CNS Drugs (2018) 32:917–938

https://doi.org/10.1007/s40263-018-0559-8

SYSTEMATIC REVIEW

Antipsychotic-Associated Symptoms of Tourette Syndrome:

A Systematic Review
David D. Kim1 · Alasdair M. Barr1 · Yunsun Chung2 · Jessica W. Y. Yuen3 · Mahyar Etminan4 · Bruce C. Carleton2,5,6 ·
Randall F. White7 · William G. Honer7 · Ric M. Procyshyn7

Published online: 18 August 2018

© Springer Nature Switzerland AG 2018

Abstract
Background Although antipsychotics are used to treat Tourette syndrome, there have been reports of paradoxical induction
of tics by first- and second-generation antipsychotics.
Objective The objective of this systematic review was to better characterize tics as the potential adverse effect of
antipsychotics.
Methods A literature search was performed, with no language restriction, using the MEDLINE, EMBASE, and PsycINFO
databases for all publications up to January 2018. To be included, studies utilizing any study design had to meet the following
criteria: (1) a temporal association of tics with antipsychotic use where tics emerged during treatment or after discontinua-
tion and (2) no diagnosis of Tourette syndrome before tic emergence. More stringent criteria were used for individuals under
18 years of age that included (1) no personal or family history of primary tic disorder and either (2) tics occurring during
antipsychotic treatment improved significantly upon discontinuation or dose reduction or (3) tics emerged after discontinu-
ation of at least 3 months of antipsychotic treatment. Data were extracted according to: age, sex, diagnosis, personal history
of motor symptoms or family history of tics, antipsychotic type and dose, treatment duration, types of symptoms emerged,
treatment strategies, and follow-up. A Fisher’s exact test was used to compare the occurrence of symptoms between first- and
second-generation antipsychotic users.
Results The search identified 1290 articles, of which 92 full-text articles were assessed leading to the inclusion of 50 articles.
Most of the included articles were case reports or series, involving a total of 60 cases. Thirty cases were associated with
treatment with first-generation antipsychotics, 27 with second-generation antipsychotics, and three with a combination of
first- and second-generation antipsychotics. Antipsychotics were being used to treat schizophrenia in 60% of the cases and
other indications included developmental, behavioral, and mood or anxiety disorders. Tics occurred during treatment (n = 44)
or following treatment discontinuation (n = 16). The occurrence of vocal tics with or without motor tics was significantly
higher in the first- vs. second-generation antipsychotic users (p < 0.0001). Significantly higher occurrences were also noted
in the first- vs. second-generation antipsychotic users for specific types of vocal tics (i.e., barking and coprolalia) and other
concurrent motor symptoms (i.e., tardive dyskinesia). In the cases identified, antipsychotic-associated tics were treated by (1)
discontinuing the offending antipsychotic, reducing its dose, or switching to different antipsychotics for tics occurring during
treatment, (2) reinitiating antipsychotic treatment for tics occurring following discontinuation, or (3) using non-antipsychotic
agents. It should be noted that symptoms were not always fully reversible and recurred at times.
Conclusion Tics can be a disturbing adverse effect of antipsychotics. Clinicians need to be particularly vigilant when initiat-
ing and modifying antipsychotic regimens.

* Ric M. Procyshyn
rprocyshyn@bcmhs.bc.ca
Extended author information available on the last page of the article

Vol.:(0123456789)
918
Key Points
Antipsychotics can induce symptoms of Tourette syn-
drome, where first-generation antipsychotics may be
associated with a greater risk of vocal tics than second-
generation antipsychotics.
Clinicians should be more vigilant for these adverse
effects particularly when initiating and modifying antip-
sychotic regimens.
1 Introduction
Antipsychotic medications are the cornerstone of pharma-
cological treatment for schizophrenia and are also shown to
be effective in other neuropsychiatric disorders. Inhibition
of certain dopaminergic pathways by these agents is linked
to therapeutic effects as well as unwanted motor adverse
effects during treatment. For instance, extrapyramidal
adverse effects, such as parkinsonism, akathisia, tremor, and
dystonia, can emerge from suppression of the nigrostriatal
dopaminergic pathway [1]. Tardive dyskinesia is another
motor adverse effect of antipsychotics, for which dopamine
supersensitivity secondary to long-term antipsychotic expo-
sure is believed to have a contributory mechanism [2]. In
general, second-generation antipsychotics (SGAs) tend to
have a higher ratio of 5-HT2A to D2 receptor antagonism than
first-generation antipsychotics (FGAs), which may have pro-
tective effects against induction of extrapyramidal symptoms
and tardive dyskinesia [1].
Some neuropsychiatric disorders with associated motor
symptoms are linked to idiopathic hyperactivity of the dopa-
minergic system in the striatum and are treated effectively
with antipsychotics. One well-known example is Tourette
syndrome (TS), which is a complex neuropsychiatric dis-
order characterized by sudden, repetitive, non-rhythmic
involuntary movements and vocalizations, known as tics
[3]. Tics can be simple or complex in nature. Simple motor
tics include eye blinking, shoulder shrugging, head shak-
ing, and grimacing, whereas complex motor tics include
hopping, jumping, imitation of others’ observed move-
ments (i.e., echopraxia), and making obscene gestures (i.e.,
copropraxia) [3]. Simple vocal tics include throat clearing,
sniffing, whistling, shouting, and making animal noises,
whereas complex vocal tics include repetition of one’s own
(i.e., palilalia) or others’ spoken words (i.e., echolalia) and
utterance of obscene words (i.e., coprolalia) [3]. Neuroimag-
ing studies have found an elevated striatal dopamine release
upon amphetamine stimulation in individuals with TS [4,
5]. In addition, for individuals with TS, both FGAs (e.g.,
D. D. Kim et al.
haloperidol and pimozide) and SGAs (e.g., risperidone) have
been efficacious and are often the first-line treatment for
severe tics [6].
Although antipsychotics can be effective against tics,
there have been paradoxical cases of de novo Tourette-like
symptoms (i.e., occurrence of concurrent motor and vocal
tics) associated with antipsychotic use [7–9]. In 1978, Kla-
wans et al. reported a case of a 28-year-old patient with
schizophrenia who developed de novo motor and vocal tics
(i.e., Tourette-like symptoms) during the month after the
discontinuation of 6 years of chlorpromazine treatment [7].
Subsequently, the phenomenon was termed “tardive Tourette
syndrome” and is believed to share similar mechanisms with
other tardive syndromes, in particular tardive dyskinesia [8].
The most current systematic review (published in 2011) has
identified 23 cases of antipsychotic-associated tardive TS,
in which 19 were FGA-associated cases and four were SGA-
associated cases [9]. It was our goal to perform an updated
review, using more databases and broader search terms.
2 Methods
2.1 Data Sources
This systematic review was conducted on the basis of the
Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) statement [10]. Two of the authors
(D.D.K. and Y.C.) independently searched the MEDLINE,
EMBASE, and PsycINFO databases to identify all published
reports up to January 2018. The following search terms were
used: (antipsychotic* OR neuroleptic*) AND ($associated
OR $induced OR $related OR secondary OR tardive) AND
(Tourette* OR Tourette-like OR tics OR tic-like). Refer-
ence lists of included and review articles were also manually
screened.
2.2 Selection of Studies
We searched for randomized controlled trials, observa-
tional studies, case series, and single case reports. Published
abstracts were also considered. To be included in our sys-
tematic review, studies had to meet the following criteria.
First, the emergence of tics was attributed to antipsychotic
use (i.e., tics emerged during antipsychotic treatment or fol-
lowing treatment discontinuation). Second, patients did not
have a diagnosis of TS before the occurrence of antipsy-
chotic-associated tics. This is because tics can wax and wane
and thus may confound the association of antipsychotic use
with tic occurrence. However, patients who had a diagno-
sis or childhood history of tic disorder of one type were
included to see whether antipsychotic use led to the emer-
gence of tic disorder of the other type (e.g., whether vocal
Tics Associated with Antipsychotics
tics emerged in a patient with chronic motor tic disorder),
making the symptoms Tourette like. Third, as primary tic
disorder occurs typically before the age of 18 years, we used
more stringent criteria ensuring that in individuals under
18 years of age, (1) there was no personal or family his-
tory of primary tic disorder and either (2) tics occurring
during antipsychotic treatment improved significantly upon
discontinuation or dose reduction or (3) tics emerged after
discontinuation of at least 3 months of antipsychotic treat-
ment. This time period was chosen because antipsychotic-
associated tics, such as tardive dyskinesia, are believed to be
linked to dopamine supersensitivity [2, 9], and the research
diagnostic criteria of tardive dyskinesia involves a history
of at least 3 months of cumulative antipsychotic exposure
[11]. No year or language restrictions were applied. Any
disagreements were resolved by consensus.
2.3 Data Extraction and Analysis
Data were extracted from the included studies according to:
age, sex, diagnosis, personal history of motor symptoms or
Fig. 1 Flow diagram of study
selection
919
family history of tics, antipsychotic type and dose, treatment
duration, types of symptoms emerged, treatment strategies,
and follow-up. Any personal history of motor symptoms
was recorded, as TS is a disorder of the basal ganglia and a
history of motor symptoms may make an individual more
susceptible to antipsychotic-associated tics. The Statistics
Package for the Social Sciences (SPSS), Version 24, was
used to compute statistical significance of the differences in
demographic and clinical variables between FGA and SGA
users. An independent samples t-test was used for the dif-
ferences in the means and a Fisher’s exact test was used for
the differences in the proportions. Values are presented as
mean ± standard deviation.
3 Results
3.1 Sample Characteristics
As presented in Fig. 1, our database searching identified
1280 records with an additional ten records identified
920
through manual searching. After removing duplicates, 820
articles were screened based on titles and abstracts, lead-
ing to the exclusion of 728 articles. Ninety-two full-text
articles were assessed and an additional 42 articles were
excluded, leaving 50 articles to be included in our systematic
review [7, 8, 12–59]. Most of the included studies were case
reports or series. A total of 60 cases were identified in our
included studies and are summarized in Tables 1, 2 and 3.
Thirty cases were FGA-associated tics (e.g., chlorproma-
zine, fluphenazine, haloperidol, mesoridazine, perphenazine,
sulpiride, thioridazine, and trifluoperazine) (Table 1) and
27 were SGA-associated tics (i.e., amisulpride, aripiprazole,
clozapine, olanzapine, paliperidone, quetiapine, risperidone,
and ziprasidone) (Table 2), and the remaining three cases
were tics occurring during combined FGA and SGA treat-
ment (Table 3).
Demographic and clinical characteristics of the included
cases are described in Table 4. The mean age of the entire
sample was 30.9 ± 17.2  years, range 5.5–71  years. The
majority 72%; n = 43/60) of the patients were male and 60%
(n = 36/60) had a diagnosis of schizophrenia. Other diag-
noses included developmental disorder (18%; n = 11/60),
behavioral disorder (7%; n = 4/60), and mood or anxiety
disorder (5%; n = 3/60). Forty-five percent of the patients
(n = 27/60) had a personal history of motor symptoms prior
to developing antipsychotic-associated tics. This included
eight individuals of whom three had a childhood history of
primary motor tics [17, 36, 56], three had chronic motor tic
disorder [27, 47, 57], and two had transient secondary tics
induced by non-antipsychotic drugs (i.e., d-amphetamine,
imipramine, and methylphenidate) [22]. The family history
of tic disorder was present in only two patients who also
had a personal history of tics [36, 57]. It should be noted,
however, that the family history was unknown in half (50%;
n = 30/60) of the patients.
No significant differences in age, sex (percent male),
diagnosis (percent schizophrenia), and personal history of
motor symptoms were noted between FGA and SGA users.
It was not feasible to examine the statistical difference in the
total treatment duration leading to tic occurrence between
FGA and SGA users because the duration of previous antip-
sychotic treatment (prior to the use of the offending antipsy-
chotic) was not provided in a considerable number of SGA
users (n = 9/27) [31, 34, 35, 44, 46, 48, 55, 59]. Nonethe-
less, the mean total treatment duration was 7.0 ± 7.0 years
in FGA users; at least 1 year with the exception of a few
cases (1 week to 2.5 months) [22, 23, 27]. In SGA users,
the mean treatment duration of the offending SGAs alone
was 0.34 ± 0.40 year; less than a year with the exception of
a couple of cases [39, 48].
D. D. Kim et al.
3.2 Symptomology
The distribution of symptoms and the comparison between
FGA and SGA users are described in Table 4. Tics occurred:
(1) during antipsychotic treatment (n = 44; a few days to
30 years after initiation) or (2) following treatment discon-
tinuation (n = 16; 1 week to 3 months after discontinuation
of treatment that ranged from 6 months to 20 years). In 45%
(n = 27/60) of the patients, tics occurred with other motor
symptoms, most of which were tardive dyskinetic or dys-
tonic movements. Of note, the occurrence of concomitant
tardive dyskinesia was significantly higher among FGA
users (47%; n = 14/30) than SGA users (15%; n = 4/27)
[p = 0.012].
Sixty-five percent of the patients (n = 39/60) developed
motor and vocal tics concurrently (i.e., Tourette-like symp-
toms). The occurrence of concurrent motor and vocal tics
was 93% and 33% in FGA and SGA users, respectively
(p < 0.0001). Whereas the occurrence of motor tics with or
without vocal tics was similar between the two groups (97%
and 89% of FGA and SGA users, respectively; p = 0.336),
the occurrence of vocal tics with or without motor tics was
significantly higher in the FGA (97%) vs. SGA (44%) users
(p < 0.0001). In the six patients who had a childhood his-
tory of primary motor tics or chronic motor tic disorder [17,
27, 36, 47, 56, 57], the severity of pre-existing motor tics
increased and/or new motor tics emerged during antipsy-
chotic treatment. Three of these patients also developed de
novo vocal tics [17, 47, 57].
Complex tics appeared to occur more often among FGA
users. For instance, the occurrence of coprolalia (including
mental coprolalia) was higher with the use of FGAs (40%;
n = 12/30) compared with SGAs (11%; n = 3/27) [p = 0.017].
Including the three individuals taking combined FGA and
SGA treatment, the overall occurrence of antipsychotic-
associated coprolalia was 27% (n = 16/60). Less common
complex vocal tics were echolalia (n = 5/60) and palilalia
(n = 4/60), which all occurred among FGA users with the
exception of the two SGA-treated patients who developed
palilalia [51, 52]. Making animal noises, specifically bark-
ing, was another disturbing vocal tic that had a higher occur-
rence among FGA users (33%; n = 10/30) than SGA users
(0%) [p = 0.001]. Complex motor tics, including copro-
praxia, exacerbated echoproaxia, door slamming, jumping,
poking others, and self-injurious behavior, were also present
in a small number of patients [15, 17, 18, 23, 30, 32, 37, 50].
3.3 Treatment
3.3.1 Tics Occurring During Antipsychotic Treatment
Tics occurring during antipsychotic treatment were, in many
cases, improved by discontinuing the offending antipsychotic
Table 1 Summary of studies on the symptoms of Tourette syndrome associated with first-generation antipsychotic (FGA) use
Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Klawans et al. 28, F; SCZ 1 (seizure disor- Chlorpromazine DC (1) < 1 month after DC: sudden Occasional Haloperidola Tics were partially
(1978), case der); 2 (none) for 6 years brief twitches of the facial dystonic pos- 30 mg/day ameliorated after
report [7] muscles, neck, shoulders, and tures in the several weeks
arms right arm and sustained for
Tics Associated with Antipsychotics

(2) > 1 month after DC: sponta- 1 year

neous vocalizations (e.g., bark-
ing, clicking sounds, grinding
of the teeth)
Pary (1979), case 19, F; SCZ None FGAs (2000– On (1) 5th year: hissing Haloperidol Only minimal eye
report [13] 4000 mg/day of (2) 6th year: paroxysmal eye 20 mg/day blinking associated
chlorpromazine blinking or facial grimacing with inarticula-
equivalent); with episodic cursing or inar- tions
total 6 years ticulations
DeVeaugh-Geiss 65, M 1* (EPS, TD); 2 FGAs (most DC Grunting and barking vocaliza- TD None Tic-like move-
(1980), case (none) recent: tions and tic-like movements in ments persisted
report [14] perphenazine the orofacial region for 4 months and
4–12 mg/day gradually disap-
during last peared over next
2 years); total 2 months
6 years
Stahl (1980), case 28, M; infantile 1 (stereotypies); FGAs (chlor- DC (tics after 2–4 Frequent bilateral lower facial (1) Haloperi- (1) Tics were com-
report [8] autism 2 (?) promazine weeks) tics, sniffing, grunting, barking, dol; (2) phys- pletely suppressed;
200 mg/day or occasional whispered copro- ostigmine (2) tics were com-
thioridazine lalia, and tic-like movements pletely suppressed
200 mg/day); of the neck, torso, abdominal after 30 min and
total 13 years muscles, and diaphragm sustained for 6 h
Seeman et al. 25, F; SCZ ? FGAs (most On and DC (1) While on (31st month): TD, blepharos- None Symptoms disap-
(1981), case recent: fluphen- facial grimacing, eye blinking, pasm peared after
report [15] azine enanthate movements around the mouth, 4 months and
12.5 mg every gritting of the teeth, and finger sustained up to
2 weeks during rolling; explosive utterances of present
last 5 months); obscenities and expletives
total 35 months (2) While on (35th month):
until DC markedly increased motor signs
with development of repetitive
snarling motion of the upper
lips; frequent grunts, some of
which ending in swear words
(3) While DC: worsened motor
symptoms
921
Table 1 (continued)
922

Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Singer (1981), case 16, M; retardation None FGAs (most DC (tics after 2 Frequent spontaneous ver- None Tics ceased within
report [16] recent: haloper- weeks) balizations, including hissing, 7 months
idol 4 mg/day); guttural, and barking sounds;
total > 1 years repetitive movements, consist-
ing at first of facial grimacing,
later replaced by jerking of the
shoulders and hands
Fog et al. (1982), 22, M; SCZ 1 (none); 2 (?) Haloperidol DC Tics of the head and body with (1) Symptoms
1) Haloperidol
case series [17] 4–10 mg/day grunting diminished some-
reinitiation;
for 2 years what; (2) fairly
(2) biperiden
good result over
6 months
55, M; SCZ and 1 (echopraxia since FGAs (mostly On Condition worsened with many TD (oral dys- (1) Pimozide; (1) Symptoms nearly
chronic motor tic childhood); 2 (?) phenothia- spells of echopraxia, as well as kinesia) (2) perphena- disappeared; (2)
disorder zines); total echolalia and howling zine was also very
8 years effective
58, M; SCZ 1 (none); 2 (?) FGAs (mostly On Sudden short spells of arm (1) Pimozide Effectiveness in
phenothiazines movements, words, and echo- or tetrabena- order of 1 < 2 < 3
and halop- lalia, as well as door slamming zine; (2)
eridol); total and shouting pimozide
14 years with tetra-
benazine; (3)
thioridazine
Klawans et al. 71, F; anxiety None Trifluoperazine DC Rapid facial tics with sponta- TD (lingual- None Abnormal move-
(1982), case 4–6 mg/day neous grinding of the teeth, facial ments persisted
series [18] for ~ 20 years grunting noises, and counting dyskinesias), for 2 years and
when seated quietly, as well as blepharos- remained essen-
occasional echolalia pasm tially stable
35, F; SCZ None FGAs (including On Tic-like movements of the face None Symptoms persisted
haloperidol, and bruxism; spontaneous for 3 years
chlorproma- grunting and barking, coprola-
zine, and lia, echolalia, and palilalia
fluphenazine);
total 9 years
D. D. Kim et al.
Table 1 (continued)
Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Mueller and 27, M; infantile 1 (stereotypies); FGAs (most DC (tics after 3 Recurrent head turning to the TD (choreo- Haloperidol Complete cessa-
Aminoff (1982), autism 2 (?) recent: chlor- weeks) right, repetitive clucking of the athetoid 6 mg/day tion of tics that
case report [19] promazine tongue, occasional clicking of finger move- sustained for
2000 mg/day the tongue, repetitive flapping ments and 13 months
Tics Associated with Antipsychotics

during last movements of the right hand, buccolingual

7 years); total shaking and tilting movements dyskinesia)
19 years of the head, and clicking gut-
tural noises that resembled ‘hi’
Haloperidol dose DC (recurred) Barking, head jerking to the TD ? ?
reduction to right, repetitive blinking of the
2 mg/day right eye, and flapping of the
right hand
Jeste et al. (1983), 44, M; SCZ None FGAs for 5 years On Motor tics, grunting, and other TD Bromocriptine 50% or greater
observational vocal tics 2 mg/day reduction in invol-
study [20] untary movements
Munetz et al. 60, F; SCZ 1* (TD); 2 (none) Mesoridazine DC (tics after Inarticulate vocal tics, stereo- TD (respira- Clonidine Vocalizations and
(1985), case 100–300 mg/ 2 months) typed staccato verbalizations, tory dyski- 0.8 mg/day involuntary move-
report [21] day and coprolalia; concomitant nesia) ments improved
for > 5 years motor tics of the head, neck,
and extremities
Mesoridazine On (recurred) Tics including coprolalia Clonidine Only occasional
reinitiation (up 0.4 mg/day vocal and motor
to 200 mg/day) with mesori- tics noted after
dazine dose 12 months
reduction to
40 mg/day
Gualtieri and Pat- 9, M; hyperactivity 1* (motor and Thioridazine On Sniffing and blinking DC Subsided within 1
terson (1986), vocal tics); 2 50 mg/day for 2 week and sustained
case series [22] (none) weeks up to present
9, M; hyperactivity 1* (motor and Haloperidol On Throat clearing Dose increase Disappeared within
vocal tics); 2 1–2 mg/day for to 3 mg/day 3 days
(none) 1 week
Medication free On (recurred; tics Head shaking and inspiratory DC Disappeared after 10
for 1 months, immediately grunts days and sustained
then haloperi- after initiation) for 1 years
dol 2 mg/day
923
Table 1 (continued)
924

Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Lal and AlAnsari 13, M; SCZ 1* (involuntary Thioridazine On and DC (1) While on (after 2–3 months): TD (pursing None Involuntary move-
(1986), case movements); 2 25–50 mg/day; involuntary movements, of the lips) ments and noises
report [23] (none) total 2.5 years inappropriate burping, and while DC gradually remitted
until DC whistling noises over 5 months
(2) While DC (1 months and sustained for
after DC): repetitive semi- 21 months
purposeful movements (e.g.,
copropraxia), jerky movements
of the head and neck, shoulder
shrugging, eye-closing tics,
rapid rotation of the head,
and tongue-in-cheek motion;
frequent repetitive spontaneous
vocalizations (e.g., grunting,
barking, sniffing, coughing,
whistling, throat clearing,
spitting, guttural noises), as
well as palilalia, echolalia, and
coprolalia
Medication free On (recurred) Infrequent facial tics and occa- TD (oral DC No tics noted after
for 21 months, sional whistling dyskinesia 7 months
then FGAs with episodic
(most recent: tongue pro-
perphenazine trusion)
4 mg/day
during last
8 months); total
9 months
Perry et al. (1989), 5.5, M; autism 1 (stereotypies); 2 Haloperidol DC (tics after 1 Many tic-like jerking move- None Only a few jerking
case report [24] (none) 1–3 mg/day week) ments of the head, neck, and movements of the
(interspersed body, as well as eye blinking head and body
with 1-month and side-to-side jaw move- with occasional,
placebo periods ments; explosive, grunting, and less explosive
after every shrieking sounds screams noted
6 months of after 1 week
treatment);
total ~ 3 years
D. D. Kim et al.
Table 1 (continued)
Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Karagianis and 10, M; behavioral None Haloperi- On and DC (1) While on (after 17 months): TD (lip smack- Oxazepam Slight transient
Nagpurkar problems dol ≤ 2.5 mg/ shoulder shrugging and twitch- ing) while on 2.5–5 mg/ decrease in move-
(1990), case day; total ing of the face day ment frequency
report [25] 19 months until (2) While DC: gradually
Tics Associated with Antipsychotics

DC increased abnormal movements

Medication-free On Coprolalia Dose increase Minimal improve-
for 5 days, to 3 mg/day ment after
then halop- 2 months
eridol ≥ 2.5 mg/
day
for < 2 months
Littlejohns et al. 10, M; Asperger’s 1 (stereotypies); 1* Haloperidol DC (tics after > 1 Sudden facial grimacing and Dystonia Haloperidol Tics were sup-
(1990), case syndrome (writhing move- 3–7.5 mg/day week) repetitive tic-like neck move- reinitiation pressed
report [26] ments); 2 (?) for 2 years ments; involuntary grunting
and barking noises and utter-
ance of obscene words
Diaz et al. (1992), 19, M; chronic 1 (motor tics); 2 (?) Haloperidol On Increased frequency of the exist- DC The new tic
case report [27] motor tic dis- 1.5 mg/day for ing motor tic and emergence disappeared and
order 7 days of a new motor tic (stereotypic the chronic tic
buccal movements without returned to its
vocalizations or sounds) initial state
Bharucha and Sethi 36, M; SCZ 1* (acute dystonia); FGAs (most On (1) 11th year: involuntary facial Thiothixene Tics decreased in
(1995), case 2 (none) recent: thiothix- movements, facial grimacing, dose reduc- severity after
report [29] ene during snorting, sniffing, grunting, and tion with 4 months
last > 9 years); barking pimozide
total 20 years (2) 16th year: worsened vocaliza- 4 mg/day
tions with development of
additional motor phenomena
(e.g., sudden jerking or shrug-
ging of the shoulders, thrusting
of the head, twisting of the
trunk); mental coprolalia
(3) 20th year: worsened motor
and vocal tics
925
Table 1 (continued)
926

Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

Jaffe et al. (1995), 28, M; SCZ 1 (none); 2 (?) FGAs (most On and DC (1) While on (after > 5 years): TD (of the Clozapine Tics were barely
case report [30] recent: halop- jumping up, hand posturing, fingers, toes, 600 mg/day noticeable after 8
eridol 20 mg/ yelling out, and screaming tongue, and weeks
day during last (2) While on (after next 2 years eyebrows)
2 years and and 8 months): poking other while on
8 months); people, shaking the open
total > 7 years hand with its index finger in
and 8 months the nose, jerking the arm up
until DC with the index finger pointed
upward while making yelp-
ing sounds, jumping up and
yelling, and screaming for no
apparent reason
(3) While DC: significantly
increased abnormal movements
Myers and 31, F; Down syn- None Thioridazine DC Grunts, vocal snorts, and loud Writhing Haloperidol Involuntary move-
Pueschel (1995), drome 600 mg/day for noises; frequent sudden move- movements 1.5 mg/day ments decreased
case series [32] 10 years ments of the head and arms, of upper
incorporating these motor jerks extremities
into intentional movements;
self-slapping
Brasić et al. (1997), 11, M; autism ? FGAs (halo- DC (tics after Motor tics (e.g., dystonic exten- TD, akathisia, Clomipramine Tics markedly
case report [33] peridol and 1 month) sions of lower extremities and and stereo- up to decreased over 17
thioridazine touching objects); vocal tics typies 200 mg/day weeks; transient
for > 2 years) (e.g., frequent utterances of recurrence with
obscenities and profanities) clomipramine
DC but gradually
subsided over
2.5 years
Reid (2004), case 48, F; SCZ None Haloperidol Abrupt DC (tics Multiple motor (tic-like move- TD (choreo- Clonazepam Significant, sus-
report [37] 10 mg/day for after 2 weeks) ments of the neck and trunk) athetoid 3 mg/day tained improve-
8 years and self-injurious behavior; movements ment for 6 months
vocal tics including coprolalia of the arms)
Yamauchi and 40, M; SCZ None FGAs (haloperi- On Barking and grunting vocaliza- Quetiapinea Complete dis-
Ohmori (2006), dol 12 mg/day tions with neck and shoulder 400 mg/day appearance
case series [42] and chlorprom- jerking for > 6 months
azine 120 mg/
day for 6 years)

Olanzapinea up On (recurred) Tics recurred Quetiapinea Symptoms persisted

to 20 mg/day 400 mg/day for > 6 months
D. D. Kim et al.
Table 1 (continued)
Author (year), Age (years), sex; Personal history of Antipsychotic, Symptoms while Tourette-like symptoms Other concur- Treatment Effectiveness of
study design current diagnosis motor symptoms dose; treatment taking medication/ rent motor treatment and
(1); family history duration (until tic DC symptoms follow-up
of tics (2) occurrence/DC)

53, M; alcohol None Sulpiride for DC (tics Grunting vocalizations with neck TD (oral dys- Haloperidol Complete disappear-
abuse 3 years after ~ 3 months) jerking kinesia) 2.5 mg ance after 3 min
IV, then and sustained
haloperidol for ~ 1 month; no
Tics Associated with Antipsychotics

1.5 mg/day recurrence with

oral switching to que-
tiapine 100 mg/day
for ~ 1 month
Cheng et al. 44, F; SCZ 1* (EPS); 2 (none) FGA/SGA DC (tics after Vocal tic Olanzapine Gradually subsided
(2007), case (mostly 2 months) 10 mg/day within 5 months
report [43] haloperidol and sustained for
5–10 mg/day 2 years
for 12 years)
Yogaratnam et al. 59, F; SCZ 1 (none); 2 (?) FGAs (chlor- On Involuntary, sudden, repetitive, Risperidonea Tics improved over
(2013), case promazine stereotyped jerky movements 4 mg/day 6 months and sus-
report [53] 600 mg/day involving bilateral shoulders; with clonaz- tained for 1 year
with fluphena- sneezing, loud shouting, and epam 1.5 mg/
zine decanoate coprolalia day
30 mg every
2–4 weeks
for > 30 years)

DC discontinuation, EPS extrapyramidal symptom, F female, IV intravenously, M male, SCZ schizophrenia, SGA second-generation antipsychotic, TD tardive dyskinesia
1* indicates personal history of motor symptoms associated with drug use
a
Antipsychotic indicates the antipsychotic that was switched to
927
 928

Table 2 Summary of studies on symptoms of Tourette syndrome associated with second-generation antipsychotic (SGA) use
Author (year), study Age (years), sex; cur- Personal history of Antipsychotic, dose; Symptoms while Tourette-like symp- Other concurrent Treatment Effectiveness of treat-
design rent diagnosis motor symptoms treatment duration taking medication/ toms motor symptoms ment and follow-up
(1); family history of (until tic occurrence/ DC
tics (2) DC)

Doepp and Buddeberg 54, M; SCZ 1* (perioral dyskinesia FGA/SGA (most On Tics and grimacing Sucking and smacking DC Returned to normal
(1975), case report and akathisia); 2 (?) recent: clozapine movements in the lip movements, within 24 h
[12] 300–450 mg/day areas of the lips, athetoid move-
during last 23 days) cheeks, and eyes ments, and ballisms
Lindenmayer et al. 51, M; SCZ 1 (none); 2 (?) FGA/SGA (most On Vocal and multiple Dose reduction to Gradual improvement
(1995), case series recent: clozapine facial motor tics 400 mg/day of involuntary move-
[31] 500 mg/day during ments
last 2 months)
47, F; SCZ 1* (minimal involun- FGA/SGA (most On Involuntary twitches Dose reduction to Symptoms almost com-
tary movements of recent: clozapine of the lips with 300 mg/day pletely disappeared
lips, tongue, and 500 mg/day during vocal tics, together
upper extremities); last 5 months) with tic-like truncal
2 (?) movements
26, M; SCZ ? Clozapine 800 mg/day On Tic-like facial involun- Clomipramine 25 mg/ Gradual improvement
for 2 months tary movements day
Landry and Cournoyer 50, M; SCZ 1* (torticollis); 2 (?) FGA/SGA (most On Facial tics at 15 mg/ Stiffness in the neck ? ?
(1998), case series recent: olanzap- day
[34] ine up to 25 mg/
day during last 14
weeks)
Poyurovsky et al. 23, M; SCZ 1* (EPS); 2 (none) FGA/SGA (most Abrupt dose reduc- Vocal and motor tics Dose increase to Tics substantially
(1998), case series recent: clozapine tion (to 150 mg/ at 150 mg/day 500 mg/day lessened after 3 days;
[35] 500 mg/day during day over 7 days) no recurrence with
last 6 months) switching to olanzap-
ine 10 mg/day for 3
months
Huang et al. (2002), 24, M; SCZ 1, 2 (childhood motor SGAs (most recent: On Eye blinking Sulpiridea,b 200 mg/ Tics disappeared for > 3
case report [36] tics) quetiapine 100 mg/ day months
day during last 1
months)
Begum (2005), case SCZ ? Clozapine up to On Facial tics, unusual Myoclonic seizures (1) Sodium valproate (1) Gradual but steady
report [38] 500 mg/day for a speech (mainly 400 mg/day; (2) clo- improvement; (2)
few days explosive), and stut- zapine dose reduc- complete attenuation
tering at 300 mg/day tion to 300 mg/day
Alonso-Navarro and 55, F; anxiety and None Amisulpride 300 mg/ On Involuntary, repetitive, DC Tics completely disap-
Jiménez-Jiménez depression day for 1 year stereotyped move- peared after 2 months
(2006), case report ments consisting of and sustained for 5
[39] eye blinking, facial months
grimacing, right
shoulder elevation,
and repetitive throat
clearing and sneez-
ing sounds
D. D. Kim et al.
Table 2 (continued)
Author (year), study Age (years), sex; cur- Personal history of Antipsychotic, dose; Symptoms while Tourette-like symp- Other concurrent Treatment Effectiveness of treat-
design rent diagnosis motor symptoms treatment duration taking medication/ toms motor symptoms ment and follow-up
(1); family history of (until tic occurrence/ DC
tics (2) DC)

Feroz-Nainar and Roy 9–15; 3 M, 1 F; 1 (epilepsy in 2 of 4); Risperidone 2–4 mg/ On Tics involving the face TD (buccal-lingual (1) Risperidone (1) Tics disappeared
(2006), observa- autism (all) 2 (?) day for > 6 months and shoulder movements) in 1 DC in 3 of 4; (2) almost completely; (2)
tional study [40] of 4 olanzapinea in 1 of 4 tics stopped
Lin et al. (2006), case 15, F; SCZ 1* (akathisia, trem- SGAs (most recent: On Frequent involuntary Acute dystonia Dose reduction to Tics remitted after 2
report [41] ors); 2 (none) amisulpride eye-blinking move- 800 mg/day days; no recurrence
Tics Associated with Antipsychotics

1000 mg/day during ments with adding que-

last 5 months) tiapine 100 mg/day
for > 1 year
Hallahan et al. (2007), 33, F; SCZ 1 (none); 2 (?) FGA/SGA (most On Facial tics and stut- Seizure Dose reduction to Tics improved
case series [44] recent: clozapine up tering 600 mg/day
to 700 mg/day dur-
ing last 8 months)
Lyall et al. (2007), 55, M; SCZ 1* (unusual limb and FGA/SGA (most On Facial tic, stammering, Persistent hiccups Dose reduction to Symptoms improved;
case series [46] trunk movements); recent: clozapine up and belching 125 mg/day clozapine was
2 (?) to 450 mg/day) switched to zuclo-
penthixol decanoate
without further
improvement
Clozapine reinitiation On (recurred) A tic-like movement Orofacial dyskinesia Sodium valproate ?
(75 mg/day) of the upper lip, 600 mg/day
involuntary contrac-
tions of the jaw, and
stuttering
Bastiampillai et al. 28, M; SCZ and 1 (motor tic); 2 (?) FGA/SGA (most On Coprolalia at 150 mg/ Haloperidolb Tics improved signifi-
(2008), case report chronic motor tic recent: clozapine day (4th day), which cantly and sustained
[47] disorder 150 mg/day during exacerbated with up to present
last 4 days) emergence of new
motor and vocal tics
as dose increased
Su et al. (2008), case 31, M; SCZ None SGAs (most recent: On Neck jerking Stiffness in the neck Aripiprazoleb 15 mg/ Tics completely remit-
report [48] risperidone 3 mg/ day ted and sustained for 5
day during last 18 months
months; total 22
months)
Willmund et al. 28, M; SCZ 1 (none); 2 (?) SGAs (most recent: On Daily vocal tics TD Quetiapineb 200 mg/ Symptoms completely
(2009), case report ziprasidone during day resolved after 4 days
[49] last 2 months) and sustained for 5
months
929
Table 2 (continued)
930

Author (year), study Age (years), sex; cur- Personal history of Antipsychotic, dose; Symptoms while Tourette-like symp- Other concurrent Treatment Effectiveness of treat-
design rent diagnosis motor symptoms treatment duration taking medication/ toms motor symptoms ment and follow-up
(1); family history of (until tic occurrence/ DC
tics (2) DC)

Fountoulakis and 22, F; SCZ 1 (none); 2 (?) SGAs (most recent: On Impulsive coprolalia, EPS Aripiprazoleb 30 mg/ Tics disappeared com-
Panagiotidis (2011), paliperidone 18 mg/ verbal insults, and day with diazepam pletely after 2 months
case report [50] day during last 2 complex motor tics 20 mg/day
months) of the trunk and
arms

Paparrigopoulos et al. 21, M; cervical 1* (cervical dystonia); SGAs (most recent: On Sniffing, repetition Torticollis and motor ? ?
(2011), case report dystonia 2 (?) risperidone during of words (palila- stereotypies
[51] last 6 months) lia?), and mental
coprolalia
Azevedo et al. (2012), 28, M; SCZ ? SGAs (most recent: On Palilalia Dose reduction to Palilalia ceased
case report [52] clozapine up to 150 mg/day
300 mg/day)
Chen et al. (2014), 16, M; bipolar None Quetiapine up to On Occasional eye blink- Dose reduction to Tics greatly resolved
case report [54] disorder 600 mg/day for 7 ing at 150 mg/day 50 mg/day after ~ 2 weeks
days (7th day); increased
frequency of facial
tics at 600 mg/day
(after next 36 days)
Quetiapine back to On (recurred) Tics recurred Haloperidola 4 mg/day Tics subsided and sus-
600 mg/day tained for 6 months
Hsieh and Chiu 30, M; SCZ 1 (none); 2 (?) SGAs (most recent: On Frequent involuntary Dose reduction to Tics remitted after
(2014), case report paliperidone up to eye-blinking move- 9 mg/day 2 weeks and sustained
[55] 15 mg/day during ment for ~ 1 year
last 1 months)
Guo et al. (2015), case 30, M; SCZ 1 (childhood motor SGAs (most recent: On Occasional eye blink- Dose reduction to Tics greatly resolved
report [56] tics); 2 (none) aripiprazole up to ing and neck jerking 5 mg/day after 1–4 weeks
25 mg/day during at 10 mg/day (5th
last 5 days) day); increased
frequency at 25 mg/
day (after next 14
days)
Aripiprazole back to On (recurred) Tics recurred Risperidoneb 5 mg/ No tics noted after 7
25 mg/day day months
Akaltun and Kara 5.5, M; ODD None Risperidone 0.5 mg/ On Repetitive blinking DC Tics disappeared
(2017), case report day; for 2 weeks and throat clearing
[58]
Risperidone reinitia- On (recurred) Tics recurred Aripiprazoleb 3 mg/ No further tics observed
tion day
D. D. Kim et al.
Tics Associated with Antipsychotics 931

or reducing its dose (n = 21/44) [12, 22, 23, 27, 29, 31,

DC discontinuation, EPS extrapyramidal symptom, F female, FGA first-generation antipsychotic, M male, ODD oppositional defiant disorder, SAD schizoaffective disorder, SCZ schizophrenia,
Tics completely disap-
peared after 27 days
Effectiveness of treat-
38–41, 44, 46, 52, 54–58]. However, discontinuation or dose

and sustained up to
ment and follow-up reduction sometimes led to worsening of target symptoms
and rechallenging patients by reinitiating or increasing the

present
dose led to worsening of tics [25, 41, 54, 56, 58]. Further-
more, four patients who developed tics during antipsychotic
treatment experienced worsening of tics after discontinuing
the offending antipsychotic [15, 23, 25, 30]. However, in two
Clozapineb 250 mg/

of these patients, tics remitted spontaneously 4–5 months

later [15, 23]. In one case, tics were completely alleviated
Treatment

when the dose of the offending antipsychotic was increased

day

[22]. Use of non-antipsychotic medications, including clon-

azepam, clomipramine, and sodium valproate, also led to
significant improvements in some cases [28, 31, 38].
Other concurrent
motor symptoms

Adding another antipsychotic or switching to one with a

different pharmacological profile was sometimes successful
in improving tics that emerged during antipsychotic treat-
ment. For instance, switching to aripiprazole led to complete
remission of tics induced by risperidone or paliperidone [48,
50]. Switching to risperidone worsened the paliperidone-
left face, neck, and
movements of the
Tourette-like symp-

Frequent, sudden,

associated tics, but a subsequent switch to aripiprazole led to

non-rhythmic

complete remission [50]. Tics occurring during aripiprazole

shoulder

treatment were completely alleviated by switching to risp-

toms

eridone [56]. Switching to quetiapine led to the complete

remission of tics induced by ziprasidone [49], and switching
taking medication/

to clozapine led to significant or complete remission of tics

Symptoms while

induced by haloperidol or olanzapine [30, 59]. Tics occur-

ring during quetiapine treatment were treated completely by
adding haloperidol or sulpiride [36, 54]. However, in one
DC

On

case, although tics occurring during FGA treatment were

treated completely when switched to quetiapine, switching
(until tic occurrence/
Antipsychotic, dose;

20 mg/day during
SGAs (most recent:
olanzapine up to
treatment duration

subsequently to olanzapine led to the recurrence of tics and

last 10 days)

switching back to quetiapine failed to treat the recurred tics

1* indicates personal history of motor symptoms associated with drug use

[42]. When no major modification was made to the antip-

sychotic regimen from which tics occurred, symptoms per-
DC)

sisted with progressive worsening and/or added complexity

Antipsychotic indicates the antipsychotic that was switched to

provided the regimen was maintained (e.g., for 1–3 years to

(1); family history of
Personal history of

as long as 9 years) [13, 18, 29, 30, 39].

motor symptoms

Antipsychotic indicates the antipsychotic that was added

3.3.2 Tics Occurring Following Antipsychotic

tics (2)

None

Discontinuation
Age (years), sex; cur-

Tics occurring following antipsychotic discontinuation

were, in many cases, improved by reinitiating an antipsy-
rent diagnosis

chotic (n = 9/16), in particular haloperidol [7, 8, 17, 19, 26,

22, M; SAD

32, 42]. Such tics were also treated with non-antipsychotic

medications, such as clomipramine, clonazepam, clonidine,
TD tardive dyskinesia

physostigmine, and biperiden [8, 17, 21, 33, 37]. When

Table 2 (continued)

haloperidol was ineffective or only partially effective, other

Author (year), study

Mills et al. (2017),

case report [59]

non-antipsychotic agents, such as clonazepam, clonidine,

and biperiden, led to greater improvements [17, 21, 37]. It
should be noted that biperiden is an antimuscarinic agent,
design

whereas physostigmine is an indirect cholinergic agonist. As

b
a
 932

Table 3 Summary of studies on the symptoms of Tourette syndrome associated with combined first- and second-generation antipsychotic (FGA and SGA) use
Author (year), study Age (years), Personal history of Antipsychotic, dose; Symptoms while Tourette-like symp- Other concur- Treatment Effectiveness of treat-
design sex; current motor symptoms treatment duration taking medication/ toms rent motor ment and follow-up
diagnosis (1); family history (until tic occurrence/ DC symptoms
of tics (2) DC)

Kuniyoshi et al. 38, F; SCZ None FGA + SGA (halop- On Vocal tic with Clonazepam Tics associated
(1992), case report eridol 8–18 mg/day coprolalia and 3 mg/day with coprolalia
[28] and levomepromazine motor tic (e.g., disappeared almost
50–100 mg/day with blinking and completely within
zotepine 200 mg/ grimacing) 3 months and sus-
day); total 17 years tained up to present
Kozian and Fried- 51, M; SCZ ? FGA + SGA (pro- On Vocal tics in which Promethazine 75 Tics disappeared
erich (2007), case methazine 75 mg/ the patient articu- mg/day with within 1 week and
report [45] day with olanzapine lated vocabulary amisulpridea 600 sustained for 2
10 ± 12.5 mg/day for words and neolo- mg/day weeks
10 years) gisms in high pitch
Mazlum et al. 15, M; chronic 1 (motor tics, con- FGA + SGA (pimoz- On Increased severity Aripiprazole DC Motor and vocal tics
(2015), case report motor tic version, Syden- ide 3 mg/day with of existing tics improved partially
[57] disorder with ham’s chorea, aripiprazole 2.5 mg/ with emergence of after 7 days
ADHD Wilson’s disease); day for 10 months; vocal tics and new
2 (tic disorder) aripiprazole added motor tics
10 days before tic
exacerbation)

ADHD attention-deficit hyperactivity disorder, DC discontinuation, F female, M male, SCZ schizophrenia

a
Antipsychotic indicates the antipsychotic that was switched to
D. D. Kim et al.
Tics Associated with Antipsychotics 933

Table 4 Demographic and clinical characteristics of included cases

Variable All (n = 60)a FGA (n = 30) SGA (n = 27) Statisticsb

Demographics
 Age, years (mean ± SD)c 30.9 ± 17.2 32.6 ± 19.2 28.6 ± 14.9 t = 0.9, p = 0.387
 Under 18 years, % (n) 27 (16) 27 (8) 26 (7) p = 1.000
Male, % (n)c 72 (43) 67 (20) 78 (21) p = 0.391
Schizophrenia, % (n)d 60 (36) 53 (16) 67 (18) p = 0.419
Previous motor symptoms, % (n) 45 (27) 47 (14) 44 (12) p = 1.000
Symptoms
 While on/discontinuation (n) (44/16) (15/15) (26/1) p < 0.0001
 Motor + vocal tics, % (n) 65 (39) 93 (28) 33 (9) p < 0.0001
 Motor tics with/without vocal, % (n) 90 (54) 97 (29) 89 (24) p = 0.336
 Vocal tics with/without motor, % (n) 70 (42) 97 (29) 44 (12) p < 0.0001
 Coprolalia, % (n) 27 (16) 40 (12) 11 (3) p = 0.017
 Barking, % (n) 17 (10) 33 (10) 0 (0) p = 0.001
 Echolalia/palilalia, % (n) 12 (7) 17 (5) 7 (2) p = 0.427
 Complex motor tics, % (n) 13 (8) 23 (7) 4 (1) p = 0.054
 Tardive dyskinesia, % (n) 30 (18) 47 (14) 15 (4) p = 0.012

FGA first-generation antipsychotic, SD standard deviation, SGA second-generation antipsychotic

a
Of the 60 cases, three patients were taking combined FGA and SGA treatment
b
Comparison between the FGA and SGA groups
c
Age and sex unknown for one patient in the SGA group
d
Diagnosis unknown for one patient in the FGA group

both agents attenuated tics, the role of the cholinergic system
in TS may be complex. In one case, tics that occurred during
rapid clozapine discontinuation were successfully treated by
resuming the initial dosage regimen [35]. When tics result-
ing from antipsychotic discontinuation were left untreated,
symptoms disappeared spontaneously within 5 months to
2 years [14, 16, 18, 23] or persisted for 1–2 years without
improvement [10, 32].
3.3.3 Follow-up
When patients were followed up, suppressed tics remained
well controlled for several months [35–37, 39, 42, 48, 49,
54] to 1–2 years [19, 22, 23, 41, 43, 53, 55]. However, in a
number of cases, tics recurred when: (1) the offending antip-
sychotic was reinitiated [21, 22, 46, 58], (2) the dose of the
offending antipsychotic was increased back to that initially
prescribed [54, 56], (3) the dose of the tic-relieving drug was
decreased or discontinued [19, 33], or (4) the tic-relieving
antipsychotic was switched to a different antipsychotic [42].
4 Discussion
4.1 General Findings
Our systematic review revealed several findings. Symptoms
of TS may occur during antipsychotic treatment or following
treatment discontinuation. It has been believed that the earli-
est case of antipsychotic-associated tics was the one reported
in 1978 [7, 9]. However, we identified an even earlier case of
clozapine-associated tics published in 1975 [12]. Our review
suggests that male individuals (72%) may be more suscepti-
ble to antipsychotic-associated tics than female individuals
(28%), which is in line with the fact that TS is more common
in male individuals [1].
The occurrence of concurrent motor and vocal tics (i.e.,
Tourette-like symptoms) was significantly higher among
FGA users (93%) vs. SGA users (33%). When symptoms
were stratified, there was a significantly higher occurrence
of vocal tics among FGA users vs. SGA users, whereas
the occurrence of motor tics was similar between the two
classes of antipsychotics (Table 4). A significantly higher
occurrence was observed among FGA users when specific
types of vocal tics (e.g., barking and coprolalia) were exam-
ined (Table 4). Of note, the National Institute of Neuro-
logical Disorders and Stroke (of the National Institutes of
Health) states that coprolalia occurs in 10–15% of individu-
als with TS [60]. The occurrence of coprolalia associated
934
with antipsychotic use in our review was much higher at
27%. The occurrence among FGA users was even higher
(40%), whereas the occurrence among SGA users (11%) was
within the general range. It should be noted, however, that
our patient population does not consist of individuals with
TS and consists mostly of individuals with schizophrenia
and other neuropsychiatric disorders, which could poten-
tially confound such differences. Nevertheless, we ensured
that there were no significant differences in patient charac-
teristics (e.g., age, sex, diagnosis, and personal history of
motor symptoms) between FGA and SGA users (Table 4).
Potential explanations as to why FGA users may experience
more severe forms of tics are further discussed in the fol-
lowing section.
Antipsychotic-associated tics often required major regi-
men modification. Improvements were seen when (1) dis-
continuing the offending antipsychotic, reducing its dose, or
switching to antipsychotics with different pharmacological
properties (for tics occurring during treatment), (2) reini-
tiating antipsychotic treatment (for tics occurring follow-
ing treatment discontinuation), or (3) using agents acting
on different neurotransmitter systems (e.g., clonazepam,
clomipramine, clonidine, and sodium valproate). However,
symptoms were not always fully reversible and recurred at
times.
4.2 Potential Mechanisms
4.2.1 Dopamine Supersensitivity
A widely accepted explanation for the emergence of tics
associated with antipsychotic use is dopamine supersensitiv-
ity. Long-term blockade of D2 receptors leads to an increase
in the number of postsynaptic D2 receptors including those
in a supersensitized state [61]. As a result, there is enhanced
D2-mediated signaling in response to endogenous dopamine,
increasing the risk of abnormal movements, such as tardive
dyskinesia [61]. A number of individuals presented with
tardive dyskinesia along with tics, indicating that the two
conditions may share similar pathophysiological mecha-
nisms. Of interest, the occurrence of vocal tics was signifi-
cantly higher among patients treated with FGAs vs. SGAs
(Table 4). This could be because FGAs generally have a
lower ratio of 5-HT2A to D2 receptor antagonism and bind
more tightly to and dissociate more slowly from D2 recep-
tors than SGAs, all leading to greater D2 blockade and a
heightened risk of extrapyramidal symptoms and tardive
dyskinesia [62, 63]. In our review, the mean total treatment
duration in FGA users was 7.0 ± 7.0 years, which is sufficient
for the development of dopamine supersensitivity [11]. In
addition, the occurrence of concomitant tardive dyskinesia
(i.e., a symptom known to be associated with dopamine
supersensitivity) was higher among patients treated with
D. D. Kim et al.
FGAs compared with those treated with SGAs (p = 0.012).
Taken together, dopamine supersensitivity may have been
more likely to occur among patients treated with FGAs and
perhaps lead to the emergence of Tourette-like symptoms
consisting of disturbing vocal tics.
It was not feasible to determine a valid mean total treat-
ment duration in SGA users because the duration of previous
antipsychotic treatment (prior to the use of the offending
SGA) was not available for a considerable number of cases
(n = 9/27) [31, 34, 35, 44, 46, 48, 55, 59]. Nevertheless, the
treatment duration of the offending SGA alone was generally
short term (mean = 0.34 ± 0.40 year). In addition, almost all
SGA-associated cases were tics occurring during treatment
(n = 26/27). Therefore, the influence of the previous antip-
sychotic (i.e., the effect of its discontinuation) cannot be dis-
counted. In other words, symptoms may be unmasked when
an antipsychotic regimen is altered such that suppression of
the nigrostriatal dopaminergic pathway is lessened during
a dopamine supersensitivity state. For instance, SGAs tend
to have a higher ratio of 5-HT2A to D2 receptor antagonism
than FGAs, promoting dopamine release via 5-HT2A recep-
tor antagonism while blocking D2 receptors. Some SGAs
have lower affinities for D2 receptors (i.e., clozapine and
quetiapine), further increasing the ratio of 5-HT2A to D2
receptor antagonism. In support of this, our review found
cases in which tics occurred after switching from an FGA
or an SGA with a higher D2 affinity to an SGA with a lower
D2 affinity (e.g., from an FGA or risperidone to clozapine or
from olanzapine to quetiapine) [12, 31, 36, 44, 46, 47, 52].
In addition, clozapine treatment that followed a period of
haloperidol treatment led to transient exacerbation of tics in
patients with TS [64]. An alternative explanation for such
cases may be tics occurring as a result of switching to an
antipsychotic that dissociates more rapidly from D2 recep-
tors (e.g., clozapine and quetiapine). There is evidence that
other SGAs (e.g., paliperidone) also have relatively faster
D2 receptor dissociation rates [63], making it a possible
explanation for the two cases of paliperidone-associated
tics that developed when the patients were switched from
antipsychotics that bind more tightly to D2 receptors (i.e.,
olanzapine and ziprasidone) [50, 55]. Furthermore, switch-
ing to or adding a D2 partial agonist may unmask dopamine
supersensitivity-related tics, which may explain the two
cases of aripiprazole-associated tics that occurred following
olanzapine treatment [56] or during pimozide treatment [57].
4.2.2 Other Mechanisms
Not all cases fit the explanation of dopamine supersensi-
tivity, particularly for those cases in which tics occurred
shortly after (≤ 2 weeks) initiating an antipsychotic without
a possible influence of the previous antipsychotic [22, 27,
54, 58] and for those cases in which tics improved upon
Tics Associated with Antipsychotics
discontinuation or dose reduction without transient exac-
erbation. One alternative explanation may be the blockade
of presynaptic D2 receptors, which increases dopamine
release [22]. The balance between presynaptic and postsyn-
aptic antagonism may be altered in a way that there is more
presynaptic dopamine release than postsynaptic blockade.
This is more likely to occur when low doses of antipsychot-
ics are used [65].
Second, some antipsychotics have other pharma-
codynamic properties that may induce or worsen tics.
For instance, many antipsychotics are antagonists of
alpha2-adrenergic receptors, leading to increased central
norepinephrine release [66]. Because tics have been suc-
cessfully treated with alpha2-adrenergic receptor agonists,
it is possible that symptoms may develop or worsen, with
antipsychotics having high affinities for alpha2-adrenergic
receptors relative to D2 receptors (e.g., clozapine). In addi-
tion, there is evidence that increasing the synaptic avail-
ability of acetylcholine (e.g., with physostigmine) is effec-
tive in the treatment of tics, whereas anticholinergic drugs
(e.g., scopolamine) may worsen tics [67, 68]. In this regard,
some atypical antipsychotics have significant anticholinergic
effects (e.g., clozapine and olanzapine) [69], which may be
another contributing mechanism. However, it needs to be
noted that biperiden (an anticholinergic agent) was effective
in one case reported in our review [17], suggesting that the
role of the cholinergic system in TS may be complex. Like-
wise, the role of other neurotransmitter systems in the induc-
tion of antipsychotic-associated tics cannot be neglected,
given successful treatment with clomipramine, clonazepam,
clonidine, and sodium valproate [21, 28, 31, 33, 37, 38].
Third, some antipsychotics, in particular clozapine, are
known to induce other symptoms that may be related to TS.
For instance, three of the nine patients who developed tics
while taking clozapine also developed obsessive-compulsive
symptoms [31, 35, 47]. It is well documented that clozapine
induces obsessive-compulsive symptoms and is believed that
its potent serotonergic antagonism may be a key mechanism
underlying the emergence of these symptoms [31, 70]. As
the comorbidity of TS and obsessive-compulsive disorder is
common and both disorders share similar pathophysiologi-
cal mechanisms (e.g., increased dopaminergic and reduced
serotonergic activity) [4, 5], antipsychotic-associated tics
may also be explained by the drug’s potential to induce
obsessive-compulsive symptoms [31]. Another four of the
nine clozapine-treated patients developed speech dysfluency,
including stuttering (n = 3) and palilalia (n = 1) [38, 44, 46,
52]. The literature suggests that tics and speech dysfluency,
such as stuttering, may share a common pathophysiology,
particularly dopamine dysregulation in the basal ganglia [71,
72]. Furthermore, palilalia itself is considered a complex
tic [1, 3]. Therefore, any effect of an antipsychotic on the
935
extrapyramidal system to induce speech dysfluency may also
lead to tics.
In summary, antipsychotic-associated tics may involve
multiple mechanisms. It is possible that FGAs and SGAs
may follow different mechanisms considering the differences
in the distribution of symptoms (e.g., a lower occurrence of
vocal tics with SGAs) between the users of each type. Of
note, mechanisms, such as dopamine supersensitivity and
presynaptic D2 blockade, were also implicated in individuals
with TS who experienced paradoxical worsening of tics with
antipsychotic treatment [73, 74].
4.3 Limitations
Several limitations require consideration. A major limita-
tion is that our systematic review was largely based on case
reports or series, which are highly subject to sampling bias
(i.e., not a random sample of patients taking antipsychotic
treatment). With case studies, it is also possible that not all
patient information and observed symptoms are reported.
For instance, the presence of a premonitory urge, which
is a basic characteristic of tics, was rarely reported in our
included studies. In addition, the majority of our included
studies did not specify whether the physicians were move-
ment disorder neurologists or psychiatrists experienced in
treating tics, which may bring into question the accuracy
of the diagnosis of tics. Taken together, any incidence rate
derived in our results should be interpreted with caution.
Our review included individuals who were under 18 years
of age (27%; n = 16/60). This is the age before which pri-
mary tic disorder is typically diagnosed, increasing the like-
lihood of overestimation of antipsychotic-associated tics.
However, we used more stringent criteria to ensure that in
these individuals, there was (1) no personal or family his-
tory of primary tic disorder and either (2) tics occurring
during antipsychotic treatment improved significantly upon
discontinuation or dose reduction or (3) tics emerged after
discontinuation of at least 3 months of antipsychotic treat-
ment. However, the fact that tics can still wax and wane
and that primary tics can be unmasked upon antipsychotic
discontinuation should not be neglected. It should also be
noted that primary tic disorder, although rare, can occur dur-
ing adulthood [75].
For some cases, the use of adjunct medications may
have been a confounding factor. For instance, in one case,
tics that developed approximately 3 months after discon-
tinuing sulpiride may have been stimulated by amanta-
dine and trihexyphenidyl hydrochloride that were initiated
approximately 2 months after sulpiride discontinuation [42].
Amantadine in this case may have triggered the develop-
ment of tics via increased dopamine release during a dopa-
mine supersensitivity state induced by sulpiride [42]. Other
medications that have the potential to induce tics, such as
936
methylphenidate and imipramine [22], were also co-pre-
scribed with antipsychotics in a few cases [25, 40].
The family history of tic disorder was unknown in half
of the patients, suggesting that familial influence may have
been underestimated. It should also be noted that a large
number of patients (45%; n = 27/60) had a personal history
of motor symptoms, which could have increased the suscep-
tibility to antipsychotic-associated tics.
5 Conclusion
Antipsychotic treatment can lead to the emergence of
symptoms of TS in a wide range of mental illnesses and age
groups. The mechanism may involve dopamine supersensi-
tivity and/or other pharmacological activities of antipsychot-
ics. Clinicians need to be particularly vigilant when initiat-
ing and modifying antipsychotic regimens (e.g., adjusting
the dose, discontinuing the treatment, or switching between
antipsychotics). Future studies should take a pharmacoepi-
demiologic approach to quantify and compare the risk of
tics between different antipsychotics and also to identify
major risk factors for such unwanted adverse effects. This
will guide clinicians to prescribe safer antipsychotics when
dealing with patients who are at risk or already experiencing
symptoms of TS.
Compliance with Ethical Standards
Funding No sources of funding were used to assist with the prepara-
tion of this article.
Conflict of interest Alasdair M. Barr has received grants from Bristol-
Myers Squibb and the Canadian Institutes of Health Research. Bruce
C. Carleton is part of the Pharmaceutical Outcomes Programme and
has received financial support for its pharmacoepidemiological re-
search from the British Columbia Provincial Health Services Author-
ity; he also serves on a data safety board for AEVI Genomic Medicine.
Randall F. White has received consulting fees or sat on paid advisory
boards for: Janssen, Lundbeck, and Otsuka; and has received a grant
from ThermoFisher/Affymetrix. William G. Honer has received con-
sulting fees or sat on paid advisory boards for: the Canadian Agency
for Drugs and Technology in Health, the Centre for Drug Research and
Development, AlphaSights, In Silico (unpaid), and Otsuka/Lundbeck.
Ric M. Procyshyn has received consulting fees or sat on paid advisory
boards for: Janssen, Lundbeck, and Otsuka; is on the speaker’s bureau
for Janssen, Lundbeck, and Otsuka; and has received grants from the
Canadian Institutes of Health Research. David D. Kim, Yunsun Chung,
Jessica W.Y. Yuen, and Mahyar Etminan have no conflicts of interest
directly relevant to the contents of this article.
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Affiliations

David D. Kim1 · Alasdair M. Barr1 · Yunsun Chung2 · Jessica W. Y. Yuen3 · Mahyar Etminan4 · Bruce C. Carleton2,5,6 ·

Randall F. White7 · William G. Honer7 · Ric M. Procyshyn7

1 5
Department of Anesthesiology, Pharmacology Division of Translational Therapeutics, Department
and Therapeutics, University of British Columbia, of Pediatrics, University of British Columbia, Vancouver,
Vancouver, BC, Canada BC, Canada
2 6
British Columbia Children’s Hospital Research Institute, Pharmaceutical Outcomes Programme, British Columbia
Vancouver, BC, Canada Children’s Hospital, Vancouver, BC, Canada
3 7
Faculty of Medicine and Centre for Brain Health, University Department of Psychiatry, University of British Columbia,
of British Columbia, Vancouver, BC, Canada Room A3-111, 938 West 28th Avenue, Vancouver,
4 BC V5Z 4H4, Canada
Department of Ophthalmology and Visual Sciences,
University of British Columbia, Vancouver, BC, Canada