Review

Safety of antipsychotic drugs:

focus on therapeutic and adverse
effects
1. Introduction
Felix-Martin Werner† & Rafael Coveñas
2. Effects of second-generation †
University of Salamanca, Institute of Neurosciences of Castilla y Leo´n (INCYL), Laboratory of
and recently admitted
Neuroanatomy of the Peptidergic Systems (Lab. 14), Salamanca, Spain
antipsychotic drugs
3. Safety evaluation of SGAs Introduction: Schizophrenia is a chronic psychiatric disease, which is treated
4. Conclusion by antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists
and have extrapyramidal side effects depending on the D2 antagonistic effect.
5. Expert opinion
Recently admitted antipsychotic drugs also have systemic side effects.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14

Clozapine, which has the strongest antipsychotic effect, can cause neutrope-
nia. A problem in the treatment of schizophrenia is poor patient compliance
leading to the recurrence of psychotic symptoms.
Areas covered: A search was carried out in Medline using the following terms:
antipsychotic drugs, antipsychotic effect, risperidone, olanzapine, clozapine,
ziprasidone, aripiprazol, asenapine, questiapine, cariprazine, lurasidone,
arrythmia, diabetes mellitus, weight gain, epileptic activity, extrapyramidal
symptoms, sexual activity, clinical trials and tolerability.
Expert opinion: Most clinical trials describe a good antipsychotic effect of the
For personal use only.

currently used antipsychotic drugs. The efficacy and safety of the antipsy-
chotic drugs also depend on the form of schizophrenia, for example, the
chronic recurrent form of schizophrenia. Clozapine and olanzapine have the
safest therapeutic effect, while the side effect of neutropenia must be
controlled by 3 weekly blood controls. If schizophrenia has remitted and if
patients show a good compliance, the adverse effects can be controlled. The
pharmacological treatment should be combined with social therapies and
psychoeducation in order to reach a good therapeutic outcome.

Keywords: aripiprazole, asenapine, cariprazine, clinical trial, clozapine, lurasidone, olanzapine,

paliperidone, quetiapine, risperidone, side effects, tolerability, ziprasidone

Expert Opin. Drug Saf. [Early Online]

1. Introduction

Antipsychotic drugs, above all atypical antipsychotic drugs are prescribed for the
treatment of chronic schizophrenia. After treatment of an acute psychosis, which
becomes manifest with positive symptoms such as paranoia and hallucinations, a
permanent medication with atypical antipsychotic drugs is necessary in most cases
in order to prevent recurrence of psychotic symptoms [1]. In schizophrenia,
dopamine hyperactivity via D2 receptors and serotonin hyperactivity via 5-HT2A
receptors occur in the mesolimbic system and the hippocampus. In schizophrenia,
some susceptibility genes, for example, neuregulin-1, dysbindin-1, glutamate decar-
boxylase 67, catechyl-O-methyl-transferase (COMT) and monoamine oxidase A/B
have been reported [2]. It has not yet been examined in experimental or clinical stud-
ies whether there is or not an interaction between the altered neurotransmitters; this
might be due to the risk genes. Dopamine hyperactivity could be due to a reduced
function of enzymes degrading dopamine, for example, COMT or monoamine oxi-
dase A/B [2].

10.1517/14740338.2014.935761 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1

All rights reserved: reproduction in whole or in part not permitted
 F.-M. Werner & R. Coveñas
Article highlights.
. This paper reviews the safe antipsychotic effect and
adverse effects, for example, extrapyramidal symptoms
(EPS), metabolic side effects, changes of the prolactin
levels and changes of the blood cell counts of
conventional second-generation antipsychotic drugs.
. Risperidone which has a similar mechanism of action like
typical neuroleptics has a safe antipsychotic effect and
produces less EPS than haloperidol.
. Olanzapine has a superior antipsychotic effect than
other second-generation antipsychotic drugs, above all
on negative schizophrenic symptoms, although it has
more severe metabolic side effects and produces more
weight gain.
. Clozapine has the strongest antipsychotic effect, but
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
neutropenia which occurs in 3% of the patients must
be excluded through 3 weekly blood cell counts.
.
The antipsychotic drugs such as lurasidone, asenapine
and cariprazine have a safe antipsychotic effect and a
promising adverse effect profile, but the effect in
long-term treatments should still be investigated.
. The effect of the recently admitted antipsychotic drugs
to improve cognitive function should be investigated in
long-term treatments.
. It should be examined whether patients treated with
two combined antipsychotic drugs, administered as an
injectable depot form, show a lower tendency to
For personal use only.
discontinue the treatment and a better outcome.
This box summarizes key points contained in the article.
The treatment of a chronic schizophrenia has been per-
formed with an injectable application of first-generation
antipsychotic drugs, for example, haloperidol and fluphen-
azine which have a high affinity for the D2 receptor, but
they do not interfere with the 5-HT2A receptor. Extrapyra-
midal symptoms (EPS) often occurred as a consequence of
the strong D2 antagonistic effect [3]. Haloperidol and
fluphenazine interfere also with adrenergic, cholinergic and
histaminergic receptors, but the main antipsychotic effect is
achieved through a D2 receptor blockade [2]. The commonly
used second-generation antipsychotic drugs (SGAs) are ris-
peridone, olanzapine and quetiapine [3]. Risperidone is a
D2 and 5-HT2A antagonist, although it shows a higher affin-
ity for the D2 receptor. Risperidone has fewer extrapyramidal
side effects than the first-generation antipsychotic drugs,
which are D2 antagonists and show no affinity for the
5-HT2A receptor [3]. Olanzapine and quetiapine, which are
often administered, have a slightly different mechanism of
action but have other side effects, for example, an increased
insulin resistance [2]. If psychotic symptoms have not remit-
ted, the antipsychotic drug clozapine is selected exerting an
antipsychotic effect which is superior to that of other anti-
psychotic drugs [4]. Because clozapine can cause neutropenia
in 3% of patients, a question must be addressed: how to deal
with this side effect [4]. Clinical trials about the safety of
other antipsychotic drugs such as ziprasidone and
2 Expert Opin. Drug Saf. (2014) 13(8)
aripiprazole and about the recently admitted antipsychotic
drugs are discussed here. Among these antipsychotic drugs,
cariprazine and lurasidone are worth mentioning because,
due to a different mechanism of action, these drugs improve
cognitive function [2,4].
2.Effects of second-generation and recently
admitted antipsychotic drugs
In the treatment of chronic schizophrenia, the most fre-
quently used SGAs are risperidone, olanzapine and quetiapine
[4]. Risperidone causes extrapyramidal side effects to a smaller
extent than the first-generation antipsychotic drugs, which are
D2 antagonists without interfering with serotonergic subre-
ceptors [3]. Risperidone can be used for the treatment of
chronic schizophrenia, autism, obsessive-compulsive disorder
and against agitation in dementia [5]. Olanzapine blocks D2
and 5-HT2A receptors and has a lower ratio of the
D2/5-HT2A receptors occupancy than risperidone and causes
less often extrapyramidal side effects than risperidone.
Olanzapine is prescribed for the long-term treatment of
schizophrenia and for dementia, major depression and bipolar
depression [5]. Quetiapine has an even lower affinity for the
D2 receptor and a higher affinity for the 5-HT2A receptor
than olanzapine and seldom causes EPS. Quetiapine is admin-
istered in patients suffering chronic schizophrenia or major
depression and exerts a therapeutic effect in generalized
anxiety disorders [4,5]. Clozapine, which exerts a D3, D4 and
5-HT2A antagonistic effect, has a stronger antipsychotic effect
than other SGAs [4]. Clozapine is administered when psy-
chotic symptoms have not remitted after treatment with other
antipsychotic drugs. Extrapyramidal side effects occur very
seldom [2]. Ziprasidone is a D2 and 5-HT2A antagonist with
a preference for the D2 receptor; it exerts a 5-HT1A agonistic
effect and has therefore good antipsychotic and antidepressant
effects. Aripiprazole with a different mechanism of action
has a D2 partial agonism and a strong 5-HT2A antagonistic
effect. Therefore, aripiprazole has antipsychotic and antide-
pressant properties and can be administered in patients with
dementia [2,5]. Aripiprazole often causes gait disturbances,
for example, akathisia [5].
Among the recently admitted antipsychotic drugs, details
about their mechanisms of action and their therapeutic effects
are presented here for asenapine, lurasidone and cariprazine.
Asenapine is a drug with a D2 and 5-HT2A antagonistic effect
and has comparable antipsychotic effects like olanzapine [6].
Apart from the antipsychotic effect, it improves cognitive func-
tion [6]. Lurasidone is an antipsychotic drug, which has a D2
and 5-HT2A antagonistic effect, a 5-HT1A agonistic effect
and a 5-HT7 antagonistic effect [7]. Lurasidone, as a conse-
quence of its mechanism of action, has a good antipsychotic
and antidepressant effect and improves cognitive function.
Clinical trials have been carried out to investigate whether
lurasidone has comparable therapeutic effects and a good toler-
ability compared with conventional antipsychotic drugs [8].

Besides, it is worth mentioning that the recently admitted
antipsychotic drug cariprazine shows a 5-HT1A agonism and
a partial agonism at D2 and D3 receptors. Clinical trials have
been undertaken in order to know whether it exerts compara-
ble antipsychotic effects and a good tolerability like other
antipsychotic drugs. Because of its mechanism of action, cari-
prazine can be used to treat major depression and bipolar
disorders [2,9].
3. Safety evaluation of SGAs
The safety of the SGAs, such as risperidone, olanzapine and
quetiapine and recently admitted antipsychotic drugs, has
been investigated in clinical trials [3,5]. In these trials, the ques-
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
tion is addressed whether these antipsychotic drugs have a
significant therapeutic effect in the treatment of an acute psy-
chosis and whether they can be applied for a maintenance
treatment in order to prevent recurrence of psychotic symp-
toms [10]. In this sense, it has been examined if long-acting
injectable applications of the antipsychotic drugs are available
and if they enable a safe maintenance treatment [11]. This
application is important because the often lacking patients’
compliance can lead to a recurrence of psychotic symptoms.
Besides, it must be considered which effects the antipsychotic
For personal use only.
drugs have on the cognitive function and whether they cause
sedation [9]. A question will be answered, whether the antipsy-
chotic drugs cariprazine and lurasidone have a positive effect
on cognitive function [9,10]. Disabling side effects of the anti-
psychotic drugs are EPS, above all akathisia. The occurrence
of this side effect can be explained through the mechanism
of action indicated above. A question will be answered,
whether its frequency can be reduced by the recently
developed antipsychotic drugs [3]. Although clozapine has an
antipsychotic effect, which is higher than other antipsychotic
drugs, its application is limited by the neutropenia, induced
in 3% of the patients. Clinical trials about the safety of cloza-
pine will be mentioned. The SGAs have other disturbing side
effects, such as liver and kidney damage, cardiac side effects,
insulin resistance and weight gain [4]. Another important issue
will be addressed if pharmacotherapy combined with psycho-
education has a positive influence on the outcome of the
disease [12].
3.1Second-generation antipsychotic drugs
3.1.1Decrease of positive and negative syndrome
total score
Risperidone is a drug which exerts its antipsychotic effect
mainly via the D2 receptor [2]. In order to assess the antipsy-
chotic effect of antipsychotic drugs, the Positive and Negative
Syndrome Scale (PANSS) total score was performed in some
clinical studies [13]. The PANSS total score was found to be
91.6 before treatment with haloperidol and 91.1, when the
antispychotic drugs risperidone, olanzapine, ziprasidone and
paliperidone were administered. The Emax of risperidone
was 0.23 compared to olanzapine, 0.39. The effective dose
Expert Opin. Drug Saf. (2014) 13(8)
Safety of antipsychotic drugs
of risperidone was 0.8 mg/day with a 30% decrease of the
PANSS total score compared with baseline and with an effec-
tive concentration of 5.2 ng/ml, that is, the minimal serum
level to achieve a therapeutic effect [13]. If the changes of the
PANSS total score in the pharmacokinetic-pharmacodynamic
model of the antipsychotic drugs haloperidol, risperidone and
olanzapine are compared, the following findings are worth to
be mentioned: olanzapine leads to a stronger decrease in the
PANSS total score than haloperidol and risperidone. Risperi-
done has a comparable effect upon positive schizophrenic
symptoms like haloperidol and has a weaker therapeutic effect
upon negative schizophrenic symptoms than olanzapine [14].
A decrease in 20% of negative symptoms can be found with
a concentration of 42.1 ng/ml of risperidone in comparison
to olanzapine (4.9 ng/ml) [14]. This could be explained
by the fact that risperidone has a higher ratio of the
D2/5-HT2A receptor occupancy than olanzapine and that
olanzapine has a faster dissociation from D2 and 5-HT2A
receptors [14].
Paliperidone was approved as a monotherapy for the
treatment of schizophrenia and for the treatment of schizoaf-
fective disorder and as an adjunctive therapy with mood
stabilizers and/or antidepressants [15]. Paliperidone is the
active metabolite of risperidone and is available as an oral
extended-release form or as a long-acting injectable form,
the paliperidone palmitate [15]. The recommended daily
dose of paliperidone extended-release is 6 mg/day and can
be increased to 12 mg/day; by increasing the dosage, an addi-
tional therapeutic effect can be obtained, but dose-related
adverse effects can also increase. The terminal half-life
is ~ 23 h. The main elimination is by renal excretion, and it
is quite different from that of risperidone; so that, paliperi-
done is recommended in patients with a liver disease [15].
Paliperidone exerts the antipsychotic effect through the same
mechanism of action like risperidone, because it is the active
metabolite of risperidone. Administering these doses of
paliperidone, a comparable decrease in the PANSS score is
achieved, like administering risperidone [14]. Paliperidone
has a comparable effect upon positive schizophrenic symp-
toms like risperidone; however, it has a weaker therapeutic
effect upon negative schizophrenic symptoms than olanzapine
[14]. Paliperidone needs a plasma concentration of 9.8 ng/ml
to achieve a 30% decrease in the PANSS total score in
comparison to risperidone, which requires 5.3 ng/ml.
A decrease in 20% of negative symptoms can be found with
a concentration of 30.0 ng/ml of paliperidone in comparison
to risperidone (42.1 ng/ml) and to olanzapine (4.9 ng/ml) [14].
Olanzapine is a SGA which exerts an antipsychotic effect
and shows a lower affinity for the D2 receptor and a higher
affinity for the 5-HT2A receptor than risperidone [2]. The
effect of olanzapine on positive and negative schizophrenic
symptoms has been examined in a meta-analysis [13,14]. The
effective concentration required to obtain a 30% decrease of
the PANSS score compared to baseline is 13.8 ng/ml, and
the effective dose per day is 7.3 mg in comparison to
3
 F.-M. Werner & R. Coveñas
risperidone with 0.8 mg/day [13]. The maximum drug effect,
that is, the Emax of olanzapine on the PANSS-positive subscale
is 0.43 compared to risperidone, 0.32, and the Emax of the
PANSS negative subscale is 0.33 compared to risperidone,
0.14. The Emax of olanzapine in the PANSS general subscale
is 0.34 compared to other antipsychotic drugs like haloperidol
(0.27), risperidone (0.19), ziprasidone (0.12) and paliperi-
done (0.24) [14]. Consequently, olanzapine has a stronger
antipsychotic effect compared to other antipsychotic drugs
and exerts a stronger therapeutic effect on negative schizo-
phrenic symptoms as a consequence of its high affinity for
the 5-HT2A receptor [2].
Quetiapine is a SGA with an even lower affinity for the D2
receptor and a higher affinity for the 5-HT2A receptor than
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olanzapine [2]. It has been examined in a randomized clinical
trial of 156 patients suffering from first-episode schizophre-
nia. Seventy-eight patients were daily administered with
705 mg of quetiapine and the other 78 patients were daily
administered with 14 mg of haloperidol [16]. In the course
of the treatment, the authors examined the PANSS score
and the Global Assessment of Functioning (GAF) scale for
overall psychosocial functioning [16]. Quetiapine had signifi-
cant better PANSS positive and negative scores than haloper-
idol; however, both antipsychotic drugs showed no differences
For personal use only.
in the total PANSS score and in the GAF score [16]. Ziprasi-
done is an antipsychotic drug which mechanism of action
has been described above. It has antipsychotic and antidepres-
sant properties [2]. The effective concentration to achieve a
20% decrease in the total PANSS score is 15.6 ng/ml in com-
parison to olanzapine with 4.89 ng/ml. A 20% decrease in the
PANSS-positive subscale can be obtained at an effective con-
centration of 8.70 ng/ml, and a 20% decrease in the PANSS-
negative subscale can be achieved at an effective concentration
of 82.8 ng/ml [14]. The therapeutic effect of ziprasidone on
negative schizophrenic symptoms is weaker than that of olan-
zapine. The antipsychotic effect of ziprasidone on the PANSS
score is comparable to that of risperidone [14].
Clozapine is an antipsychotic drug which can be adminis-
tered if other antipsychotic drugs did not exert a sufficient
antipsychotic effect [2,4]. Among the treatment-resistant schizo-
phrenic patients, 30% of them respond after 6 weeks to cloza-
pine administration, another 20% after 3 months and another
10 -- 20% after 6 months. The side effects, for example, neu-
tropenia which occurs in 3% of patients and agranulocytosis
which occurs in 0.8% of patients can be managed by reducing
the daily dosage [4]. It has been reported in a meta-analysis
carried out in a Chinese population suffering schizophrenia
that clozapine achieved a 55.4% decrease in the total PANSS
score with half of the Emax., for example, 296 mg/day [17].
The antipsychotic effect of clozapine which is superior to
that of other SGAs can be explained by its mechanism of
action. Clozapine has a high affinity for the 5-HT2A receptor
and it interferes with other dopaminergic subreceptor than
the D2 receptor, namely with the D3 and D4 receptors [4].
The blockade of D4 receptors stabilizes D2 dopaminergic
4 Expert Opin. Drug Saf. (2014) 13(8)
neurons in the hippocampus, because in this region D4 dopa-
minergic neurons exert a postsynaptic excitatory impulse upon
D2 dopaminergic neurons [2].
Aripiprazole is a SGA with a different mechanism of action,
which it has been pointed out in a previous section. It has a
good antipsychotic effect through the 5-HT2A antagonistic
effect, which is not weakened by the D2 partial agonism.
Besides, it exerts antidepressant properties through the
5-HT1A agonistic effect [2].
It has been performed a meta-analysis about the safety and
tolerability of aripiprazole in schizophrenic patients in com-
parison to other SGAs such as clozapine, quetiapine, risperi-
done, ziprasidone and olanzapine, and it has been reported
that aripiprazole led to a comparable decrease in the PANSS
total score like the other antipsychotic drugs but that patients
obtaining aripiprazole had a better quality of life [18]. In a clin-
ical trial with 59 patients suffering a first-episode schizophre-
nia, aripiprazole achieved an at least 20% decrease in the
PANSS total score after 3 weeks [19].
Lurasidone is a drug with an additional antagonistic effect
at the 5-HT7 receptor. It exerts a good antipsychotic and
antidepressant effect and improves cognitive functions as a
consequence of the blockade of 5-HT7 receptors in the hippo-
campus [2]. It has been performed a clinical study with 198
schizophrenic or schizoaffective out-patients treated with
lurasidone [20]. From the 198 out-patients, 98 patients
obtained the study medication. It was found that the most
frequent adverse effects were insomnia, nausea, akathisia and
anxiety [20]. The dosage of lurasidone was 40, 80 or
120 mg/day. According to this study, adverse effects such as
weight gain, glucose or cholesterol increases or hyperprolacti-
nemia were not observed. No meaningful disorders were seen
in schizophrenic patients [20]. The PANSS, Clinical Global
Impressions-Severity and the calgary depression scale for
schizophrenia decreased in all participating patients compared
to baseline scores. These results demonstrate that lurasidone
exerts a good antipsychotic and antidepressant effect [20].
Asenapine is a recently admitted antipsychotic drug, which
in addition to its antipsychotic effect, improves cognitive
functions [2]. It has been performed a pooled, post-hoc analy-
sis with schizophrenic patients treated with asenapine, olanza-
pine, risperidone, haloperidol or placebo. The PANSS score
was defined at weeks 2 and 6 [21]. It was found that all antipsy-
chotic drugs, except olanzapine which had a higher effect, had
a decrease in 20% in the PANSS score in the second week of
treatment and caused a remission of psychotic symptoms in
the sixth week with a further decrease in the PANSS score [21].
In another study, it was compared the effect of asenapine and
olanzapine on negative schizophrenic symptoms on evaluating
two 26-week core studies and extensions and found that there
were no differences between asenapine and olanzapine in
reducing persistent negative symptoms, but that asenapine
had a superior effect compared to olanzapine in improving
negative schizophrenic symptoms in the extension study [22].
In a pooled meta-analysis about the treatment of acute

schizophrenia, it has been compared the effect of asenapine
and other SGAs on the PANSS score. Asenapine had a supe-
rior effect compared to placebo, had a greater decrease in the
PANSS score than ziprasidone, but exerted a smaller effect
than olanzapine [23]. Moreover, it has been found in two ran-
domized, controlled trials of asenapine monotherapy that ase-
napine had a decrease in the negative symptom assessment-16
total score comparable to olanzapine [24]. Cariprazine is a new
antipsychotic drug with a partial agonism at D2 and D3 recep-
tors, although shows a preference for the D3 receptor [25].
Doses of more than 1.5 mg/day achieve a D2/D3 receptor
occupancy of at least 75%, as it was measured by positron
emission tomography [25]. Besides, cariprazine has a 5-HT1A
agonism and exerts an antidepressant effect in addition to
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the antipsychotic effect [2]. Four Phase II and III clinical trials
were performed, and cariprazine achieved a superior effect
than placebo and led to decrease in the PANSS total score
at doses of 1.5, 3.0, 4.5, 6.0 and 9.0 mg/day [26]. It has
been performed a double-blind, randomized, placebo- and
active-controlled clinical trial in patients with exacerbation
of schizophrenia [27]. The patients obtained 1.5, 3.0 or
4.5 mg of cariprazine per day, 4.0 mg risperidone per day
or placebo for 6 weeks and a safe dose of an effective antipsy-
chotic drug for 2 weeks. Of the 732 included patients, 64%
For personal use only.
completed the study. In this period, the decrease in the
PANSS score was measured. During the 6 weeks, the PANSS
score improvement for patients obtaining 1.5 cariprazine per
day, 3.0 cariprazine per day and 4.5 cariprazine per day was
-7.6, -8.8 and -10.4, respectively, p < 0.001, whereas this
value in the patients treated with 4.0 mg risperidone per day
was at 15.1, p < 0.001 [27]. The observed adverse effects
were identical to those reported by other authors [25,26].
In sum, among the antipsychotic drugs, olanzapine shows a
higher effect than other SGAs, above all upon negative schizo-
phrenic symptoms. Asenapine is a recently admitted antipsy-
chotic drug which has a comparable antipsychotic effect like
olanzapine. Risperidone, quetiapine and ziprasidone have
similar antipsychotic properties. Aripiprazole has a good anti-
psychotic effect and offers a good quality of life. Clozapine
can be used in treatment-resistant schizophrenia; however,
the adverse effects must be considered. The long-term effect
of lurasidone and cariprazine should still be examined.
3.1.2 Extrapyramidal symptoms
Because risperidone exerts a strong D2 antagonistic effect, it
can cause EPS if the D2 receptor occupancy exceeds 80%
[2]. Risperidone has a lower risk for EPS than first-generation
antipsychotic drugs, such as haloperidol, because risperidone
has a faster dissociation from the D2 receptor and because
it interferes with the 5-HT2A receptor, but it has a higher
risk for EPS than olanzapine [3]. However, risperidone has
stronger extrapyramidal side effects than other SGAs as a
consequence of its high affinity for the D2 receptor. As some
patients need an antipsychotic drug exerting this antidopami-
nergic effect, the extrapyramidal side effect could be
Expert Opin. Drug Saf. (2014) 13(8)
Safety of antipsychotic drugs
ameliorated in the course of the treatment by decreasing the
dose [2,3].
Because paliperidone has a comparable mechanism of
action like risperidone, it can cause EPS to the same extent
like risperidone [2]. Because olanzapine has a weaker affinity
for the D2 receptor than risperidone and paliperidone, it
causes EPS less seldom and to a smaller extent than these
antipsychotic drugs [2,3].
It is worth mentioning as well that quetiapine had less
seldom and fewer extrapyramidal side effects than haloperidol
as a consequence of its preference for the 5-HT2A receptor,
which counteracts the D2 antagonistic effect that takes place
in the putamen [16].
Ziprasidone can cause extrapyramidal side effects, but to a
smaller extent than risperidone. Clozapine very seldom and
to a small extent causes extrapyramidal side effects, because
it does not block D2 receptors in the extrapyramidal system
[4,28].
Patients treated with aripiprazole achieved a better Brief
Psychiatric Rating Scale score and had fewer EPS than risper-
idone [18]. This reduced side effect can be explained by the
partial D2 agonism [2]. The two most commonly observed
side effects of lurasidone were akathisia in 13% of the patients
and insomnia in 11% of them [29]. The adverse effects such as
EPS, hyperprolactinemia, weight gain and increases of glucose
and lipid levels were found to be low [24]. It has been exam-
ined 67 articles about the safety of asenapine, and it was found
that asenapine had comparable antipsychotic effects like other
antipsychotic drugs in the treatment of schizophrenia and
bipolar disorder [30]. The most common adverse effects were
found to be somnolence in 13 -- 24% of patients, EPS in
7 -- 12% of patients and dizziness in 11% of them [30]. In
clinical trials, cariprazine was revealed to have a superior ther-
apeutic effect in schizophrenia and bipolar mania and caused
the following side effects: insomnia, EPS, akathisia, sedation,
nausea, dizziness and constipation [25].
In sum, among the SGAs, risperidone and paliperidone
cause EPS to a high extent. However, antipsychotic drugs
like olanzapine, quetiapine, ziprasidone and aripiprazole
have extrapyramidal side effects to a smaller extent. Clozapine
has few EPS. Lurasidone and cariprazine lead to akathisia in
11% of patients.
3.1.3 Metabolic and cardiac side effects
The question whether risperidone can cause cardiovascular
adverse effects was studied in a post-hoc analysis [31]. Thus,
observed symptoms were syncope through the a1 noradrener-
gic antagonistic effect, tachycardia, palpitations, peripheral
edema and transient ischemic attack, while the incidence of
death related to a cardiovascular disease was comparable to
that found in the control group [31].
Rummel-Kluge et al. [32] included 48 studies about the
metabolic side effects of the SGAs and performed a meta-
analysis. The side effects to be examined were as follows:
weight gain, hyperlipidemia and glucose increase [32]. These
5
 F.-M. Werner & R. Coveñas
authors found that risperidone produces weight gain, less
severely than clozapine, olanzapine and quetiapine but more
severely than ziprasidone and aripiprazole [32]. Risperidone
can cause an increase in glucose, but less severely than aripir-
azole, clozapine and olanzapine, and to the same extent than
quetiapine; in this aspect, only ziprasidone has a more
favorable effect [32]. Regarding the metabolic side effects,
paliperidone can cause weight gain, but less severely than clo-
zapine, olanzapine and quetiapine [32]. Paliperidone can cause
an increase in glucose and cholesterol to the same extent like
risperidone [32].
It has been examined a Swedish cohort of 809 schizophrenic
patients treated with 10 different antipsychotic drugs and stud-
ied metabolic parameters such as hyperglycemia, hypertriglycer-
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idemia, high-density lipoprotein (HDL) levels, hypertension
and waist circumference [33]. According to these examinations,
a metabolic syndrome occurred in 17% of patients taking olan-
zapine and risperidone, in 9% of patients taking clozapine and
in 3% of patients taking ziprasidone [33]. Among the patients
taking antipsychotic drugs, 34% of patients suffered from
hyperglycemia, 40% from hyperlipidemia and 61% of patients
had an elevated blood pressure [33]. Consequently, schizo-
phrenic patients treated with olanzapine showed increased
cardiovascular risk factors, because they also have a significantly
For personal use only.
reduced HDL level [33]. According to the meta-analysis con-
ducted by Rummel-Kluge et al. [32], olanzapine leads to weight
gain in the same extent like clozapine, but stronger than other
antipsychotic drugs like risperidone, aripiprazole, quetiapine
or ziprasidone. Olanzapine causes a stronger increase in choles-
terol than the above-mentioned antipsychotic drugs. Besides,
olanzapine causes a stronger increase in glucose than the
above-mentioned antipsychotic drugs, except clozapine [32].
Although olanzapine exerts a strong antipsychotic effect, it
causes metabolic side effect that must be considered by the
physician [32,33]. Due to the metabolic side effects, quetiapine
causes weight gain and produces an increase in glucose to the
same extent than risperidone, ziprasidone and clozapine and
significantly less severely than olanzapine. There are no differen-
ces in the increase of cholesterol between quetiapine and risper-
idone as well as between quetiapine and ziprasidone. The
increase of cholesterol due to olanzapine is significantly higher
than that of quetiapine [32]. According to a meta-analysis, a
metabolic syndrome occurs in only 39% of the patients treated
with quetiapine [33].
Regarding to the metabolic side effects of ziprasidone, a
metabolic side effect occurred in 43% of the treated patients
in comparison to olanzapine (54%) [33]. Ziprasidone causes
less weight gain than olanzapine; no differences in this aspect
were seen between ziprasidone and quetiapine or risperi-
done [32]. Ziprasidone produces a smaller increase in choles-
terol than risperidone, olanzapine and quetiapine [32]. The
increase in glucose of ziprasidone is smaller than in the treat-
ment with olanzapine, no difference in this metabolic side
effect was observed in the treatment with ziprasidone
compared to that of risperidone and quetiapine [32].
6 Expert Opin. Drug Saf. (2014) 13(8)
Clozapine causes metabolic side effects in 45% of the
treated patients [33]. Clozapine leads to weight gain to the
same extent like olanzapine; however, this side effect is more
severe compared with the treatment with risperidone and
quetiapine [32]. Clozapine causes a larger increase in choles-
terol than risperidone; no differences in this side effect were
seen in comparison to the treatment with olanzapine [32].
The increase in glucose is more severe than in the treatment
with olanzapine and risperidone [32]. Like olanzapine, cloza-
pine can lead to an insulin resistance [2,32]. According to the
metabolic side effects, aripiprazole causes weight gain to a
smaller extent than olanzapine and risperidone [32]. The
increase in cholesterol and glucose levels in patients treated
with aripiprazole are smaller than those reported in patients
treated with olanzapine [32].
It has been performed a 6-week, double-blind, placebo-
controlled study with lurasidone at a dose of 40 or 120 mg
once daily or olanzapine at a dose of 15 mg once daily in
schizophrenic patients, which was extended to a 6-month,
open-label extension study [29]. Of 254 patients, 133
(44.5%) performed the whole study. During this trial,
patients receiving lurasidone experienced decreases in weight
and in lipid levels (total cholesterol: - 6.5 mg/100 ml; trigly-
cerides: - 8.5 mg/100 ml), and patients treated with olanza-
pine had a smaller decrease of weight and lipid levels,
whereas patients who were treated with lurasidone in the
6-week, double-blind study and during its continuation, as
well in the 6-month extension study had minimal changes
in these parameters [29]. It has also been examined 17 asena-
pine trials and it was studied the effect of asenapine on meta-
bolic parameters and the weight in comparison with placebo
and olanzapine groups [34]. The authors found that in the
treatment of schizophrenia and bipolar disorder, asenapine
produced weight gain and an increase in glucose and total
cholesterol, which was greater than in the placebo group,
but smaller than in the olanzapine group. Metabolic side
effects, an increase in prolactin or an increased QT interval
in the electrocardiogram were not observed [26].
Metabolic and cardiac side effects occur during the treat-
ment with antipsychotic drugs. The SGAs risperidone,
paliperidone, quetiapine and ziprasidone cause an increase
in glucose and cholesterol to the same extent. The metabolic
side effects found during the treatment with olanzapine and
clozapine were more severe than those found during the
treatment with other antipsychotic drugs. Lurasidone and
asenapine had more favorable results in this regard than
olanzapine. Blood pressure was seen to be elevated, as well
as cardiac side effects (e.g., a ST segment prolongation was
observed).
3.1.4 Hyperprolactinemia
Hyperprolactinemia is a side effect which occurs during the
treatment with some SGAs; however, some SGAs are
prolactin-sparing antipsychotic drugs. This dysfunction is
also due to the D2 antidopaminergic effect exerted, above all

of risperidone [35]. Prolactin is synthesized in the lactotroph
cells of the anterior pituitary gland and its synthesis is con-
trolled by D2 receptors. A blockade of these receptors removes
the dopaminergic inhibition of prolactin synthesis and leads
to increased prolactin levels [36]. In a cohort of 617 Chinese
psychiatric patients with four different diagnoses, hyperpro-
lactinemia was found in 59.6% of schizophrenic patients [35].
Hyperprolactinemia was less often found in schizophrenic
patients treated with clozapine and aripirprazole [35]. As a con-
sequence of the strong D2 antagonistic effect, paliperidone
can as well lead to hyperprolactinemia, which can be found
in 59.6% of the schizophrenic patients [25].
Hyperprolactinemia is an adverse effect in schizophrenic
patients treated with antipsychotic drugs which is often
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
neglected. Eighteen per cent of men and 47% of women
treated with an antipsychotic drug showed prolactin levels
above the normal range [36]. However, it seems that the faster
the antipsychotic-drug dissociates from D2 receptors, the lesser
an increase in prolactin and hence a less severe hyperprolactine-
mia appears [36]. Olanzapine belongs to the prolactin-sparing
antipsychotic drugs. Thus, the treating physician must exam-
ine symptoms like sexual dysfunction, gynecomestia and infer-
tility in men and amenorrhea and galactorrhea in women [36].
It is impossible to treat hyperprolactinemia using a D2 agonist,
For personal use only.
because this treatment would worsen the mental illness [36].
Among the SGAs, quetiapine is a prolactin-sparing antipsy-
chotic drug, that is, it does not raise prolactin levels as a conse-
quence of the weak D2 antagonistic effect. In a double-blind,
12-week trial, treatment-resistant schizophrenic patients were
treated with either risperidone, quetiapine or fluphenazine.
The patients taking quetiapine were the only group showing
normal levels of prolactin and had the greatest benefit among
these drugs regarding sexual functioning [37]. In contrast to
the antipsychotic treatment with risperidone, patients admin-
istered with clozapine have a low serum level of prolactin.
These patients have a significant lower incidence of sexual
dysfunction compared to patients treated with haloperidol or
risperidone [35]. Because clozapine does not block D2 receptors,
the dopaminergic effect inhibiting prolactin release is not
decreased [35].
As ziprasidone is a prolactin-sparing antipsychotic drug,
hyperprolactinemia occurs but only in a small number of
treated patients [19].
Aripiprazole is a prolactin-sparing antipsychotic drug, and as
a consequence of its partial D2 agonism, prolactin levels are not
increased [35]. Patients administered with lurasidone had mini-
mal changes in prolactin levels. Metabolic side effects, an
increase in prolactin or an increased QT interval in the electro-
cardiogram were not observed [26]. Asenapine and cariprazine
are as well prolactin-sparing antipsychotic drugs [36].
In sum, hyperprolactinemia occurs in about half of the
patients treated with antipsychotic drugs. Risperidone and pal-
iperidone raise prolactin levels, but clozapine and aripiprazole
do not raise these levels. The SGAs olanzapine, quetiapine,
ziprasidone and the recently admitted SGAs lurasidone,
Expert Opin. Drug Saf. (2014) 13(8)
Safety of antipsychotic drugs
asenapine and cariprazine only increase prolactin
concentrations to a small extent and in a small number of
patients.
3.1.5 Liver and kidney damage
Risperidone can cause liver damage. A disturbed liver func-
tion was found in 10% of the schizophrenic patients receiving
a risperidone long-acting injectable depot [38]. Compared to
other antipsychotic drugs such as olanzapine, quetiapine and
ziprasidone, risperidone has less metabolic side effects than
olanzapine and quetiapine and causes less often weight gain
than olanzapine. The administration of paliperidone should
be preferred rather than that of risperidone, if patients suffer
from a liver disease [15]. Olanzapine has a liver metabolism
and when liver function is impaired the concentration of
olanzapine is unchanged [39]. The main excretion of olanza-
pine is through the kidneys. If the renal function is impaired,
the renal clearance would be reduced. In this case, the dose of
olanzapine should be reduced taking into consideration that
schizophrenic symptoms do not worsen [39]. Quetiapine has
a liver metabolism and is excreted through the kidney [39].
A liver impairment does not alter the serum level of quetia-
pine; however, a renal impairment augments quetiapine
serum concentration so that the dosage must be reduced [39].
3.1.6Neutropenia and agranulocytosis
Neutropenia and agranulocytosis is a serious side effect in the
treatment of schizophrenic patients with clozapine. The
administration of clozapine should be restricted to patients
with a treatment-resistant form of schizophrenia. In order to
find out neutropenia in these patients, a 3 weekly white cell
count should be performed. In the case of clozapine discon-
tinuation, the psychotic symptoms can get worse again. It
has been reviewed patients’ histories showing that a clozapine
continuation can be achieved after administration of granulo-
cyte colony-stimulating factors, which increases the number
of matured granulocytes within the bone marrow [40]. On
controlling the white cell count, the physician can use cloza-
pine in treatment-resistant schizophrenic patients, because
clozapine exerts a higher antipsychotic effect than other
SGAs and because it shows significantly fewer EPS [2,4,40].
Agranulocytosis can occur as an adverse effect in the
treatment with other antipsychotic drugs than clozapine. In
a population-based cohort study in Sweden from 2006 till
2009, agranulocytosis was observed only in 23 patients [41].
3.1.7Summary of the safe and adverse effects of
antipsychotic drugs
Risperidone is available as a long-acting injectable antipsy-
chotic, namely risperidone microspheres [11]. Risperidone has
a good safety and tolerability, and the post-injection delirium/
sedation syndrome only occurs with a frequency of 5 -- 7%, in
the treated patients, versus 3% of the patients receiving
placebo [11]. Outpatient medication compliance is enhanced
during treatment with long-acting injectable risperidone
7
 F.-M. Werner & R. Coveñas
compared to orally administered risperidone [42]. Paliperidone
is available as a long-injection form, namely paliperidone palmi-
tate in order to ensure the patients’ often lacking compliance [15].
If the treating physician takes into consideration the adverse
effects, olanzapine is a safe antipsychotic drug with a good
therapeutic effect [2]. Quetiapine is a safe antipsychotic drug
with fewer movement disturbances and metabolic side effects
in comparison to other SGAs and in addition it is a prolactin-
sparing antipsychotic drug [2,32,37]. It can be concluded that in
first-episode schizophrenia quetiapine has greater efficacy on
positive and negative schizophrenia symptoms and fewer extra-
pyramidal side effects than haloperidol [16]. As ziprasidone is a
prolactin-sparing antipsychotic drug, hyperprolactinemia
occurs but only in a small number of treated patients [19]. The
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
discontinuation in the treatment of first-episode schizophrenia
with ziprasidone occurred in a lower number of patients than
in those treated with quetiapine, but occurred more often
than those treated with aripiprazole [43].
Aripiprazole is a safe antipsychotic drug with fewer meta-
bolic side effects and fewer movement disturbances than
risperidone and olanzapine and offers a good quality of
life [18,44]. A decrease in the PANSS total score was observed
at -- 8.7 in patients treated with lurasidone after a 6-month
treatment [29]. From these findings, it can be concluded that
For personal use only.
lurasidone is a safe and well-tolerated antipsychotic drug
which decreases the PANSS total score and shows fewer
metabolic side effects than olanzapine [29]. From the above-
mentioned studies, it can be concluded that asenapine has a
comparable antipsychotic effects like olanzapine and that it
decreases the negative schizophrenic symptoms at the same
extent like olanzapine, but the metabolic side effects were
smaller than those observed in the olanzapine group
[21-24,30,34]. Consequently, cariprazine is a safe antipsychotic
drug which is effective in the treatment of schizophrenia and
which has a good profile of adverse effects [25-27].
3.2 Combination of antipsychotic drugs
If a patient with a first-episode of schizophrenia does not
respond to the treatment with a single antipsychotic drug, the
dose of the antipsychotic drug can be increased. If the treat-
ment resistance still exists, an antipsychotic drug with another
receptor-binding profile can be chosen. An alternative is to
administer clozapine which shows a high antipsychotic effect.
In some cases, two antipsychotic drugs showing a different
affinity for dopaminergic and serotonergic subreceptors are
administered, for example, risperidone and quetiapine. Both
antipsychotic drugs are D2 and 5-HT2A antagonists, although
risperidone has a higher affinity for the D2 receptor and quetia-
pine for the 5-HT2A receptor [45]. It has been carried out a
nationwide study in Hungary, and it was compared the mono-
therapy and polypharmacy treatments in schizophrenia [46].
Two groups were formed. The patients of the first group
received an antipsychotic drug and then they were switched
to another antipsychotic drug after 60 days. The second group
was treated with a monotherapy for 60 days and then treated
8 Expert Opin. Drug Saf. (2014) 13(8)
with two antipsychotic drugs after this period. The authors of
the study examined the discontinuation rate in both groups
and found in monotherapy and polypharmacy the following
discontinuation median times: 192 and 100 days for aripipra-
zole; 222 and 86 days for olanzapine; 176 and 91 days for que-
tiapine; and 157 and 93 days for risperidone. Although a
combination of antipsychotic drugs leads to faster discontinua-
tion rates, it has a smaller likelihood of hospitalization and
mortality and it is more efficacious against the exacerbation
of the psychotic symptoms. A way to reduce the high discon-
tinuation rate is to administer an injectable depot form of the
combined antipsychotic drugs [46].
4. Conclusion
Among the conventional antipsychotic drugs, risperidone
decreases the PANSS score like haloperidol but improves the
negative schizophrenic symptoms less than olanzapine. As
described above, risperidone often causes EPS and hyperpro-
lactinemia. It causes weight gain and metabolic side effects
less severely than olanzapine and clozapine. Paliperidone has
similar antipsychotic and adverse effects like risperidone, but
it can be administered instead of risperidone if the liver
function is impaired, because it is excreted mainly through
the kidneys. Olanzapine has a superior antipsychotic effect
and improves better negative schizophrenic symptoms than
other antipsychotic drugs. It causes less seldom EPS due to
its mechanism of action. However, it causes metabolic side
effects and weight gain to a larger extent than risperidone, ari-
piprazole, quetiapine or ziprasidone. Due to its mechanism of
action, olanzapine is a prolactin-sparing antipsychotic drug.
Quetiapine has a better antipsychotic effect than haloperidol
as a consequence of the strong 5-HT2A antagonistic effect
and seldom causes EPS. It leads to metabolic side effects
and weight gain like risperidone, but less severely than olanza-
pine. In the treatment with quetiapine, sexual dysfunction
occurs seldom. Ziprasidone is a safe antipsychotic drug and
also has an antidepressant effect. It seldom has extrapyramidal
side effects and causes more metabolic side effect than risper-
idone and olanzapine. Hyperprolactinemia is described in a
small number of patients. Clozapine has the strongest antipsy-
chotic effect among the antipsychotic drugs and very seldom
causes EPS, because it blocks other dopaminergic subrecep-
tors than D2 receptors. It increases glucose and cholesterol
levels and causes weight gain like olanzapine but does not
increase prolactin levels. In order to diagnose patients with
neutropenia which occurs in 3% of them, blood cell count
should be taken every 3 weeks. Aripiprazole has different
mechanisms of action. It has a similar antipsychotic effect
like other antipsychotic drugs and exerts an antidepressant
effect. EPS occurs very seldom and patients do not suffer
sexual dysfunction. It causes metabolic side effects and weight
less than risperidone and olanzapine.
Among the recently admitted antipsychotic drugs, we
have mentioned lurasidone, asenapine and cariprazine.

Lurasidone has a comparable antipsychotic effect like other
SGAs, exerts antidepressant properties and improves cogni-
tive functions. The metabolic side effects and changes
in the prolactin levels are minimal. Akathisia occurs in
11% of the patients. Asenapine has an antipsychotic effect,
improves negative schizophrenic symptoms like olanzapine
and also improves cognitive functions. Metabolic side
effects, EPS and changes in the prolactin levels were found
to be low. As previously mentioned, cariprazine has a differ-
ent mechanism of action. It decreases the PANSS total
score; however, the long-lasting antipsychotic effect should
be investigated in clinical trials. Metabolic side effects,
weight gain and changes in the prolactin levels were not
observed. EPS occurs infrequently.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
When two antipsychotic drugs are combined in a first-
episode of schizophrenia, the discontinuation rate is higher
than when a monotherapy treatment was chosen. However,
patients treated with that medication have a lower risk of mor-
tality and hospitalization. A question arises, whether the
combined antipsychotic drugs should be administered in an
injectable depot form. In order to maintain a continuous
decrease in the PANSS total score, it would be favorable
to continue the treatment with two antipsychotic drugs
administered in an injectable depot form.
For personal use only.
In conclusion, the mentioned antipsychotic drugs are safe
and tolerable drugs for long-term treatment of schizophrenia.
However, clinical trials on the long-term efficacy in the treat-
ment of schizophrenic patients with lurasidone, asenapine and
above all with cariprazine should still be carried out. Clozapine
and olanzapine have a superior therapeutic effect and more
side effects. The side effects should be observed, and if cloza-
pine is administered, a regular blood cell count is necessary.
5. Expert opinion
The described antipsychotic drugs are essential for the treat-
ment of schizophrenia. The SGAs are safe and tolerable drugs,
but the followings aspects should still be considered. As most
schizophrenic patients show a recurrence of positive and nega-
tive psychotic symptoms, clinical trials should be carried out
for a period of some years in order to know whether psychotic
symptoms are treated sufficiently or whether these symptoms
appear again. The post-hoc analysis about the psychotic effect
and side effects performed by Rummel-Kluge [32] merits com-
ment because it indicates a necessary serum concentration of
the antipsychotic drug administered in order to maintain a
decrease in the total PANSS score. Long-term examinations
are necessary. The discontinuation rate of schizophrenic
patients in taking antipsychotic drugs should be considered
in depth. This fact is important in many aspects. On one
hand, if patients decide on their own to take no longer this
treatment, it can worsen the mental illness and makes an addi-
tional treatment necessary. On the other hand, the reasons for
the discontinuation of the antipsychotic treatment should be
elucidated. Possible reasons could be EPS or the lacking
Expert Opin. Drug Saf. (2014) 13(8)
Safety of antipsychotic drugs
patients’ insight in the disease. Consequently, a long-term anti-
psychotic treatment combined with a social therapy and with a
psychoeducation should be compared to a single pharmaco-
therapy. By a psychoeducation, patients should recognize
disease symptoms, differentiate them from adverse effects and
learn an insight in the disease. The appropriate antipsychotic
drug which achieves a long-term reduction of psychotic symp-
toms should be put in relation to the susceptibility genes.
These genes should be examined in a large cohort of schizo-
phrenic patients in order to differentiate the patients which
profit from a treatment with antipsychotic drugs such as risper-
idone which shows a higher affinity for the D2 receptor and
those patients which can be better treated with antipsychotic
drugs such as quetiapine which shows a lower ratio of the
D2/5-HT2A receptor occupancy. Using these recommenda-
tions, the physician would have a technique to better choose
the appropriate antipsychotic drug. EPS occurs in the adminis-
tration of recently admitted antipsychotic drugs. Akathisia
occurs in 11% of the patients treated with lurasidone. There-
fore, a score should be developed in order to quantify the
severeness of EPS, that is, parkinsonian symptoms, dyskinesia
and akathisia. Besides, it should be examined the occurrence
of permanent dyskinesia which appears frequently after the
administration of typical antipsychotic drugs such as haloperi-
dol. It is known that aripiprazole improves the quality of life.
Examinations about different aspects of quality of life should
be performed after the administration of other antipsychotic
drugs. Aripiprazole and cariprazine have a partial D2 agonism
and achieve a better quality of life. However, because the
different mechanism of actions of aripiprazole and cariprazine
does not exclude that dopamine hyperactivity occurs again,
long-term examinations about the safe antipsychotic effect of
such drugs are necessary. The antipsychotic drugs asenapine,
lurasidone and cariprazine are found to improve cognitive
functions. A question should be answered, whether patients
obtaining these drugs are able to exert a profession for a
constant period of time in comparison with patients treated
with conventional antispychotic drugs. The long-term exami-
nations about the safety of aripiprazole and cariprazine are
very important, because basic scientists should know whether
it is worth developing new antipsychotic drugs with a partial
agonism at dopaminergic and serotonergic subreceptors. It
should be also examined whether treatment-resistant schizo-
phrenic patients treated with two combined antipsychotic
drugs, administered as an injectable depot form, have or not
a better outcome and a lower discontinuation rate. On devel-
oping new antipsychotic drugs, a question arises whether the
interaction with other dopaminergic and serotonergic, nico-
tinic cholinergic or glutaminergic ionotropic or metabotropic
subreceptors, receptors of peptides (e.g., CCKA subreceptor)
or cannabinoid receptors could occur. This review is focused
on the treatment of the paranoid and hallucinatory form of
schizophrenia. The question arises whether auditory hallucina-
tions can be treated sufficiently by conventional antipsychotic
drugs. It should be investigated whether new antipsychotic
9
 F.-M. Werner & R. Coveñas

drugs such as CCKA receptor agonists or cannabinoid CB1 Declaration of interest

receptor antagonists could achieve progress in the treatment
of these psychotic symptoms.
Acknowledgements
The authors wish to thank Mr Nicholas Skinner (University of
Salamanca) for supervising the English text and Mrs Carmen
Payán (University of Salamanca) for technical assistance.
The authors have no relevant affiliations or financial
involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.

Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
antipsicóticos. Actas Esp Psiquiatr total score and clinical utility.
2009;37:330-42 Schizophr Res 2013;146:146-52
.. This review develops a
8. Nasrallah HA, Silva R, Philipps D, et al.
pharmacokinetic-pharmacodynamic

1. Klosterkoetter J. Indicated prevention of Lurasidone for the treatment of acutely

schizophrenia. Dtsch Arztebl Int
2008;105:532-9
2. Werner FM, Coveñas R. Classical
. This study evaluates the antipsychotic
neurotransmitter and neuropeptides
involved in schizophrenia: how to choose
the appropriate antipsychotic drug?
Curr Drug Ther 2013;8:132-43
9.
3. Vasilyeva I, Biscontri RG, Enns MW,
et al. Movement disorders in elderly
For personal use only.
psychotic patients with schizophrenia:
a 6-week, randomized, placebo-controlled
study. J Psychiatr Res 2013;47:670-7
efficacy and the side effects in an acute
exacerbation of schizophrenia in
comparison to placebo.
Caccia S, Invernizzi RW, Nobili A, et al.
A new generation of antipsychotics:
pharmacology and clinical utility of
model from 12 clinical trials and
compares clinical utility of SGAs.
14. Venkatesh PR, Kozielska M,
Suleiman AA, et al.
Pharmacokinetic-pharmacodynamic
modeling of antipsychotic drugs in
patients with schizophrenia part II: the
use of subscales of the PANSS score.
Schizophr Res 2013;146:153-61
. This review compares the clinical

users of risperidone and first generation utility of SGAs according to a

antipsychotic agents: a Canadian
population-based study. PLoS One
2013;8:e64217
4. Thomas SP, Nandhra HS, Singh SP.
Pharmacological treatment of first-
eipsode schizophrenia: a review of the
literature. Prim Care Companion
CNS Disord 2012;14:PCC.11r01198
. This review is a meta-analysis over the
last 25 years about the efficacy and the
adverse effects of the second-generation
antipsychotic drugs (SGAs).
5. Maher AR, Theodore G. Summary of
the comparative effectiveness review on
off-label use of atypical antipsychotics.
J Manag Care Pharm 2012;18:S1-20
.. This review summarizes the efficacy
and tolerability of conventional and
newer antipsychotic drugs in the
treatment of schizophrenia and related
psychiatric diseases.
6. Elsworth JD, Groman SM, Jentsch JD,
et al. Asenapine effects on cognitive and
monamine dysfunction elicited by
subchronic phencyclidine administration.
Neuropsychopharmacology
2011;62:1442-52
7. Tajima K, Fernández H, López-Ibor JJ,
et al. Tratamientos para la esquizofrenia.
Revisión crı́tica sobre la farmacologı́a y
mecanismos de acción de los
cariprazine in schizophrenia. Ther Clin
Risk Manag 2013;9:319-28
. This review summarizes the
pharmacokinetics and
pharmacodynamics of cariprazine and
discusses the results of short-term
controlled clinical trials.
10. Stahl SM, Cucchiaro J, Simonelli D,
et al. Effectiveness of lurasidone for
patients with schizophrenia following
6 weeks of acute treatment with
lurasidone, olanzapine, or placebo:
a 6-month, open-label, extension study.
J Clin Psychiatry 2013;74:507-15
11. Novakovic V, Adel T, Peselow E, et al.
Long-acting injectable antipsychotics and
the development of postinjection
delirium/sedation syndrome (PDSS).
Clin Neuropharmacol 2013;36:59-62
12. Klingberg S, Herrlich J, Wiedemann G,
et al. Adverse effects of cognitive
behavioural therapy and cognitive
remediation in schizophrenia: results of
the treatment of negative symptoms
study. J Nerv Ment Dis
2012;200:569-76
13. Venkatesh PR, Kozielska M,
Suleiman AA, et al. Pharmacokinetic-
pharmacodynamic modeling of
antipsychotic drugs in patients with
schizophrenia part I: the use of PANSS
pharmacokinetic-pharmacodynamic
model and finds that olanzapine has a
superior antipsychotic effect than
other SGAs.
15. Citrome L. Oral paliperidone extended-
release: chemistry, pharmacodynamics,
pharmacokinetics and metabolism,
clinical efficacy, safety and tolerability.
Expert Opin Drug Metab Toxicol
2012;8:873-88
16. Amr M, Lakhan SE, Sanhan S, et al.
Efficacy and tolerability of quetiapine
versus haloperidol in first-episode
schizophrenia: a randomized clinical trial.
Int Arch Med 2013;6:47
. This randomized clinical trial
compares the efficacy and the side
effects of quetiapine and haloperidol in
the acute treatment of schizophrenia,
while the assessment was performed at
the beginning of the study and after
6 and 12 weeks.
17. Shang DW, Li LJ, Wang XP, et al.
Population pharmacokinetic/
pharmacodynamic model for clozapine
for characterising the relationship
between accumulated exposure and
PANSS scores in patients with
schizophrenia. Ther Drug Monit
2014;36(3):378-86
.
This review establishes a
pharmacokinetic/pharmacodynamic

10 Expert Opin. Drug Saf. (2014) 13(8)


model in order to characterize a
relationship between the accumulated
clozapine dosage and the changes in
the positive and negative syndrome
scale total score.
18. Khanna P, Suo T, Komossa K, et al.
Aripiprazole versus other antipsychotics
for schizophrenia. Cochrane Database
Syst Rev 2014;1:CD006569
. This review is a meta-analysis of
174 randomized clinical trials
comparing the effectiveness and the
adverse effects of aripiprazole with
other SGAs.
19. Park YW, Kim Y, Lee JH.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14
Antipsychotic-induced sexual dysfunction
and its management. World J
Mens Health 2012;30:153-9
20. Citrome L, Weiden PJ, McEvoy JP,
et al. Effectiveness of lurasidone in
schizoprenia or schizoaffective patients
switched from other antipsychotic drugs:
a 6-month, open- label, extension study.
CNS Spectr 2013;16:1-10
.. This clinical trial is a 6-month,
open-label, extension study with stable,
For personal use only.
schizophrenic patients, who were
switched to lurasidone. Lurasidone is a
safe, well-tolerated treatment of
schizophrenia and
schizoaffective disorder.
21. Leucht S, Zhao J. Early improvement as
a predictor of treatment response and
remission in patients with schizophrenia:
a pooled, post-hoc analysis from the
asenapine development program.
J Psychopharmacol 2014;28:387-94
22. Potkin SG, Phiri P, Szegedi A, et al.
Long-term effects of asenapine in
patients with persistent negative
symptoms of schizophrenia: a pooled
analysis. Schizophr Res 2013;150:442-9
23. Szegedi A, Verweij P,
van Duijnhoven W, et al. Meta-analysis
of the efficacy of asenapine for acute
schizophrenia: comparisons with placebo
and other antipsychotics.
J Clin Psychiatry 2012;73:1533-40
. This review includes four clinical trials
about the efficacy and safety of
asenapine in the treatment of acute
schizophrenia. Asenapine has a
superior therapeutic effect than
placebo and exerts a comparable
therapeutic action to those carried out
by other SGAs.
24. Weber J, McCormack PL. Asenapine.
CNS Drugs 2009;23:781-92
25. Citrome L. Cariprazine: chemistry,
pharmacodynamics, pharmacokinetics,
and metabolism, clinical efficacy, safety
and tolerability. Expert Opin Drug
Metab Toxicol 2013;9:193-206
26. Citrome L. Cariprazine in schizophrenia:
clinical efficacy, tolerability, and place in
therapy. Adv Ther 2013;30:114-26
27. Durgam S, Starace A, Li D, et al. An
evaluation of the safety and efficacy of
cariprazine in patients with acute
excacerbation of schizophrenia: a phase II
randomized, clinical trial. Schizophr Res
2014;152:450-7
.. This is a multi-national, double-blind,
placebo- and active-controlled Phase II
clinical trial about the safety and
tolerability of asenapine in the
exacerbation of schizophrenia.
28. Werner FM, Coveñas R. Possible
therapeutic options in Parkinson’s disease
according to a neuronal network.
Neurol Rehabil 2012;18:420-1
29. Stahl SM, Cucchiaro J, Simonelli D,
et al. Effectiveness of lurasidone for
patients with schizophrenia following
6 weeks of acute treatment with
lurasidone, olanzapine or placebo:
a 6-month, open-label, extension study.
J Clin Psychiatry 2013;74:507-15
30. Stoner SC, Pace HA. Asenapine:
a clinical review of a second-generation
antipsychotic. Clin Ther
2012;34:1023-40
31. Gopal S, Hough D, Karcher K, et al.
Risk of cardiovascular morbidity with
risperidone or paliperidone treatment:
analysis of 64 randomized, double-blind
trials. J Clin Psychopharmacol
2013;33:157-61
32. Rummel-Kluge C, Komossa K,
Schwarz S, et al. Head-to-head
comparison of metabolic side effects of
second generation antipsychotics in the
treatment of schizophrenia: a systematic
review and meta-analysis. Schizophr Res
2010;123:225-33
.. This meta-analysis reviews the
metabolic side effects of the commonly
used SGAs and finds that SGAs
produce more metabolic side effects
than typical neuroleptics.
33. Bodén R, Edman G, Reutfors J, et al.
A comparison of cardiovascular risk
factors for ten antipsychotic drugs in
clinical practice.
Neuropsychiatr Dis Treat 2013;9:371-7
Expert Opin. Drug Saf. (2014) 13(8)
Safety of antipsychotic drugs
34. Kemp DE, Zhao J, Cazorla P, et al.
Weight change and metabolic effects of
asenapine in patients with schizophrenia
and bipolar disorder. J Clin Psychiatry
2014;75(3):238-45
35. Wang ZM, Xiang YT, An FR, et al.
Frequency of hyperprolactinemia and its
association with demographic and clinical
characteristics and antipsychotic
medications in psychiatric inpatients in
China. Perpect Psychiatric Care
2013;doi: 10.1111/ppc.12050
36. Besnard I, Auclair V, Callery G, et al.
Antipsychotic-drug-induced-
hyperprolactinemia: pathophysiology,
clinical features and guidance. Encephale
2013;40:86-94
37. Yeon WP, Yooseok K, Yun HL.
Antipsychotic-induced sexual dysfunction
and its management. World J
Mens Health 2012;30:153-9
38. Najim H, Islam N. Checking physical
care of people on risperidone long term
injectable depot. Psychiatr Danub
2013;25:S171-3
39. Caccia S. Biotransformation of
post-clozapine antipsychotics:
pharmacological implications.
Clin Pharmacokinet 2000;38:393-414
40. Khan AA, Harvey J, Sengupta S.
Continuing clozapine with granulocyte
colony-stimulating factor in patients with
neutropenia. Psychopharmacol
2013;3:266-71
41. Ringbäck Weitoft G, Berglund M,
Lindstr€om EA, et al. Mortality,
attempted suicide, rehospitalization and
prescription refill for clozapine and other
antipsychotics in Sweden-a register-based
study. Pharmacoepidemiol Drug Saf
2014;23:290-8
42. Duncan EJ, Woolson SL, Hamer RM.
Treatment compliance in veterans
administration schizophrenia spectrum
patients treated with risperidone
long-acting injectable.
Int Clin Psychopharmacol
2012;27:283-90
43. Crespo-Facorro B, de la Foz VO,
Mata I, et al. Treatment of first-episode
non- affective psychosis: a randomized
comparison of aripiprazole, quetiapine
and ziprasidone over 1 year.
Psychopharmacology (Berl)
2013;231:357-66
.. This randomized clinical trial
compares the effectiveness and the
discontinuation rate of quetiapine,
11
 F.-M. Werner & R. Coveñas

ziprasidone and aripiprazole in a

1-year treatment of schizophrenia.
44. Park JI, Cho DH, Hahn SW, et al. The
advantage of using 3-week data to
predict response to aripiprazole at week
6 in first-episode psychosis.
Int Clin Psychopharmacol 2014;29:77-85
45. Dold S, Leucht M. Pharmacotherapy of
treatment-resistant schizophrenia:
a clinical perspective. Evid Based
Ment Health 2014;17:32-7
46. Katona L, Czobor P, Bitter I. Real-world
effectiveness of antipsychotic
monotherapy vs. polypharmacy in
schizophrenia: to switch or to combine?
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by 94.134.203.11 on 06/30/14

A nationwide study in Hungary.

Schizophr Res 2014;152:246-54

Affiliation
Felix-Martin Werner†1,2 & Rafael Coveñas2
†
Author for correspondence
1
H€ohere Berufsfachschule für Altenpflege und
Ergotherapie der Euro Akademie P€oneck,
Carl-Gustav-Vogel-Str. 13, P€oneck 07381,
Germany
2
University of Salamanca, Instituto de
For personal use only.

Neurociencias de Castilla y León (INCYL),

Laboratory of Neuroanatomy of the Peptidergic
Systems (Lab. 14), c/Pintor Fernando Gallego,
1, 37007-Salamanca, Spain
Tel: +34 923 29 44 00 ext 1856;
Fax: +34 923 29 45 49;
E-mail: felixm-werner@versanet.de

12 Expert Opin. Drug Saf. (2014) 13(8)