Expert Opinion on Investigational Drugs

ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20

Iloperidone: a new benzisoxazole atypical

antipsychotic drug. Is it novel enough to impact
the crowded atypical antipsychotic market?

Lawrence James Albers MD, Alessandro Musenga PharmD & Maria Augusta
Raggi

To cite this article: Lawrence James Albers MD, Alessandro Musenga PharmD & Maria Augusta
Raggi (2008) Iloperidone: a new benzisoxazole atypical antipsychotic drug. Is it novel enough to
impact the crowded atypical antipsychotic market?, Expert Opinion on Investigational Drugs,
17:1, 61-75

To link to this article: http://dx.doi.org/10.1517/13543784.17.1.61

Published online: 20 Dec 2007.

Submit your article to this journal

Article views: 126

View related articles

Citing articles: 3 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ieid20

Download by: [University of Pennsylvania] Date: 05 November 2015, At: 16:27

 Drug Evaluation

Iloperidone: a new benzisoxazole

atypical antipsychotic drug.
Is it novel enough to impact
1. Introduction the crowded atypical
2. Iloperidone
3. Expert opinion and conclusions antipsychotic market?
Lawrence James Albers, Alessandro Musenga & Maria Augusta Raggi†
†University
of Bologna, Department of Pharmaceutical Sciences, Via Belmeloro 6,
40126 Bologna, Italy
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

Iloperidone is a new-generation atypical antipsychotic agent, acting as a

serotonin/dopamine (5-HT2A/D2) antagonist, under development by Vanda
Pharmaceuticals for the treatment of schizophrenia, bipolar disorder and
other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like
risperidone, and shows a multiple receptor binding profile, sharing this
feature with the other atypical antipsychotic agents. Administered orally,
the drug is highly bound to plasma proteins and extensively metabolised.
Several clinical trials have been carried out, to check efficacy, safety and
side effects. In order to introduce iloperidone as an agent for the treatment
of schizophrenia, a short overview of the disease and of the most
important antipsychotic drugs available or under development will be
reported. Iloperidone pharmacokinetics and pharmacodynamics are
presented herein, together with an evaluation of clinical safety and
efficacy results.

Keywords: atypical antipsychotic, iloperidone, pharmacodynamics, pharmacokinetics,

schizophrenia treatment, therapeutic drug monitoring

Expert Opin. Investig. Drugs (2008) 17(1):61-75

1. Introduction

1.1 Schizophrenia: incidence, symptoms and aetiology

The incidence of schizophrenia is estimated at ∼ 1% of the world population [1]
and, although the predominant opinion is that schizophrenia incidence shows
scarce variations, recent studies concluded that it is ∼ 40% higher in men than
in women; moreover, incidence is higher in migrants and people living in
urban areas [2].
In developed countries, schizophrenia plays an important role in healthcare
expenditure: it accounts for 1.9% of the total healthcare budget in European
countries and 2.5% in the US [3].
Schizophrenia is a thought disorder characterised by gross distortion of reality,
apathy, avolition and affective blunting. Schizophrenia is an organic disorder of
the brain, causing loss of autonomy and mental capacity. Symptoms can be
divided into positive and negative, but cognitive dysfunction and a decline in
psychosocial functioning are also relevant. Positive symptoms include delusions,
hallucinations, disorganised speech and behaviour, and distortions in language
such as loose associations, tangentiality and neologisms. The main negative
symptoms are emotional and social withdrawal, apathy, anhedonia, alogia, flat
affect and poverty of ideas. Aggression, hostility, irritability, depressed mood as

10.1517/13543784.17.1.61 © 2008 Informa UK Ltd ISSN 1354-3784 61

 Iloperidone

well as cognitive problems such as impaired attention, deficits akathisia and acute dystonias, but also anticholinergic,
and impaired executive functioning, are also present [4,5]. antihistaminic and antiadrenergic effects. These features
The aetiology and pathophysiology of the illness is often lead to medication discontinuation [1,4,13]. Significant
not fully understood yet; nevertheless, the introduction advances in the treatment of schizophrenia were obtained
in clinical practice of a number of new drugs has drastically with the introduction of the atypical antipsychotics,
improved the quality of life of many schizophrenic leading to drastic changes in the quality of life of many
patients [6]. Most experts believe schizophrenia is a multi- schizophrenic patients. One of the main characteristics of
factorial disease, in which not only biological, but also these second-generation antipsychotic drugs is a higher
genetic, psychological, cultural and environmental factors affinity for serotonin 5-HT2 receptors than for dopamine D2
play a role [1]. receptors. In fact, the 5-HT/D affinity ratio
According to the dopaminergic theory, the first to be (Meltzer’s ratio) can be used to distinguish classical
developed, schizophrenia is due to alterations in the neuroleptics (pK < 1.09) from atypical antipsychotics
dopaminergic transmission in the CNS. In particular, (pK > 1.12) [14].
increased dopamine transmission in the mesolimbic pathway Atypical antipsychotics present three common properties
leads to positive symptoms, while reduced dopamine trans- that differ from classical neuroleptics [15,16]: i) atypical
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

mission in the mesocortical pathway would explain negative antipsychotics have low tendency for extrapyramidal
symptoms [4]. Although dopamine may not be the neuro- symptoms (EPS) and tardive dyskinesia, which are the main
chemical origin of schizophrenia, dopamine deregulation is side effects of classical neuroleptics that lead to poor
the final common pathway of others factors, playing a role medication adherence; ii) some atypical antipsychotics
in positive, negative and cognitive symptoms [7]. (e.g., clozapine) do not cause hyperprolactinemia, like
There is evidence that schizophrenia can be more classical neuroleptics; and iii) most atypical antipsychotics
effectively treated with drugs presenting a multiple receptor are effective against negative symptoms of schizophrenia.
binding profile, and many researchers agree that many other According to the serotonin/dopamine hypothesis of
receptors are directly or indirectly involved in the patho- schizophrenia, the blockade of 5-HT2A receptors in part
physiology of schizophrenia [8]. Serotonin plays a pivotal reduces the blockade of dopamine transmission. Little
role [9], but glutamate may also be involved, as the cortico- tendency for EPS or tardive diskynesia would result from the
striatal glutamate pathway may inhibit dopamine function reversed D2 blockade in the striatum. Again, the antagonist
from the ventral striatum and decreased glutamate trans- activity at 5-HT2A receptors in the mesocortical pathway
mission may increase dopaminergic activity at the limbic area, and the consequent increased dopamine transmission may
determining positive symptoms of schizophrenia [1,10]. explain the efficacy against negative symptoms [4].
The present review reports an overview of the new Moreover, atypical antipsychotics are known for acting
antipsychotic drug iloperidone, summarising available on a wide range of brain receptors, other than serotonin
literature data, and presenting an evaluation of its safety and and dopamine. For example, clozapine (the first atypical
efficacy. For comparison, a short overview of the most antipsychotic), also interacts with adrenergic (α1, α2),
important antipsychotic drugs available or under histaminic (H1) and muscarinic (M1) receptors [4]. The
development is presented now. interaction with α2 adrenergic receptor has been correlated
with improvements in cognitive function [17]. The action of
1.2 Schizophrenia: classical neuroleptics atypical antipsychotic on muscarinic receptors can be
and atypical antipsychotics related to mitigation of EPS (but also anticholinergic side
The first drug introduced for the treatment of schizophrenia effects) [18], even if this role is considered complex and
was chlorpromazine, an agent carrying the brand name of controversial [19]. Overall, each atypical antipsychotic
Largactyl® due to its effect on a large number of CNS shows a peculiar spectrum of receptor interaction, resulting
receptors. Several other drugs were then developed, such as in a characteristic pharmacological profile. Atypical
phenothiazines (e.g., levomepromazine), butyrophenones antipsychotics are not devoid of side effects, such as
(e.g., haloperidol) and thioxanthenes (navane and weight gain, diabetes, hyperlipidemia, agitation, insomnia
clopenthixol). All ‘first-generation’ classical neuropleptics and antimuscarinic effects (dry mouth, constipation);
are antagonists at the dopamine D2 receptor [4,11]. According moreover, drug-related cardiac changes (QTc prolongation)
to the dopaminergic theory of schizophrenia, the blockade should be considered [20,21].
of dopamine receptors in the mesolimbic pathway by classical
neuroleptics results in controlling positive symptoms 1.2.1 Established atypical antipsychotics
of schizophrenia in ∼ 70% of treated patients [4,12]. Thus, The first atypical antipsychotic drug introduced
∼ 30% of patients with schizophrenia are treatment (during the 1970s) for the treatment of schizophrenia
refractory. Classical neuroleptics have poor efficacy in was clozapine (8-chloro-11-(4-methyl-1-piperizinyl)-5H-
controlling negative symptoms and present relevant side dibenzo[b,e][1,4]diazepine). The drug is a dibenzodiazepine
effects: extrapyramidal symptoms, hyperprolactinemia, and is effective against both negative and positive symptoms,

62 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

F
O
N

N
O

Iloperidone
F
O S
N N
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

O
N N

N
O

Cl N
N H
Risperidone Ziprasidone

Figure 1. Chemical structures of iloperidone, risperidone and ziprasidone.

including patients who are treatment resistant to classical Aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]

neuroleptics. Clozapine presents high efficacy, but causes butoxy]-3,4-dihydro-2(1H)-quinolinone) by Bristol-Myers
agranulocytosis in ∼ 1% of treated patients. For this reason, Squibb and Otsuka America Pharmaceutical was approved in
it was withdrawn from the market in 1975, but reintroduced November 2002. Its receptor affinity consists in a partial
in 1990 due to its ability to improve symptoms in treatment- agonism at the dopamine D2 and serotonin 5-HT1A receptors.
resistant patients. To minimise the risk of agranulocytosis, However, some authors suggest a different mechanism of action,
patients treated with clozapine need constant monitoring of consisting in the stabilization of dopamine receptors rather than
their haematological parameters [11,22]. their blockade [29]. Aripiprazole is efficacious in the treatment
Another compound, risperidone (3-[2-[4-(6-fluoro-1,2- of the positive and negative symptoms of schizophrenia and
benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2- has a low incidence of extrapyramidal symptoms with the
methyl-4H-pyrido[1,2-a]pyrimidin-4-one, Figure 1), was exception of akathisia, which is more prominent [30,31].
introduced into the market in the early 1990s. Like In June 2002 an injectable formulation containing
iloperidone, this drug is a benzisoxazole antipsychotic agent; ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]
therefore, it does not share with the previously mentioned ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, Figure 1) mesilate
compounds the tricyclic ring in the chemical structure. It shows (by Pfizer) was approved for rapid control of agitated behaviour
efficacy towards the negative and the positive symptoms. and psychotic symptoms in patients with acute exacerba-
At high dosages, risperidone produces EPS and displays tions of schizophrenia. Ziprasidone hydrochloride had been
other side effects similar to classical neuroleptics, such as previously approved (February 2001) for the treatment of
hyperprolactinemia, that decrease with dosage reduction [23-25]. psychotic disorders. In vitro, the drug presents a 5-HT2A/D2
Two other compounds, respectively a thienobenzodiazepine receptor affinity ratio higher than that of the other atypical
and a dibenzothiazepine, were introduced in the antipsychotic agents [32]. Ziprasidone has low propensity for
market more recently: olanzapine ((2-methyl-4-(4-methyl-1- causing weight gain, but a higher tendency to prolong the
piperazinyl)-10H thieno[2,3b][1,5]-benzodiazepine) (approved QTc interval [33].
by the FDA in 1996) and quetiapine ((2-(2-[4- Binding profile, advantages and disadvantages of these
(dibenzo[b,f][1,4]thiazepin-11-yl)piperazin-1-yl]ethoxy)ethanol) established atypical antipsychotics are summarised in Table 1.
(introduced in USA in 1997). Compared with clozapine, Chemical structures, together with clinical chemical
olanzapine and quetiapine do not cause agranulocytosis [26-28]. correlations, were previously reported [15,28].

Expert Opin. Investig. Drugs (2008) 17(1) 63

 Iloperidone

Table 1. Established atypical antipsychotics.

Drug Receptor affinity Dosage (mg/day) Advantages/therapeutic effects Disadvantages/adverse

effects

Clozapine D1; D2; D3; D4 200 – 600 Active on positive and Possible agranulocytosis
5-HT1A; 5-HT2A; negative symptoms (1% of treated patients)
5-HT2C; 5-HT3; 5-HT6; Efficacious on non-responder patients Seizures (at very
5-HT7 Very low propension for EPS high doses)
α1; α2 Weight gain
H1
M1
Olanzapine D1; D2; D4 5 – 20 Active on positive and Weight gain
5-HT2A; 5-HT2C; 5-HT3 negative symptoms Sedation
α1 Very low propension for EPS Dry mouth
H1
M1 – 5
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

Quetiapine D1; D2 300 – 500 Active on positive and Hortostatic hypotension

5-HT2A negative symptoms Short half-life
α1; α2 Very low propension for EPS
H1 Safe in case of overdosage
M1
Risperidone D2; D3; D4 4 – 16 Active on positive and Weight gain
5-HT2A; 5-HT7 negative symptoms EPS at high doses
α1; α2
H1
Ziprasidone D2; D3; D4 20 – 80 Low propensity for causing weight QTc prolongation
5-HT1A; 5-HT1D; gain, hyperprolactinemia and EPS
5-HT2A; 5-HT2C
Aripiprazole D1; D2 5 – 30 Low propensity for causing weight Insomnia, anxiety
5-HT1A; 5-HT2 gain, hyperprolactinemia and EPS
α1
H1

EPS: Extrapyramidal symptoms.

Another group of antipsychotic drugs available in little tendency for EPS and efficacy against positive and
some countries are the benzamides (such as levosulpiride negative symptoms. Unfortunately, its most serious side
and amisulpride). These drugs present chemical structures effect is QTc prolongation, which led the manufacturer
and binding profiles that differ from other atypical anti- (Abbot Laboratories) in 1998 to voluntarily withdraw
psychotics; in fact, these drugs are dopamine antagonists sertindole from the market. In 2006, after clinical and
at receptors D2 and D3. Nevertheless, like atypical anti- epidemiological trials involving > 17000 patients, the drug
psychotics, they are also active against negative symptoms was reintroduced by Lundbeck in some European countries
of schizophrenia [15,34,35]. (Serdolect®) for the treatment of patients intolerant to
at least one other antipsychotic treatment, but has a
1.2.2 Recent atypical antipsychotics and requirement for ECG monitoring [37,38].
drugs under development Janssen obtained the approval for paliperidone by the
A limited number of antipsychotic agents have been FDA at the end of 2006 for the treatment of schizophrenia.
approved by the FDA in the last 5 years for the treatment The oral extended-release formulation consists of the active
of schizophrenia [36]. No drug of this therapeutic class metabolite of risperidone (9-hydroxy-risperidone), which
has been approved by the FDA between 2003 and 2005 acts as a dual antagonist of dopamine D2 receptors in the
and only one compound (paliperidone) has been approved mesolimbic pathway and 5-HT2A receptors in the prefrontal
in 2006. cortex [39]. It is effective against positive and negative
Sertindole is an atypical antipsychotic drug presenting symptoms, and personal and social functioning improve-
an imidazolidinone group in its chemical structure. It has ments have been reported [40]. The most common side
high affinity for dopamine D1 and D2 receptors, effects are tachycardia, headache and somnolence, together
serotonin 5-HT2A and 5-HT2C and α1 receptors. The drug with dose-related mild-to-moderate extrapyramidal symptoms;
presents the advantages of being non-sedating, with orthostatic hypotension and syncope were observed in

64 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

some patients [40,41]. Moreover, a modest increase in the in June 2004 [53]. The company recently announced that
QTc interval has been reported [42]. Phase III trials for the treatment of schizophrenia are
Behind iloperidone, a number of antipsychotic drugs are completed [54] and a new drug application (NDA) with the
in the late stages of development. For comparison, some FDA will be filed in the near future.
examples of drugs under late clinical studies (Phase III or
waiting for approval) are reported herein. 2.1 Chemistry, synthesis and structure–activity
Bifeprunox mesilate is a novel atypical antipsychotic relationship
agent under development by Solvay Pharmaceuticals in Iloperidone (Figure 1) is a piperidinyl-benzisoxazole
collaboration with Wyeth Pharmaceuticals and Lundbeck. derivative; its chemical structure does not present the
At the moment the drug is in Phase III clinical trials. The tricyclic structure that characterised the first antipsychotic
drug is a partial agonist/antagonist at D2 receptors and clozapine and the subsequent developed olanzapine and
presents various levels of 5-HT1A activation, which may quetiapine. On the contrary, it presents the piperidinic
contribute to therapeutic efficacy with reduced extrapyramidal group bonded to the fluoro-benzisoxazole group in common
symptoms. The main side effects of bifeprunox are gastro- with risperidone; a similar chemical class is represented by
intestinal (e.g., vomiting) [43,44]. Bifeprunox shows a positive benzisothiazoles: ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

side effect profile with respect to weight gain, lipid profile yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one)
and cardiac rhythm [44]. However, very recently, Wyeth and perospirone. Apart from the chemical structures,
announced that bifeprunox was not approved by FDA that benzisoxazoles and benzisothiazoles share some common
considered efficacy data not sufficient for approval [45]. metabolic pathways [55]. For comparison, the chemical
Asenapine (ORG-5222) (Organon – Akzo Nobel) is a structures of iloperidone, risperidone and ziprasidone are
new drug under development (Phase III) for the treatment reported in Figure 1.
of bipolar disorder and schizophrenia. In a placebo and The synthesis of iloperidone includes the preparation
risperidone controlled trial, asenapine led to improvements of 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole and 4-(3-
in speed of processing and verbal learning and memory [46]. chloropropoxy)-3-methoxyacetophenone, which are condensed
Data presented at the American Psychiatric Association to give the final compound [56,57].
meetings showed that asenapine is well tolerated and efficacious Strupczewski et al. [57] synthesised and selected
against acute schizophrenia and acute mania associated with iloperidone among a series of 3-[[(aryloxy)alkyllpiperidinyl]-
bipolar I disorder [47,48]. In vitro studies show that the drug has 1,2-benzisoxazoles. In particular, in regard to
high affinity for 5-HT2A, D2 and α1 adrenergic receptors [49]. structure–activity relationship studies, it was found that
Cardiovascular side effects have been reported [10]. the best antipsychotic activity was obtained with the
Blonanserin (AD-5423) is a dopamine D2 and serotonin propyl chain between the aryloxy group and the piperidine
5-HT2 antagonist under development by (Dainippon Sumitomo and the fluoro subsitutent on the position 6 of the
Pharma). The drug is in Phase II clinical trials in the US and 1,2-benzisoxazole ring.
Europe for the treatment of schizophrenia, and the company
announced that a new drug application (NDA) has been filed 2.2Preclinical studies
in Japan [50]. The drug shows efficacy against positive, negative 2.2.1In vitro studies: pharmacodynamics and
and cognitive symptoms, with a good side-effect profile [10]. receptor profile of iloperidone
The main features of recently approved atypical antipsychotics The receptor profile of iloperidone has been well
and drugs under development are summarised in Table 2. delineated by studies on animal receptors [57-60], cloned
human receptors [59-62] and postmortem normal human
2. Iloperidone brain receptors [18].
Iloperidone shows higher affinity values for 5-HT2A than
Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- for D2 receptors [18,57-60].
piperidinyl]propoxy]-3-methoxyphenyl]ethanone, Figure 1) This was demonstrated in rat frontal cortex and
is a new-generation atypical antipsychotic agent, acting as a striatum [57,58], but also on membranes from cells expressing
5-HT2A/D2 antagonist, first developed by Hoechst Marion human and rat receptors [59]. Binding affinities were
Roussel Pharmaceuticals (US) and licensed to Titan evaluated on different dopamine and serotonin receptors
Pharmaceuticals (US) in January 1997, who sublicensed to subtypes. Higher affinity was found for the 5-HT2A than for
Novartis AG (CH) (November 1997) worldwide excluding the 5-HT2C receptor; high affinity was also observed for
Japan; however, in April 2001 Japan was included with a the 5-HT6 and 5-HT7 receptors. In regard to dopamine
new agreement [51,52]. receptor subtypes, iloperidone showed higher affinity for the
The drug is under development for the treatment of D3 receptor than the D4 receptor [59].
schizophrenia, bipolar disorders and other psychiatric Radioligand receptor binding assays were carried out on
conditions by Vanda Pharmaceuticals, who acquired the both animal and human receptors; dopamine, serotonin and
worldwide rights to develop and commercialise iloperidone noradrenaline receptors were analysed. In addition to finding

Expert Opin. Investig. Drugs (2008) 17(1) 65

 Iloperidone

Table 2. Recently approved atypical antipsychotics and drugs under development.

Drug Company Current stage Advantages Disadvantages

Sertindole Lundbeck Withdrawn (1998) Non-sedating, little tendency for EPS, efficacy QTc prolongation
(Abbot Laboratories) Reintroduced in against positive and negative symptoms
Europe (2006)
Paliperidone Janssen Approved (2006) Efficacy against positive and negative Tachycardia, headache,
symptoms; improvements in social functions somnolence,
dose-related EPS
Bifeprunox Solvay Phase III Low tendency for EPS, weight gain, Gastrointestinal
Wyeth cardiac rhythm disorders
Lundbeck
Asenapine Organon – Akzo Nobel Phase III Efficacy against positive, negative, Cardiovascular
depressive and cognitive symptoms side effects
Blonanserin Dainippon Sumitomo Phase II Efficacy against positive, negative and Akathisia, tremor,
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

Pharma cognitive symptoms insomnia

EPS: Extrapyramidal symptoms.

higher affinity for the 5-HT2A than for the D2 receptors Iloperidone affinity for the dopamine and noradrenaline
(confirming previous studies [57-59]), high affinity was found receptors was confirmed in vivo: the drug demonstrated to
for the noradrenaline α1 receptor and intermediate affinity be able to prevent the prepulse inhibition-disruptive effect
for the α2C, D4, 5-HT1A, 5-HT1B, 5-HT2C and 5-HT6 of apomorphine (a direct dopamine receptor agonist) and
receptors. Moreover, it was demonstrated that iloperidone cirazoline (a α1 receptor agonist) [64].
has a very low affinity for the muscarinic M1 – M5 and The potential efficacy of iloperidone as an antipsychotic
histamine H1 receptors [60]. was demonstrated in several behavioural assays including
Similar results on serotonin as well as dopamine, antagonised apomorphine-induced climbing behaviour in
noradrenaline, muscarine and histamine receptors were mice, pole climb avoidance in rats and continuous avoidance
obtained from binding studies on postmortem human responding behaviour in monkeys [58,64]. Potential efficacy
brain receptors [18]. of iloperidone against negative symptoms of schizophrenia
The functional characterization of iloperidone at was demonstrated by a series of experiments conducted in
dopamine, serotonin and noradrenaline receptors was rodents. Iloperidone, like other atypical antipsychotics, was
more recently carried out by Kalkman et al. [61,62]. able to increase social behaviour in unfamiliar rats, a prop-
Iloperidone behaved as a pure surmountable antagonist erty not observed when testing classical neuroleptics such as
at human receptors (in order of decreasing potency) D3, haloperidol [58,66]. Positive results were obtained in the
α2C, 5-HT1A, D2A and 5-HT6. rat-elevated plus maze assay [58], suggestive of an anxiolytic
The main iloperidone receptor interactions are profile of iloperidone.
summarised in Table 3, together with the corresponding More recently, the effect of iloperidone on working
expected therapeutic or adverse effects. memory of rats was examined and compared with
Iloperidone interacts with a wide range of receptors in the effects of clozapine and haloperidol using a
accordance with the idea that schizophrenia therapy ‘delayed non-matching-to-position’ paradigm. The study
benefits from a drug interacting with multiple receptors [28]. demonstrated that iloperidone, differently from haloperidol
Considering its serotonin–dopamine antagonism profile, and clozapine, was able to improve choice accuracy in rats
which has been further confirmed from ex vivo studies in (suggestive of a positive effect on working memory), although
rats [63], iloperidone can be defined an atypical antipsychotic an impaired task performance was obtained [67].
also according to the so-called Meltzer ratio [14,18]. From the In vivo experiments were carried out to demonstrate
observed receptor affinity profile, iloperidone should iloperidone’s low tendency for causing EPS [58,65]. Iloperidone,
have efficacy for both positive and negative symptoms of compared with risperidone and haloperidol, resulted much
schizophrenia, and improve cognitive symptoms with scarce less potent in causing catalepsy (ED50 = 30.7 mg/kg
or little side effects. for iloperidone; ED50 = 0.65 mg/kg for haloperidol and
ED50 = 5.7 mg/kg for risperidone). Iloperidone was also
2.2.2 In vivo studies: effects of iloperidone much less potent in preventing apomorphine-induced
in animal models stereotyped behaviour (ED50 = 34.8 mg/kg for
A series of behavioural pharmacology studies were conducted iloperidone; ED50 = 0.6 mg/kg for haloperidol and
in different animals [58,64-67]. ED50 = 3.2 mg/kg for risperidone). Both assays can be

66 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

Table 3. Iloperidone binding profile.

Receptor Affinity Possible therapeutic effects Possible adverse effects Ref.

Serotonin 5-HT2A High Efficacy against negative symptoms; – [18,59]

reduction of EPS; reduction of anxiety
5-HT1A Moderate Enhance cognition (by increasing – [18,61]
extracellular glutamate concentrations)
5-HT2C Moderate Efficacy against begative symptoms; Weight gain [18,59,60]
anxiolytic effect
5-HT6 Moderate 5-HT6 blockade could improve – [60,65]
cognitive function; reduction of EPS
Dopamine D3 High Efficacy against positive symptoms Extrapyramidal symptoms: [18,61]
of schizophrenia; D3 antagonism parkinsonism, dystonia,
D2 Moderate may reduce substance abuse akathisia, tardive dyskinesia;
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

D4 Moderate endocrine effects:

hyperprolactinaemia
Norepinephrine α1 High α1 blockade may contribute to Postural hypotension, dizziness, [18,60]
antipsychotic activity reflex tachycardia; potentiation of
the effect of prazosin, terazosin,
doxazosin and labetalol
α2C Moderate α2C blockade may improve attention α2 blockade may oppose to the [18,61]
and cognitive function (by increasing therapeutic effect of clonidine,
postsynaptic levels of dopamine guanabenz, methyldopa
and norepinephrine)
Histamine H1 Low Sedation Sedation, weight gain, drowsiness [18]

Muscarine M Low Mitigation of EPS Dry mouth, tachycardia, [18]

urinary retention, constipation,
memory disfunction

EPS: Extrapyramidal symptoms.

used to evaluate EPS liability; in fact, it should be noted Iloperidone is highly bound to proteins (93%) in humans
that clozapine does not present cataleptic activity and does over the concentration range 5 – 500 ng/ml; most of the
not inhibit apomorphine-induced stereotyped behaviour administered dose (orally or intravenously) is recovered in
even at toxic doses. the faeces; therefore, a biliary excretion is likely the main
elimination pathway [68].
2.2.3 Pharmacokinetics: distribution and metabolism Recently, a clinical–chemical correlation was established
Iloperidone is well absorbed when administered orally [68]. for iloperidone minimal effective exposure level; it was
The pharmacokinetic profile in humans can be depicted demonstrated that plasma iloperidone concentration
from Phase I studies conducted on healthy volunteers [69]. corresponding to 5 ng/ml can be considered the minimal
Iloperidone was administered once at 3 or 5 mg. The Cmax concentration of therapeutic range [73].
observed increased with the dose (2.2 ng/ml for the 3-mg Iloperidone is extensively metabolised to a number
and 5.2 ng/ml for the 5-mg administration), and Tmax values of compounds which differ in humans, rats and dogs.
were 2 – 3 h after administration. Elimination was slow, Mutlib et al. employed liquid chromatography with mass
with half-life corresponding to 13.5 – 14 h. Food coadmini- spectrometry (LC-MS) and NMR detection to identify all
stration did not alter pharmacokinetics significantly. A slight the metabolites produced in vitro and in vivo in rats, dogs
increase in Tmax (from 2.2 to 4.3 h) and Cmax (from 2.3 to and humans. In particular, it was found that both in rats
2.0 ng/ml) was observed when iloperidone was administered and humans the main metabolic pathway was the reduction
after food intake, but the bioavailability was unchanged [69]. of the acetophenone ring structure of iloperidone, forming
In Phase III clinical trials iloperidone was administered in reduced iloperidone (compound I, Figure 2) [55,74,75]. This
doses from 4 mg/day up to 24 mg/day [70,71]. Lower doses biotransformation is probably primarily mediated by cytosolic
(0.5 – 6 mg/day) were tested out in a clinical trial on elderly enzymes; CYP450 isoforms may be involved as well, as
patients with dementia [72]. assessed by chemical inhibitor studies [76]. It has been

Expert Opin. Investig. Drugs (2008) 17(1) 67

 Iloperidone

F F O
O O
N N
H
O

OH
O O
N N O
OH

(III) (IV)

CYP3A4 CYP2D6

F
O
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

O
Cytosolic
enzymes N O

Iloperidone

F F O
O O
N N
H H
O O

O O
N O N O

(I) (II)

Figure 2. Main metabolic pathways of iloperidone.

reported that, in dogs, the metabolite reduced iloperidone half-life was increased by 88% for iloperidone and 46% for
interconverts to iloperidone [77]; to our best knowledge no reduced iloperidone [79].
data are available regarding the possible role of this Further metabolic steps are represented by oxidation and
reaction in humans. More recently, another compound conjugation with glucuronic acid [55].
(metabolite (II), Figure 2) was identified. This is the other Studies have been carried out in order to evaluate the
main circulating metabolite in humans; it is formed via receptor binding profile and the potential therapeutic/side
oxidation and decarboxylation of an α-hydroxy keto effects of the two most abundant iloperidone metabolites
metabolite [78]. In humans, both metabolite (I) and (II) (compounds (I) and (II)). In particular, it was found that
reach plasma concentrations higher than the parent reduced iloperidone has a D2 affinity comparable to that of
compound. Cmax values corresponding to 25 ng/ml for the parent compound, while its affinity for 5-HT2A receptor
compound (I) and to 40 ng/ml for compound (II) have is 2.5-times lower. Its pharmacokinetic profile similar to that
been reported at the steady-state after administration of of the parent compound suggests a likely contribution of
iloperidone 16 mg/day (iloperidone Cmax was 20 ng/ml) [78]. reduced iloperidone to antipsychotic activity; however,
Other metabolites are O-desmethyl iloperidone despite its high affinity for 5-HT2A receptors, metabolite (II)
(compound (III), Figure 2) and 2-hydroxyl iloperidone does not cross the blood–brain barrier and most probably
(compound (IV), Figure 2), formed via CYP3A4 and plays a role in side effects, but not therapeutic efficacy [78].
CYP2D6, respectively [74,76], even if their concentration in A study has been carried out to evaluate iloperidone
biological fluids is much lower in humans. However, it has pharmacokinetics in subjects with chronic severe renal
been shown that in poor CYP2D6 metabolisers, elimination impairment or with mild-to-moderate hepatic impairment,

68 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

after administration of a single dose corresponding to the Positive and Negative Syndrome Scale (PANSS)
3 or 2 mg, respectively. As a result, the pharmacokinetic compared with placebo using a LOCF analysis. There was
profile of iloperidone and of its main metabolite were not no difference in EPS between the iloperidone groups
significantly altered in renal or hepatic impaired patients and placebo. More cardiovascular effects were noted
(in the latter group, the exposure to the metabolite was with iloperidone compared with placebo, including
moderately increased) [80]. orthostatic hypotension.
Another Phase II study [56,65] addressed the maximum
2.3 Clinical studies tolerated once daily dose of iloperidone and evaluated
A Phase I clinical trial was designed to study the safety, orthostatic blood pressure changes in 24 stable out-patients
tolerability and effect of food on pharmacokinetics of with schizophrenia. Subjects either received doses of 2, 4, 6,
iloperidone in healthy volunteers [69]. Twenty seven male 8, 12, 16, 20, 24, 28 and 32 mg with increases every 3 days
volunteers age 18 – 40 years participated. Subjects received or doses of 1, 2, 4, 8, 12, 16, 20 and 24 mg with dose
either active drug or placebo with a plan to give single doses titration every 2 days. A third group received the latter
of 1, 5, 10, 25 and 50 mg. Intolerance was noted at 5 mg dose range, but the dose increases occurred every day.
and thus dose escalation did not proceed. Single 1-mg doses The highest dose in each group was continued for 4 days.
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

were well tolerated, with only one volunteer experiencing This study revealed that iloperidone doses up to 32 mg/day
nausea; however, five of the six subjects had dizziness with were well tolerated. Mild side effects such as grogginess
the 5 mg dose. In three subjects, the dizziness prevented and light-headedness, agitation, as well as dose-dependent
standing comfortably and lasted up to 7 h. Peak orthostatic elevations of prolactin less than or equal to twice the
blood pressure changes were noted at 6 h post dose, upper limit of normal for doses between 6 and 16 mg and
with four subjects experiencing an increase in heart rate < 2.7-times the normal range for doses between 20 and
> 60 beats per minute from supine to standing. Two subjects 32 mg were noted. Prolactin levels returned to normal by
had a decrease of > 40 mmHg in systolic blood pressure 08:00 the next morning except in one subject. Little EPS
6 – 8 h post dose. One subject experienced a brief syncopal was noted. A Phase II clinical trial was performed to
episode. In addition, some subjects receiving 5 mg experi- evaluate the iloperidone in elderly demented patients [68].
enced nasal congestion, dry mouth, nausea, headache, The study was a randomised, double-blind, placebo control
fatigue, sedation and impaired balance. Single 3-mg doses led protocol using doses of iloperidone 0.5 – 6 mg/day in two
to lightheadedness, lethargy, drowsiness, nasal congestion, divided doses versus placebo. Iloperidone was noted to be
headache, nausea, irritably and dry mouth. Three of the six well tolerated and safe up to 6 mg/day in these patients with
subjects receiving 5 mg had marked orthostatic increase dementia with psychotic and behavioural disturbances.
in heart rate of > 50 beats per minute, but less change in Several Phase III trials of iloperidone have been conducted.
systolic blood pressure compared with the 5-mg group. One study [51] compared iloperidone at doses of 4, 8, 12 or
In a separate study of normal volunteers by Sainati [69] 16 mg/day with haloperidol 15 mg/day in 621 patients
designed to study the effect of food on iloperidone revealed for 6 weeks. After 6 weeks, the subjects were randomised to
the rate of absorption was decreased, but no effect on iloperidone flexibly dosed at 4 – 16 mg/day, placebo or
overall bioavailability when taken with food. Coadministration haloperidol for a 1-year double-blind phase. Iloperidone at
with food had no significant effect on AUC, Tmax or Cmax the 12 mg dose led to significant improvement in PANSS
(maximum plasma concentration). and BPRS ratings, while lower doses were not efficacious in
Another Phase I trial was conducted in 18 male subjects this protocol. Iloperidone had EPS ratings comparable to
with schizophrenia who subsequently received iloperidone placebo and less than haloperidol. A second study, a 35-day
4 mg b.i.d. for 4 weeks in a double-blind protocol [56]. study of 120 patients [51], compared a rapid titration of
The data for Cmax, Tmax, AUC and half-life were consistent iloperidone up to 12 mg/day by day 4 with slower titration
with the data from the aforementioned healthy volunteers. to 12 mg/day by day 7 with a haloperidol comparator of
The side effects most often reported were elevated heart 15 mg/day. At the end of the study, both agents showed
rate, dizziness, orthostatic hypotension and all were felt comparable efficacy on the PANSS with no elevation of
to be mild-to-moderate. prolactin by iloperidone. Twenty-eight per cent of the
In a subsequent 6-week Phase II clinical trial, patients dropped out of the study, but none were from the
iloperidone was administered in a fixed-dose regimen slow iloperidone titration arm. Decreases in blood pressure,
of either 4 or 8 mg/day after titration to this dosage increased heart rate, dizziness and headache were seen
over 3 – 10 days [56,65,68]. A total of 104 male and frequently in the rapid titration group, but were much
female hospitalised subjects with acute or relapsing reduced with a slower titration or with twice a day dosing.
schizophrenia participated in the placebo-controlled Dizziness affected 29% who received rapid titration versus
study. While all treatment groups improved, the 22% with slow titration and was not seen at all with
8 mg/day group showed a statistically significant haloperidol. The third study was placebo controlled
improvement with a mean total score reduction of 18 in and investigated two dosing schedule of iloperidone

Expert Opin. Investig. Drugs (2008) 17(1) 69

 Iloperidone

(20 – 24 or 12 – 16 mg/day) over a 6-week time period. and individuals with a history of cardiac arrhythmias.
The higher iloperidone dose group revealed statistically The prolongation of the QTc interval with iloperidone
significant improvement in the PANSS and 18-item BPRS appears comparable to ziprasidone. Ziprasidone was not
compared with placebo, while the lower-dose iloperidone licensed in the UK due to concerns about market share
group had statistically significant results at weeks, 3, 4 and 5, if a cardiovascular work-up including an electrocardiogram
but not at week 6. was required. The QTc interval changes seen with
Data presented at the American Psychiatric Association iloperidone may lead to similar difficulties to those
meeting in 2007 demonstrated that iloperidone either improved experienced by ziprasidone.
or had no significant incidence of akathisia [81]. Subjects • Although the effect of iloperidone on prolactin does not
were treated for 6 weeks with iloperidone 12 – 16 mg/day appear pronounced, there does appear to be a potential
(n = 228), iloperidone 20 – 24 mg/day (n = 140), for prolactin elevations in some subjects and this deserves
risperidone 6 – 8 mg/day (n = 148) or placebo (n = 154). further investigation.
A statistically significant greater proportion of patients
receiving 12 – 16 mg/day of iloperidone had improvement or
2.3.2 Efficacy
no change in akathisia, as measured by the Barnes Akathisia
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

The clinical studies previously discussed support the efficacy

Scale and the Extrapyramidal Symptom Rating Scale
of iloperidone in the treatment of schizophrenia in regard to
versus placebo. No significant difference was seen with the
positive and negative symptoms in studies up to 1 year in
20 – 24 mg/day group. Another study presented at the same
duration. There is insufficient published data to make
meeting addressed iloperidone tolerability in subjects with
adequate comparisons between the efficacy of iloperidone
renal or hepatic impairment after single doses of 2 or 3 mg
and other atypical antipsychotic agents with the exception of
of iloperidone [80]. Another study presented at the same
comparable efficacy to risperidone.
meeting evaluated the pharmacokinetics of iloperidone in
extensive and poor CYP2D6 metabolisers [79]. In poor
metabolisers, elimination half-life was increased by 88% for 2.3.3 Side effects and therapeutic drug monitoring:
iloperidone and 46% for its major metabolite (reduced a comparison between iloperidone and risperidone
iloperidone). From a clinical standpoint, the inhibition of As already reported both iloperidone and risperidone present
CYP2D6 via a potent inhibitor of this polymorphic enzyme the benzisoxazole group in their chemical structure and share
such as fluoxetine will not have a significant effect on the some common metabolic pathways [54].
pharmacokinetics of iloperidone in poor metabolisers as Risperidone has been marketed since the early 1990s;
there is no significant CYP2D6 activity to inhibit. For therefore, safety and tolerability profiles of the drug are
extensive metabolisers at CYP2D6, inhibition of this enzyme well known, considering that > 10 million patients received
may lead to marked elevation of the parent compound treatment with risperidone [28]. Iloperidone was evaluated in
iloperidone and changes to other pharmacokinetic parameters a number of clinical trials started > 10 years ago and many
compared with metabolism in the absence of the inhibitor. data are available, even if the drug has not been approved
As iloperidone is metabolised by both CYP2D6 and yet and pharmacovigilance information are obviously missing
CYP3A4, the inhibition of CYP3A4 may have a more as well as poisoning case reports.
pronounced drug–drug interaction in poor metabolisers at Both iloperidone and risperidone resulted to be highly
CYP2D6, as both pathways will be impaired, thus leading efficacious against negative symptoms of schizophrenia, as
to marked differences in metabolism in these patients when well as positive symptoms [24]. Iloperidone presents a low
adding a CYP3A4 inhibitor to their medication regimen. tendency for EPS and weight gain [68]; risperidone may
cause EPS at high dosages, but this side effect decreases with
dose reduction [24,25].
2.3.1 Safety
A recent trial compared iloperidone, risperidone and placebo
The primary adverse side effects of iloperidone identified so
regarding akathisia symptoms. As a result, iloperidone deter-
far in psychotic patients are:
mined improvements or no change in akathisia in a greater
• Orthostatic hypotension with subsequent compensatory proportion of treated patients compared with risperidone [81].
elevations in heart rate. These side effects are minimised by QTc prolongation is a significant side effect of a number
slow titration and twice-daily dosing. of atypical antipsychotics, including ziprasidone and sertin-
• Dizziness and headache occur with iloperidone dole. An increase of QT interval in elderly patients has been
administration, but are also reduced with slower titration reported for risperidone, but this effect is small and was
and twice-daily dosing. not related to increased risks of arrhythmia [83].
• Iloperidone, like most antipsychotic agents, has the ability Iloperidone can cause QTc prolongation; a 6-week trial on
to prolong QTc intervals [82], which can lead to arrhythmias ∼ 150 patients showed QTc prolongation from iloperidone
in subjects receiving other medications that prolong the QT treatment similar to that caused by ziprasidone, which has
interval, in patients with congenital long QT syndrome, been recently approved [82].

70 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

The importance of therapeutic drug monitoring of atypical comparators, with the exception of one study
antipsychotics for the optimisation and individualization of showing comparable efficacy to risperidone. Lacking more
the therapy, avoiding severe side effects and raising the extensive comparison data, one can speculate based on
patient compliance, has been highlighted elsewhere [15,28,84]. available clinical data and preclinical data, suggesting a
Risperidone, for example, is known for determining mechanism of action that involves a variety of receptors
dose-dependent EPS in a number of patients [24,25]; there- and impacts dopamine and serotonin neurotransmission
fore, treatment would benefit from therapeutic drug similar to many of the available atypical agents. Given these
monitoring. Risperidone’s main metabolite, 9-hydroxy- data, these authors postulate that iloperidone will have
risperidone, presents a pharmacologic activity similar to the comparable efficacy in the treatment of positive, negative
parent compound; therefore, it is normally determined and cognitive symptoms similar to available atypical anti-
together with the parent compound (the sum of their psychotic agents, with the exception of clozapine, which has
plasma concentrations is called ‘active moiety’) for therapeutic clearly established itself as the most efficacious atypical agent
drug monitoring [15]. particularly for treatment resistant patients [86]. There is no
A clinical–chemical correlation has been recently established data available to assess iloperidone in regard to efficacy in
for iloperidone [73]; the authors reported the therapy with treatment resistant schizophrenia. Based on available clinical
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

iloperidone would benefit from individualisation, in order data, we do not believe that iloperidone will have any
to obtain efficacious plasma concentrations, thus avoiding particular advantage in treatment-resistant patients.
side effects. Considering the receptor affinity of reduced In regard to metabolic syndrome, clinical studies to date
iloperidone and its likely pharmacological activity [78], indicate minimal effects on weight comparable to ziprasidone
therapeutic drug monitoring would be more efficacious and aripiprazole, the two atypical antipsychotic agents with
when iloperidone is determined simultaneously to the lowest propensity to induce weight gain [84]. Data also
metabolite plasma levels. support a low incidence of diabetes [87]; however, detailed
LC-MS and LC-NMR methods have been employed to data on lipid changes with iloperidone are not readily
identify and determine iloperidone and metabolites in available. One can only speculate that with low weight gain
biological fluids [74,76,85]; in particular, a very sensitive and a low incidence of diabetes that iloperidone will have a
(limit of quantitation corresponding to 250 pg/ml of plasma) modest likelihood of producing metabolic syndrome.
method, based on HPLC with MS detection and a In regard to medication adherence, it is clear that many
solid-phase extraction sample pretreatment procedure, patients with chronic psychotic illnesses have difficulty
was developed [85]. Very sensitive and reliable, these adhering to regular administration of antipsychotic
methods require expensive and not customary equipments. medications. The CATIE study revealed that 74% of patients
It would be desirable that other analytical methods are discontinued antipsychotic medication before the 18 month
developed when iloperidone obtains approval and will be study was completed [88]. EPS is a major reason for
marketed worldwide. medication discontinuation and the low incidence of EPS
with iloperidone should bode positively for this agent in
3. Expert opinion and conclusions regard to medication adherence. The development of a
long-acting depot formulation may also assist with
3.1 Clinical opinion on iloperidone compliance as long as patients are agreeable to monthly
In today’s market, a successful new medication needs to injections. The inclusion of iloperidone in future head to
have novel characteristics to prevent it from being lost head trials such as CATIE will give a more clear-cut
among the crowd of multiple atypical antipsychotic assessment of medication adherence.
agents available to clinicians worldwide. Among the In addition to efficacy, metabolic syndrome and medication
factors that should be considered when evaluating a new adherence, potential novel characteristics of new atypical
antipsychotic are: agents will likely lead to more success. Novel characteristics
that may help determine the impact of iloperidone in the
• efficacy, including efficacy in treatment resistant patients
treatment of schizophrenia and other major mental illnesses
• propensity to cause metabolic syndrome
include potential for approval of an extended-release depot
• medication adherence
formulation that only needs to be administered once every
• novel properties
4 weeks as mentioned; however, the most exciting aspect
In regard to efficacy, the Phase II and III clinical trials to of iloperidone is its potential to be used in personalised
date indicate that iloperidone has the ability to reduce medicine via recent pharmacogenetic findings that may
positive and negative symptoms of schizophrenia. There is help identify patients that are more likely to respond to
not enough published data to determine its efficacy on iloperidone [87]. Vanda Pharmaceuticals has reported that
cognitive symptoms. Symptom reduction is clearly they have identified a common gene mutation that occurs in
comparable to haloperidol, but there is not enough data ∼ 70% of patients with schizophrenia. Per Vanda, 70% of
yet to determine how iloperidone will measure up to other the schizophrenic patients who have this genetic mutation

Expert Opin. Investig. Drugs (2008) 17(1) 71

 Iloperidone

respond 20% better to iloperidone than the overall led to significant adverse effects in ziprasidone patients over
population of patients with schizophrenia. This polymorphism the years, it has led to marked reluctance of clinicians to
may be used to select patients that are more likely to respond prescribe this agent and it has never achieved a significant
to iloperidone. What is not known is whether patients with market share despite good efficacy data and a low incidence
this polymorphism will also respond better to other atypical of metabolic syndrome. If iloperidone can avoid any
antipsychotic agents. untoward labelling on the QTc interval, it should garner a
In conclusion, iloperidone is a new atypical antipsychotic modest market share. Of note, paliperidone has similar
that appears to have good efficacy in treating the positive effects on QTc and similar product labelling as ziprasidone,
and negative symptoms of schizophrenia. It will likely have but has managed to avoid much QTc publicity and it is
a generally favourable profile in regard to not producing possible that iloperidone may avoid this as well. Iloperidone
metabolic syndrome, as well as minimal EPS such that is unlikely to obtain a significant market share as there
treatment adherence should be good. In terms of predicting are too many agents available such that it will need to
where iloperidone will end up in the next 5 – 10 years, the distinguish itself from the others. Iloperidone can distinguish
two biggest factors to consider are related to QTc interval itself in a manner that would generate significant interest
changes and to any novel effect it has in personalised and subsequent significant market share if its genetic bio-
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

medicine in regard to response to specific genotypes in marker clearly produces a better clinical response than other
schizophrenic patients. Iloperidone does have some effect atypical agents. Only time will tell regarding the genetic
on QTc interval such that clinicians may be reluctant to use biomarker response and we will need to wait for Vanda to
it as was seen with the launch of ziprasidone, despite lack publish the genetic data and see if other agents share the
of any significant adverse drug reactions related to this same benefit.
property. If iloperidone ends up with similar warnings and
publicity as ziprasidone in regard to QTc, we predict a poor Declaration of interest
launch in the antipsychotic marketplace and that iloperidone
is unlikely to gain much use in the treatment of schizophrenia The authors have no conflict of interest to declare and no fee
or other psychotic illnesses. Although the QTc issue has not has been received for preparation of the manuscript.

Bibliography refractory schizophrenia. N Engl J Med with enduring symptoms. J Clin Psych
Papers of special note have been highlighted 1997;337:809-15 1999;60(Suppl 23):10-3
as either of interest (•) or of considerable 7. Di Forti M, Lappin JM, Murray RM. 13. Martindale – The Complete Drug
interest (••) to readers. Risk factors for schizophrenia – all roads Reference. Sweetman SC, editor.
1. Akhondzadeh S. Pharmacotherapy of lead to dopamine. Eur Neuropsychopharm London: Pharmaceutical Press;
schizophrenia: the past, present and future. 2007;17:S101-S107 2004; p. 675-8
Curr Drug Ther 2006;1:1-7 • Interesting explanation of the importance 14. Meltzer HY, Matsubara S, Lee JC.
• An interesting overview of the treatment of dopamine for schizophrenia. The ratios of serotonin2 and
of schizophrenia. 8. Raggi MA. Pharmacological treatment dopamine2 affinities differentiate
2. McGrath JJ. Variations in the incidence of schizophrenia: recent antipsychotic atypical and typical antipsychotic
of schizophrenia: data versus dogma. drugs and new therapeutic strategies. drugs. Psychopharmacol Bull
Schizophr Bull 2006;32:195-7 Current Medicinal Chemistry. 1989;25:390-2
Raggi MA, editor. Chicago: Bentham 15. Raggi MA. Therapeutic drug monitoring:
3. Bernardo M, Azanza JR, Rubio-Terres C,
Publisher; 2004; p. 1-396 chemical-clinical correlations of atypical
Rejas J. Cost-effectiveness analysis of
schizophrenia relapse prevention. 9. Meltzer HY. Role of serotonin in the antipsychotic drugs. Curr Med Chem
An economic evaluation of the action of atypical antipsychotic drugs. 2002;9:1397-409
ZEUS (Ziprasidone-Extended-Use-In- Clin Neurosci 1995;3:64-75 16. Conley RR, Kelly DL. A review of current
Schizophrenia) study in Spain. 10. Singh AN. Trend of new antipsychotics drug targets and pharmacology of
Clin Drug Invest 2006;26:447-57 in development for schizophrenia. antipsychotic treatment. Med Chem Rev
4. Stahl SM. Psychopharmacology of Int Med J 2005;12:175-80 2005;2:177-82
antipsychotics. London: Martin Dunitz; 11. Raggi MA, Mandrioli R, Sabbioni C, 17. Friedman JI, Temporini H, Davis KL.
1999 Pucci V. Atypical antipsychotics: Pharmacologic strategies for augmenting
•• An excellent concise book on the pharmacokinetics, therapeutic drug cognitive performance in schizophrenia.
pharmacology of schizophrenia. monitoring and pharmacological Biol Psychiatry 1999;45:1-16
5. Freedman R. Schizophrenia. N Engl J Med interactions. Curr Med Chem 18. Richelson E, Souder T. Binding of
2003;349:1738-49 2004;11:279-96 antipsychotic drugs to human brain
6. Rosenheck R, Cramer J, Xu W, 12. Emsley RA. Partial response to receptors-focus on newer generation
et al. A comparison of clozapine and antipsychotic treatment: the patient compounds. Life Sci 2000;68:29-39
haloperidol in hospitalized patients with

72 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

19. Bymaster FP, Felder CC, Tzavara E, receptor-binding properties and real-world wyeth_html/home/news/pressreleases/
et al. Muscarinic mechanisms of psychiatric practice. J Clin Psychiat 2007/1186749065400.html
antipsychotic atypicality. 2003;64(Suppl 19):6-12 46. Fleming K, Potkin SG, Binneman B,
Progr Neuro-Psychoph 2003;27:1125-43 33. Taylor D. Ziprasidone in the management et al. Asenapine cognitive function effects
20. Ananth J, Parameswaran S, Gunatilake S. of schizophrenia: the QT interval issue in in acute schizophrenia: a placebo- and
Side effects of atypical antipsychotic drugs. context. CNS Drugs 2003;17:423-30 risperidone-controlled trial. NCDEU,
Curr Pharm Design 2004;10:2219-29 34. Racagni G, Canonico PL, Ravizza L, Boca Raton, USA: 47th Annual Meeting,
21. Dorado P, Berecz R, Penas-Lledo EM, et al. Consensus on the use of substituted 2007; Session I-72
Llerena A. Antipsychotic drugs and benzamides in psychiatric patients. 47. Potkin SG. Asenapine safety and
QTc prolongation: the potential role Neuropsychobiology 2004;50:134-43 tolerability during acute schizophrenia:
of CYP2D6 genetic polymorphism. 35. Pani L, Gessa GL. The substituted a placebo- and risperidone-controlled
Expert Opin Drug Metab Toxicol benzamides and their clinical potential on trial. American Psychiatric Association,
2007;3:9-19 dysthymia and on the negative symptoms Toronto, Canada: 159th Annual Meeting,
22. Martindale – The Complete Drug of schizophrenia. Mol Psychiatr 2006; NR420
Reference. Sweetman SC, editor. London: 2002;7:247-53 48. Hirschfeld RM. Asenapine in acute mania:
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

Pharmaceutical Press; 2004. p. 685-9 36. Thomson Centerwatch website, 2007. a randomized, double blind, placebo- and
23. Yoshimura R, Ueda N, Nakamura J. Available from: URL: http://www. olanzapine-controlled trial (ARES
Possible relationship between combined centerwatch.com/patient/drugs/ 7501005). San Diego, USA:
plasma concentrations of risperidone plus area17.html American Psychiatric Association,
9-hydroxyrisperidone and extrapyramidal 160th Annual Meeting, 2007; NR333
37. Lindstroem E, Levander S. Sertindole:
symptoms. Neuropsychobiology efficacy and safety in schizophrenia. 49. Andree B, Halldin C,
2001;44:129-33 Expert Opin Pharmacother Vrijmoed-De Vries M, Farde L.
24. Pajonk FG. Risperidone in acute and 2006;7:1825-34 Central 5-HT2A and D2 dopamine
long-term therapy of schizophrenia – a receptor occupancy after sublingual
38. Serdolect website, 2006. Available from:
clinical profile. Progr Neuro-Psychoph administration of ORG 5222
http://www.serdolect.com/content/
2004;28:15-23 in healthy men. Psychopharmacology
downloadarea/pdf/serdolect_monograph.pdf
1997;131:339-45
25. Love RC, Nelson MW. Pharmacology and 39. Revill P, Serradell N, Bolos J. Paliperidone.
clinical experience with risperidone. 50. Dainippon Sumitomo Pharma Co.
Antipsychotic agent, treatment of bipolar
Expert Opin Pharmacother 2000;1:1441-53 website, 2007. Available from: URL:
disorder, dual dopamine D2/5-HT2A
http://www.ds-pharma.co.jp/english/rd/
26. Tarsy D, Baldessarini RJ, Tarazi FI. receptor antagonist. Drug Future
pdf/prof_20070730e.pdf
Effects of newer antipsychotics on 2006;31:579-84
extrapyramidal function. CNS Drugs 51. Keppel Hesselink JM. Iloperidone.
40. Owen RT. Extended-release paliperidone:
2002;16:23-45 IDrugs 2002;5:84-90
efficacy, safety and tolerability profile of a
27. Gaszner P, Makkos Z. Clozapine new atypical antipsychotic. Drugs Today 52. Titan Pharmaceuticals, Inc. website press
maintenance therapy in schizophrenia. 2007;43:249-58 release, 2001. Available from: URL:
Progr Neuro-Psychoph 2004;28:465-9 http://www.titanpharm.com/press/
41. Yang LPH, Plosker GL. Paliperidone
Zomaril_Japan.html
28. Raggi MA, Mandrioli R, Pucci V, extended release. CNS Drugs
Sabbioni C. Advances in therapeutic 2007;21:417-25 53. Titan Pharmaceuticals, Inc. website press
drug monitoring of atypical release, 2004. Available from: URL:
42. FDA website, 2007. Available from: URL:
antipsychotic drugs. Med Chem Rev http://www.titanpharm.com/press/
http://www.fda.gov/cder/foi/
2004;1:299-316 IloperidoneLicense.htm
label/2006/021999lbl.pdf
29. Stahl SM. Dopamine system stabilizers, 54. Vanda Pharmaceuticals, Inc. website,
43. Auclair AL, Galinier A, Besnard J, et al.
Aripiprazole, and the next generation of 2007. Available from: URL:
Putative antipsychotics with pronounced
antipsychotics, part 1, “Goldilocks” actions http://www.vandapharmaceuticals.com/
agonism at serotonin 5-HT1A and
at dopamine receptors. J Clin Psychiat development.html
partial agonist activity at dopamine
2001;62:841-2 D2 receptors disrupt basal PPI of the 55. Caccia S. Biotransformation of
30. Davies MA, Sheffler DJ, Roth BL. startle reflex in rats. Psychopharmacology post-clozapine antipsychotics.
Aripiprazole: a novel atypical antipsychotic 2007;193:45-54 Clin Pharmacokinet 2000;38:393-414
drug with a uniquely robust pharmacology. •• Interesting overview of
44. Wadenberg M-LG. Bifeprunox: a novel
CNS Drug Rev 2004;10:317-36 antipsychotic metabolism.
antipsychotic agent with partial
31. Swainston HT, Perry CM. Aripiprazole. agonist properties at dopamine D2 56. Mucke HA, Castaner J. Iloperidone.
A review of its use in schizophrenia and serotonin 5-HT1A receptors. Drug Future 2000;25:29-40
and schizoaffective disorder. Drugs Future Neurol 2007;2:153-65 57. Strupczewski JT, Bordeau KJ, Chiang Y,
2004;64:1715-36 45. Wyeth Pharmaceuticals, Inc. website press et al. 3-(Aryloxy)alkyllpiperidinyl-1,2-
32. Stahl SM, Shayegan DK. The release. Available from: URL: http://www. benzisoxazoles as D2/5-HT2 antagonists
psychopharmacology of ziprasidone: wyeth.com/news?nav=display&pnavTo=/ with potential atypical antipsychotic

Expert Opin. Investig. Drugs (2008) 17(1) 73

 Iloperidone

activity: antipsychotic profile of iloperidone 68. Jain KK. An assessment of iloperidone 78. Subramanian N, Kalkman HO.
(HP 873). J Med Chem 1995;38:1119-31 for the treatment of schizophrenia. Receptor profile of P88-8991
58. Szewczak MR, Corbett R, Rush DK, et al. Expert Opin Investig Drugs and P95-12113, metabolites of
The pharmacological profile of iloperidone, 2000;9:2935-43 the novel antipsychotic iloperidone.
a novel atypical antipsychotic agent. • Good review summarising available Progr Neuro-Psychoph
J Pharmacol Exp Ther 1995;274:1404-13 data on iloperidone. 2002;26:553-60
• Preclinical studies on iloperidone. 69. Sainati M, Hubbard JW, Chi E, et al. 79. Wolfgang C. Genotyping facilitates
59. Kongsamut S, Roehr JE, Cai J, et al. Safety, tolerability, and effect of food on the individualized prediction of
Iloperidone binding to human and pharmacokinetics of iloperidone (HP 873), pharmacokinetic response to iloperidone
rat dopamine and 5-HT receptors. a potential atypical antipsychotic. J. Clin in extensive and Poor CYP2D6
Eur J Pharmacol 1996;317:417-23 Pharmacol 1995;35:713-20 metabolizers. San Diego, USA:
70. Fairweather DB, Young E, Zaninelli R. American Psychiatric Association,
60. Kalkman HO, Subramanian N, Hoyer D.
Iloperidone is effective and well tolerated 160th Annual Meeting, 2007; NR508
Extended radioligand binding profile of
iloperidone: a broad spectrum in the long term treatment of 80. Sedek G, Wolfgang C. Iloperidone is
dopamine/serotonin/norepinephrine schizophrenia and schizoaffective well tolerated by subjects with renal or
disorder. Eur Neuropsychopharm hepatic impairment in single-dose clinical
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

receptor antagonist for the

management of psychotic disorders. 2001;12(Suppl 3 P.2.054) pharmacokinetic studies. San Diego, USA:
Neuropsychopharmacology 2001;25:904-14 71. Vanda Pharmaceuticals Inc. website press American Psychiatric Association,
release, 2006. Available from: URL: 160th Annual Meeting, 2007; NR476
61. Kalkman HO, Feuerbach D, Loetscher E,
Schoeffter P. Functional characterization of http://phx.corporate-ir.net/phoenix. 81. McCollough K, Wolfgang C. Iloperidone,
the novel antipsychotic iloperidone at zhtml?c=196233&p=irol-newsArticle_ a novel atypical antipsychotic, is associated
human D2, D3, α2C, 5-HT6 and 5-HT1A Print&ID=939941&highlight= with improvement, or no change, in
receptors. Life Sci 2003;73:1151-9 72. El-Bizri H, Fairweather DB, Guven A, akathisia symptoms. San Diego, USA:
Zaninelli R. Efficacy and tolerability American Psychiatric Association,
62. Kalkman HO, Loetscher E.
of iloperidone in elderly patients with 160th Annual Meeting, 2007; NR475
α2C-adrenoceptor blockade by clozapine
and other antipsychotic drugs. psychotic and behavioral symptoms 82. Titan Pharmaceuticals, Inc. website press
Eur J Pharmacol 2003;462:33-40 associated with dementia. release, 2002. Available from: URL:
Eur Neuropsychopharm http://www.titanpharm.com/press/
63. Szczepanik AM, Brougham LR, Roehr JE,
2001;12(Suppl 3 P.2.055) Iloperidone_EKG.html
et al. Ex vivo studies with iloperidone
(HP 873), a potential atypical antipsychotic 73. Baroldi P, Wolfgang C. A Pharmacokinetic 83. Yerrabolu M, Prabhudesai S, Tawam M,
with dopamine D2/5-hydroxytryptamine2 (PK)-Pharmacodynamic (PD) relationship et al. Effect of risperidone on QT interval
receptor antagonist activity. J Pharmacol exist for efficacy of iloperidone: a novel and QT dispersion in the elderly. Heart Dis
Exp Ther 1996;278:913-20 investigation atypical antipsychotic agent. 2000;2:10-2
San Diego, USA: American Psychiatric 84. Albers LJ, Ozdemir V.
64. Barr AM, Powell SB, Markou A,
Association, 160th Annual Meeting, Pharmacogenomic-guided rational
Geyer MA. Iloperidone reduces
2007; NR507 therapeutic drug monitoring: conceptual
sensorimotor gating deficits in
pharmacological models, but not a 74. Mutlib AE, Strupczewski JT, Chesson SM. framework and application platforms for
developmental model, of disrupted Application of hyphenated LC/NMR and atypical antipsychotics. Curr Med Chem
prepulse inhibition in rats. LC/MS techniques in rapid identification 2004;11:297-312
Neuropharmacology 2006;51:457-65 of in vitro and in vivo metabolites of 85. Mutlib AE, Strupczewski JT.
iloperidone. Drug Metab Dispos Picogram determination of iloperidone
65. Corbett R, Griffiths L, Shipley JE, et al.
1995;23:951-64 in human plasma by solid-phase
Iloperidone: preclinical profile and early
clinical evaluation. CNS Drug Rev 75. Caccia S. New antipsychotic agents extraction and by high-performance
1997;3:120-47 for schizophrenia: pharmacokinetics liquid chromatography-selected-ion
•• Interesting review on preclinical and and metabolism update. Curr Opin monitoring electrospray mass
early clinical trials for iloperidone. Invest Drugs 2002;3:1073-80 spectrometry. J Chromatogr B
76. Mutlib AE, Klein JT. Application of liquid 1995;669:237-46
66. Corbett R, Hartman H, Kerman LL,
et al. Effects of atypical antipsychotic chromatography/mass spectrometry in 86. Kane J, Honigfeld G, Singer J, Meltzer H.
agents on social behavior in rodents. accelerating the identification of human Clozapine for the treatment-resistant
Pharmacol Biochem 1993;459-17 liver cytochrome P450 isoforms involved in schizophrenic. A double-blind comparison
the metabolism of iloperidone. J Pharmacol with chlorpromazine. Arch Gen Psychiat
67. Gemperle AY, McAllisteR KH, Olpe HR.
Exp Ther 1998;286:1285-93 1988;45:798-6
Differential effects of iloperidone,
clozapine, and haloperidol on working 77. Chesson SM, Hsu RS, Dileo EM, 87. Titan Pharmaceuticals, Inc. website, 2006.
memory of rats in the delayed Strupczewski JT. Pharmacokinetics of Available from: URL:http://
non-matching-to-position paradigm. HP 873, a potential atypical antipsychotic, www.titanpharm.com/pdf/
Psychopharmacology 2003;169:354-64 in rats and dogs abstract. Pharmacologist VANDA-Iloperidone-Prospectus.pdf
1991;33:177-82

74 Expert Opin. Investig. Drugs (2008) 17(1)

 Albers, Musenga & Raggi

88. Lieberman JA, Stroup TS, McEvoy JP, et al.

Effectiveness of antipsychotic drugs in
patients with chronic schizophrenia.
N Engl J Med 2005;353:1209-23

Affiliation
Lawrence James Albers1 MD,
Alessandro Musenga2 PharmD &
Maria Augusta Raggi†2, Professor
†Author for correspondence
1University of California at Irvine,

Department of Psychiatry,
Long Beach VA Healthcare System,
5901 East Seventh Street,
Long Beach, CA 90822, USA
2University of Bologna,
Downloaded by [University of Pennsylvania] at 16:27 05 November 2015

Laboratory of Pharmaco-Toxicological Analysis,

Department of Pharmaceutical Sciences,
Via Belmeloro 6,
40126 Bologna, Italy
Fax: +39 0512099740;
E-mail: [email protected]

Expert Opin. Investig. Drugs (2008) 17(1) 75

Downloaded by [University of Pennsylvania] at 16:27 05 November 2015