Revisão Atípicos

EXCLI Journal 2014;13:1163-1191 – ISSN 1611-2156
Received: June 20, 2014, accepted: July 27, 2014, published: October 13, 2014
Review article:
CLINICAL PHARMACOLOGY OF ATYPICAL ANTIPSYCHOTICS:

AN UPDATE
M.C. Mauri1*, S. Paletta1, M. Maffini1, A. Colasanti2, F. Dragogna1, C. Di Pace1,
A.C. Altamura1
1
Department of Neuroscience and Mental Health, Pychiatric Unit, Clinical Neuropsycho-
pharmacology Unit, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale
Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy
2
Center for Affective Disorders, Department of Psychological Medicine, Institute of
Psychiatry, King's College Denmark Hill, London SE5 8AF, England
* Corresponding author: M.C. Mauri, Clinical Psychiatry, Clinical Neuropsychopharmacology

Unit, University of Milan, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico,
Via F. Sforza 35, 20122 Milano, Italy. Telephone number: +390255035997;
fax number: +390255035990; e-mail: [email protected]
ABSTRACT
This review will concentrate on the clinical pharmacology, in particular pharmacodynamic
data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que-
tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and caripra-
zine. A summary of their acute pharmacokinetics properties are also reported.
Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone
and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents
are advisable for the lower propensity to give weight gain and metabolic abnormalities in
comparison with older second-generation antipsychotics such as olanzapine or clozapine. Ac-
tually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight
and metabolic variables.
Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs
because there are no unequivocal data supporting a relationship between plasma drug levels
and clinical outcomes or side effects. The exception can be represented by clozapine for
which plasma levels of 350-420 ng/ml are reported to be associated with an increased proba-
bility of a good clinical response. Also for olanzapine an established therapeutic range (20-
50 ng/ml) is proposed to yield an optimal response and minimize side effects.
INTRODUCTION These symptoms are specific to the group as

a whole and generally associated with high
The primary distinction between classical
doses but in some cases also at clinically ef-
and second-generation antipsychotics has
fective dosages. The second-generation or
been made on clinical basis. Actually con-
“atypical” antipsychotic drugs can be differ-
ventional or “typical” antipsychotics are
entiated from traditional antipsychotics by
characterized by undesirable side effects
their low or negligible levels of these un-
such as extrapyramidal symptoms (EPS),
wanted side effects, by effectiveness and in
hyperprolactinaemia, tardive dyskinesia and
general supposed increased safety. This latter
possible neuroleptic malignant syndrome.
1163
has been recently questioned for the inci- state, with dissociation constants lower than
dence of symptoms linked to metabolic syn- that for dopamine. On the contrary, the atyp-
drome. icals bind more loosely than dopamine to the
The multiple clinical and adverse effects dopamine D2 receptor, with dissociation con-
of different antipsychotics depend on the stants higher than that for dopamine. A typi-
combination of receptors occupancy, but the cal example is represented by clozapine and
dopamine pathway is still considered the quetiapine (Seeman, 2002; Meltzer, 2002).
primary common target for all antipsychotic Rapid dissociation from D2 receptors is
drugs. More specifically, no drug has yet one explanation for the improved EPS pro-
been identified with antipsychotic action file of atypical antipsychotics, and one that is
without a significant affinity for D2 recep- also consistent with the theory of a lower
tors. affinity for D2 receptors for these drugs
There are 5 types of dopamine receptors (Miyamoto et al., 2005; Horacek et al.,
in human beings: types 1 and 5 are similar in 2006).
structure and drug sensitivity, and these two The dopamine-serotonin antagonism the-
receptors are referred to as the "D1like" ory generally predicts a separation between
group or class of receptors. Dopamine recep- typicals and atypicals, except that out of 20
tor types 2, 3, and 4 are also similar in struc- antipsychotics there are apparent exceptions
ture and are, therefore, grouped together as to this theory: amisulpride and remoxipride
the "D2like" group. Dopamine receptors 2, 3 are an important exception.
and 4, however, have significantly different Blockade of 5HT2A and D2 receptors was,
sensitivities to antipsychotic drugs. in 1989, first labelled a pharmacodynamic
Although the D1like receptors are men- mechanism that differentiated conventional
tioned as a primary target for antipsychotic from atypical antipsychotics. Meltzer (2002)
drugs, several findings indicate that they are defined atypical antipsychotics as drugs
not clinically relevant. showing a higher affinity for 5HT2A recep-
Of the 3 D2like receptors, only the D2 tors than for D2 receptors and a lower affini-
receptor itself is blocked by antipsychotic ty for D2 receptors than was seen with con-
drugs in direct relation to their clinical anti- ventional antipsychotics. For the nigrostriatal
psychotic potencies. In particular the clinical dopaminergic pathway, a model was sug-
efficacy of antipsychotics is associated with gested in which blockade of 5HT2A receptors
a blockade of 60 % to 80 % of D2 receptors should lead to increased output of dopamin-
in the brain as measured by positron emis- ergic neurons into the striatum leading to
sion tomography (PET) or single photon displace the antipsychotic drug from its bind-
emission tomography (SPET). ing to D2 receptors. This could decrease the
D2 receptor blockade in the brain is a risk of EPS development (Horacek et al.,
general pharmacodynamic property of all 2006) (Figure 1).
antipsychotics, and without it a drug will There is the theory which predicts that
not show any antipsychotic properties. new antipsychotics stimulate S-HT2A recep-
With conventional antipsychotics the tors by inverse agonism. Although it has
level of D2 receptor blockade is directly long been known that the stimulation of
related to the antipsychotic effect but with 5HT1A receptors in animals can alleviate cat-
atypical agents the situation is more com- alepsy caused by D2 blockade, there do not
plicated (Seeman, 2002; Meltzer, 2002). appear to be any antipsychotics that have this
Three theories for atypical antipsychotic 5HT1A stimulating action combined with D2
action are reported. The "fast-off-D2" theory blocking action. It has been proposed that the
proposes that typical antipsychotics bind stimulation of 5HT2A receptors by an inverse
more tightly than dopamine to the dopamine action is an important contribution to atypi-
D2 receptor in its functional high-affinity cal antipsychotic action. However, although
1164
some authors proposed that M100,907 has histaminergic, 5-HT1A, 5-HT1C and others)
the desired stimulating action, this com- are designated as multi-acting receptor-
pound has shown no antipsychotic activity in targeted antipsychotics (MARTA) (clozap-
humans. ine, olanzapine, quetiapine, asenapine).
Drugs that preferentially block D2 and D3
subtypes of the D2-like receptors are classi-
fied as combined D2/D3 receptor antagonists
(amisulpride). A final class of atypical anti-
psychotics are the partial dopamine receptor
agonists (aripiprazole and cariprazine)
(Horacek et al., 2006) (Figure 2, Table 1).
Neuroplasticity refers to the ability of the
nervous system to adapt to environmental
changes and includes both synaptic plasticity
consisting of remodelling of the synapses or
development of new neuronal connections
and neurogenesis with the development of
new neurons. Atypical antipsychotics are
reported to induce restructuring of neuronal
networks by inducing neuroplastic changes.
This effect contributes to a more substantial
description of the interaction between anti-
psychotics and the neurodevelopmentally
altered function and structure of the brain in
schizophrenic patients. Moreover it can ex-
plain the longterm antipsychotic effect, sug-
gesting a remodelling of neuronal structures
Figure 1: Atypical antipsychotics: proposed me- (Miyamoto et al., 2005).
chanisms of action (modified by Seeman, 2002) On the other hand there are evidences to
indicate dysfunctions in the connectivity of
On the other hand the original classi- glutamatergic neurons in schizophrenia. For
fication of antipsychotics according to their example, reductions in the density of pre-
chemical structure (i.e. phenothiazines, thio- frontal cortex pyramidal cell dendrites, the
xanthenes, butyrophenones and diphenyl- number of glutamatergic synaptosomes and
piperidines) and prevailing sedative or anti- the expression of messenger RNA (mRNA)
psychotic (incisiveness) potential is still rele- for the synaptic density marker synaptophy-
vant for the conventional antipsychotic sin are found post mortem in patients who
agents. The classification of atypical anti- had schizophrenia (Horacek et al., 2006).
psychotics is linked essentially to their The theory of glutamatergic dysfunction in
pharmacodynamic properties, which reflect schizophrenia is also supported by the fact
their affinities for specific receptors. Atypi- that phencyclidine and other antagonists of
cal antipsychotics with a high selectivity for glutamatergic NMDA receptors may, from
serotonin 5-HT2A receptors and dopamine D2 the phenomenological point of view, model
receptors (and also α1-adrenoceptors) are the schizophrenic symptoms in healthy per-
called serotonin-dopamine antagonists sons better than serotonergic psychotomi-
(SDA) (risperidone, its metabolite paliperi- metic drugs (e.g. LSD). Moreover these sub-
done, ziprasidone, iloperidone, lurasidone). stances can aggravate or exacerbate psycho-
Drugs showing an affinity for 5-HT2A, D2 sis in patients with schizophrenia. All the
and receptors of other systems (cholinergic,
1165
Figure 2: Simplified receptor binding affinity profiles for atypical antipsychotics

Blue, potentially therapeutics, red, potentially side effects, receptor binding affinities. The two recep-
tors with asterisks 5HT2C and D2 should be both therapeutic and side effects inducing. The yellow line
indicates the D2 affinity level for each drug (modified by Cutler et al., 2008)
1166
Table 1: Proposed mechanisms of action of atypical antipsychotics (modified by Horacek et al., 2006)
Dopaminergic modulation
- Blockade D2 - blockade of 65-75 % leads to effectiveness with preserved safety (EPS and hy-
perprolactinaemia)
- Blockade D1 - is localized in PFC: therapeutic effect on negative and cognitive symptoms. D1
modulate activity of D2 (potentiation of efficiency). D1 antagonism alone no antipsychotic effect
- Blockade D4 - decreases catalepsy and induces dopamine release in the basal ganglia and PFC.
D4 antagonism alone no antipsychotic effect
- Blockade of D2/D3 - preferential antagonism of inhibitory D2 autoreceptors; increased striatal
(lower risk of EPS) and neocortical dopamine release (cognitive and negative symptoms)
- Blockade of D3 receptors in temporal cortex, leads to stereoselectivity and efficacy on positive
symptoms without induction of EPS
- Rapid dissociation from D2 (“fast OFF”) - shorter duration of drug binding to D2 is sufficient for an
antipsychotic action but insufficient to induce EPS and hyperprolactinaemia (particularly quetia-
pine and clozapine)
- Partial D2 agonism - aripiprazole, 30-40 % of intrinsic D2 receptor agonism in connection with
high D2 blockade exerts an antipsychotic effect with a low risk of EPS and hyperprolactinaemia
Serotonergic modulation
- Blockade of 5-HT2A - 5-HT2A receptors integrate cortical and subcortical inputs. Antagonism of 5-
HT2A blocks the effect of NMDA antagonists and induces striatal and neocortical dopamine re-
lease
- 5-HT1A agonism - induces dopamine release into the striatum and neocortex (analogous to 5-
HT2A blockade) and also into limbic structures
- Blockade of 5-HT2C - induces neocortical dopamine release
- Modulation of 5-HT2A, 5-HT1A and 5-HT2C alone no antipsychotic effect
Induction of neuroplasticity
- Phosphorylation of receptors, potentiation of glutamate/glycine and induction of neuronal growth
factors (NGF and BDNF): reinforcement of NMDA receptor activity and development of new syn-
apses or their remodelling
BDNF = brain-derived neurotrophic factor; EPS = extrapyramidal side effects; NGF = nerve growth
factor; PFC = prefrontal cortex
antipsychotic drugs affect the glutamatergic aspartate (NMDA) receptor activity, thereby
system directly as partial agonists at the targeting at least theoretically an important
NMDA receptor-associated glycine recogni- pathway in the treatment of psychiatric dis-
tion site and indirectly by the blockade of orders, especially schizophrenia (Green et
glycine and glutamate transporters at the al., 2011). However, clinical trials on this
synaptic level. By this mechanism, deficient type of molecules do not seem to always an-
glutamatergic signalling would be potentiat- swer to desired expectations.
ed (Table 2). The aim of this review is to update the
This explanation is supported by the data relating to the pharmacodynamics and
finding that the glutamate coagonist glycine pharmacokinetics of atypical antipsychotics.
and its derivatives (D-serine, D-cycloserine), It will consider the following currently avail-
as well as inhibitors of glycine reuptake, able second-generation antipsychotics,
might potentiate the clinical effect of con- clozapine, risperidone, paliperidone, olan-
ventional antipsychotics. zapine, quetiapine, aripiprazole, ziprasidone,
Actually, bitopertin is an oral, small mol- amisulpride, asenapine, iloperidone, lura-
ecule first-in-class glycine reuptake inhibitor sidone and cariprazine.
(GRI). Bitopertin enhances N-methyl-D-
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Table 2: Potential clinical efficacy and benefits related to the mechanisms of action of antipsychotics
(modified by Miyamoto et al., 2005)
Mechanisms of action Clinical efficacy Possible effects
D2 antagonism ↓ positive symptoms EPS
↓negative symptoms
↑ cognitive symptoms
D2 partial agonism ↓ positive symptoms little or no EPS
↓ negative symptoms behavioral activation
↓ cognitive symptoms
↑DA and NE release in the ↓ negative symptoms behavioral activation

PFC ↓ cognitive symptoms
↓ depressive symptoms
ACh release in the PFC ↓ cognitive symptoms
5-HT2A antagonism ↓ negative symptoms ↓ EPS
5-HT1A partial agonism ↓ negative symptoms
↓ anxiety symptoms
↓ depressive symptoms
Muscarinic antagonism ↓ EPS ↓ anticholinergic symptoms
e.g. dry mouth, constipation,
tachycardia
Muscarinic agonism ↓ psychotic symptoms
Glutamate modulation ↓ positive symptoms

↓ negative symptoms
↓ illness progression
NE, norepinephrine; ACh, acetylcholine; PFC, prefrontal cortex; EPS, extrapyramidal symptoms
Clozapine toninergic receptor subtypes (5HT2A 5HT2C)

Clozapine (CLZ), still actually the main and adrenergic (α1), histamine (H1) and mus-
stone of atypical antipsychotics, belongs to carinic receptors (M1) (Meltzer, 1992).
the chemical class of the dibenzodiazepines. In an extended series of patients, PET
It has many unique clinical advantages over studies (Nordstrom et al., 1995) confirm that
typical neuroleptic agents, including its effi- CLZ is atypical with regard to degree of D2
cacy in treatment-refractory schizophrenia, a receptor occupancy, a finding that may ex-
low propensity to induce extrapyramidal plain the lack of extrapyramidal side effects.
symptoms (EPS), particularly tardive dyski- The combination of relatively high D1, low
nesia, and it does not increase serum prolac- D2, and very high 5-HT2 receptor occupancy
tine levels. In addition to being efficacious rates is unique to CLZ.
against positive symptoms, CLZ may also be Furthermore, binding studies have shown
beneficial in treating negative symptoms. It that the concentrations capable of blocking
has been demonstrated to prevent suicidal 75 % of D4 dopamine receptors match the
tendencies and some types of cognitive defi- therapeutic concentrations (Seeman and Van
cits associated with schizophrenia (Meltzer Tool, 1995). On the other hand, another
et al., 1989). study suggested that inherited variants of D4
CLZ has much greater antagonistic activ- may explain some of the interindividual var-
ity on cortical and limbic dopamine D4 than iation seen in patients’ response to CLZ
D2 receptors. It also antagonizes 5HT2 sero- (Zhao et al., 2005).
1168
From the pharmacokinetic point of view, strong CYP1A2 inhibitor (e.g. fluvoxamine)
CLZ is rapidly absorbed after oral admin- (Eap et al., 2004). Moreover, the high inter-
istration. Food does not seem to affect the individual and low intraindividual variability
amount of drug absorbed. Only 27-50 % of of plasma CLZ levels confirm the usefulness
the dose reaches the systemic circulation un- of monitoring them.
changed due to extensive first-pass metabo-
lism. Risperidone
CLZ shows a wide interindividual range Risperidone (RSP) is an approved anti-
with mean half-lives ranging from 9.1 to psychotic agent for the treatment of schizo-
17.4 h. The time to peak plasma concentra- phrenia and the acute manic phase of bipolar
tion is between 1.1 and 3.6 h, plasma clear- disorder. It is effective in both the short- and
ance between 8.7 and 53.3 L/h and distribu- longterm treatment of schizophrenia, has a
tion volume between 1.6 and 7.3 L/kg (Jann rapid onset of action, and is efficacious in
et al., 1993). Steady-state plasma concentra- treating both positive and negative symp-
tions are reached after 7-10 days of dosing. toms (Rabinowitz and Davidson, 2001). It
CLZ is 95 % bound to plasma proteins, pri- has a lower acute incidence of side effects
marily alpha1-glycoprotein (Choc et al., than haloperidol at least at therapeutical dos-
1990). ages of 4-6 mg/day (Peuskens, 1995; Ems-
Several studies have assessed the rela- ley, 1999).
tionship between plasma CLZ levels and RSP is a benzisoxazole derivative, and
clinical responses (Perry et al., 1991; Potkin has a strong binding affinity for serotonin (5-
et al., 1994; Kronig et al., 1995; Mauri et al., HT2A and 5-HT7) and dopamine D2 receptors
2004a). It has been suggested that monitor- (its affinity for D3 and D4 receptors is three
ing plasma CLZ concentrations might be times lower), with a 5HT2A/D2 affinity ratio
useful in clinical management, but the effec- of about 20. It also has a high affinity for ad-
tive plasma CLZ window remains debated renergic (1 and 2) receptors, and a low af-
(Freeman and Oyewumi, 1997; Khan and finity for histamine (H1) receptors (Ereshef-
Preskorn, 2005). Most researchers find that a sky and Lacombe, 1993; Leysen et al.,
threshold plasma level of 350-420 ng/ml of 1998).
CLZ is associated with an increased proba- From a pharmacokinetic point of view
bility of a good clinical response to the drug. RSP is rapidly absorbed after oral admin-
Moreover, much of the reviewed data indi- istration, with peak plasma concentrations
cate that increasing the oral CLZ dose in non being reached in about one hour; its rather
responder patients to achieve a plasma level good oral bioavailability is about 70-85 %. It
of at least 350-420 ng/ml can increase the mainly undergoes 9-hydroxylation in the liv-
number of CLZ responders (Potkin et al., er that yields the active 9-hydroxy-risperi-
1994; Fabrazzo et al., 2002; Mauri et al., done metabolite (9-OH-RSP), a step that is
2007a). Plasma CLZ concentrations (and the mainly catalysed by CYP2D6 and, to a lesser
probability of reaching a given threshold) extent, CYP3A4; alicyclic dehydroxylation
may be influenced by many factors such as and oxidative N-dealkylation are minor met-
age, gender and smoking (Schulte, 2003). abolic pathways (Mannens et al., 1993). As
Therapeutic drug plasma level monitor- the pharmacological properties of 9-OH-RSP
ing (TDM) is useful in the case of suspected are similar to those of RSP, both are regard-
poor compliance and for patients with altered ed as being able to contribute to the drug’s
pharmacokinetics, such as those character- overall antipsychotic effects in the treatment
ized by ultrarapid CYP1A2 activity. This of schizophrenia, and thus represent “the ac-
could lead to low plasma CLZ levels and a tive moiety”.
non-response that requires the use of very Genetic influences, such as CYP2D6 sta-
high CLZ doses or the co-administration of a tus, play an important role in determining the
1169
variability of its pharmacokinetic parameters. It is available also a long-acting injecta-

The mean half-life of RSP is three hours in ble RSP (RSP microsphere). RSP has been
extensive metabolizers (the majority of pop- the first atypical antipsychotic agent to be
ulation), and 22 hours in poor metabolisers; available in a long-acting formulation: the
the mean half-life of the “active moiety” intramuscular depot formulation called
(RSP and its main metabolite) is almost con- "long-acting injectable (LAI) RSP" is an
stant at about 22 hours in both groups. aqueous suspension in a matrix of glycolic
Steady-state levels are reached within five acid-lactate polymer.
days of treatment. RSP and its main metabo- Gefvert et al. (2005) studied the relation-
lite are 89 % and 77 % bound to plasma pro- ship between brain D2 receptor occupancy
teins (Leysen et al., 1998). The mean plasma and LAI RSP in 13 patients with schizophre-
clearance of RSP is 5.4 ± 1.4 ml/min/kg, and nia two weeks after the third and fifth injec-
the distribution volume is 1.1 l/kg. Most of tions. Injections of 25, 50 and 75 mg respec-
the 9-OH-RSP is removed by means of renal tively led to D2 receptor occupancy rates of
excretion; it undergoes little further hepatic 25-48 %, 59-83 % and 62-72 %, and plasma
metabolism. active moiety levels of 4.4-8.8, 15.0-31.1
Aravagiri et al. (2003) showed a large in- and 22.5-26.3 ng/ml. The results indicate
tra- and interindividual variation in the plas- that brain D2 receptor occupancy at steady-
ma concentrations of both RSP and 9-OH- state after injections of LAI RSP is within
RSP. The latter seems to be the major circu- the range observed in patients effectively
lating active moiety and its plasma concen- treated with 2-6 mg of oral RSP.
trations are 22-fold higher than those of RSP. From a pharmacokinetic point of view
The authors described a weak relationship the plasma concentrations of free RSP in-
between the daily dose and plasma concen- crease gradually, peak after about five
trations of RSP, but a close relationship with weeks, and are detectable for up to seven
the concentrations of 9-OH-RSP and those of weeks after a single intramuscular injection.
the total active moiety. The same authors Administration intervals of approximately
showed that the administered dose and dura- two weeks are commonly used (Kelleher et
tion of treatment did not have any effect on al., 2002).
the metabolism of RSP to 9-OH-RSP. The The single dose pharmacokinetic profiles
concentrations of RSP seemed to vary more of LAI and oral RSP were extrapolated to
widely than those of its metabolite, and the steady-state in a study by Mannaert et al.
relationship of both 9-OH-RSP and the ac- (2005). Plasma concentrations of the active
tive moiety to the administered dose was moiety (unchanged RSP+9-OH-RSP) were
closer than that of RSP. The authors con- measured by radioimmunoassay up to 72 h
cluded that measuring the plasma levels of after a single oral dose of RSP 1 mg in 12
the parent compound (RSP) alone may lead healthy volunteers, and up to 84 days after a
to erroneous interpretations in plasma level single intramuscular injection of LAI RSP
monitoring studies (Aravagiri et al., 1998, 50 mg in 26 schizophrenic patients. The
2003). most interesting results obtained at steady-
Other authors have also reported that state were that LAI RSP a lower than pre-
there is a linear but often weak relationship dicted peak plasma level (46 vs 62 ng/ml)
between the RSP dose and mean plasma and a lower than predicted degree of fluctua-
RSP, 9-OH-RSP and active moiety levels tion between Cmax and Cmin (53 vs 145 %).
(Ereshefsky and Lacombe, 1993; Grant et The pharmacokinetic profile of LAI RSP
al., 1994; Spina et al., 2001; Riedel et al., administered every two weeks ensures the
2005) but Mauri et al. (2001) and Chen et al. maintenance of steady-state.
(2004) found no significant relationship. It has been demonstrated a bioequiva-
lence of the LAI and oral formulations, but
1170
the mean peak steady-state peak concentra- useful when medication is switched from the
tions of the active moiety were 25-32 % oral to the depot form, or vice versa (Bau-
lower with LAI than oral RSP, and their mann et al., 2004).
fluctuations were 32-42 % lower (Eerdekens
et al., 2004; Nesvag et al., 2006). Paliperidone
In some patients who had previously re- Paliperidone is a novel antipsychotic
ceived oral RSP, switching to the LAI for- agent belonging to the benzisoxazole-
mulation led to an average increase in the derivatives class. Paliperidone is the major
C/D ratio of 33 % (range 12 %-68 %) (Cast- active metabolite of risperidone (OH-RSP).
berg and Spigset, 2005). Paliperidone is a centrally active dopa-
The available data do not make it possi- mine D2 antagonist with predominant sero-
ble to establish the value of RSP therapeutic tonergic 5-HT2A antagonistic activity. Pali-
drug monitoring in absolute terms. The over- peridone is also active as an antagonist at α1
all pharmacological effects of RSP depend and α2 adrenergic receptors and H1 hista-
on the sum of the plasma concentrations of it minergic receptors. Paliperidone has no af-
and its 9-OH-RSP metabolite (the “total ac- finity for cholinergic muscarinic or β1- and
tive moiety”), and so monitoring the plasma β2-adrenergic receptors. The pharmacologi-
levels of the parent compound (RSP) alone cal activity of the (+)– and (-)- paliperidone
can lead to erroneous interpretations (Arava- enantiomers is qualitatively and quantitative-
giri et al., 2003). It seems that monitoring the ly similar.
plasma levels of the active moiety may be Paliperidone extended-release (ER) is
useful, but further investigations are required approved in the United States, Europe, and
in order to clarify the discrepancies in the globally for the treatment of schizophrenia in
results obtained so far. adults and in adolescents aged 12-17 years. It
It is important to understand whether is also approved for the treatment of adults
there is a positive correlation between clini- with schizoaffective disorder, both as a
cal responses and plasma levels of active monotherapy and as adjunctive therapy to
moiety: some authors have reported a nega- mood stabilizers and/or antidepressants.
tive correlation (Riedel et al., 2005) which It is formulated using OROS® (osmotic
conflicts with previously published data controlled-release system, ALZA Corpora-
(Mauri et al., 2001; Odou et al., 2000). This tion, CA, USA) technology, which reduces
discrepancy may be due to the large variabil- peak-to-trough variations in plasma concen-
ity in plasma drug levels and the lack of trations and eliminates the need for initial
studies using fixed dosages. No therapeutic dose titration (Conley et al., 2006). Paliperi-
plasma level range for RSP has yet been done ER is also minimally metabolized in
clearly established: the plasma threshold for the liver and thus has a lower potential for
parkinsonian side effects has been found to clinically significant pharmacokinetic drug
be of 74 ng/ml (Peuskens et al., 1995; interactions with drugs that are metabolized
Marder and Meibach, 1994) but it is not by the cytochrome P450 (CYP450) enzyme
clear what is the minimum effective plasma system. Furthermore, no dose adjustment of
concentration of the active moiety. Some da- paliperidone ER is needed in patients with
ta suggest that the normal range is between mild-to-moderate hepatic impairment.
15 and 60 ng/ml, but they need to be con- In a 6-week dose-finding study of pali-
firmed (Mauri et al., 2001; Odou et al., 2000; peridone ER in male patients with schizo-
Darby et al., 1997). According to the AGNP phrenia using positron emission tomography,
consensus guidelines, RSP TDM is recom- paliperidone ER at 6-9 mg/day resulted in an
mended and the proposed plasma RSP con- estimated dopamine D2 receptor occupancy
centrations are between 20 and 60 ng/ml. of between 70 and 80 % in the striatum and
Moreover, RSP TDM should be particularly in the temporal cortex (Citrome, 2012a).
1171
Paliperidone palmitate is the long-acting not dopaminergic striatal (A9) neuron fire
injectable (LAI) formulation of the approved and, in animal studies, counteracts condi-
oral antipsychotic paliperidone ER for the tioned avoidance behavior (test of antipsy-
treatment of schizophrenia. chotic efficacy) at a dose that is not suffi-
Paliperidone palmitate is an ester in an cient to induce catalepsy (test of motor side
aqueous-based nano-suspension. It has very effect) (Chiodo and Bunney, 1983; Stockton
low water solubility. After injection, paliper- and Rasmussen, 1996; Frampton, 2010).
idone palmitate slowly dissolves and is hy- More recently, preclinical studies have
drolyzed to paliperidone by esterases in the shown that OLZ efficacy on psychotic and
muscle tissue. It is intended for once- cognitive symptoms of schizophrenia may be
monthly intramuscular injection and it does represented by its facilitating effect on N-
not require any oral supplementation (Gilday methyl-D-aspartic acid, which can favor
and Nasrallah, 2012). brain derived neurotrophic factor (BDNF)
expression (Horacek et al., 2006). According
Olanzapine to another study, treatment with OLZ mark-
Olanzapine (OLZ) is a thienobenzodiaz- edly restored the reduction of both BDNF
epine derivate structurally similar to clozap- and tyrosine kinase (TrkB) receptors in hip-
ine that is effective in treating schizophrenia pocampus, associated with previous treat-
and acute manic episodes, and in preventing ment with haloperidol (Parikh et al., 2004).
the recurrence of bipolar disorders (McCor- Other studies mentioned that OLZ efficacy
mack and Wiseman, 2004). It is as effective on negative and depressive symptoms of
and safe as haloperidol in acute reducing the schizophrenia might be related to inhibition
psychopathological symptoms of psychosis of norepinephrine transporter and modula-
and has been shown to have some therapeu- tion of cytokine plasma level, as interleukin-
tic advantages over other classic antipsychot- 2 declined after 8-week olanzapine treatment
ics in terms of symptom reduction and its (Hikaru et al., 2007; Schatzberg and Neme-
adverse event profile. It has a low propensity roff, 2013).
to cause extrapyramidal effects or sustained Approximately 85 % of an oral OLZ
increases in prolactin levels (Lieberman et dose is absorbed but, as about 40 % is inacti-
al., 2003). Nevertheless, treatment with OLZ vated by first-pass hepatic metabolism, its
(like CLZ) is associated with a higher risk of oral bioavailability is about 60 %. OLZ has a
weight gain and, more extensively, metabol- mean half-life in healthy individuals of
ic syndrome than other typical and atypical 33 hours (range 21-54 hours). Peak plasma
antipsychotics (Lambert et al., 2005; Duggan concentrations are reached within six hours.
et al., 2005). The drug is approximately 93 % bound to
OLZ shares higher affinity to 5-HT2A re- plasma proteins, mainly albumin (90 %) and
ceptors than D2 receptors (high 5-HT2A/D2 alpha 1-acid glycoprotein (77 %). Its distri-
ratio). In comparison to the other atypicals, bution volume is 16.4 ± 5.1 L (SD). Mean
olanzapine presents high affinity for seroto- apparent plasma clearance is 26 L/h (range
ninergic 5-HT2A, 5-HT2C, 5-HT3, and 5-HT6 12-47 L/h). Smokers and men show greater
receptors, medium affinity for dopaminergic OLZ clearance than women and non-smok-
D1, D2, D3, D4, D5, and muscarinic M1–M5 ers (Callaghan et al., 1999). After the admin-
receptors, 18 low affinity for adrenergic α1 istration of [14C]-OLZ in a single load phar-
and α2 receptors, and the highest affinity for macokinetic study, approximately 87 % of
histamine H1 receptors (olanzapine is the the radioactivity was excreted, with 30 %
most potent histamine H1 antagonist known) appearing in the feces and 57 % in the urine
(Bymaster et al., 1999). (Kassahun et al., 1997). Approximately half
OLZ selectively reduces the activity of of the radiocarbon was excreted within three
dopaminergic mesolimbic (A10) neurons but
1172
days, and >70 % of the dose was recovered metabolism and/or clearance (Gex-Fabry et
within seven days. al., 2003; Fellows et al., 2003).
OLZ is metabolized to its 10-N- and 4'- Only short-term studies of the relation-
N-glucuronides, 4'-N-desmethylolanzapine ships between clinical responses and plasma
(by CYP1A2), and olanzapine-N-oxide (by OLZ levels have been carried out, none of
flavin mono-oxygenase 3). Metabolism to 2- which had a treatment period of more than
hydroxymethylolanzapine via CYP2D6 is a six weeks. The reviewed studies strongly in-
minor pathway. The 10-N-glucuronide is the dicate a relationship between clinical out-
most abundant metabolite (Callaghan et al., comes and plasma OLZ concentrations (Per-
1999). ry et al., 1997; Lane et al., 2002; Mauri et al.,
OLZ does not inhibit CYP isozymes. No 2005). Furthermore, given the large inter-
clinically significant metabolic interactions patient variability in plasma OLZ levels at
have been found between OLZ and diaze- the same doses, the monitoring of blood
pam, alcohol (ethanol), imipramine, racemic OLZ concentrations can be considered very
mixture - R and –S warfarin, aminophylline, useful in assessing therapeutic efficacy and
biperiden, lithium or fluoxetine. Fluvoxam- controlling adverse events. A therapeutic
ine, an inhibitor of CYP1A2, increases the range of between 20 ng/ml and 50 ng/ml has
plasma concentrations of OLZ, whereas the been found (Lane et al., 2002; Fellows et al.,
inducers of CYP1A2 (including tobacco 2003; Mauri et al., 2005).
smoking) and UDP-glucuronyltransferase PET studies by Kapur et al. (1998) ana-
and CYP3A4 (such as carbamazepine) de- lyzed the differences in D2 receptor occu-
crease them (Kassahun et al., 1997; Calla- pancy on the basis of OLZ dose/plasma OLZ
ghan et al., 1999). levels, and found that the relationship be-
A number of studies have investigated tween plasma OLZ levels and D2 occupancy
the relationship between the daily OLZ dose was described by a saturating rectangular
and plasma OLZ concentrations showing hyperbola. OLZ is a potent 5-HT2 blocker
that the latter increase linearly with the daily and shows greater 5-HT2 than D2 occupancy
oral dose (0.12<r<0.68) (Kelly et al., 1999; at all doses. At a plasma concentration of
Gex-Fabry et al., 2003; Mauri et al., 2005). 10.3 ng/ml, OLZ occupied 50 % of the avail-
Moreover, some authors have demonstrated able D2 receptors. Within the usual clinical
a linear relationship between the prescribed range of 10-20 mg/day, D2 occupancy varies
daily dose and the plasma concentration of from 71 % to 80 % (Kapur et al., 1998). Re-
the major N-desmethylolanzapine metabolite cently, Attarbaschi et al. (2007) have ex-
(Olesen and Linnet, 1999). plored the relationship between striatal D2
These studies showed that mean plasma receptor occupancy and EPS in 17 bipolar
OLZ concentrations vary widely, depending patients receiving OLZ 5-45 mg/day for at
on factors such as the prescribed daily dose least 14 days, and found a significant corre-
and the duration of treatment. Given their lation between plasma levels and occupancy
lower OLZ clearance, women have signifi- (R2= 0.55, P=0.001). The bipolar patients
cantly higher mean plasma OLZ levels, did not show any EPS at D2 occupancy lev-
which become evident after the fifth week of els of 28-80 %.
treatment (Kelly et al., 1999; Gex-Fabry et According to the AGNP-TDM consensus
al., 2003). At commonly used daily OLZ group, OLZ TDM is strongly recommended
doses (5-30 mg/day), mean plasma concen- as an established therapeutic range (20-
trations can range from 10 to 54 ng/ml. Con- 50 ng/ml) is proposed to yield an optimal
siderable inter-patient variability has some- response and minimize side effects (Bau-
times been observed, possibly due to unre- mann et al., 2004).
ported co-medications, non-compliance, and Intramuscular OLZ is a fast-acting for-
intrinsic interindividual variability in drug mulation that is also indicated for use in pa-
1173
tients with agitation associated with schizo- QTP and the active human plasma me-
phrenia or bipolar mania. This OLZ formula- tabolite, norquetiapine (N-desalkylquetia-
tion is at least as effective as intramuscular pine) (N-QTP), interact with a broad range
haloperidol or lorazepam in treating patients of neurotransmitter receptors. QTP and N-
with acute agitation associated with schizo- QTP exhibit affinity for brain serotonin
phrenia or bipolar mania, and has a faster (5HT2) and dopamine D2 receptors. QTP has
onset of action (Wright et al., 2003; Lind- a lower affinity for D1 receptors. This com-
borg et al., 2003). At doses of between 2.5 bination of receptor antagonism with a high-
and 10.0 mg per injection, the response is er selectivity for 5HT2 relative to D2 recep-
dose related. The drug has a favourable safe- tors seems to contribute to the clinical anti-
ty profile (Breier et al., 2002). psychotic properties and low extrapyramidal
It is now available also OLZ long-acting undesirable effect (EPS) liability of QTP
formulation. OLZ long-acting injection compared to typical antipsychotics. Addi-
(OLAI) is a crystalline salt composed of tionally, N-QTP has high affinity for the
olanzapine and pamoic acid, that is suspend- norepinephrine transporter (NET). QTP and
ed in an aqueous solution which permits a N-QTP also have high affinity at histaminer-
depot intramuscular formulation of olanzap- gic and adrenergic α1 receptors, with a lower
ine. Once injected in the gluteal muscle, the affinity at adrenergic α2 and serotonin
two components of the salt slowly dissociate 5HT1A, 5HT2A and 5HT2C receptors. QTP
into separate molecular compounds, olanzap- has no appreciable affinity at muscarinic or
ine and pamoic acid. The rate of dissolution benzodiazepine receptors (Small et al.,
of the salt is slow, allowing for a gradual re- 2002).
lease of olanzapine into the circulation over On the other hand the dissociation time-
2 to 4 weeks. course of QTP at dopamine D2 receptors and
The half-life of olanzapine pamoate is 30 at serotonin (5-HT) receptors should be con-
days, and its steady state is reached approx- sidered: QTP such as other atypicals, CLZ,
imately at 12 weeks. Oral supplementation OLZ, ziprasidone and amisulpride all bind
of olanzapine should not be required during more loosely than dopamine to the dopamine
OLAI initiation, although a study indicates D2 receptors and have dissociation constants
that ≥60 % of D2 receptor occupancy was higher than that for dopamine. These tight
reached only by the fifth injection cycle and loose binding data agree with the rates of
(Lindenmayer, 2010; Di Lorenzo and Brogli, antipsychotic dissociation from the human-
2010). cloned D2 receptor. For instance, radioactive
haloperidol and chlorpromazine, all dissoci-
Quetiapine ate very slowly over a 30-minute time span,
Quetiapine (QTP) is a dibenzothiazepine while radioactive QTP, CLZ and amisulpride
derivate approved for the management of dissociate rapidly, in less than 60 seconds.
acute and chronic psychotic disorders, the These data also match clinical brain-imaging
acute phase of mania and bipolar depression. findings that show haloperidol remaining
QTP has been shown to be at least as effica- constantly bound to D2 in humans undergo-
cious as the typical antipsychotics chlor- ing 2 positron emission tomography (PET)
promazine and haloperidol in the short-term scans 24 hours apart. Conversely, the occu-
treatment of schizophrenia (Arvanitis et al., pation of D2 by QTP or CLZ has mostly dis-
1997; Peuskens and Link, 1997). Controlled appeared after 24 hours (Seeman, 2002).
clinical trials have shown that it is well toler- At doses within the recommended thera-
ated, not associated with a sustained increase peutic range, QTP instant release (IR) has a
in plasma prolactin concentrations, and has a linear pharmacokinetic profile. QTP is rapid-
low propensity to cause extrapyramidal ly absorbed following the oral administration
symptoms (Small et al., 1997). of all dose levels, with a median time to Tmax
1174
of 1-1.5 hours. Its coadministration with (2004b) found higher levels/doses per kg in
food only marginally increases Cmax and women than men.
AUC values (DeVane and Nemeroff 2001). The coadministration of drugs that are
There are no absolute bioavailability data known to induce CYP3A4 (e.g. phenytoin,
because of the lack of an injectable formula- carbamazepine) may lead to a clinically rele-
tion, but preliminary data indicate that about vant decrease in QTP levels (Grimm et al.,
70 % is absorbed. Apparent oral clearance 2006).
ranges from 55 to 87 l/h, and Cmax values of Only a few studies have investigated the
53-117 µg/L were observed after the single relationship between plasma QTP levels and
administration of a 25 mg dose. Multiple clinical responses, all of which are short-
dose studies show Cmax values of 778- term and none have used a treatment period
1080 ng/ml at doses of 250 mg/day. The ap- of more than six weeks. Although some data
parent oral volume of distribution ranges argue in favour of the existence of a relation-
from 513 to 710 L. The drug is approximate- ship between plasma QTP levels and clinical
ly 83 % bound to plasma proteins, and is responses, they only provide some prelimi-
eliminated with a mean half-life of approxi- nary information about the meaning of plas-
mately six hours. The primary route of elim- ma QTP levels (Gefvert et al., 1998; Mauri
ination is hepatic metabolism (DeVane and et al., 2004b; Mauri et al., 2007b). Other au-
Nemeroff, 2001). thors have failed to identify an optimal ther-
QTP is extensively metabolized (at least apeutic range for QTP (Fabre et al., 1995;
20 metabolites have been identified): only Small et al., 1997).
two, 7-hydroxy-quetiapine and 7-hydroxy-N- A suggested therapeutic range of 70-
desalkyl-quetiapine (N-QTP) are pharmaco- 170 ng/ml has been proposed by AGNP
logically active (Grimm et al., 1997). In par- guidelines. TDM is therefore recommended
ticular, N-QTP, a potent norepinephrine as “useful” in order to check whether plasma
reuptake inhibitor and partial serotonin 5- concentrations are plausible for a given dose
HT1A receptor agonist, has been suggested as and optimize the clinical response in non re-
a putative mediator of QTP antidepressant sponder patients with low concentrations
activity (Altamura et al., 2012). (Baumann et al., 2004).
After single subclinical doses, the mean Given the few data concerning the rela-
plasma clearance of QTP is reduced by only tionship between clinical responses and
25 % in patients with severe renal impair- plasma QTP levels, some clues can be ex-
ment (creatinine clearance 10-30 ml/min/ trapolated from PET studies of receptor
1.73 m2) or hepatic impairment (stable alco- blockades. A number of studies have inves-
holic cirrhosis) (Gunasekara and Spencer, tigated the relationship between the time-
1998). The oral clearance of QTP seems to course of CNS dopamine and serotonin re-
be lower (30-50 %) in elderly patients (63-85 ceptor blockade and plasma drug concentra-
years) receiving 300-750 mg/day than in tions after the discontinuation of QTP treat-
younger patients on similar regimens ment, and shown that the disappearance of
(Grimm et al., 2006). It shoud be noted that QTP from plasma is much more rapid than
an age of >70 years has been found to be as- the decrease in serotonin receptor occupancy
sociated with a marked decline in the hepatic (Gefvert et al., 1998; Kapur et al., 2000; Ge-
content of CYP3A4. Dose titration may fvert et al., 2001). A better, but not perfect,
therefore need to be slower in the elderly, correspondence was observed between D2
and the daily dose lower than in younger pa- receptor dissociation and plasma QTP half-
tients. QTP does not generally show any life. These data indicate a discrepancy be-
clinically relevant gender-related pharmaco- tween the time-course of receptor occupancy
kinetic changes (DeVane and Nemeroff and plasma QTP concentrations (Gefvert et
2001; Grimm et al., 2006) but Mauri et al. al., 2001).
1175
Kapur et al. (2000) found a clear curvi- generation antipsychotic which has been ap-
linear relationship between 5-HT2A receptor proved for the treatment of schizophrenia. It
occupancy and plasma QTP levels, but only seems to be as effective as haloperidol in
a weak relationship between plasma QTP controlling the positive symptoms of schizo-
levels and D2 receptor occupancy. In an albe- phrenia, and more effective than haloperidol
it very small patient sample (n=5), Gevfert et in controlling negative and depressive symp-
al. (2001) found an apparently clear correla- toms (Carriere et al., 2000).
tion between plasma QTP levels and D2 re- AMI is a substituted benzamide deriva-
ceptor occupancy in a study that used tive, and highly selective dopamine D2 and
PANSS, CGI and SAS to assess clinical out- D3 receptor antagonist. In ex vivo binding
comes. The results showed that the data at studies, it is twice as selective for D3 recep-
QTP doses of <300 mg/day and >450 mg/ tors as D2 receptors. It has no affinity for the
day were collected from individuals who dif- D1, D4 and D5 receptor subtypes, and little
fered clinically in that the former were un- affinity for adrenergic, histaminergic, sero-
controlled and the latter were controlled on tonergic or cholinergic receptors (Perrault et
QTP treatment. These results suggest that a al., 1997). It has also demonstrated preferen-
certain threshold plasma level and definite tial affinity for presynaptic D2 and D3 recep-
D2 occupancy is required for the efficacy of tors at low doses (<10 mg/kg), leading to
the treatment. enhanced dopamine transmission, whereas
It is also available QTP extended release higher doses antagonise postsynaptic D2 and
(XR) formulation: once-daily dosing of the D3 receptors, thus reducing dopamine trans-
XR formulation showed peak and trough mission.
plasma levels and central D2 receptor occu- On the other hand atypicality of AMI,
pancy comparable to twice-daily dosing of such as other atypical antipsychotics, could
the IR formulation (Mamo et al., 2008). be attributed by transiently occupying D2
More recently XR exhibited a less pro- receptors and then rapidly dissociating to
nounced D2 receptor occupancy peak recep- allow normal dopamine neurotransmission.
tor occupancy levels remaining higher for This could help also AMI to keep prolactin
longer compared with IR formulation (Bui et levels generally normal, to spare cognition
al., 2013). and to obviate EPS (Seeman, 2002).
Once-daily quetiapine XR produced a Finally, it shows preferential affinity for
similar area under the plasma concentration- limbic rather than nigro-striatal regions (Per-
time curve (AUC), minimum plasma concen- rault et al., 1997).
tration (Cmin) and a slightly lower maximum AMI is rapidly absorbed after oral ad-
plasma concentration (Cmax) than the equiva- ministration, and has an absolute bioavaila-
lent dose of IR formulation given twice dai- bility of 50 %. Cmax is 42-56 μg/L, and is
ly. In a crossover, head-to-head study, total reached in 1-4 hours (Tmax); steady-state is
daily exposure, measured by AUC at steady reached after 2-3 days. Its distribution vol-
state, was less variable with XR versus IR ume is 5.8 L/kg and plasma protein binding
(percent coefficient of variation 39.2 % ver- is about 17 %. Its plasma elimination half-
sus 51.2 %, respectively). Compared with life is 12 hours, with renal clearance of 17-
fasting, a high-fat meal increased the AUC 20 L/h. Excretion occurs mainly via the kid-
and Cmax for XR formulation, whereas a light neys, with 22-25 % of an oral dose being re-
meal had no significant effect on these pa- covered in the urine as unchanged drug. In
rameters (Bui et al., 2013). patients with renal impairment, the drug‘s
half-life is unchanged but systemic clearance
Amisulpride is reduced by one-third and so dose adjust-
Amisulpride (AMI) might be considered ments are required (Rosenzweig et al.,
from a clinical point of view a second- 2002).
1176
AMI undergoes minimal metabolism in and Cooper, 2002). It has been associated
the liver, and produces only two main me- with a low incidence of sedative effects, little
tabolites, both of which are inactive. It is likelihood of extrapyramidal symptoms and
mainly eliminated renally and, interestingly postural hypotension, no anticholinergic ef-
enough, its rate of renal excretion is about fects, and only mild transient hyperprolacti-
2.5 times higher than that which might be naemia (Gunasekara et al., 2002). Unlike
expected from mere glomerular filtration. It most atypical antipsychotic drugs, ZPS is not
is therefore likely that active drug secretion associated with weight gain, hyperlipidemia
occurs. or high plasma glucose levels (Caley and
AMI is unlikely to interact with other Cooper, 2002).
drugs, and does not affect the activity of the This clinical profile may be related to its
cytochrome P450 system (Rosenzweig et al., unique combination of pharmacological ac-
2002). tivities at human receptors: it is a dopamine
Age and gender have a significant effect D2 and serotonin 5-HT2A receptor antagonist
on dose-corrected AMI plasma concentra- (with greater in vitro affinity for the 5-HT2A
tions, which are higher in older patients and receptor) (Schmidt et al., 2001; Caley and
women (Bergemann et al., 2004), possibly Cooper, 2002), a 5-HT1A agonist, and a 5-
because of a gender difference in the drug’s HT2C and 5-HT1B/D antagonist. Like antide-
renal clearance. Co-medication with lithium pressant drugs, it also inhibits the reuptake of
and clozapine increases dose-corrected AMI serotonin and noradrenaline (Schmidt et al.,
plasma concentrations (Mauri et al., 1996; 2001; Gunasekara et al., 2002).
Bergemann et al., 2004). A significant positive correlation be-
Little is known about the therapeutic sig- tween plasma ZPS levels and the occupancy
nificance of plasma AMI concentrations. On- of both D2 and 5-HT2 receptors has been re-
ly one study has considered the range of ported, with the relationship described by a
therapeutic plasma AMI levels, and the cor- hyperbolic curve (Mamo et al., 2004).
relation beween daily oral doses and plasma From a pharmacokinetic point of view
concentrations (Bergemann et al., 2004). the absolute bioavailability of a 20 mg oral
There was a positive correlation (r = 0.50, dose of ZPS under fed conditions is 60 %.
p <0.001) between the daily AMI dose and The duration and extent of ZPS absorption
plasma concentrations. As in the case of may be as much as doubled in the presence
most antipsychotics, patients commonly of food, whereas its half-life is shorter than
show great interindividual variance in plas- under fasting conditions. ZPS has a mean
ma AMI levels. The therapeutic plasma AMI apparent distribution volume of 1.5 L/kg. It
levels of about 367 ng/ml were associated is highly bound to plasma proteins, primarily
with stable clinical improvement. The thera- albumin and alpha-1-acid glycoprotein. It’s
peutic range of 100-400 ng/ml has been pro- pharmacokinetics seem to be linear as both
posed by the AGNP-TDM consensus guide- AUC and Cmax linearly increase with increas-
lines, which is based on data from non- ing doses, and its half-life of ZPS at steady-
systematic clinical experiences (Baumann et state has been reported to be 8-10 hours
al., 2004). (Miceli et al., 2000; Wilner et al., 2000). Age
and gender do not have a clinically signifi-
Ziprasidone cant influence on the pharmacokinetics of
Ziprasidone (ZPS) is a benzothiazolylpi- ZPS (Stimmel et al., 2002).
perazine developed from the chemically- ZPS is highly metabolized in humans,
related antipsychotic tiospirone, and has with less than 5 % of the administrated dose
been reported to be effective on positive, being excreted in unchanged form. The ini-
negative and depressive symptoms in the tial metabolic pathway involves CYP3A4,
short-term treatment of schizophrenia (Caley which is responsible for two alternative oxi-
1177
dation pathways: oxidation at the sulphur of intramuscular ZPS have been reported
atom of the benzisothiazole ring to yield ZPS (Miceli et al., 2005).
sulfoxide, and oxidative cleavage to yield
benzisothiazole piperazine (BITP) (Beedham Aripiprazole
et al., 2003). These metabolites themselves Aripiprazole (ARI) might be considered
undergo varying degrees of subsequent me- a “third-generation” antipsychotic agent.
tabolism. CYP3A4 is also thought to be the ARI has been reported to be effective and
enzyme responsible for the formation of ZPS well tolerated in short-term and longer-term
sulfone, the only metabolite that may con- studies in patients with schizophrenia or
tribute to the clinical activity of ZPS. There schizoaffective disorders (Swainston and
are 12 different circulating metabolites of Perry, 2004; Stip and Tourjman, 2010). In
ZPS, four of which are major: BITP- addition, a potential role for ARI in acute
sulfoxide, BITP-sulfone, ZPS-sulfoxide and mania so as in depression is supported by the
S-methyldihydro ZPS (Prakash et al., 1997). findings of clinical trials in patients with bi-
Clinical studies have shown mean plasma polar I or major depressive disorder (Weber
concentrations of 35-109 ng/ml at the doses et al., 2008; De Fazio et al., 2010; Brown et
commonly used in clinical settings (80- al., 2013; Stewart et al., 2014).
160 mg/day), with steady-state being reached The most frequent reported adverse ef-
by the seventh day (Daniel et al., 1999; Mau- fects are headache, anxiety, insomnia, nau-
ri et al., 2007c). There are no published stud- sea, vomiting, and lightheadedness. The in-
ies of the relationships between plasma ZPS cidence of extrapyramidal symptoms is low-
levels and clinical responses, and so the op- er than with haloperidol. The increase in pro-
timal therapeutic range is still poorly de- lactin levels and QTc prolongation are re-
fined. According to the AGNP consensus ported to be similar in patients treated with
guidelines, TDM is “probably useful” in pa- ARI and placebo.
tients receiving ZPS because of the current ARI is a quinolinone derivative. It shows
lack of valid clinical data. It may be useful to a high affinity for dopamine D2 and D3 re-
check whether plasma concentrations are ceptors, and serotonin 5-HT1A, 5-HT2A and
plausible for a given dose (Baumann et al., 5-HT2B receptors. In particular ARI has par-
2004). tial-agonist activity at dopamine D2 and D3
It is available the ZPS mesylate intra- receptors and serotonin 5-HT1A receptors,
muscular formulation. Its pharmacokinetics and antagonist activity at 5-HT2A receptors
include the rapid attainment of therapeutic (Lawler et al., 1999; Jordan et al., 2002; Bur-
drug levels (Tmax <60 minutes post-dosing), a ris et al., 2002).
mean terminal elimination half-life of 2-5 Really the mechanism of action of ARI is
hours, approximately 100 % bioavailability, not yet known, but evidence suggests that its
drug exposure that increases in a dose- efficacy in the treatment of the positive and
related manner, and little drug accumulation negative symptoms of schizophrenia and its
even after three days of repeated intramuscu- lower propensity for extrapyramidal symp-
lar administrations, with low concentrations toms (EPS) may be attributable to ARI par-
of ZPS 12-18 hours after the last intramuscu- tial agonist activity at dopamine D2 recep-
lar injection (Preskorn, 2005). The rapid tors. At serotonin 5-HT1A receptors, in vitro
plasma clearance of ZPS after intramuscular studies have shown that aripiprazole acts as a
administration leads to little or no persis- partial agonist whereas at serotonin 5-HT2A
tence of plasma drug levels when switching receptors aripiprazole is an antagonist. The
from intramuscular to oral drug administra- main active metabolite, dehydro-aripipra-
tion. No clinically significant age, sex or zole, has affinity for dopamine D2 receptors
race related effects on the pharmacokinetics and thus has some pharmacological activity
similar to that of the parent compound.
1178
A positron emission tomography study in contribution to ARI’s clinical effects has not
patients with schizophrenia found that at been assessed. Excretion occurs via the kid-
10 mg/day ARI had high mean occupancy at ney and liver, with 25 % of the dose being
striatal D2 receptors (putamen, 87 %; cau- recovered in the urine (<1 % unchanged) and
date, 93 %; ventral striatum, 91 %), lower 55 % in the feces (18 % unchanged) (Cit-
mean occupancy at 5-HT2 receptors (54 %– rome et al., 2005; Mallikaarjun et al., 2004).
60 %), and lower mean occupancy at 5-HT1A According to the manufacturer, no dose ad-
receptors (16 %). A study that analyzed the justments are required on the grounds of he-
relationship between occupancy at the D2 patic or renal impairment, age, gender, race
receptor and clinical response in schizophre- or smoking status.
nia suggested that at least 60 % of receptors The dosage adjustment of ARI is neces-
must be blocked for psychotic symptoms to sary when it is coadministered with CYP3A4
be reduced (Mamo et al., 2007). and CYP2D6 inhibitors (since aripiprazole
As it has partial agonist activity on do- concentration is increased) and with inducers
pamine D2 and serotonin 5-HT1A receptors, of CYP3A4 (since aripiprazole concentration
and also antagonizes 5-HT2A receptors, is is decreased) (Mallikaarjun et al., 2004).
considered a "dopamine-serotonin stabilizer" There are no published data concerning
(Yokoi et al., 2002; McGavin and Goa, plasma ARI levels, and so it is not known if
2002). a therapeutic plasma concentration range
From a pharmacokinetic point of view even exists: studies of the relationships be-
ARI is well absorbed, with peak plasma con- twen plasma levels and clinical responses are
centrations occurring within 3-5 hours of required.
administration. Oral availability is 87 %. The There are two ARI formulations for in-
mean elimination half-life is about 75 hours tramuscular use with different dosages, dos-
for ARI and 94 hours for its active metabo- ing frequencies, and indications.
lite. A linear pharmacokinetic profile has ARI injection (9.75 mg per vial) is a
been observed at all doses between 5 and short-acting formulation indicated for agita-
30 mg/day, with peak plasma concentrations tion in patients with schizophrenia or mania.
being reached within 3-5 hours and steady- ARI Depot is a long-acting ARI formula-
state plasma concentrations being reached by tion, available in several countries in Europe
day 14. The elimination half-life is 48-68 and USA, with 4 week dosing intervals indi-
hours, distribution volume 404 L (4.9 L/kg), cated for the treatment of schizophrenia.
and oral clearance 3.3-4.0 L/h. Protein bind- ARI long-acting activity is presumably
ing is extensive (>99 %), primarily to albu- primarily due to the parent drug, aripipra-
min (Winans, 2003). zole, and to a lesser extent, to its major me-
It has been found that therapeutic doses tabolite, dehydro-aripiprazole, which has
of lithium and divalproex have no clinically been shown to have affinities for D2 recep-
significant effects on the pharmacokinetics tors similar to the parent drug and represents
of ARI in patients with schizophrenia or about 29 % of the parent drug exposure in
schizoaffective disorder (Citrome et al., plasma.
2005; DeLeon et al., 2004). ARI absorption into the systemic circula-
Metabolism takes place in the liver via tion is slow and prolonged following intra-
CYP3A4 and CYP2D6, primarily as a result muscular injection due to low solubility of
of dehydrogenation, hydroxylation and N- ARI particles. Following a single intramus-
dealkylation. At steady-state, about 40 % of cular dose, the plasma concentrations of ARI
the plasma ARI level is represented by the gradually rise to reach maximum plasma
major metabolite, dehydroARI. Although it concentrations at a median Tmax of 5-7 days.
is known that the affinity of dehydroARI to The mean ARI terminal elimination half-life
D2 receptors is similar to that of ARI, its is 29.9 days and 46.5 days after every 4-
1179
week injection of ARI long-acting 300 mg tors. Low affinity to muscarinic receptors
and 400 mg, respectively, and steady state would theoretically predict a low propensity
concentrations are attained by the fourth for causing anticholinergic side effects. The
dose. Approximate dose-proportional in- remaining complex pharmacodynamic pro-
creases in ARI and dehydro-aripiprazole file of ASN is of potential interest, particu-
concentrations and AUC parameters are ob- larly for the serotonin 5-HT7 receptor where
served after every four week ARI long- there are pre-clinical findings of a possible
acting injections of 300 mg and 400 mg. pro-cognitive effect (Ballaz et al., 2007). An-
Elimination of aripiprazole is mainly tagonism at serotonin 5-HT2C receptors can
through hepatic metabolism involving two also theoretically be expected to produce de-
P450 isozymes, CYP2D6 and CYP3A4. Ari- sirable clinical effects, including improve-
piprazole is not a substrate of CYP1A1, ments in both cognition and mood (Shayegan
CYP1A2, CYP2A6, CYP2B6,CYP2C8, and Stahl, 2004; Citrome, 2013a).
CYP2C9, CYP2C19, or CYP2E1 enzymes. In vitro studies have demonstrated that
ASN is metabolized to N-desmethylasena-
Asenapine pine, asenapine N-oxide, 11-hydroxyasena-
Asenapine (ASN), available as an orally pine. The main metabolite, N-desmethyl-
disintegrating tablet administered sublingual- asenapine, and the phase II metabolite,
ly, differs from other oral antipsychotics in asenapine N+-glucuronide, show affinities
that it is absorbed through the oral mucosa. that are 10- to 100-fold lower than that of
ASN has recently been added as a treat- asenapine for the most relevant of these re-
ment option for schizophrenia for adults by ceptors; an exception is 5-HT1A, for which
the US Food and Drug Administration and as the affinity of N-desmethylasenapine is simi-
monotherapy or adjunctive therapy with lith- lar to that of ASN (Peeters et al., 2011).
ium or valproate in the treatment of manic or The pharmacokinetic characteristics of
mixed episodes associated with bipolar I dis- ASN are reported in Table 3. It is rapidly
order. ASN is also indicated in the European absorbed. Absolute bioavailability is 35 %,
Union for the treatment of moderate to se- mean Cmax is approximately 4 ng/mL, and
vere manic episodes associated with bipolar I Tmax is 0.5 to 1.5 h. Steady-state concent-
disorder (Szegedi et al., 2012; Bobo, 2013). rations are reached within 3 days of twice-
A sedative profile of the drug is generally daily dosing. Food or water may decrease
proved. asenapine exposure. It is rapidly distributed
The human receptor signature of ASN is throughout the body. Vd is approximately 20
characterized by high affinity for serotonin to 25 L/kg; 95 % bound to plasma proteins.
(5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, ASN is metabolized in the liver by direct
5-HT5, 5-HT6, 5-HT7), α-adrenergic (α1, α2A, glucuronidation by UGT1A4 and by oxida-
α2B, α2C), dopamine (D1, D2, D3, D4) and his- tive metabolism by CYP-450 isoenzymes
tamine (H1, H2) receptors, but minimal affin- (predominantly CYP1A2). Elimination is
ity for muscarinic receptors (Peeters et al., 50 % in urine and 40 % in feces. The mean
2011). terminal half-life is approximately 24 h.
In particular, ASN has substantially Plasma Cl after IV administration is 52 L/h.
higher affinity (Ki in nM) to serotonin 5- Pharmacokinetics are similar in patients with
HT2C (0.03), 5-HT2A (0.06), 5-HT7 (0.13), 5- varying degrees of renal impairment com-
HT2B (0.16), 5-HT6 (0.25), and dopamine D3 pared with healthy patients. The effect of
(0.42) receptors than to dopamine D2 recep- dialysis on the pharmacokinetics of asenap-
tors (1.3). Binding affinity to histamine H1 ine has not been studied. Severe hepatic im-
(1.0), dopamine D4 (1.1), norepinephrine α1 pairment exposure was 7 times higher than
(1.2), and norepinephrine α2 (1.2) receptors in healthy patients; mild or moderate hepatic
approximates that for dopamine D2 recep-
1180
Table 3: Pharmacokinetic characteristics of new oral antipsychotics (modified by Citrome, 2013a)

Iloperidone Asenapine Lurasidone Cariprazine
(CRP)
Pharmacokinetics
Time to peak 2–4 h 0.5–1.5 h 1–3 h 3–4 h

PL
Elimination CYP2D6 exten- 24 h 18 h 2-5 days

T1/2 sive metaboliz- (at 40 mg/day)
ers: 18 h (23-26
for metabolites);
CYP2D6 poor
metabolizers:
33 h (31-37 for
metabolites)
Protein-bound 95 % 95 % 99 % Pending
Route of metabolism CYP2D6, UGT1A4, CYP3A4 CYP3A4,

CYP3A4 CPY1A2 CYP2D6
Important metabolites P88 (in equili- Activity is pri- Two active me- Desmethyl-
brium; crosses marily due to tabolites with CRP,
the BBB), P95 the parent drug shorter t1/2 didesmethyl-
(does not cross than the parent CRP the latter’s
the BBB) compound t1/2 longer than
that for CRP (-3
weeks)
PL, Plasma Levels; BBB, Blood Brain Barrier; t1/2, half-life
impairment exposure was 12 % higher than receptor antagonism, might be beneficial for
in healthy patients. In elderly patients ASN mood and cognition (Harvey et al., 2011;
Cl is decreased, increasing exposure by 30 % Luoni et al., 2014).
to 40 % (Peeters et al., 2011; Citrome, 2014). LRS also has high affinity for the 5-HT1A
subtype, with which it interacts as a partial
Lurasidone agonist such as the benzisothiazoles perospi-
Chemically, lurasidone (LRS) is structur- rone and ziprasidone, but not risperidone and
ally related to perospirone and ziprasidone iloperidone (Harvey et al., 2011). 5-HT1A
and other benzisothiazoles including the receptors, widely expressed in the central
benzisoxazole derivatives risperidone, its nervous system and upregulated in the
active metabolite paliperidone, and iloperi- frontal cortex, have been implicated in the
done. LRS has shown efficacy in the treat- enhancement of cognitive function in the
ment of acute exacerbation of schizophrenia schizophrenic patients. The stimulation of
in a series of short-term placebo controlled these receptors could normalize frontal cor-
studies and in a more recent longterm studies tex function and reduce side effects induced
(Bobo, 2013; Stahl et al., 2013). by dopamine D2 receptor blockade such as
LRS has high affinity for the dopamine EPS, including dystonia and diskinesia, and
D2 and 5-HT2A receptors. However, it has the the iperprolactinemia (Citrome, 2012b).
highest affinity of any atypical antipsychotic In addition to the other unique binding
for the 5-HT7 receptor and its potent 5-HT7 profiles of other monoamine receptors, the
1181
lack of affinity for the dopamine D4 receptor α1 receptors and an intermediate to high af-
by LRS might also contribute, at least partly, finity for norepinephrine α2C receptors. It
to its cognitive enhancing effect (Murai et shows an intermediate affinity for dopamine
al., 2014). D2A and D4 receptors, 5HT1A, 5HT2C, and
LRS has affinity for α2C-adrenergic re- 5HT6 receptors. Moreover ILP shows low
ceptors and low affinity for α1-adrenergic affinity for norepinephrine α2A, α2B, ß1, ß2,
receptors (orthostatic hypotension) (Citrome, receptors, histamine H1 receptors, dopamine
2013b). D1 and D5 receptors. Negligible affinity is
It has minimal affinity for 5-HT2C recep- for muscarinic μ1–μ5 receptors, dopamine
tors and it has negligible affinity for hista- and norepinephrine reuptake transporters
mine H1 and muscarinic receptors, which are (Rado and Janicak, 2014).
linked to sedation and weight gain, and have Of clinical importance is the relatively
negative cognitive effects. high affinity for noradrenergic α1 receptors
From a pharmacokinetic point of view (Ki 0.36 nM), compared with the affinity for
LRS is rapidly absorbed, reaching peak con- serotonin 5-HT2A and dopamine D2 receptors
centrations within 1.5–3 hours (Tmax) after (Ki 5.6 and 6.3 nM, respectively). This is the
single and multiple oral doses. Its pharmaco- explanation for iloperidone’s potential for
kinetics was linear in the range of 20 to dizziness and orthostatic hypotension and
160 mg in healthy and schizophrenic sub- this potent effect at noradrenergic α1 recep-
jects, but interindividual variability was high tors is the principal reason for the require-
(30 %–60 %) in terms of plasma maximum ment that ILP be titrated to its therapeutic
concentrations (Cmax) and area under the target dose range of 12–24 mg/day.
curve (AUC). Absorption increased when the The randomized controlled trials of ILP
drug was taken with food AUC and Cmax in- tested several doses of ILP vs placebo, and
creasing two- to three-fold. LRS has high all employed twice daily (bid) dosing even
binding to human plasma albumin and alpha- though the elimination half-life approximates
1-glycoprotein (99 %). 24 h, which would possibly justify once-
Elimination is essentially by metabolism, daily dosing once titration to a tolerable dose
primarily involving CYP3A4. The two main has taken place. An open-label extension
metabolites, the acidic derivative ID-20219 study did suggest that 12 mg given once dai-
and its hydroxylated derivative ID-20220, ly at bedtime was efficacious and tolerable
have negligible affinity for the D2 receptors (Cutler et al., 2013).
and 5-HT1A, 5-HT2A, and 5-HT7 receptors. Other receptor-binding characteristics
The mean terminal half-life at steady may be important clinically. Low affinity to
state in patients with schizophrenia ranges muscarinic receptors would theoretically
28.8 and 37.4 hours. Thus, after repeated predict a low propensity for causing anticho-
oral doses in schizophrenic patients, steady- linergic side effects, including cognitive dys-
state concentrations of lurasidone were function and gastrointestinal disturbances, at
achieved within 7 days (Caccia et al., 2012; clinically relevant doses (Citrome, 2013a).
Citrome, 2013b) (Table 3). Low affinity to histamine H1 receptors would
theoretically predict a low propensity for
Iloperidone causing sedation or weight gain (Shayegan
Iloperidone (ILP) was recently approved and Stahl, 2004). However, proof that these
by the US Food and Drug Administration for receptor binding affinities are clinically rele-
the acute treatment of schizophrenia (Arif vant in the day-to-day treatment of patients
and Mitchell, 2011; Rado and Janicak, requires the conduct of clinical trials to test
2014). these hypothesized effects.
ILP shows high affinity for dopamine D3 Pharmacokinetic studies have determined
receptors, 5HT2A receptors, norepinephrine that iloperidone is well absorbed orally, with
1182
a bioavailability of 96 %. Peak plasma con- CRP is also a partial agonist at serotonin

centration (Cmax) of ILP is reached 2–4 hours 5-HT1A receptors with a Ki of 3. Differing
after oral administration. Its elimination half- from many other second generation antipsy-
life ranges from 18 hours for extensive cyto- chotics, the binding of CRP at serotonin 5-
chrome P450 2D6 (CYP2D6) metabolizers HT2A receptors is relatively weaker, with a
to 33 hours for poor metabolizers. It is me- Ki of 19. Theoretically, dopamine D3-
tabolized in the liver by the CYP3A4 and preferring agents may exert pro-cognitive
CYP2D6 enzyme pathways and circulates effects, as evidenced in animal studies
95 % bound to serum proteins. ILP has two (Gyertyán et al., 2011). Serotonin 5-HT1A
major metabolites: P88-8991 and P95- partial agonism, a property CRP also shares
12113. P88-8991 shares similar receptor with ARI and LRS, is also thought to possi-
binding affinities with the parent compound. bly benefit negative symptoms and cognitive
P95-12113 exhibits a lower affinity for the deficits (Blier and Ward, 2003; Ohno, 2011).
5HT2A receptor, does not cross the blood– CRP is rapidly absorbed, reaching peak
brain barrier, and therefore does not contrib- concentrations between 3 and 4 hours after
ute to the clinical effects of ILP. P95-12113 oral dosing in healthy subjects. Food mar-
binds to receptors with a significantly lower ginally delayed the absorption of cariprazine,
affinity than ILP. The main pharmacokinetic but did not affect the extent of its absorption
characteristics of iloperidone are reported in after a single 2 mg oral dose. Its pharmaco-
Table 3 (Citrome, 2013a; Rado and Janicak, kinetics were linear in terms of area under
2014). the concentration–time curve (AUC) but
maximum concentrations were more than
Cariprazine proportional within the dose range from 3 to
Cariprazine is a potential antipsychotic 5 mg in healthy subjects. Mean half-life was
awaiting approval from the US Food and 2–5 days (1.5–12.5 mg/day). Cariprazine is
Drug Administration. CRP is in late-stage then primarily cleared by hepatic metabo-
clinical development for the treatment of lism, as are most lipophilic antipsychotics.
schizophrenia, bipolar disorders and as an There are two active metabolites of note:
adjunctive agent for the treatment of major desmethyl-cariprazine and didesmethyl-
depressive disorder. Clinical trials showed cariprazine. The half-life of didesmethyl-
that CRP should be titrated to target doses cariprazine is substantially longer than that
(3-9 mg/day) (Citrome, 2013b). of cariprazine, and systemic exposure to
Cariprazine (CRP) is a dopamine D2- and didesmethyl-cariprazine can be several times
D3-receptor partial agonist, with higher affin- higher than that for CRP (Caccia et al.,
ity for D3 receptors, as opposed to the D2 an- 2013). The pharmacokinetic properties of
tagonism of most older antipsychotic agents CRP are reported in Table 3.
(Seneca et al., 2011; Caccia et al., 2013). In
particular CRP is a dopamine D3-preferring GENERAL CONCLUSIONS
D3/D2 receptor partial agonist presently con- The choice of the best antipsychotic
sidered for the treatment of schizophrenia treatment for an individual patient appears
and bipolar disorders (Citrome, 2013a-c). complex. It should be considered the phar-
Binding affinities (Ki) for dopamine D3 re- macological anamnestic history of the pa-
ceptors (0.085) are an order of magnitude tients including the previous history of ther-
higher than for D2 receptors (0.49–0.69). At apeutic response and tolerability with other
present, ARI and CRP are the only dopamine medications so as individual patient prefer-
D2 partial agonists commercially available ences. Patients may also have specific sensi-
for the treatment of psychiatric disorders tivities to certain adverse effects of medica-
(Citrome, 2013b). tion, such as akathisia, sedation, or weight
gain. Having different options in order to
1183
optimize efficacy and tolerability for the in- In any case, it is necessary to consider
dividual patient is desirable. the value of acute pharmacokinetic data to
Four new second-generation antipsychot- characterize the new drug and the heuristic
ics are available iloperidone, asenapine, value of plasma level determination together
lurasidone and in the next future cariprazine. with its medico-legal importance in the case
Similar to ziprasidone and aripiprazole, these of intoxication, etc. Moreover, the im-
new agents have a lower propensity for portance of drug plasma level monitoring
weight gain and metabolic abnormalities remains when it comes to identifying “pseu-
than older second-generation antipsychotics do-pharmacoresistance” problems such as
such as olanzapine or clozapine; lurasidone poor compliance, high individual levels of
is reported be best in class in terms of mini- metabolism, excessive water consumption by
mizing untoward alterations in body weight patients, excessive smoking, drug abuse, as
and metabolic variables. Asenapine generally well as the appearance of unpredictable side
have a more sedative profile. effects and possible drug interactions.
However, iloperidone, asenapine, lura-
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EXCLI Journal 2014;13:1163-1191 – ISSN 1611-2156

CLINICAL PHARMACOLOGY OF ATYPICAL ANTIPSYCHOTICS:

* Corresponding author: M.C. Mauri, Clinical Psychiatry, Clinical Neuropsychopharmacology

INTRODUCTION These symptoms are specific to the group as

Figure 2: Simplified receptor binding affinity profiles for atypical antipsychotics

↑DA and NE release in the ↓ negative symptoms behavioral activation

Glutamate modulation ↓ positive symptoms

Clozapine toninergic receptor subtypes (5HT2A 5HT2C)

variability of its pharmacokinetic parameters. It is available also a long-acting injecta-

Table 3: Pharmacokinetic characteristics of new oral antipsychotics (modified by Citrome, 2013a)

Time to peak 2–4 h 0.5–1.5 h 1–3 h 3–4 h

Elimination CYP2D6 exten- 24 h 18 h 2-5 days

Route of metabolism CYP2D6, UGT1A4, CYP3A4 CYP3A4,

a bioavailability of 96 %. Peak plasma con- CRP is also a partial agonist at serotonin

Citrome L. Cariprazine: chemistry, pharmacodynam- Duggan L, Fenton M, Rathbone J, Dardennes R, El-

Di Lorenzo R, Brogli A. Profile of olanzapine long- Gefvert O, Lundberg T, Wieselgren I, Bergstrom M,

Gefvert O, Eriksson B, Persson P, Helldin L, Bjorner Horacek J, Bubenikova-Valesova V, Kopecek M,

Seeman P. Atypical antipsychotics: mechanism of Stockton ME, Rasmussen K. Electrophysiological

Wright P, Lindborg SR, Birkett M, Meehan K, Jones

Yokoi F, Grunder G, Biziere K, Stephane M, Dogman

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