic question is the degree of differential efficacy—differences in response at an individual level—among iloperidone and other antipsychotics.

The differential efficacy among iloperidone and other antipsychotics is unknown. Our clinical experience and iloperidone’s unique structure suggest, however, that this agent might be helpful for certain patients who do not fully respond to or are unable to tolerate other antipsychotics.

How iloperidone works

Like other antipsychotics, iloperidone’s efficacy presumably is based on its ability to block [antagonize] dopamine D2 receptors. Its chemical structure is most similar to risperidone, paliperidone, and ziprasidone, but its receptor binding profile is distinguished by a relatively lower affinity for serotonin receptors 5-HT1A and 5-HT2C than ziprasidone, and a relative lack of muscarinic and histaminic antagonist properties (Table 2).

The relatively higher affinity of iloperidone (and its metabolite P95) for the NEα1 receptor correlates with the drug’s propensity to cause orthostatic hypotension during initial up-titration.1 Differences in iloperidone’s receptor binding profile compared with other antipsychotics likely are responsible for its different side-effect profile.2,3

Table 2

Relative receptor binding affinities of 3 atypical antipsychotics*

Binding affinity
Dopamine D2HighHighHigh
Serotonin 5-HT1ALowHighLow
Serotonin 5-HT2AHighHighHigh
Serotonin 5-HT2CModerateHighModerate†
Norepinephrine NEα1HighModerateModerate‡
Histamine H1ModerateModerateLow
Muscarinic M1NegligibleNegligibleNegligible
* Cross-comparison of binding strengths reflects the subjective judgment of the authors. The goal is to demonstrate differences in overall binding patterns, and these estimates should not be considered an exact cross-comparison
† Published reports of binding affinity of iloperidone show considerable variation for the 5HT2C site
‡ One metabolite of iloperidone [P95] does not have CNS activity but has potent alpha-1 antagonism and may contribute to the initial orthostatic hypotension seen in clinical trials


Iloperidone is administered twice daily and can be taken with or without food. The bioavailability of iloperidone tablets is 96%, and peak plasma concentrations are achieved 2 to 4 hours after ingestion.

Like all antipsychotics except paliperidone, iloperidone is metabolized by the liver’s cytochrome P450 (CYP) system. The enzyme pathways CYP3A4 and CYP2D6 transform iloperidone into 2 metabolites: one with CNS activity (P88) and one that does not cross the blood-brain barrier and is not active in the CNS (P95) but likely has peripheral effects.

Genetic variations in CYP2D6 activity can substantially alter how individual patients metabolize iloperidone. The half-life of iloperidone and its active metabolites differs depending on whether someone is a poor metabolizer (no functional CYP2D6 activity), intermediate metabolizer (reduced CYP2D6 activity), or extensive metabolizer (“normal” CYP2D6 activity). The usual half-life of iloperidone (approximately 18 hours in extensive metabolizers) can be almost 50% longer (>24 hours) in CYP2D6 poor metabolizers.

There are no recommendations to test patients for genetic variants that result in poor metabolism from CYP2D6. Rather, clinicians simply need to be aware that this could be the source of interindividual differences they see in iloperidone tolerability, just as it is for any other medication that is a substrate for the CYP2D6 enzyme system.

Interactions. Medications that inhibit the CYP3A4 or CYP2D6 systems can increase iloperidone plasma level when taken concurrently with iloperidone, even if intrinsic liver metabolism activity is normal. Fluoxetine and paroxetine are potent CYP2D6 inhibitors. Concurrent treatment with either of these selective serotonin reuptake inhibitors could increase iloperidone plasma concentration by 100% or more.4

Similarly, cotreatment with a potent CYP3A4 inhibitor such as ketoconazole (or drinking grapefruit juice) will decrease metabolism and increase plasma concentrations of iloperidone and its active metabolites by about 50%. Smoking status should not influence iloperidone plasma concentration because this drug is not a primary substrate for CYP1A2, the enzyme induced by cigarette smoking.

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