Iloperidone was approved by the Food and Drug Administration (FDA) in May of 2009. This article reviews clinically significant aspects of this new drug including: the FDA-approved indications, mechanism of action, administration, drug interactions, adverse effects, clinical trial evidence, innovative properties and place in therapy.

The attending psychiatrist on your unit has a patient with schizophrenia and a history of medication non-adherence, as well a past medical history significant for Type 2 diabetes and hyperlipidemia, who is experiencing akathisia from his current antipsychotic, ziprasidone. The psychiatrist does not want to decrease the dose due to the risk of clinical decompensation nor does he want to add an additional agent to treat this side effect. Instead, he would prefer to switch the patient to an antipsychotic that causes few metabolic abnormalities and is associated with less akathisia. The psychiatrist recently heard of a newer second-generation antipsychotic, iloperidone (Fanapt®), and is wondering if this is a viable treatment option in this patient.

Iloperidone (Fanapt®), approved May 2009, is indicated for the treatment of schizophrenia in adults.1 It has shown clinical efficacy in both four- and six-week trials. Iloperidone is not FDA approved for treatment of bipolar disorder or major depressive disorder.

Iloperidone is an atypical antipsychotic with antagonistic effects primarily at dopamine and serotonin receptors. It displays high binding affinity for serotonin 5-HT2A and dopamine D2 and D3 receptors, and moderate binding affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and α1 receptors, accounting for its orthostatic properties. 5-HT7 serotonin receptors are found in many areas of the brain and are believed to play a role in mood and cognition. Iloperidone has low binding affinity for serotonin 5-HT1A, dopamine D1, and histamine H1 receptors. Iloperidone has no appreciable affinity for cholinergic muscarinic receptors. An active metabolite of iloperidone, P88, is thought to have equal or less affinity for the same receptors as the parent drug, while another active metabolite, P95, only shows affinity for 5-HT2A and adrenergic receptors α1A, α1B, α1D, α2C.1 

Iloperidone is dosed twice daily and should be titrated to a target dose of 12 to 24 mg/day. The initial dosing regimen is 1 mg twice daily followed by 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. Iloperidone is available in a four-day initiation package to aid in patient adherence with the titration schedule. Prior to initiating iloperidone, patients should be educated on signs and symptoms of orthostasis. In patients missing greater than 3 days of iloperidone, it is recommended that the initial titration schedule be followed to avoid the development of orthostasis. Iloperidone can be administered without regard to meals. Steady state blood levels are reached 3 to 4 days after target doses have been achieved or after a change in dose. The mean elimination half-life of iloperidone and its active metabolites is 18–26 hours in CYP2D6 extensive metabolizers and 31–37 hours in CYP2D6 poor metabolizers.1 

Iloperidone is metabolized by 3 pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6), and O-demethylation (medicated by CYP3A4). Iloperidone dosing should be reduced by one-half when co-administered with a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine), a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin), or when administered to poor CYP2D6 metabolizers. When these concomitant agents are discontinued, iloperidone should be returned to its original dose. Co-administration of ketoconazole (200 mg for 4 days) with a 3 mg one time dose of iloperidone showed an increase in the AUC of iloperidone and its metabolites, P88 and P95, by 57%, 55%, and 35% respectively. Co-administration of fluoxetine (20 mg twice daily for 21 days) with 3 mg one time dose of iloperidone displayed an increase in the AUC of iloperidone and its metabolite, P88, by about 2–3 fold, while showing a decrease in AUC of its other metabolite, P95, by one-half.1 

Due to its α1 antagonist effect, orthostatic hypotension can occur, especially upon initiation of treatment and subsequent dosage increases. It is important that the titration schedule be followed to help minimize orthostasis. Iloperidone has been shown to increase the QTc by 9 msec at a dose of 12 mg twice daily. When co-administered with both a CYP2D6 inhibitor and a CYP3A4 inhibitor, the same iloperidone dose caused a QTc prolongation of 19 msec. Along with orthostasis, other common side effects include dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, and weight increases. Dizziness, tachycardia, and weight gain appear to be dose-dependent. Treatment-emergent extrapyramidal side effects were reported in 13.5% and 14.1% of patients receiving doses of 10–16 mg/day and 20 to 24 mg/day, respectively, as compared to 11.6% with placebo. Similar to the other antipsychotic agents, iloperidone carries a black-box warning for increased mortality in elderly patients with dementia-related psychosis.1 

In a four-week, phase III, placebo-controlled multicenter study, patients with schizophrenia were randomized to receive treatment with iloperidone 12 mg twice daily, ziprasidone 80 mg twice daily with food (active control), or placebo.2 The primary efficacy measure was change in Positive and Negative Syndrome Scale Total (PANSS-T) score from baseline to endpoint. Both iloperidone and ziprasidone produced significantly greater improvement in PANSS-T scores compared to placebo at study endpoint (p<0.01 and p<0.05, respectively); however, ziprasidone produced a significant decrease (p<0.05) in PANSS-T score as early as day 10 compared to placebo, while iloperidone did not significantly separate from placebo until day 21 of treatment (p <0.05). Iloperidone was associated with lower rates of sedation, EPS, akathisia, anxiety, restlessness, and agitation compared to ziprasidone (no p-values provided). The percentage of patients experiencing an improvement or no change in Barnes Akathisia Scale total score were similar in the iloperidone and placebo groups; however, a significantly higher percentage of patients in the ziprasidone treatment arm experienced worsening of akathisia compared to placebo (p=0.002). The mean maximum change in QTc interval were similar for iloperidone and ziprasidone groups (16.2 msec vs. 12.3 msec, respectively) and were significantly greater than changes observed with placebo (-2.4 msec, p <0.001 for both). The mean change from baseline in QTc interval were 7.2 and 6.1 msec with iloperidone and ziprasidone, respectively (p<0.001 for both compared to placebo). Mean weight increases at endpoint were 2.8 kg, 1.1 kg, and 0.5 kg with iloperidone, ziprasidone, and placebo, respectively. The incidence of clinically significant weight gain at endpoint, defined as 7% increase from baseline, were 21% with iloperidone, 7% with ziprasidone, and 3% with placebo. Iloperidone caused greater increases in blood glucose (7.9 mg/dL with iloperidone, 4.7 mg/dL with ziprasidone, and 3.2 mg/dL with placebo) and total cholesterol (8.1 mg/dL with iloperidone, 4.1 mg/dL with ziprasidone, and −0.5 mg/dL with placebo), but produced the least change in trigylcerides (0.8 mg/dL with iloperidone, 4.6 mg/dL with ziprasidone, and 19.5 mg/dL with placebo). Iloperidone also produced the greatest mean change in prolactin of 2.6 ng/mL compared to 1.9 ng/mL and −6.3 ng/mL observed with ziprasidone and placebo, respectively.

Three additional 6-week, double-blind, placebo- and active-controlled phase III studies were conducted in 1943 subjects with schizophrenia or schizoaffective disorder.3 In the first study, patients were randomized to one of five treatment groups: iloperidone 4 mg/day, iloperidone 8 mg/day, iloperidone 12 mg/day, haloperidol 15 mg/day, or placebo. The primary outcome was change in total PANSS score from baseline. Neither iloperidone 4 mg/day nor 8 mg/day showed a significant difference from placebo. Iloperidone 12 mg/day did demonstrate superiority to placebo (p=0.047); however a greater decrease in PANSS total score from baseline was observed with haloperidol (9.3 point improvement in haloperidol group vs. placebo [p<0.001] and 5.3 point improvement in iloperidone group vs. placebo [p=0.047]). In the second study, patients were randomized to iloperidone 4–8 mg/day, iloperidone 10–16 mg/day, risperidone 4 to 8 mg/day, or placebo, while in the third study patient were randomized to iloperidone 12–16 mg/day, risperidone 6–8 mg/day, or placebo. The primary efficacy measure for both studies was the change in Brief Psychiatric Rating Scale (BPRS) score for baseline to endpoint. Significant changes in BPRS score versus placebo were observed for iloperidone at doses of 4–8 mg/day (p=0.012), 10–16 mg/day (p=0.001), and 20 to 24 mg/day (p=0.010); however, no significant improvement in BPRS score was observed with iloperidone 12–16 mg/day compared to placebo (p=0.090). In both of these studies, risperidone and haloperidol produced a significant decrease in BPRS score from baseline to endpoint as compared to placebo. Additionally, these active comparators produced a greater mean change in BPRS total score compared to iloperidone at all doses studied; however, these studies were not designed to directly compare iloperidone to these active treatment arms.

A pooled analysis of these three studies showed that iloperidone caused significant dose-related increases in the QT interval at all doses (up to 9.1 msec at 20–24 mg/day).4 Other agents in this class had lower to almost no increase in the QT interval, including haloperidol and risperidone (5 msec at 15 mg/day and 0.6 msec at 4–8 mg/day, respectively). The pooled analysis also showed iloperidone had an average weight gain close to that of risperidone (1.5–2.1 kg with iloperidone vs. 1.5 kg with risperidone). Iloperidone was also associated with less EPS compared to haloperidol and risperidone. With regards to metabolic parameters, mild changes in blood glucose were observed in all treatment groups. Additionally, there were minimal to no changes in total cholesterol with all treatment groups and triglycerides were found to decrease with all doses of iloperidone. Prolactin levels were also shown to decrease with all iloperidone doses, but prolactin levels were not available for iloperidone doses of 20–24 mg/day.

From inception to the present, iloperidone has been sponsored and developed by 4 different companies, finally stopping at Vanda Pharmaceuticals for marketing. While iloperidone does offer another choice in treating schizophrenia, it does not appear to offer any distinct advantages to set it apart from other more established treatment options with similar pharmacodynamic profiles. Though iloperidone does have a lower risk of EPS than haloperidol, and a lower risk of akathisia than ziprasidone, its likelihood of causing orthostatic hypotension when titrated too quickly makes it a potentially poor choice for acute treatment of schizophrenia. It may also cause clinically relevant QTc prolongation similar to ziprasidone.

Though iloperidone is associated with fewer metabolic side effects, such as weight gain, elevated blood glucose, triglycerides, and cholesterol, relative to other second generation antipsychotics, it does not appear to offer any unique qualities to set it apart from other second generation antipsychotics. While iloperidone is a viable option for treatment of schizophrenia, it is less of a "go-to" drug and more of a "me-too" drug with considerable potential for side effects and titration restrictions. With the many choices available in this class of medication, it is difficult to justify prescribing a new product that has not shown consistent superiority over more affordable options that have the advantage of faster titration for quicker response. Future comparative trials to other second generation antipsychotics may help determine its niche in the treatment of schizophrenia.

As a follow-up to the patient case, the psychiatrist does believe that iloperidone would be less likely to cause akathisia in this patient; however, he is reluctant to switch to iloperidone due to the need to re-titrate the dose if greater than 3 days of medication are missed. Because this patient has a history of medication non-adherence, the psychiatrist would like to do a trial of an antipsychotic with less stringent dosing requirements.

1.
Fanapt [package insert]
.
Vanda Pharmaceuticals Inc
,
Rockville, Maryland
.
May 2009
. .
2.
Cutler
AJ
,
Kalali
AH
,
Weiden
PJ
,
Hamilton
J
,
Wolfgang
CD.
Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia
.
J Clin Psychopharmacol
.
2008
;
28
(
2 Suppl 1
):
S20
8
. .
3.
Potkin
SG
,
Litman
RE
,
Torres
R
,
Wolfgang
CD.
Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies
.
J Clin Psychopharmacol
.
2008
;
28
(
2 Suppl 1
):
S4
11
. .
4.
Weiden
PJ
,
Cutler
AJ
,
Polymeropoulos
MH
,
Wolfgang
CD.
Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials
.
J Clin Psychopharmacol
.
2008
;
28
(
2 Suppl 1
):
S12
9
. .