1521-0103/347/3/542–546$25.00
207209
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright ª 2013 by The American Society for Pharmacology and Experimental Therapeutics
Perspectives in Pharmacology
Nonhuman Primates: Translational Models for Predicting
Antipsychotic-Induced Movement Disorders
Roger D. Porsolt, Vincent Castagné, Eric Hayes, and David Virley
Porsolt Research Center, Porsolt SAS (France), Le Genest-Saint-Isle, France
Received June 14, 2013; accepted September 12, 2013
ABSTRACT
Repeated haloperidol treatment administered to nonhuman
primates (NHPs) over several months or even years leads to the
gradual appearance of drug-induced dystonic reactions in the
orofacial region (mouth opening, tongue protrusion or retraction,
bar biting) and in the whole body (writhing of the limbs and trunk,
bar grasping). The propensity of antipsychotics to induce
dystonia in NHPs is not correlated with their propensity to
induce catalepsy in rodents, suggesting that the two types of
effects are dissociated and may represent distinct aspects of
the extrapyramidal symptoms induced by antipsychotics. In
Introduction
A major side effect of first-generation antipsychotics
(chlorpromazine, haloperidol, fluphenazine) is the occurrence
of extrapyramidal symptoms (EPS) that occur either early in
the course of treatment (Parkinsonism, akathisia, acute
dystonia) or at a much later stage (tardive dyskinesia). The
early phenomena are a direct consequence of drug adminis-
tration, decrease when drug administration ceases, and can
be attenuated by anticholinergic agents. Tardive dyskinesia
occurs during sustained antipsychotic therapy or on reduction
or cessation of treatment, can be suppressed by reinstatement
of treatment, and is generally exacerbated by anticholinergic
agents. For a more comprehensive review of EPS induced by
antipsychotics in patients, see Casey (2004). EPS were
initially considered to be intrinsic to antipsychotic action
(Haase, 1978). The discovery of the antipsychotic activity of
clozapine challenged this notion because clozapine was shown
to be an effective antipsychotic without inducing EPS (Hippius,
1989; Meltzer, 1989).
Since the discovery of clozapine, the pharmaceutical industry
has invested heavily in the research for novel substances,
frequently termed atypical antipsychotics or second- and third-
generation antipsychotics, which like clozapine were intended
dx.doi.org/10.1124/jpet.113.207209.
ABBREVIATIONS: 3-PPP, 3-(3-hydroxyphenyl)-N-(1-propyl) piperidine; 5-HT, 5-hydroxytryptamine (serotonin); DA, dopamine; EPS, extrapyrami-
dal symptoms; MD 790501, (exo)-2,3 dimethoxy-N-[8-(phenylmethyl)-8-azabiocyclo [3.2.1]oct-3-yl; NHP, nonhuman primate; THIP, 4,5,6,7-
tetrahydroisoxazolo[5,4-c]epyridine-3-ol.
542
http://dx.doi.org/10.1124/jpet.113.
J Pharmacol Exp Ther 347:542–546, December 2013
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view of the clear homology to clinically observed phenomena,
antipsychotic-induced dystonias in antipsychotic-primed NHPs
would appear to possess a high degree of translational validity.
These NHP phenomena could therefore serve as a useful
model for predicting the occurrence of similar abnormal
movements with novel substances developed for the treatment
of schizophrenia or other psychotic disorders. Moreover, the
NHP dystonia model could possibly serve as a biomarker for
substances that will eventually cause tardive dyskinesia in
patients.
to be clinically more effective than first-generation antipsy-
chotics but have a lower incidence of EPS.
The results have been generally disappointing. With the
possible exception of olanzapine, none of the more recently
developed antipsychotics have been shown to be superior to
first-generation antipsychotics or even to attain the level of
clinical efficacy achieved with clozapine (Attard and Taylor,
2012; Hartling et al., 2012). The results are also equivocal
concerning the incidence of EPS in which, apart from
clozapine itself, no clear improvement in EPS profiles with
newer antipsychotics has been demonstrated (Bakker et al.,
2011; Pringsheim et al., 2011; Gurevich et al., 2012; Haddad
et al., 2012; Peluso et al., 2012). This failure is perhaps not
surprising given the lack of clarity/validity of the distinction
between typical versus atypical antipsychotics, or the distinc-
tion between first-, second-, and third-generation antipsy-
chotics. Sophisticated biochemical/molecular approaches based
on these classifications [e.g., Maheux et al. (2005)] may not
facilitate the discovery of more efficacious or safer antipsychotic
treatments unless the clinical endpoints are taken more clearly
into account. Indeed, one can ask whether classifying anti-
psychotics in this manner really represents an adequate way of
distinguishing between the clinical effects of the numerous
available antipsychotics, even those of the first generation.
The quest for more efficacious antipsychotic drugs with a
lower incidence of EPS therefore remains highly topical and

represents an unmet research need in the discovery of novel
treatments not only for schizophrenia, but also for other disorders
in which psychosis constitutes an important feature, such as
Huntington’s disease (Alpay and Koroshetz, 2006; Johnston, 2011).
This article reviews EPS models in rodents and nonhuman
primates (NHPs). Although there are clear differences
between early EPS (Parkinsonism, akathisia, acute dystonia)
and tardive dyskinesia, the literature and experimental data
reviewed below suggest that even the early EPS phenomena
can be dissociated in animal models and likely clinically as
well. For example, there is an absence of correlation between
the propensity of novel substances to induce catalepsy in rats,
a putative predictor of antipsychotic-induced Parkinsonism in
patients, and their propensity to induce dystonic signs in
NHPs, a highly probable predictor of antipsychotic-induced
acute dystonia in patients (Table 1). We argue that the
antipsychotic-induced dystonia model in NHPs has higher
translational validity to humans than any available procedure
Antipsychotic-Induced Movement Disorders in NHPs 543
and crouching, which have been assimilated to Parkinsonian-
like akinesia (Auclair et al., 2009). The muscular rigidity
observed in NHPs after antipsychotic treatment has also been
assimilated to that observed in patients (Casey, 1996). The
literature is less clear concerning tremor. Although some
reports suggest the occurrence of antipsychotic-induced
tremor in some species of NHP, as described for example by
Liebman and Neale (1980) in squirrel monkeys or by
Peacock et al. (1999) in cebus monkeys, no Parkinsonian-
like tremors were observed in rhesus monkeys (Porsolt and
Jalfre, 1981) and none were clearly described by Auclair
et al. (2009) in cynomolgus monkeys. In most of the pub-
lications concerning cebus monkeys, the EPS-like signs
observed were grouped under the heading of dystonia (see
below).
Animal Models of Antipsychotic-Induced

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in rodents (Porsolt, 2013), and should thereby be best able to
predict the occurrence of at least this type of antipsychotic-
induced movement disorder in humans. Moreover, this review
suggests that data obtained in the NHP dystonia model could
possibly serve as a biomarker for substances that will eventually
cause tardive dyskinesia in patients.
Animal Models of Antipsychotic-Induced
Parkinsonism
Parkinsonism, both antipsychotic-induced and idiopathic, is
characterized in patients by a triad of symptoms: tremor in
the extremities, rigidity, and akinesia [see Casey (2004) for
a review]. None of these phenomena can be clearly identified in
rodent behavior. On the other hand, most first-generation
antipsychotics, but not clozapine or several second-generation
antipsychotics (remoxipride, quetiapine, or aripiprazole), in-
duce catalepsy in rodents as indicated by the time an animal
will remain in an unusual position imposed by the experi-
menter (Arnt and Skarsfeldt, 1998). Although catalepsy bears
only a superficial resemblance to Parkinsonism, thereby
decreasing its translational validity, available data suggest
that catalepsy in rodents represents a reasonable predictor of
antipsychotic-induced Parkinsonism in patients (Castagné
et al., 2009; Porsolt et al., 2010).
Antipsychotics generally reduce locomotor activity in
animals. This type of effect in NHPs includes static posture
Akathisia
Akathisia, which involves subjective feelings of unrest
accompanied by signs of motor agitation [see Casey (2004)
for a review], does not appear to have any clear parallel in
rodent or NHP behavior. The major problem is that most, if
not all, antipsychotics do not induce behavioral agitation but
in fact decrease spontaneous activity. It has been suggested
that antipsychotic-induced increases in defecation in rats
parallel the incidence of akathisia in patients with the same
drugs (Sachdev and Brüne, 2000). On the other hand, this
type of observation does not take into account the effects of
these substances on gastrointestinal transit. More impor-
tantly, enhanced defecation in rats has no obvious trans-
lational link to humans.
Animal Models of Antipsychotic-Induced
Dystonia
Acute dystonia is characterized by involuntary muscle
spasms, accompanied by briefly sustained or fixed abnormal
postures including bizarre positions of the limbs and trunk,
oculogyric crises, tongue protrusion, and torticollis [see Casey
(2004) for a review].
Early-onset vacuous chewing movements have been reported
in rats after repeated treatment with certain antipsychotics
(haloperidol, cis-flupenthixol, trifluoperazine, fluphenazine,

TABLE 1
Effects of different antipsychotics on apomorphine antagonism versus catalepsy in the rat and apomorphine antagonism
versus dystonias in the rhesus monkey

Rat Minimum Effective Dose Rhesus Monkey Minimum Effective Dose

Test Substance
Apomorphine Catalepsy Ratio Apomorphine Dystonia Ratio
Antagonism Antagonism

mg/kg i.p. mg/kg i.m.

Haloperidol 0.31 3.3 10.6 0.015 0.05 3.3
Clozapine 2 .20 .10 1a .10 .10
Chlorpromazine 9.7 15.4 1.6 0.28 .2.5 .9
Thioridazine 45 60 1.3 5.09 .20 .4
Sultopride 20.4 .200 .10 0.75 1.25 1.7
Tropapride (MD 790501) 0.44 27.1 61.6 0.0004 0.001a 2.5
Data from Porsolt and Jalfre (1981), Porsolt et al. (1982), Jalfre et al. (1983), and Castagné et al. (2009).
a
Unpublished data from Delalande (now Sanofi).
544 Porsolt et al.
sulpiride), but not clozapine. They are attenuated by centrally
active, but not peripherally active, anticholinergic agents.
These data parallel the clinical profiles of these substances
(Stewart et al., 1988; Waddington, 1990; Egan et al., 1996).
Vacuous chewing in rodents appears, nonetheless, remote
from the above-described clinical phenomena.
More encouraging data have been obtained in NHPs.
Dystonia-like phenomena have been observed in a wide range
of NHP species, including squirrel monkeys (Weiss et al.,
1977; Liebman and Neale, 1980, Neale et al., 1982), cebus
monkeys (Gunne and Bárány, 1976, 1979; Häggström, 1984;
Gerlach and Casey, 1990; Casey, 1996; Peacock and Gerlach,
1999; Peacock et al., 1999; Casey et al., 2001; Shiigi et al.,
2003; Andersen et al., 2003; Brandt-Christensen et al., 2006;
Madsen et al., 2011), rhesus monkeys (Porsolt and Jalfre,
1981; Porsolt, 1984), cynomolgus monkeys (Gunne and
Bárány, 1976; Auclair et al., 2009), green monkeys (Casey
et al., 1980), marmosets (Fukuoka et al., 1997), and baboons
(Meldrum et al., 1977).
Of particular interest is the recent article by Auclair et al.
(2009) that describes the evaluation of a whole range of first-,
second-, and third-generation antipsychotics on a variety of
symptoms in the cynomolgus monkey. Among the various
signs observed were static posture (halting and then pausing
before initiating another movement, crouching) and the
occurrence of unusual positions or movements (persistent
limb extension, twisted torso, tongue protrusion, biting metal
grids, or perseverative pushing of the head or body against
cage walls). These two types of phenomena would appear to
parallel drug-induced Parkinsonism and acute dystonia,
respectively. Clearly differential profiles were observed with
the drugs investigated. Haloperidol induced unusual move-
ments but surprisingly did not cause any static posture/
crouching (see below). Risperidone and olanzapine induced
both types of symptoms, whereas only increased static
posture/crouching was observed with clozapine. Two more
recent substances, quetiapine and aripiprazole, had no effects
on the investigated parameters, whereas the substituted
benzamide remoxipride induced only abnormal movements
and ziprasidone induced only static posture/crouching. If it
can be assumed that static posture/crouching could also
reflect the hypolocomotor component of drug action, these
differential profiles would appear to correspond to the known
clinical profiles of these substances (Gerlach, 2002) with the
possible exception of haloperidol. Some of these data in
cynomolgus monkeys have been replicated in our own
laboratory (Hayes et al., 2012; Porsolt, 2013). In contrast to
the study by Auclair et al. (2009), we observed both static
posture/crouching and unusual positions/movements with
haloperidol, a result that is more in accordance with haloper-
idol’s clinical effects.
The above experiments were carried out in monkeys with
little or no prior experience with antipsychotics (nonprimed).
In experiments performed many years ago, rhesus monkeys
were repeatedly administered different antipsychotics over
extended periods (months and even years) (Porsolt and Jalfre,
1981; Porsolt, 1984). In contrast to the marked sedation and
catalepsy observed during the early phases of antipsychotic
treatment, several of the monkeys gradually developed
dystonias in the orofacial region (mouth opening, tongue
protrusion or retraction, bar biting) and in the whole
body (writhing of the limbs and trunk, bar grasping). The
symptoms occurred with two first-generation antipsychotics
(haloperidol, fluphenazine) but not with two other first-
generation antipsychotics (chlorpromazine, thioridazine) or
clozapine at doses that were clearly behaviorally active. The
dystonias could be attenuated by anticholinergic treatment.
Clinical psychiatrists invited to observe these animals
confirmed that the behavioral symptoms corresponded closely
to what they had seen in patients. Moreover, the differential
profiles observed in the monkeys corresponded to the then-
described clinical profiles of these drugs (Deniker et al.,
1980).
A remarkable feature of antipsychotic-induced dystonia in
rhesus monkeys was that the sensitivity of antipsychotic-
primed rhesus to haloperidol remained unaltered even when
the monkeys were left without exposure to antipsychotic
treatment of periods of up to 1 year (Porsolt, 1984). Similarly,
when the same cebus monkeys were used repeatedly [e.g., by
Gunne and Bárány (1976, 1979), Gerlach and Casey (1990), or
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Casey (1996)], there were no reports of tolerance. In contrast,
Neale et al. (1982) reported that squirrel monkeys showed
clear signs of tolerance to these effects after repeated treatment.
There are, however, too few published data to determine
whether the occurrence of tolerance depends on the type of
NHP species used.
Catalepsy in Rats versus Dystonia in NHPs
Because catalepsy in rats has traditionally been the
behavioral sign taken to evaluate the EPS liability of putative
antipsychotics during the drug discovery phase, it is in-
structive to compare the cataleptogenic potential of different
substances in rats with their capacity to induce dystonias in
rhesus monkeys. Table 1 shows results obtained many years
ago with the first-generation antipsychotics haloperidol,
chlorpromazine, and thioridazine, the atypical antipsychotic
clozapine, and the substituted benzamides sultopride and
tropapride [(exo)-2,3 dimethoxy-N-[8-(phenylmethyl)-8-
azabiocyclo [3.2.1]oct-3-yl] (MD 790501)], the latter being an
experimental substance that was subsequently dropped from
development.
The data indicate that haloperidol antagonized apomor-
phine in both species and induced clear catalepsy in rats and
dystonias in monkeys. Clozapine weakly antagonized apo-
morphine in the two species but induced neither catalepsy nor
dystonias. The two phenothiazines (chlorpromazine, thiorid-
azine) were clearly cataleptogenic in rats at doses close to
those that antagonized apomorphine but induced no signs of
dystonia in monkeys at doses well above those that antago-
nized apomorphine. The two substituted benzamides (sul-
topride, tropapride) were only weakly cataleptogenic in rats,
but induced clear dystonias in monkeys at doses close to those
that antagonized apomorphine. These data suggest a dissoci-
ation between two indices of EPS as assessed in the two
species in a manner that would appear to reflect the clinical
profiles of the drugs investigated, in which Parkinsonism
is associated with most phenothiazines but less so with
benzamides, dystonias are associated with most benzamides
but not with all phenothiazines, and haloperidol clearly
induces both types of EPS, whereas clozapine induces neither
Parkinsonism nor dystonia (Deniker et al., 1980; Gerlach,
2002).

Animal Models of Antipsychotic-Induced Tardive
Dyskinesia
Tardive dyskinesia is a syndrome of involuntary abnormal
movements that occur during sustained antipsychotic therapy
or on reduction or cessation of treatment. The movements
include chewing, tongue protrusion, lip smacking, puckering,
paroxysms of rapid eye blinking, and choreoathetoid move-
ments of the limbs and trunk. Some of the features, such as
orofacial movements, may resemble or even occur simulta-
neously with acute dystonia, making differential diagnosis
difficult. Tardive dyskinesia is characterized by the fact that
once manifest, it appears irreversible. It can be reduced by
reinstatement of antipsychotic treatment but appears to be
exacerbated by anticholinergic treatment [see Casey (2004)
for a review].
Vacuous chewing movements have been observed in rats
after cessation of long-term haloperidol administration for
periods of up to 1 year (Waddington, 1990; Egan et al., 1996;
Turrone et al., 2002). On the hypothesis that long-term
antipsychotic treatment induces supersensitivity of post-
synaptic dopamine (DA) receptors, some authors described
an increased behavioral response to DA agonists after long-
term neuroleptic treatment (Clow et al., 1979), whereas
others related the phenomena to continued DA D2 receptor
occupancy (Turrone et al., 2002). However, in contrast
to the clinical syndrome, the vacuous chewing movements
or the increased response to DA agonists in the rodent
disappear spontaneously over a few days or weeks (Clow
et al., 1979; Waddington, 1990; Egan et al., 1996; Turrone
et al., 2002).
More convincing signs of tardive dyskinesia have been
shown in NHPs. These studies were recently reviewed by
Blanchet et al. (2012). An early publication by Gunne and
Bárány (1976) reported the occurrence of dyskinetic move-
ments persisting for up to 6 years in two of three cebus
monkeys after cessation of 3 or 12 months of once-daily oral
treatment with haloperidol (doses escalating from 0.5 to 8 mg/
kg per day). All three cebus monkeys showed signs of acute
dystonia after each haloperidol administration as did two
cynomolgus monkeys, also included in the study, which did
not develop tardive dyskinesia. The anticholinergic biperiden
reduced the dystonia but reinstated the signs of tardive
dyskinesia. In a later study with the same two cebus monkeys,
the same authors reported that chlorpromazine, thioridazine,
clozapine, melperone, and fluphenazine attenuated the signs
of tardive dyskinesia (Gunne and Bárány, 1979). In sub-
sequent studies, the same group of authors showed that acute
treatment with two putative antipsychotics, the DA autoreceptor
receptor agonist 3-(3-hydroxyphenyl)-N-(1-propyl) piperidine
(3-PPP) (Häggström et al., 1983) and the benzamide sulpiride
(Häggström, 1984), suppressed these signs. Other findings
by these authors suggested the effectiveness of the GABA
agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]epyridine-3-ol (THIP)
(Andersson and Häggström, 1988), Similar findings were
reported for 3-PPP in cebus monkeys in which tardive
dyskinesia was induced by long-term treatment with fluphen-
azine enanthate (Kovacic et al., 1988). Another study included
a total of 24 cebus monkeys that had been previously primed
with antipsychotics for periods of up to 2 years (Casey, 1996).
Among these animals, there were seven that could be con-
sidered very aged (23–29 years), four of which showed signs of
Antipsychotic-Induced Movement Disorders in NHPs 545
spontaneous tongue protrusions in the absence of antipsychotic
treatment. These phenomena seemed assimilable to tardive
dyskinesia, which is clearly more prevalent in older human
populations (Jeste et al., 1995). The spontaneous tongue protru-
sions were attenuated by acute administration of sertindole,
risperidone, and haloperidol.
Conclusions
The above-reviewed findings suggest that catalepsy in
rodents may represent a good predictor for the propensity of
novel substances to induce Parkinsonism in patients. On the
other hand, antipsychotic-induced Parkinsonism in NHPs is
not a clear occurrence.
There are no convincing models of akathisia in rodents or in
NHPs.
There are no convincing models of acute dystonia or tardive
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dyskinesia in rodents.
With regard to tardive dyskinesia in NHPs, the available
data suggest their translational validity. Such models,
however, do not lend themselves readily for drug development
purposes because they are extremely time-consuming and the
numbers of animals eventually manifesting signs of tardive
dyskinesia appear limited in relation to the numbers of animals
initially included in the programs.
The situation is different for NHP models of dystonia.
Although chronic antipsychotic priming appears necessary to
induce reliable and clearly identifiable dystonic signs, once
established in rhesus or cebus monkeys, the phenomena
appear stable and can be reinvoked on demand even in animals
that have not received antipsychotics for longer periods.
Available findings suggest that antipsychotic-induced dys-
tonia in NHPs represents a direct homology of the acute
dystonias observed with the same drugs in patients. More-
over, although antipsychotic-induced dystonia is distinct from
tardive dyskinesia, it seems plausible that the capacity to
induce dystonia in NHPs could possibly serve as a biomarker
for substances that will eventually cause tardive dyskinesia in
patients after long-term treatment.
Despite the number of years since most of the work on
antipsychotic-induced dystonias in NHPs was performed,
recent clinical and preclinical publications suggest that such
disorders remain high on the antipsychotic research agenda.
It is suggested that the NHP dystonia model would be of
interest to any pharmaceutical company, research founda-
tion, or public agency wishing to develop new treatments
for schizophrenia or other psychotic disorders, whether for
positive symptoms, negative symptoms, or both. The techni-
ques do not depend on any assumptions concerning the
neuroanatomical substrates of acute or tardive EPS (nigros-
triatal, limbic, or cortical pathways) or on any notions
concerning the neurochemical mechanisms whereby antipsy-
chotic agents exert their therapeutic effects (antagonism of
DA D1 or D2 receptors, modulation of noradrenergic and/or
serotonergic 5-HT2 transmission). On the contrary, they
concern evaluation of behavioral phenomena in NHPs that
are clearly homologous to symptoms observed in human patients
and thereby possess a high degree of translational validity.
Acknowledgments
The authors thank Nathalie de Cerchio-Dorczynski for secretarial
assistance.
546 Porsolt et al.
Authorship Contributions
Wrote or contributed to the writing of the manuscript: Porsolt,
Castagné, Hayes, Virley.
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Address correspondence to: Roger D. Porsolt, Porsolt SAS (France), Z.A. de
Glatigné, 53940 Le Genest-Saint-Isle, France. E-mail: rporsolt@porsolt.com