Review Not peer-reviewed version

The Clinical Antipsychotic Effect of

Recently Developed Antipsychotic
Drugs in Schizophrenia

Felix-Martin Werner * and Rafael Coveñas

Posted Date: 20 May 2024

doi: 10.20944/preprints202405.1223.v1

Keywords: antipsychotic drug; M4 and M1 receptor agonist; negative schizophrenia symptoms; neural
network; schizophrenia; trace-amine-associated receptor 1 agonist; ulataront; xanomeline

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Review

The Clinical Antipsychotic Effect of Recently

Developed Antipsychotic Drugs in Schizophrenia
Felix-Martin Werner 1,2,* and Rafael Coveñas 2,3
1 Grone Gesundheitsakademie, Weimar, Germany
2 Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic
Systems, University of Salamanca, Salamanca, Spain
3 Group GIR USAL: BMD (Bases Moleculares del Desarrollo), Salamanca, Spain

* Correspondence: [email protected]; Tel.: +34/923/29 44 00, extension 1856; Fax: +34/923/29 45 49

Abstract: Schizophrenia and schizoaffective disorder are generally treated with second-generation
antipsychotic drugs. These drugs are mostly D2 and 5-HT2A antagonists. They improve positive
schizophrenia symptoms sufficiently well; however, they ameliorate negative schizophrenia
symptoms and cognitive functions to a small extent. We review novel antipsychotic drugs exerting
a partial agonism at dopaminergic and serotonergic receptors such as cariprazine, brexipiprazole
and lumateperone. Besides, the mechanisms of actions of non-anti-dopaminergic antipsychotic
drugs are pointed out. Updated neural networks are used to explain the mechanism of action of M 4
and M1 receptor agonists, for example xanomeline combined with trospium or emraclidine, and
trace-amine-associated receptor 1 agonists (TAAR1), for example ulataront. Phase 3 clinical trials of
new third generation antipsychotic drugs are presented. Novel antipsychotic drugs with a partial
agonism at D2 and D3 receptors improve positive and negative schizophrenia symptoms as well as
cognitive symptoms better than second generation antipsychotic drugs. Besides, they are well
tolerated. M4 and M1 receptor agonists, i.e., xanomeline combined with trospium or emraclidine,
and TAAR1 agonists, i.e., ulataront, have promising results in clinical trials; they well improve
negative schizophrenia symptoms and cognitive functions. Phase 3 clinical trials offer promising
results for anti-dopaminergic and non-anti-dopaminergic novel antipsychotic drugs. These new
non-anti-dopaminergic antipsychotic drugs better emend negative schizophrenia symptoms, and
they better improve cognitive functions than second-generation antipsychotic drugs. Promising
new antipsychotic drugs are cariprazine, brexipiprazole, lumateperone, ulataront, and xanomeline
combined with trospium. Although phase 3 clinical studies are not yet completed, they showed a
therapeutic effect superior to those achieved by second-generation antipsychotic drugs. They are
tolerated very well, and they better treat negative schizophrenia symptoms and improve cognitive
functions.

Keywords: antipsychotic drug; M4 and M1 receptor agonist; negative schizophrenia symptoms;

neural network; schizophrenia; trace-amine-associated receptor 1 agonist; ulataront; xanomeline

1. Introduction
Schizophrenia and schizoaffective disorder are chronic disabling diseases with positive,
negative, affective, and cognitive symptoms. Generally, these mental diseases are treated with
antipsychotic drugs. Schizophrenic disorders have a genetic etiology in 80% of cases. The disposable
antipsychotic drugs have different therapeutic effects on positive and negative schizophrenic
symptoms, and they can cause movement disturbances, that is extrapyramidal symptoms (EPS). The
often-prescribed antipsychotic drugs have an antagonism at D2 and 5-HT2A receptors [1,2]. Some new
antipsychotic drugs have been developed, among them the third-generation antipsychotic drugs
which exert a partial agonism at dopaminergic and serotonergic receptors. Antipsychotic drugs
without exerting an antagonism or a partial agonism at dopaminergic receptors are available as well.

© 2024 by the author(s). Distributed under a Creative Commons CC BY license.

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Xanomeline, combined with trospium, an anticholinergic drug, and trace-amine associated receptor
1 (TAAR1) agonists, have been developed and are being examined in clinical studies [3]. M4 and M1
receptor agonists, i.e., xanomeline combined with trospium, exert an antipsychotic effect, because an
agonism at M4 and M1 muscarinic cholinergic receptors promotes the blockade of D2 dopaminergic
receptors. In this review, the neural networks involved in the prefrontal cortex in schizophrenia are
updated. Clinical studies should still be carried out to know whether these new antipsychotic drugs
are therapeutically comparable or superior to often used antipsychotic drugs [1]. In the first clinical
studies performed, cariprazine, brexipiprazole, lumateperone, xanomeline, and ulataront well
treated negative schizophrenia symptoms and improved cognitive functions [4,5]. The aim of this
review is to update the therapeutic advantages of third-generation antipsychotic drugs in comparison
to second-generation antipsychotic drugs and to point out the results of first phase 3 clinical studies.

2. Clinical Antipsychotic Effect of Second-Generation Antipsychotic Drugs

Second-generation antipsychotic drugs such as risperidone, olanzapine, quetiapine, and
clozapine are used in the treatment of schizophrenia and schizoaffective disorder in a wide range.
Most of these drugs are D2 and 5-HT2A receptor antagonists and only clozapine has a D3 and D4 and
5-HT2A antagonistic effect and a 5-HT1A agonistic effect. Clozapine can be administered in treatment-
resistant psychotic disorders. All second-generations antipsychotic drugs can cause movement
disturbances, i.e., EPS. Only clozapine does not have these side effects, because it does not block the
D2 receptor [6,7]. These drugs have a good antipsychotic effect, they improve above all positive
antipsychotic schizophrenia symptoms, and also negative schizophrenia symptoms, but to a lesser
degree. Olanzapine better improves mutism, depression, social withdrawal than other second-
generation antipsychotic drugs [7]. Olanzapine, quetiapine and clozapine have a prolactin-sparing
effect; risperidone in contrast raises prolactin levels, because it has a high affinity for the D2 receptor
[4–6].

3. Mechanisms of Action of Recently Developed Antipsychotic Drugs

Some third-generation antipsychotic drugs have been developed. Cariprazine, brexipiprazole
and lumateperone have a partial agonistic effect at dopaminergic and serotonergic receptors. This
partial agonism at D2 and 5-HT2A receptors might better improve negative schizophrenia symptoms,
because these symptoms are associated to hypoactive dopaminergic and serotonergic neurons in the
prefrontal cortex [5,8–12]. Three new third-generation antipsychotic drugs do not block
dopaminergic receptors, namely TAAR1 agonists, M4 and M1 receptor agonists. The antipsychotic
effects of these new drugs appear in Table 1 [13,14].

4. Why Is the Development of Novel Antipsychotic Drugs Necessary, What Are the Missing
Clinical Effects in the Efficacy of Second-Generation Antipsychotic Drugs?
Although second-generation antipsychotic drugs are widely used in the treatment of
schizophrenia patients, they have lacking therapeutic effects and cause many negative adverse
effects. First of all, they do not treat sufficiently negative schizophrenia symptoms such as mutism,
social withdrawal and depression. Besides, it could not be shown that these drugs improve cognitive
functions. They can cause movement disturbances, and libido is reduced [8]. However, antipsychotic
drugs like cariprazine, brexipiprazole, and lumateperone better ameliorate cognitive functions.
Besides, they do not reduce libido, and they do not influence movement. Promising new drugs like
ulataront and xanomeline combined with trospium have a good therapeutic effect in improving
cognitive functions [15].
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Table 1. Mechanism of action and therapeutic effects in phase 3 clinical trials of novel antipsychotic
drugs.

Xanome-line
Luma-
_ Cariprazine Brexipiprazole SEP 363856 combined
teperone
with trospium
Approved for The approval
Ulataront (SEP
treatment of of xanomeline,
Approved for Approved for 363856) has got
Food and schizophrenia and combined with
treatment of treatment of a break-through
Drug as an adjunctive trospium for
schizophrenia adult patients therapy
Administratio therapy for major treatment of
and acute mania with schizo- designation for
n (FDA) depression and for schizophrenia
in bipolar phrenia in treatment of
approval agitated patients is expected in
disorder in 2015 2019 schizophrenia
with Alzheimer’s September,
by FDA
disease in 2015 2024
An agonistic
effect at
A partial
An agonistic M1/M4
agonism at
effect at receptors.
A partial D2/5-HT2A
TAAR1/5-HT1A M1/M4
agonism at receptors;
receptors. It muscarinic
D2/D3 receptors A partial agonism blocks
stabilizes mono- cholinergic
Mecha-nisms with a higher at D2/D3 receptors serotonin
aminergic neurons
of action affinity for D3 and has a 5-HT1A reuptake, and
neurotransmissi stimulation
receptors and an agonism interferes
on, i.e., leads to the
agonism at 5- with
dopaminergic blockade of D2
HT1A receptors glutamate
and serotonergic dopa-minergic
neurotrans-
neurons neurons in the
mission
prefrontal
cortex
emends well
positive and emends well
Ameliorates improves well
Improves positive negative positive and
positive and positive and
and negative schizo- negative
negative negative
Thera-peutic schizophrenia phrenia schizophrenia
schizophrenia schizo-phrenia
effects symptoms and symptoms symptoms and
symptoms and symptoms and
depressive and improves
depressive cognitive
symptoms ameliorates cognitive
symptoms functions
social functions
capabilities
Thera-peutic
effects on Good
positive Improves Improves Ameliorates therapeutic improves well
schizo-phrenia effect
symptoms
Thera-peutic
effects on Good
Good therapeutic
negative therapeutic Ame-liorates Improves Improves
effect
schizo-phrenia effect
symptoms
Good Good Good
Thera-peutic Good therapeutic therapeutic therapeutic therapeutic
Good anti-
effects on effect on effect on effect on effect on
depressive and
affective depressive and depressive depressive and depressive and
antimanic effects
symptoms manic symptoms and manic manic manic
symptoms symptoms symptoms
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Thera-peutic
Improves
effects on
Improves Improves social Improves Improves
cognitive
capabilities
symptoms
Movement
disturbances are It caused very
Movement Movement
reduced; few adverse
The frequency of disturbances distur-bances
however, effects, for
movement and metabolic and metabolic
akathisia example
Adverse disturbances, and and cardiac and cardia
appears in 11% movement
effects cardiac and adverse adverse effects
of patients. disturbances or
metabolic adverse effects are are seen
Metabolic and cardiac and
effects are reduced largely scarcely and
cardiac adverse metabolic
reduced rarely
effects are adverse effects
reduced
[3,9,10,14,16–
References [19–22] [22–25] [26,27] [28–36]
19]

4.1. Cariprazine
Cariprazine is a new third-generation antipsychotic drug which was approved by FDA in 2015
for the treatment of schizophrenia and affective disorders. It can be applied for the treatment of acute
mania in bipolar disorder [37]. Cariprazine has a partial agonism at D 2 and D3 receptors with a 10-
fold higher affinity for the D3 receptor. Besides, it has an agonism at 5-HT1A receptors. Its
antidopaminergic effects is stronger than with aripiprazole and brexipiprazole [38]. It exerts
antipsychotic, antimanic and antidepressive effects. In clinical trials, it showed comparable
antipsychotic effects like risperidone. In these trials, cariprazine improved psychotic symptoms,
namely positive as well as negative schizophrenia symptoms and cognitive functions. Cariprazine is
an activating antipsychotic drug, therefore it can cause sleep disturtances [39]. However, cariprazine
can cause akathisia in 11 % of the patients treated. Moreover, cariprazine exerts antimanic and
antidepressive actions (see Table 2) Cariprazine can emend psychotic, depressive and manic
symptoms, the treatment with this drug better improves quality of life than a pharmacotherapy with
risperidone. It can be used in treatment-resistant forms as an alternative of clozapine
[2,8,13,15,17,18,37–39].

4.2. Brexipiprazole
Brexipiprazole is a third-generation antipsychotic drug which was approved for the treatment
of schizophrenia and major depression bipolar disorder in 2015. It can be used as an augmentation
therapy in the treatment of major depression [37].This drug has a partial agonism at D 2 and D3
receptors and an agonism at 5-HT1A receptors and an antagonism at 5-HT2A receptors. [20,38]. The
occurrence of adverse effects is reduced, i.e., movement disturbances and metabolic and cardiac side
effects. Brexipiprazole causes adverse effects like akathisia, headache, somnolence, tremor, weight
gain. Brexipiprazole is neither sedating nor activating, it seldom causes sleep disturbances [39]. 86
clinical trials were undertaken to study the antipsychotic effects of brexipiprazole; it improved
negative schizophrenia symptoms, as well as affective and cognitive symptoms (see Table 2)
[20,21,37–40].

4.3. Lumateperone
Lumateperone is a new antipsychotic drug which was approved for the treatment of adult
patients suffering from schizophrenia in 2019 [23]. It exerts a partial agonism at D2 and 5-HT2A
receptors, blocks serotonin reuptake and interferes with the glutamatergic neurotransmission [24,25].
Lumateperone reduces dopamine release, therefore dopamine activity is more reduced than with
other antipsychotic drugs [40]. It has an antidepressive effects by the blockade of the serotonin release
and by the antagonism of 5-HT2A receptors. The occurrence of movement disturbances, i.e., EPS and
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metabolic and cardiac side effects have been largely reduced. 20 clinical trials were performed with
1,900 participants, and it was shown that lumateperone improved negative schizophrenia symptoms
and social capabilities (see Table 2) The short-term effects of these newer antipsychotic drugs show
less adverse effects and a good therapeutic effects on negative schizophrenia symptoms, however
long-term studies are very rare. [23–26,39,40].

4.4. TAAR1 Agonists

Trace-amine-associated receptor 1 agonists (TAAR1 agonists) play a key role in the monoamine
neurotransmission; through a 5-HT1A agonistic effect and an agonism at trace-amine-associated 1
receptors (TAAR 1), they also might have a therapeutic effect in schizophrenia, anxiety, and
addiction. Ulataront (SEP 363856), a TAAR1 agonist, has being examined in clinical trials in phase 3
for the treatment of schizophrenia [27]. In these trials, it improved positive and negative
schizophrenia symptoms. Ulataront activates TAAR1 and 5-HT1A receptors. In clinical trials, it also
improved positive and negative schizophrenia symptoms in an exacerbation of this disorder. It did
not cause movement disturbances nor raised prolactin levels [27]. In the first clinical trial (NCT
02969382) performed with ulataront (SEP 363856), this TAAR1 agonist improved not only positive,
but also negative schizophrenia symptoms and cognitive symptoms. This new drug caused very few
adverse effects, for example EPS and metabolic and cardiac side effects. An exacerbation of acute
schizophrenia can be observed as an adverse effect in the treatment with SEP 363856 [28]. TAAR1
agonists stabilize the monoamine neurotransmission also through a 5-HT1A agonistic effect [28]. By
stimulating TAAR 1 and 5-HT1A receptors, monoamine neurons, i.e., dopaminergic and serotonergic
neurons are stabilized, namely that a normoactive neurotransmission is enabled (see Table 2) [14].

4.5. Xanomeline Combined with Trospium

M4 and M1 receptor agonists are promising antipsychotic drugs that might be used in the
treatment of schizophrenia. Xanomeline, an M4 and M1 receptor agonist, combined with trospium, an
anticholinergic drug, can be approved by FDA for the treatment of schizophrenia patients. The
decision about this approval will be taken on September 26, 2024. Dose-dependent cholinergic side
effects such as nausea, vomiting, diarrhea, sweating and hypersalivation can be reduced by the
administration of the anticholinergic drug trospium [13]. In a phase I trial, a group of healthy
volunteers receiving xanomeline alone was compared with a group treated with xanomeline,
combined with trospium. The results was that the cholinergic adverse effects were reduced by 49 %,
and the antipsychotic effects were not changed [40,41]. The long-term effect of stimulating M1 and
M4 receptors indicates a weakening of the receptor occupancy and activation [42,43]. The effect of
xanomeline on the sleep architecture was examined in animal experiements. It was found that a direct
stimulation of muscarinic cholinergic neurons produces increases in wake and arousal an decreases
in the non-rapid eye movement [44].Three clinical studies in comparison with placebo have been
performed. Xanomeline, combined with trospium ameliorated positive and negative schizophrenia
symptoms, improved cognitive deficits, and it was well tolerated [28–30]. Xanomeline, combined
with trospium, improved cognitive and negative schizophrenia symptoms in phase 2 and 3 clinical
trials, because in schizophrenia a reduced cholinergic signaling occurs in the hippocampus,
dorsolateral prefrontal cortex, and basal ganglia (see Table 2) [31–35]. According to the neural
networks involved schizophrenia, a direct interaction between D2 dopaminergic and M1 and M4
muscarinic cholinergic neurons exists in the hippocampus and prefrontal cortex (see Figure 1). M1
and M4 muscarinic cholinergic neurons activate medium spiny neurons in the prefrontal cortex,
namely GABAergic and somatostatinergic neurons, which strongly presynaptically inhibit D2
dopaminergic neurons via GABAA and somatostatin 1 receptors. D2 dopaminergic neurons activate
GABAergic neurons, and the latter neurons inhibit glutamatergic neurons, which transmit an
activating potential via NMDA receptors to muscarinic cholinergic neurons [36].
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Table 2. Therapeutic effects of second- and third-generation antipsychotic drugs.

Second-generation antipsychotic drugs

Criterium 2nd generation antipsychotic drugs
Good therapeutic effect on positive
Therapeutic effect on disorder symptoms
schizophrenia symptoms
Therapeutic effect on negative schizophrenia Reduced therapeutic effect on negative
symptoms schizophrenia symptoms
Therapeutic effect on cognitive symptoms No therapeutic effect on cognitive symptoms
References 5 - 36
Mechanism of action of 3rd generation antipsychotic drugs
Antipsychotic drug Mechanism of action
Partial agonism at D2 and D3 receptors and an
Cariprazine
agonism at 5-HT1A receptors
Partial agonism at D2 receptors and an agonism
Brexipiprazole
at 5-HT1A receptors
Partial agonism at D2 and 5-HT2A receptors,
Lumateperone blocks serotonin reuptake and interfers with the
glutamate neurotransmission
Agonism at TAAR1 receptors and 5-HT1A
Lumataront
receptors
Agonism at M4 and M1 receptors, which
Xanomeline
interacts with a D2 receptor blockade
Therapeutic and adverse effects of 3rd generation antipsychotic drugs
Therapeutic effects on positive schizophrenia
Improves well.
symptoms
Therapeutic effects on negative schizophrenia
Improves well.
symptoms
Therapeutic effects on cognitive symptoms Exerts a good therapeutic effect.
Movement disturbances Very reduced
Metabolic and cardiac adverse effects Very rarely and very reduced
References 5 - 37

Figure 1. Mechanisms of action of novel antipsychotic drugs in the brain centers involved in
schizophrenia.
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A positive allosteric modulator of the M4 receptor is emraclidine, which has been tested in a
phase 2 clinical trial in comparison to placebo. In this trial, emraclidine ameliorated positive, negative
and cognitive schizophrenia symptoms [37].
Neural pathways involved in schizophrenia in the prefrontal cortex. Classical neurotransmitters
and neuropeptides: Ach: acetylcholine; DA: dopamine; GABA: gamma-aminobutyric acid; Glu:
glutamate; SST: somatostatin. Specific receptors: D2: dopaminergic receptor; GABAA: GABAergic
receptor; M1: muscarinic cholinergic receptor; NMDA: ionotropic glutamatergic receptor; SST 1:
somatostatin receptor. A minus mark signifies a presynaptic inhibitory potential, and a plus mark
signifies a postsynaptic excitatory potential. A minus and plus mark signifies a partial agonism at the
specific receptor. The presynaptic inhibitory neurotransmitters and receptors are painted in grey. The
therapeutic effect of new antipsychotic drugs, namely the TAAR1 agonist ulataront and the M1 and
M4 receptor agonist xanomeline combined with trospium, cariprazine (Car), brexipiprazole (Brex)
and lumateperone (Lum) are included in the figure.

5. Phase III Clinical Studies

The recently developed second-generation antipsychotic drugs such as cariprazine,
brexipiprazole, lumateperone, the non-antidopaminergic antipsychotic drugs such as TAAR1
agonists, and the combination of the M1 and M4 receptor agonist xanomeline with trospium,
underwent all phase 3 clinical studies. In a phase 3b randomized, double-blind clinical study,
cariprazine was compared to risperidone in the treatment of predominant negative schizophrenia
symptoms. 227 patients were included in the cariprazine group, and 229 patients belonged to the
risperidone group. The treatment was continued for 26 weeks. Cariprazine improved PANSS
(Positive and Negative Schizophrenia Syndrome Scale) better than risperidone, above all negative
schizophrenia symptoms [45]. A 3 to 8-week pivotal study about the effect of cariprazine on cognitive
function was performed, including the Cognitive Drug Research System attention battery. An
improvement of cognitive functions in power of attention was observed when 3 mg cariprazine was
administered, but not for 6 mg cariprazine. An improvement in continuity of attention was observed
with 3 and 6 mg cariprazine [46].
In a retrospective, observational study in Japan, the discontinuation rate was compared in a
cohort of 978 patients treated with brexipiprazole and 4898 patients treated with other atypical
antipsychotics, for example aripiprazole, olanzapine, quetiapine or risperidone. Patients treated with
brexipiprazole were less likely to discontinue the treatment than patients treated with the above
mentioned atypical antipsychotics. Consequently, brexipiprazole might contribute to continue
antipsychotic treatment [47]. Brexipiprazole, examined in clinical studies, ameliorated positive and
negative schizophrenia symptoms, besides depressive and manic and cognitive symptoms [21,22].
In a randomized, placebo-controlled clinical study, 450 patients were enrolled and were treated
in a short-term treatment with lumateperone or with placebo. After treatment, the PANSS and the
Clinical Global Impression-Severity of Illness (CGI-S) scores were determined. Both scores were
improved in comparison to placebo, and no motor, cardiovascular nor endocrine adverse effects were
seen [48].
The TAAR1 agonist ulataront has been examined in phase 3 clinical trials, and it improved
positive and negative schizophrenia symptoms. Besides, it ameliorated cognitive functions, however
an acute schizophrenia exacerbation has been reported as an adverse effect. It did not cause
movement disturbances, nor did it raise prolactin levels [27,28].
M1 and M4 subreceptors stimulation in schizophrenia might be a new pharmacological strategy,
because a reduced muscarinic cholinergic activity decreased cognitive function and caused negative
schizophrenia symptoms [13]. Positive allosteric modulators of M 1 and M4 receptors exerted
antipsychotic activities in amphetamine- and MK 801-induced hyperlocomotion tasks in animal
experiments [13]. Emraclidine, a positive allosteric modulator of the M 4 receptor, and xanomeline,
combined with trospium were examined in a phase 3 clinical trial. Both compounds improved
positive and negative schizophrenia symptoms, as well as depressive and manic and cognitive
symptoms [29].
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6. Discussion
Schizophrenia and schizoaffective disorder are generally treated with second-generation
antipsychotic drugs, which are mostly D2 and 5-HT2A receptor antagonists. These drugs improve
positive schizophrenia symptoms very well; however, they treat negative schizophrenia symptoms
to a small extent, nor do they improve cognitive functions. Movement disturbances, i.e., EPS still
occur, and raised prolactin levels are often seen. The antipsychotic drug clozapine does not alter
movement, nor does it raise prolactin levels, as a consequence of a different mechanism of action.
Another question that should be answered in long-term clinical studies, is whether the new
antipsychotic drugs are secure in preventing rehospitalization of schizophrenia patients, after
psychotic symptoms get worse. Genetic techniques should also be applied to choose the appropriate
antipsychotic drug, the SNP’s of some important risk genes for schizophrenia should be examined
and might be correlated with an improved therapeutic effect of a specific antipsychotic drug. Thus,
an antipsychotic drug with a higher therapeutic effect could be selected. Some second-generation
antipsychotic drugs such as cariprazine, brexipiprazole and lumateperone have a partial agonism at
dopaminergic and serotonergic receptors. In phase 3 clinical studies, it was found that these new
drugs better treat positive and negative schizophrenia symptoms, and above all cognitive functions.
The discontinuation rate was better than with other second-generation antipsychotic drugs. Some
new antipsychotic drugs have been reported, which do not have an antagonism at dopaminergic
receptors. The TAAR1 ulataront stimulates TAAR1 receptors and stabilizes the monoamine
neurotransmission. In phase 3 clinical trials, it improved positive and negative schizophrenia
symptoms, it ameliorated cognitive functions and ameliorated affective symptoms. It did not cause
movement disturbances, nor did it raise prolactin levels. An acute schizophrenia exacerbation can
occur as an adverse effect. New promising antipsychotic drugs are the M4 and M1 receptor agonist
xanomeline, in combination with trospium, and the positive M4 receptor allosteric modulator
emraclidine. These drugs exert antipsychotic effects, which can be explained by the neural networks
involved in schizophrenia. M1 and M4 muscarinic cholinergic neurons and D2 dopaminergic neurons
exert an interaction upon each other in the prefrontal cortex. A stimulation of M 1 and M4 receptors
leads to antagonism at D2 dopaminergic neurons. Besides, it improves cognitive functions. In phase
3 clinical studies, these new drugs improved positive and negative schizophrenia symptoms well,
they improved cognitive functions, and ameliorated depressive and manic symptoms. The
occurrence of movement disturbances and endocrine and cardiovascular adverse effects were largely
reduced. The approval of xanomeline by FDA is expected in September 2024.

7. Conclusion and Future Perspectives

In order to compare the therapeutic effects of widely used second-generation antipsychotic
drugs with novel antipsychotic drugs, more clinical trials should be performed. In these clinical
studies, PANSS score should be determined, above all that regarding the negative schizophrenia
symptoms. Besides, cognitive functions should be evaluated by an assessment. The results might give
a hint to replace the second-generation antipsychotic drugs by novel antipsychotic drugs.

Conflicts of interest: The authors declare that they have no conflicts of interest.

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