Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar I disorder.

Abstract

Asenapine is a new atypical antipsychotic agent currently under development for the treatment of schizophrenia and bipolar disorder. It has high affinity for various receptors including antagonism at 5HT(2A), 5HT(2B), 5HT(2C), 5HT(6) and 5HT(7) serotonergic receptor subtypes, alpha(1A), alpha(2A), alpha(2B) and alpha(2C) adrenergic and D(3) and D(4) dopaminergic receptors. As with other atypicals, asenapine exhibits a high 5HT(2A):D(2) affinity ratio. Although similar to clozapine in its multi-target profile, it shows no appreciable affinity for muscarinic receptors. Asenapine has shown efficacy in alleviating both positive and negative symptoms of schizophrenia compared with placebo. Although promising, further studies are required in order to determine whether it has advantages over placebo and other antipsychotics in alleviating cognitive impairment associated with schizophrenia. It has also shown long-term efficacy comparable with olanzapine in bipolar I disorder. Asenapine is generally well tolerated and appears to be metabolically neutral. It has low propensity to cause weight gain and prolactin elevation. There were no concerns in the studies about its effects on the cardiovascular system and QTc prolongation. The incidence of extrapyramidal symptoms with asenapine however has been found to be higher than that with olanzapine. It may be a useful alternative to aripiprazole in schizophrenia and bipolar disorder in patients who are at high risk of metabolic abnormalities.

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Neuropsychiatric Disease and Treatment
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Asenapine monotherapy in the acute treatment
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r e v i e w
Delia Bishara1
David Taylor1,2
1Pharmacy Department, South London
and Maudsley NHS Foundation Trust,
Denmark Hill, London, UK; 2Division
of Pharmaceutical Sciences, King’s
College, London, UK
Correspondence: Delia Bishara
Pharmacy Department, Maudsley Hospital,
Denmark Hill, London Se5 8AZ, UK
Tel +44 (0)20 3228 5044
Fax +44 (0)20 3228 3448
email delia.bishara@slam.nhs.uk
Abstract: Asenapine is a new atypical antipsychotic agent currently under development for
the treatment of schizophrenia and bipolar disorder. It has high affinity for various receptors
including antagonism at 5HT2A, 5HT2B, 5HT2C, 5HT6 and 5HT7 serotonergic receptor subtypes,
α1A, α2A, α2B and α2C adrenergic and D3 and D4 dopaminergic receptors. As with other atypicals,
asenapine exhibits a high 5HT2A:D2 affinity ratio. Although similar to clozapine in its multi-
target profile, it shows no appreciable affinity for muscarinic receptors. Asenapine has shown
efficacy in alleviating both positive and negative symptoms of schizophrenia compared with
placebo. Although promising, further studies are required in order to determine whether it has
advantages over placebo and other antipsychotics in alleviating cognitive impairment associated
with schizophrenia. It has also shown long-term efficacy comparable with olanzapine in bipolar
I disorder. Asenapine is generally well tolerated and appears to be metabolically neutral. It has
low propensity to cause weight gain and prolactin elevation. There were no concerns in the
studies about its effects on the cardiovascular system and QTc prolongation. The incidence of
extrapyramidal symptoms with asenapine however has been found to be higher than that with
olanzapine. It may be a useful alternative to aripiprazole in schizophrenia and bipolar disorder
in patients who are at high risk of metabolic abnormalities.
Keywords: asenapine, schizophrenia, bipolar I disorder, antipsychotics
Introduction
Schizophrenia
The symptoms of schizophrenia are thought to result from the dysfunction of several
neurotransmitters mainly dopamine1 and serotonin2 although noradrenaline, acetyl-
choline and glutamate have also been implicated.3 The multidimensional facet of the
disorder means that life-long therapeutic intervention with psychotropic agents and
principally antipsychotics is often warranted. Although the specific mechanism of action
of antipsychotics is still not fully understood, the antagonism of dopamine transmission
is likely to play a major role. The dopamine system affects the mesolimbic, striatal and
cortical areas of the brain. Neurones in the midbrain release dopamine which interacts
with dopamine receptors. Antipsychotics block dopaminergic transmission by binding
to these dopamine receptors, in particular D2 receptors, the affinity for which correlates
with the clinical dose in many cases.4
The history of antipsychotic drug development has been haphazard. In 1952, the
accidental use of chlorpromazine revolutionized the treatment of schizophrenia. In the
following years, several other first-generation or typical antipsychotics were launched
and although this group of antipsychotic agents were effective in managing the positive
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symptoms of schizophrenia, they demonstrated relatively
poor efficacy for negative symptoms and associated cognitive
impairment. Typical antipsychotics have also been associated
with severe and devastating extrapyramidal symptoms (EPS)5
and tardive dyskinesia,6 thus limiting their long-term use. In
addition, adverse effects relating to elevation in serum prolactin7
also made their use problematic. It is thought that the blockade
of dopamine D2 receptors is responsible for the antipsychotic-
induced movement disorders and rise in prolactin.4
The introduction of second generation, or atypical
antipsychotics, over the last 20 years has contributed
considerably to the advancement in the treatment of schizo-
phrenia, both in terms of scope of efficacy and more favorable
tolerability in some respects. Atypical antipsychotics have
demonstrated clinical effectiveness comparable to that with
typical antipsychotics with regards to positive symptoms8 and
are argued to be more effective in the management of negative
symptoms9,10 and cognitive impairment.11,12 Moreover, they
are associated with a significantly lower incidence of EPS.13
As a result, atypicals quickly replaced the older typical
antipsychotics and for many years they were considered the
treatment of choice in the management of schizophrenia.14
The atypical antipsychotic clozapine which was actually
synthesized shortly after chlorpromazine in the 1950s, has
a unique pharmacological profile in view of its affinity for
a diverse range of receptors. These include D1, D2 and D4
dopaminergic, α1 and α2 adrenergic, H1 histaminergic and
muscarinic receptors as well as various serotonin receptor
subtypes.15 Consequently, clozapine has unique properties in
the prevention of suicide16 and treatment-refractory schizo-
phrenia (TRS),17 although there has been some suggestion
that other antipsychotics such as olanzapine may also be
effective in TRS at higher than typically prescribed doses.18
In addition to clozapine’s superior efficacy profile, it has a
more favorable motor system side effect profile, with minimal
risk of causing EPS or tardive dyskinesia.19 Its use however
is somewhat limited by its potential to cause neutropenia and
agranulocytosis,20 of possibly fatal consequence if it were not
for the strict haematological monitoring requirements which
are obligatory with the use of clozapine.
Several hypotheses have been put forward to explain the
differences in clinical and adverse effect profiles between
typical and atypical antipsychotic drugs. It has been
suggested that atypical drugs have a stronger 5HT2A receptor
affinity compared with that for the D2 receptor21 leading to
their lower propensity to cause EPS and prolactin elevation.
This hypothesis, however, has been challenged with the
suggestion that the “atypicality” of atypical agents is actually
due to the fast dissociation from the D2 receptor, resulting in
transient and easily reversible occupancy of this receptor.22
In addition, the fact that atypicals have a moderate D2 receptor
occupancy23 compared with typicals has also been proposed
as an explanation for their different profiles.
However, despite atypicals having shown more favorable
tolerability for movement disorders and prolactin-related
adverse effects, other serious safety concerns have surfaced
over the years with certain agents in this class. Metabolic24
and cardiovascular disease25 including weight gain, increased
plasma lipids, new onset diabetes, prolongation of QTc
interval and sudden death are the most concerning adverse
effects of atypical agents, which were once considered
relatively safe.
In the last decade, drug development in the field
of schizophrenia has slowed somewhat, with the only
advancement having been the introduction of the dopamine
partial agonist, aripiprazole. Dopamine partial agonists
are thought to exert their effects by acting as dopamine
antagonists in the mesolimbic system where there is a high
concentration of dopamine, however, in the mesocortical
system where reduced dopamine activity is thought to
produce negative symptoms and cognitive impairment, they
act as dopamine agonists, thus the concept of dopamine
system stabilization.26,27 Since the launch of aripiprazole in
2004, no new antipsychotics have emerged on the market.
Bipolar disorder
The complexities of managing bipolar disorder are numerous.
Firstly, the diagnostic criteria used for diagnosing bipolar
disorder by psychiatrists in different parts of the world varies,
resulting in a lack of clear distinction between schizophrenia
and bipolar disorder thus influencing the management of
the condition worldwide. Secondly, different treatments
need to be considered separately for the specific manic,
hypomanic, mixed and depressive episodes in addition to
whether control of the acute state or maintenance of therapy is
required. Furthermore, the pathogenesis and neurochemistry
of bipolar disorder remains unclear, although serotonergic,
noradrenergic and dopaminergic transmitter systems appear
to be targeted during therapy.
For over 50 years, traditional mood stabilizers such as lithium
have been the mainstay of therapy in bipolar disorder. However,
increasingly atypical antipsychotics are also establishing them-
selves, with several agents having received regulatory approval
for use in both bipolar depression and mania.
Of the atypicals, olanzapine28 and quetiapine29 have shown
significantly greater efficacy than placebo in the treatment

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of bipolar depression. Both agents are known to antagonize
5HT2A receptors as well as D2 receptor blockade. Their
antagonistic effects on 5HT2A receptors, which are present
on presynaptic dopamine neurons, are thought to lead to an
increase in dopamine levels in the prefrontal cortex. It would
appear therefore that a selective balance between dopamine
and serotonin in specific regions of the brain is necessary in
order to stabilize mood. In addition, quetiapine’s metabolite
N-desalkylquetiapine, has been shown to be a potent nor-
adrenaline re-uptake inhibitor and partial 5HT1A agonist,
also contributing to its antidepressant activity.30 Furthermore,
olanzapine also exhibits potent antagonistic activity at α1
adrenergic receptors leading to substantial increases in the
firing neurons in the locus ceruleus with resulting increase
in noradrenaline release in the prefrontal cortex.31
Atypicals are generally thought to owe their antimanic
properties to their antagonism at dopamine receptors,
although it is believed that antagonism at α1 adrenergic, H1
histaminergic and serotonergic receptors may also play a role.
However, unlike with bipolar depression, the importance of
blocking 5HT2A serotonergic receptors in the treatment of
mania is still unclear.32
Asenapine
Pharmacology and mode of action
Asenapine is novel pharmacological agent currently under
clinical development for the treatment of schizophrenia and
bipolar disorder. This new antipsychotic has high affinity for
a number of receptors including antagonism at 5HT2A, 5HT2B,
5HT2C, 5HT6 and 5HT7 serotonergic receptor subtypes, α1A, α2A,
α2B and α2C adrenergic and D3 and D4 dopaminergic receptors.
As with atypical antipsychotics, asenapine also exhibits an
appreciable affinity for D2 receptors with a high 5HT2A: D2
affinity ratio. Although similar to clozapine in its high affinity
for a variety of different receptors, it has no appreciable affinity
for muscarinic receptors, with the highest ratio of separation
existing for its affinity for D2: M1, M2, M3 and M4 receptors.33
The multi-target nature of this new atypical antipsychotic
agent has led to certain expectations for both its efficacy
and tolerability. The higher affinity of asenapine for 5HT2A
receptors relative to D2 receptors gives it its “atypicality” as
it is an important mechanism thought to be responsible for
enhanced efficacy of antipsychotics and reduced potential to
cause EPS.34,35 In addition, antagonism at 5HT2A receptors,
leading to an increase in dopamine activity in the prefrontal
cortex, has also been suggested as a possible mechanism for
alleviating negative symptoms2,35 and enhancing cognition36 in
schizophrenia and other disorders. Findings from rat studies
deduced that asenapine causes a dose-dependent increase in
cortical37 and hippocampal dopamine37, noradrenaline38 and
acetylcholine38 comparable to previous reports with clozapine
and quetiapine. Similarly, the 5HT2C receptor may also have
a similar role as 5HT2A and its antagonism has been linked to
improvement in negative symptoms.39 Therefore, the combined
antagonism at 5HT2A and 5HT2C which occurs with asenap-
ine may prove promising for the management of negative
symptoms.
The resulting clinical effects of a high affinity for other
serotonin receptor subtypes such as 5HT6 and 5HT7 are still
unclear. Emerging evidence however suggests that 5HT6
antagonism may afford benefits for cognition40 and that 5HT7
antagonism may confer benefits for anxiety management and
mood regulation as well as cognition.41 Such claims with
asenapine however remain to be explored further.33 Similarly,
activity at α-adrenergic receptors has also been suggested
to improve negative and cognitive symptoms by antagonism
of α2 receptors, whereas improvement in positive symptoms
is via α1 receptor antagonism.42 Since asenapine appears to
have relatively high affinity for adrenergic receptors, and
more specifically α2 receptors43, it may potentially offer these
therapeutic benefits.
Data from preclinical studies also suggests that
antagonism at D3 receptors may help ameliorate negative and
cognitive symptoms,44 although again the clinical evidence
with asenapine for this is still lacking. Indeed, in animal
models, asenapine did not improve cognition in rats, but
rather, at doses greater than those required for antipsychotic
activity, it impaired cognitive performance due to disturbance
of motor function.45 This effect has also been observed with
both olanzapine and risperidone. In contrast, in studies with
monkeys, asenapine produced substantial improvement in
executive functions which were maintained across a period of
long-term dosing.46 Further studies in rat brain have indicated
that chronic treatment with asenapine exerts regional and
dose-dependent effects on inotropic glutamate receptors,47
thus another potential mechanism for its effectiveness in
schizophrenia.
Since olanzapine and clozapine’s high muscarinic receptor
binding affinity is thought to be responsible for contributing
to their anticholinergic adverse effects and potentially causing
metabolic syndrome (via M3 antagonism),48 asenapine’s
minimal antimuscarinic activity means that it may therefore
be less likely to cause these effects.33 In the animal models,
asenapine induced a marked increase in dopamine in the
nucleus accumbens compared to the core region, sharing a
similar profile to other atypical antipsychotics. In addition,

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results from microdialysis and electrophysiological techniques
found that asenapine potentiates prefrontal dopaminergic
as well as glutaminergic transmission, indicating a highly
potent antipsychotic activity with very low propensity for
EPS.49 Whether this receptor binding profile and related
pharmacology of asenapine will actually translate into such
clinical benefits in practice still remains to be ascertained
by ongoing studies in the management of schizophrenia and
bipolar disorder.
Pharmacokinetics
Results from separate phase I studies assessing the
pharmacokinetic interactions between asenapine and several
cytochrome P450 (CYP) modulators and the glucuronyl
transferase (UGT) inhibitor valproate found that asenapine
exposure was increased by fluvoxamine but was otherwise
minimally affected. Asenapine was found to have a maximum
plasma concentration occurring at 0.5 to 1.5 hours after oral
administration and an elimination half life of approximately
24 hours, following single dosing. In addition, there were
no significant correlations between creatinine clearance
and asenapine exposure in renal impairment. However,
although mild or moderate hepatic impairment did not affect
asenapine exposure, severe hepatic impairment increased
exposure 7-fold. Furthermore, smoking was found not to
affect exposure to asenapine therapy.50
Efficacy and safety studies
in schizophrenia
In a 6-week, double-blind study investigating the efficacy and
tolerability of asenapine in acute schizophrenia,51 patients
were randomly assigned to receive twice daily doses of
sublingual asenapine 5 mg, placebo or oral risperidone 3 mg.
Results for the primary efficacy outcome measure, the Positive
and Negative Syndrome Scale (PANSS) total score52 for the
intention to treat population comprising 174 patients found
mean changes at end point from baseline were –15.9 with
asenapine, vs –5.3 with placebo (P  0.005); the change
with risperidone (–10.9) compared with placebo however
was non-significant. Asenapine produced significantly greater
decreases in PANSS total scores compared with placebo from
week 2 onward.51
Secondary efficacy measures included the PANSS
positive subscale, which showed mean changes at endpoint
from baseline of –5.5 for asenapine vs –2.5 for placebo
(P = 0.01) and –5.1 for risperidone (P  0.05). Asenapine
produced significant reductions in PANSS positive subscale
scores from week 3 onward. PANSS negative score results
showed mean changes at endpoint from baseline of –3.2
for asenapine vs –0.6 for placebo (P = 0.01) and a non-
significant change of –1.05 with risperidone compared with
placebo. Significant decreases in PANSS negative subscale
scores were again seen with asenapine from week 3 onward.
For Clinical Global Impression-Severity (CGI-S) scores,53
both active treatments were associated with significantly
greater decreases in CGI-S scores from week 4 onward.
At endpoint, mean changes from baseline were –0.74 for
asenapine and –0.75 for risperidone vs –0.28 for placebo
(P  0.01 and P  0.005 respectively). Overall, the main
efficacy findings from this study suggest that asenapine
5 mg twice daily is superior to placebo in treating positive
and negative symptoms of schizophrenia. Risperidone 3 mg
twice daily, however, was superior to placebo in alleviating
the positive symptoms but its effects on negative symptoms
were non-significant compared with placebo,51 in contrast
to previous studies showing significant improvements in
negative symptoms with risperidone.10,54
In the same study,51 investigations into the safety
and tolerability of asenapine found that 83% of patients
assigned to the drug experienced at least 1 adverse event
compared with 79% of patients assigned to placebo and
90% assigned to risperidone. The most frequently reported
adverse events in the asenapine group were insomnia (11%),
somnolence (11%), nausea (11%) and anxiety (10%).51
The incidence of clinically significant weight gain with
asenapine was equivalent to that seen with placebo, whereas
the incidence with risperidone was higher, in accordance with
previous reports. Similarly, asenapine had minimal effects
on prolactin and metabolic parameters. The proportion
of patients with normal baseline prolactin levels but with
post-baseline levels of 2 times the laboratory upper limit of
normal (ULN) were 9%, 2% and 79% for asenapine, placebo
and risperidone groups respectively. Similarly, post-baseline
fasting glucose levels 20% above ULN were observed
in 14%, 12% and 20% of patients assigned asenapine,
placebo and risperidone respectively. Moreover, mean
changes from baseline in total cholesterol were –0.4, –1.7
and +2.3 mmol/L and mean changes in fasting triglycerides
were 0, –0.1 and 0 mmol/L for asenapine, placebo and
risperidone groups respectively.51
Cardiovascular assessments found no clinically important
differences between the groups with respect to blood
pressure, heart rate and ECG changes.51
A further study examined the long-term safety of
asenapine in patients with schizophrenia.55 The phase III,
double-blind, 1-year-long trial included 1219 patients,

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randomly assigned (3:1 ratio) to asenapine 10 to 20 mg and
olanzapine 20 to 40 mg a day. The 2 groups were comparable
in terms of frequency of adverse events experienced (60%
and 61% in asenapine and olanzapine groups respectively)
and withdrawals due to serious adverse events (6.3% and
6.8% respectively).55
In contrast, differences were apparent with regards
to incidence of EPS (18% vs 8%), mean weight gain
(1.6 kg vs 5.6 kg) and significant weight gain of 7% of
original body weight (14.7% vs 36.1%) for asenapine and
olanzapine groups respectively. Cardiovascular assessments
found that the incidence of QTcF (Fridericia’s correction
formula) 500 ms or prolongation 60 ms was 0% and
0.3% for asenapine and olanzapine respectively. In addition,
both groups showed small mean declines in prolactin levels
and small mean changes were noted for fasting glucose,
cholesterol and triglycerides.55
The effects of asenapine on cardiovascular parameters
were compared with those for quetiapine and placebo in a
16-day multicenter, randomized, double-blind, parallel-group
study of 148 patients with schizophrenia or schizoaffective
disorder.56 Patients were randomized to one of the 4 following
groups: asenapine 5 mg twice daily for 10 days then
asenapine 10 mg twice daily for 6 days; asenapine 15 mg
twice daily for 10 days then asenapine 20 mg twice daily
for 6 days; quetiapine 375 mg twice daily for 16 days and
placebo twice daily for 16 days.
Results showed no statistically significant differences
between asenapine and quetiapine and no reports of QTc
interval 500 ms in any patient in any group. In addition, there
were no reports of QTc increase from baseline 60 ms with
asenapine, although there was 1 with quetiapine 375 mg twice
daily and 2 with placebo. Furthermore, exposure-response
modeling depicted a small positive relationship between
QTc and plasma levels of both asenapine and quetiapine. In
summary, although doses of asenapine 30 mg and 40 mg a
day (but not 10 mg) showed a significant QTc prolongation
compared with placebo, this was comparable to the increase
seen with quetiapine.56
The effects of asenapine on cognitive function were
assessed in a 6-week randomized, double-blind placebo-
and risperidone-controlled study of 180 patients with acute
exacerbation of schizophrenia.57 Patients were assigned
to fixed doses of asenapine 5 mg twice daily, risperi-
done 3 mg twice daily or placebo. Patients treated with
asenapine demonstrated improvement on all cognitive
tests related to verbal learning and memory which are
important domains of cognitive function in schizophrenia.
Overall, the effects size compared with placebo on most
cognitive function measures, was greater with asenapine
than with risperidone, although the authors concluded that
further investigations were needed in order to confirm
these results.57
Efficacy and safety studies
in bipolar disorder
The efficacy of asenapine in bipolar I disorder was evaluated
in two 3-week multinational, randomized, double-blind,
placebo- and olanzapine-controlled trials in patients with
manic or mixed episodes associated with bipolar I disorder.58
A total of 976 patients was randomly assigned in a 2:2:1
ratio to flexible-dosing of asenapine 10 mg twice daily
(adjustable to 5 mg twice daily), olanzapine 15 mg daily
(adjustable to 5 to 20 mg daily) or placebo treatment. Results
from these 2 studies found that the lean squares (LS) mean
change in Young Mania Rating Scale (YMRS)59 score from
baseline to day 21 were significantly greater (all P  0.05)
with asenapine (-14.2 and -13.1) and olanzapine (-16.1
and –13.9) than placebo (-10.8 and -7.4) in the 2 studies
respectively. The active agents demonstrated superiority as
early as day 2 of treatment.58
Asenapine was well tolerated in both studies and caused
low incidence of weight gain. In the all-treated popula-
tion, the incidence of clinically significant weight gain was
reported as 7% and 6% for asenapine, 19% and 13% for
olanzapine and 1.2% and 0% for placebo in the 2 studies
respectively.58
Following these 2 trials, a subsequent 9-week double-blind
extension study60 was carried out comprising patients who
had completed the initial 3-week phase. In addition, those
who completed the 9-week extension period were also
screened for an additional 40-week extension, focusing
on safety of asenapine, thus bestowing a total treatment
period of 1 year. Flexible doses of asenapine 5 to 10 mg
twice daily or olanzapine 5 to 10 mg daily were initiated at
the maintenance dosages used in the initial 3-week phase.
The efficacy of asenapine was assessed using the mean
change from baseline in YMRS total score which was –24.4
with asenapine vs –23.9 with olanzapine. Inferential analysis
indicated that asenapine was not inferior to olanzapine
(P  0.0001). This comparable efficacy was maintained
throughout the 40 week extension phase. In addition, more
than 90% of patients showed response (YMRS total score
reduced by 50%) or remission (total score 12) in both
groups, and rates for completion and discontinuation were
similar between the groups.60