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Review

Update on the pharmacological treatment of tics with dopamine-modulating agents Sabine Mogwitz, Judith Buse, Nicole Wolff, and Veit Roessner ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.7b00460 • Publication Date (Web): 02 Mar 2018 Downloaded from http://pubs.acs.org on March 3, 2018

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ACS Chemical Neuroscience Mogwitz et al.

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1

Invited Review Update on the pharmacological treatment of tics with dopamine-modulating agents

Sabine Mogwitz1), Judith Buse1), Nicole Wolff1), Veit Roessner1)

1) Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Germany

Corresponding author: Prof. Dr. Veit Roessner

Faculty of Medicine Carl Gustav Carus, TU Dresden Department of Child and Adolescent Psychiatry Fetscherstrasse 74 01307 Dresden. Germany Phone: 0049 –351 458 – 2244 Fax: 0049 – 351 458 – 5754 Email: [email protected]

Word count: 10291 (including tables) Keywords: Dopamine receptor antagonist, dopamine receptor agonist, atypical antipsychotics, typical antipsychotics, benzamides, haloperidol, risperidone, tiapride, sulpiride, pimozide, fluphenazine, clozapine,

quetiapine,

amisulpride,

ziprasidone,

tetrabenazine,

deutetrabenazine,

pergolide,

aripiprazole, ecopipam, Traditional Chinese Medicine Note: •

Publications not including patients with tics are marked with an asterisk (*) (publications on patients with tics are not marked)

•

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

ACS Paragon Plus Environment


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Abstract More than forty years of research and clinical practice have proven the effectiveness of dopamine receptor antagonists in the pharmacological treatment of tics. A blockade of the striatal dopamine-D2 receptors is mainly responsible for their tic-reducing effect. A broad spectrum of dopaminemodulating agents, such as typical and atypical antipsychotics, but also dopamine receptor agonists are used with an immanent discord between experts about which of them should be considered as first choice. The present article outlines the state of the art on pharmacological treatment of tics with dopamine-modulating agents by giving an systemativ overview of studies on their effectiveness and a critical discussion of their specific adverse effects. It is considered as an update of a previous review of our research group published in 2013. The review closes with a description of the current resulting treatment recommendations including the results of a first published revised survey on European expert’s prescription preferences. Based on the enormously growing evidence on its effectiveness and safety, aripiprazole currently seems to be the most promising agent in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride), which are commonly used in Europe, have proven their excellent effectiveness-tolerability profile over decades in clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, pharmacological treatment of tics remains an indiviual choice depending on each patient’s own specific needs.


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1 Introduction Tic disorders are characterized by the occurrence of sudden, rapid, recurrent, nonrhythmic motor movements and/or vocalizations. According to the DSM-5,1* tic disorders can be classified as rather persistent (more than one year since first tic onset) or provisional (less than one year since first tic onset), whereas the tic onset is always before the age of 18. Tourette syndrome (TS), a subtype of tic disorders, is defined by the occurrence of multiple motor tics, and at least one vocal tic that has persisted for at least one year. TS has a prevalence of 0.77 %, chronic tic disorders of 1.61 % and transient tic disorders of 2.99 %.2 Tics may cause functional impairment and constrain the patients quality of life, especially in severe cases, by affecting their emotional status, their sleep quality and their subjective comfort (i.e. pain or injury) or even lead to sustained social problems (i.e. bullying or isolation).3-8 If drawbacks to quality of life are sufficient to outweigh the risks of current therapeutic options,4 treatment becomes necessary. If behavioral therapy such as habit reversal training (HRT) is ineffective or not available pharmacological treatment is recommended, either alone or in combination with HRT.5 In severe cases initiation of pharmacological treatment might even be considered as first option.6 Further, pharmacological treatment should be considered if psychiatric comorbidities responsive to pharmacological treatment are present.7 Although pharmacological treatment of tics is the fastest and most promising treatment option,6 it is symptomatic: to best of our knowledge pharmacological treatment alleviates the tics at best, but does not cure them.8 Since a complete remission of tics by pharmacological treatment is unlikely, tic reduction resulting in improved quality of life should be targeted.4 More than 35 years of experience with the pharmacological treatment of tics have established a list of promising agents, but the decision about treatment is still an individual choice, highly depending on the physician´s preferences and patient´s needs. The effectivenss of pharmacological treatment of tics varies between different patients and in clinical practice, it remains common to try reasonable options until an effective medication is found.9



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Tics have been associated with a dysfunction of the dopamine system. Based on findings from nuclear imaging studies, four hypotheses on dopamine dysfunction in tic disorders are recently discussed: 1) dopamine hyper-innervation, 2) supersensitive dopamine receptors, 3) pre-synaptic dopamine abnormality and 4) dopamine tonic-phasic dysfunction.10,11 According to the latter hypothesis, which currently seems to be most dominant in the literature, reduced levels of tonic dopamine in the extracellular space lead to an increase of phasic dopamine release.10 However, there are also several lines of evidence raising doubt about these assumptions.12 For example, if the predominant dysfunction in patients with tics was reduced tonic dopamine than pharmacological inhibition of the dopamine transporter should be an excellent treatment for tics, which is not the case. Alternatively, it has recently been suggested that both tonic and phasic dopamine might be increased in patients with tics. According to this alternate hypothesis, exaggerated motor habits (tics) are learned through abnormal, increased phasic dopamine signals, while elevated tonic dopamine levels increase the tendency to execute learned tics.12 Beside the apparent evidence for deviances in the dopamine system, suggestions concerning imbalances in other neurotransmission systems like the serotonergic, the noradrenergic, the glutamatergic, the GABAergic, the cholinergic and the opioid system have been made.13,14 However, until today dopamine-modulating agents remain the most effective drugs in treating tics and are still commonly used in clinical practice.6,9 Depending on their individual receptor binding profile, each agent bears the risk for adverse effect. Therefore taking the potential adverse effects of each agent into consideration is an important step on the way to a decision about the best treatment. In general, the major adverse effects of dopaminemodulating agents include extrapyramidal syndromes (EPS), weight gain, increase of prolactin levels, QTc-prolongation and sedation. But the spectrum of potential adverse effects is broad ranging from acute dystonia, parkinsonism, and akathisia over temperature dysregulation, orthostatic hypotension and sexual dysfunction to more ‘behavioral’ adverse effects like depression, aggression, anxiety, and agitation.15–20(15,16,17,18*)


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5

Consequently, the individual treatment of a patient should be planned by considering the available diagnostic information, the level of the patient’s impairment, the availability, effectiveness and tolerability of the treatment options as well as the patient’s preferences.6,21*

The following chapters describe all dopamine-modulating agents used in the pharmacological treatment of tics, including an overview of studies on their effectiveness in reducing tics. Since the present review is considered as an update on our previous review on the same topic22, we included details like the sample size and the dosing scheme only for those studies and reviews published after 2012 (see table 1). Studies published before 2012 are only briefly mentioned and a broad overview on their results is given. When reviews or meta-analysis on the effectiveness of a dopamine-modulating agent were available we referred mainly to those summarizing publications and refrained from citing the original studies in the text. Table 1 gives an overview of the cited publications and lists which original studies are included in which review or meta-analysis. Each chapter also includes a critical discussion of the specific tolerability profile of each agent with a main focus on the most intensively discussed adverse effects, i.e. EPS, weight gain, increase of prolactin levels, QTc-prolongation and sedation. We primarly included information on adverse effects observed in patients treated for their tics. However, when the body of evidence on adverse effects in patients with tics was low for a particular agent, we included additional information derived from studies on patietns with other indications (mostly schizophrenia). Thorough the manuscript we marked citations referring to studies not primary focusing on patients with tics with an asterisk.

2 Systematic review of dopamine receptor antagonists for the treatment of tics 2.1 Typical antipsychotics (TA) TA are long known to be effective in the treatment of tics.23,24 Besides the strong antagonism at dopamine D2 receptors of most TA, which raises the risk for extrapyramidal symptoms (EPS),25* each agent has individual effects on other receptors (dopamine D1 and D3 receptors, adrenergic receptors, 5-HT receptors, histamine receptors and muscarinic acetylcholine receptors), leading to an individual profile of potential adverse effects.25*


ACS Chemical Neuroscience

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Mogwitz et al.

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While TA were once the first line option for the pharmacological treatment of tics, most publications with treatment recommendations list them as second or third line options by now.6,19,26,27

2.1.1 Haloperidol Haloperidol, a butyrophenone derivate, was the first TA proven to be effective in the treatment of tics. Beside its strong dopamine antagonism, specifically at dopamine D2 receptors, haloperidol blocks muscarinic acetylcholine receptors and adrenergic receptors. However, the relevance of haloperidol in the treatment of tic disorders has declined within the last decade from being a first line agent to being used only in patients refractory to other treatment options.

Update on the studies on the effectiveness of haloperidol in the treatment of tics Until 2012 numerous studies on the effectiveness of haloperidol in the treatment of tics have been conducted, mostly in the 80s and 90s of the 20th century. As described in our previous review,22 four RCTs,23,28–30(30*) one naturalistic study31 and one retrospective chart review32 proved haloperidol to be effective in reducing tics. However in one RCT, haloperidol failed to have a significant effect on tics.29 Later publications on the effectiveness of haloperidol in the treatment of tics have been constricted to systematic reviews/meta-analyses of older trials or to studies using haloperidol as a control agent.

Table 1. Overview on studies on the effectiveness of dopamine-modulating agents in the treatment of tics Agent

Review or Meta-Analysis

Original Study

Year

Patients N(males)

Study Design

Dose mg/day

Age range in years

Duration in weeks

Haloperidol

Wang (2017)33

Cheng34 Zheng35 Yoo36 Guo37 Liang38 Ren39 Sun40 Zhao42 Guo37 Gao43 Ren39 Yoo36 Cheng34 Liang38 Liang38 Sallee29

2012 2015 2011 2013 2010 2012 2014 2011 2013 2013 2012 2011 2012 2010 2010 1997

62 (39) 61 (42) 48 (33) 80 (55) 80 (64) 68 (58) 87 (56) 108 (72) 80 (55) 48 (33) 68(58) 48 (33) 62 (39) 80 (64) 80 (64) 22 (77%)

com com com, ot com com com

2.5-10 2-12 0.75-4.5 1-16 6-16 1-8 1-10 2-12 1-16 1-8 1-8 0.75-4.5 0.5-10 6-16 6-16 1–8

5-16 6-12 6-15 4-16 4-16 5-16 3-13 4-15 4-16 mean: 11.2 5-16 6-15 5-16 4-16 4-16 7-16

8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 24

Yang (2015)41

Zheng (2016)44 Hollis (2016)45

com comb com com com, ot com com com RCT, pc, db, co


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Waldon (2013)47

Weisman (2013)50

7

Ross & M.28 Shapiro23 Yoo36 Ji46 Silver48 Ross & M.28 Sallee49 Sallee29 Shapiro23 Shapiro23 Sallee29

1978 1989 2011 2005 2001 1978 1996 1997 1989 1989 1997

9 (78%) 57 (72%) 48 (33) 60(95%) 70 9 (78%) 26 22 (77%) 57 (72%) 57 (72%) 22 (77%) 741

RCT, pg, db, co RCT, pc, pg pg, com, ot RCT, pg RCT, pgf, dbg RCT, pg, db, co RCT, db, coh RCT, pc, db, co RCT, pc, pg RCT, pc, pg RCT, pc, db, co 12 RCTsa

Yang52 Gilbert53 Sallee29

2012 2004 1997

71 19 (79%) 22 (77%)

Bruggeman54 Shapiro23 Shapiro55 Ross & M.28 Gulisano56 Shapiro23 Bruggeman54

2001 1989 1984 1978 2011 1989 2001

50(88%) 57 (72%) 20 (65%) 9 (78%) 50 (86%) 57 (72%) 50 (88%)

Gilbert53 Ross & M.28 Sallee49 Sallee29 Shapiro55 Onofrj57 Sallee29 Shapiro23 Gilbert53 Bruggeman54

2004 1978 1996 1997 1984 2000 1997 1989 2004 2001

19 (79%) 9 (78%) 26 22 (77%) 20 (65%) 4 22 (77%) 57 (72%) 19 (79%) 50 (88%)

Vicario58 Wijemanne59

2015 2014

9 (9) 268

Ghanizadeh60 Scahill61 Dion62 Gilbert53

2014 2003 2002 2004

60 (49) 34 48 (18%) 19 (79%)

Bruggeman54 Ghanizadeh60 Bruggeman54

2001 2014 2001

50 (88%) 60 (49) 50 (88%)

Gilbert53 Dion62 Scahill61 Gaffney63

2004 2002 2003 2002

19 (79%) 48 (18%) 34 21

RCT RCT, db, co RCT, pc, db, co RCT, pg, db, multic RCT, pc, pg RCT, co RCT, pg, db, co pg, com RCT, pc, pg RCT, pg, db, multic RCT, db, co RCT, pg, db, co RCT, db, coh RCT, pc, db, co RCT, co RCT, db, co RCT, pc, db, co RCT, pc, pg RCT, db, co RCT, pg, db, multic case series retrosp. chart review RCT, db RCT, pg, pc, db RCT, pg, pc, db RCT, db, co RCT, pg, db, multic RCT, db RCT, pg, db, multic RCT, db, co, RCT, pg, pc, db RCT, pg, pc, db RCT, pg, db

Scahill61 Dion62 Gilbert53 Bruggeman54

2003 2002 2004 2001

34 48 (18%) 19 (79%) 50 (88%)

Gaffney63

2002

21

Cheng (2012)51 [in Chinese] Pimozide

Hollis (2016)45

Waldon (2013)47

Weisman (2013)50

Fluphenazine Risperidone

Wang (2017)33 Hollis (2016)45

Yang (2015)41 Waldon (2013)47

Weisman (2013)50

Cheng (2012) [chinese]51 Paliperidone Aripiprazole

Wang (2017)33

Sari64 Guan65 Yamamuro66 Wang67 Ghanizadeh60 Wang68 Liu69 Ren39 Guo37 Liang38 Sun40 Zheng35

RCT, pg, pc, db RCT, pg, pc, db RCT, db, co, RCT, pg, db, multic RCT, pg, db

2-12 0.5-10 0.75-4,5 2-12

8-28 18-65 6-15 8-16

2-12 1-8 0.5-10 0.5-10 1-8

8-28 7-13 7-16 18-65 18-65 7-16

4 6 8 4 6,5 4 6 24 6 6 24

1-4 1-6

7-17 7-16

12 4 24

1-6 1-20 1-20 2-12 mean: 4.4 1-20 1-6

11-65 18-65 11-53 8-28 6-18 18-65 11-65

12 6 6 4 24 month 6 12

1-4 2-12 1-6 1-20 2-4 1-6 1-20 1-4 1-6

7-17 8-28 7-13 7-16 11-53 19-40 7-16 18-65 7-17 11-65

4 4 6 24 6 52 24 6 4 12

2-10 0.5–12.0

8.3±1 4.1–70.2

12 26 years

0.25-3 0.5-4 0.5-6 1-4

6-18 6-62 14-49 7-17

8 8 8 4

1-6 0.25-3 1-6

11-65 6-18 11-65

12 8 12

1-4 1-6 0.5-4 0.03-0.06 mg/kg 0.5-4 1-6 1-4 1-6

7-17 14-49 6-62 7-17

4 8 8 8

6-62 14-49 7-17 11-65

8 8 4 12

7-17

8

11 20

4 years 1.5

5-18 6-18 6-15 5-17 5-16 4-16 4-16 3-13 6-12

9 8 8 12 8 8 8 8 8

0.03-0.06 mg/kg

a

2012

741

12 RCTs

2014 2013 2014 2015 2014 2013 2011 2012 2013 2010 2014 2015

1 1 (0) 3 45 (38) 60 (49) 60 (41) 195 (156) 68 (58) 80 (55) 80 (64) 87 (56) 61(42)

case study case report case series RCT, db RCT ct, multic com com com com


mean: 6 mean: 3-6 2.5-20 1.25-15 2,5-10 2,5-25 5-20 2.5-12.5 5-30 2.5-7.5 2.5-10


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8

Liu (2016)76

Hollis (2016)45

Zheng (2016)44 Yang (2015)41

Ghanizad.(2012)86

Olanzapine Ziprasidone

Clozapine Quetiapine Tiapride

45

Hollis (2016) Waldon (2013)47 Hollis (2016)45 Weisman (2013)50

Wang (2017)33

Hollis (2016)45 Zheng (2016)44

Cheng70 Yoo71

2012 2013

62 (39) 61 (53)

Yoo36 Zhao42 Liu72 Zhang73 Zhang74 Su & Chen75 Murphy77 Yoo78 Yoo79 Seo80 Lyon81 Murphy82 Cui83

2011 2011 2010 2014 2015 2015 2005 2006 2007 2008 2009 2009 2010

48 (33) 108 (72) 65 (57) 76 (56) 80 (51) 69 (58) 6 (6) 14 (14) 24 (18) 15 (15) 11 (10) 16 (16) 72 (72)

Yoo71

2013

61 (53)

Ghanizadeh60 Ho84

2014 2014

60 (49) 81 (55)

Gulisano56 Liu69 Yoo36 Rizzo85 Gulisano56 Ghanizadeh60 Yoo71

2011 2011 2011 2012 2011 2014 2013

50(86%) 195(156) 48 (33) 75 (67) 50 (86%) 60 (49) 61 (53)

Yoo36 Wang68 Liu72 Liu69 Cheng70 Ren39 Zhao42 Guo37 Gao43 Liang38 Yoo36 Liu72 Gulisano56 Budman87 Lyon81 Cui83

2011 2013 2010 2011 2012 2012 2011 2013 2013 2010 2011 2010 2011 2008 2009 2010

48 (33) 60 (41) 65 (57) 195 (156) 62 (39) 68 (58) 108 (72) 80 (55) 48 (33) 80 (64) 48 (33) 65 (57) 50 (86%) 37 11 (10) 72 (72)

pg, com ct, multic pg, com, ot com pg, com RCT, db RCT, pc, db, multic pg, com, ot RCT com ct, multic com com com com com com pg, com, ot com pg, com retrospective trial ot ot

Sallee88 Ghanizadeh89 Wang90 Pozzi91 Diomsina92 Bhatia93 Ho84

2017 2016 2016 2016 2015 2014 2014

133 36 26 (22) 184 33 1 (1) 81 (55)

RCT, db, multic RCT ot ot naturalistic co case report ot, naturalistic

Masi94 Wenzel95

2012 2012

28 100(78)

ot retrospective

Neuner96 Ji46 Onofrj57 Sallee97 Sallee97 Sallee98 Lan99 Lan99 Liu69 Wang68 Wang67 Zhang73 Liu72 Liu69 Wang68 Liu72

2012 2005 2000 2000 2000 2006 2015 2015 2011 2013 2015 2014 2010 2011 2013 2010

20 60 (95%) 4 28 (79%) 28 (79%) 24 1 1 195 (156) 60 (41) 45 (38) 76 (56) 65 (57) 195 (156) 60 (41) 65 (57)

retrospective RCT, pg RCT, db, co RCT, pg, pc RCT, pg, pc ot case report case report ct, multic RCT

com RCT, pc, db, multic pg, com, ot com com com RCT ct, multic ot ot ot ot ot ot ot RCT, pc, db, multic RCT, db ot, naturalistic

com com ct, multic RCT RCT


2.5-10 2-20

5-16 6-18

8 10

5-20 5-15 2.5-10 2.5-10 0.5-3 2.5-10 mean: 11.7 mean: 10.89 mean: 9.8 mean: 8.2 mean: 4.5 ± 3.0 mean: 3.3 0.1-0.6 mg/kg//d 2-20

6-15 4-15 6-14 3-17 5-12 4-14 8-19 7-17 7-18 7-19 9-19 8-17 6-18

8 8 12 12 12 12 12 8 8 12 10 8

6-18

10

1.25-15 mean: 2.84 ± 0.48 mean:5.3 2,5-25 5-20 1.25-15 mean:5.3 1.25-15 2-20

6-18 4-18

8 14

6-18 5-17 6-15 mean: 11.6 6-18 6-18 6-18

24 months 12 8 24 months 24 months 8 10

5-20 2.5-10 2.5-10 2,5-25 2.5-10 2.5-20 5-15 2.5-12.5 2.5-20 5-30 5-20 2.5-10 mean:10.6 2.5-40 mean: 4.5 ± 3.0 0.1-0.6 mg/kg//d 5 or 10 1.25-7.5 mean: 8.0 ± 4.0

6-15 6-15 6-14 5-17 5-16 5-16 4-15 4-16 mean: 11.2 4-16 6-15 6-14 6-18 8-18 9-19 6-18

8 8 12 12 8 8 8 8 8 8 8 12 24 months 12 10 8

7-17 1 years >1 year 12 8 9 12 12 12 8 12

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Yang (2015)41

Tetrabenazine

9

Wang68 Liu72 Liu69 Yang52 Poulopoulos10

2013 2010 2011 2012 2013

60 (41) 65 (57) 195 (156) 71

RCT com ct, multic RCT case report

50-300 25-400 25-500 150-300 25-37.5

6-15 6-14 5-17

8 12 12 12

0

Deutetrabenazine Jankovic101 2016 23(17) ot 18-36 12-18 8 Ecopipam Gilbert102 2014 18 (15) ot. multic 18-63 List of all studies on dopamine-modulating agents in the treatment of tics included in the current review. The third column shows which original studies were included in the reviews/meta-analysis listed in the second column. Original studies not included in any review or metaanalyses are listed under the reviews /meta-analyses on this agent separated with crosslines (the second column is left blank for those studies). All information given in English in the reviews/meta-analyses or original studies are listed, i.e. blank cells signal unavailability of data. a RCT= randomized controlled trial b com = comparative study c ct = controlled trial d multic = multicenter e ot = open trial f pg = parallel group g db = double-blind h co = crossover i pc = placebo controlled

Since 2012, seven reviews /meta-analysis33,41,44,45,47,50,51 summarizing the results of trials on haloperidol in the treatment of tics and one RCT52 not included in a review have been published (see table 1). All of these publications reported haloperidol to be effective in reducing tics and to be similar effective as compared to risperidone, pimozide, ziprasidone, aripiprazole and tiapride.33,41,44,45,47,50–52

Characteristic adverse effects of haloperidol As described in our previous review, haloperidol produces relatively strong adverse effects including EPS, tardive dyskinesia, akathisia, restlessness, parkinsonism, and neuroleptic malignant syndrome103,104,105. Also hyperprolactinemia and symptoms of the anxiety and depressive spectrum, agitation, euphoria, insomnia, confusion and drowsiness can be observed.20,105,106 From studies on patients with schizophrenia we know that haloperidol bears a marginal risk for QTcprolongation.107* However, in a controlled trial with 57 children treated with haloperidol for their tics no cardiac effects were observed.108 Recent reviews and meta-analyses including studies using haloperidol for the treatment of tics support above mentioned adverse effects: EPS, tremor, tardive dyskinesia, drowsiness, fatigue, headache, nausea/vomiting, dry mouth, emotional hypersensivity, insomnia, irritability and nightmares.33,44,41



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Furthermore, paradoxical worsening of tics with haloperidol has been reported in a single case in 1987 109

and again in a single case in 2015. 110

Table 2. Current dosing recommendations in the treatment of tics

Haloperidol

Starting dose in mg/day 0.25-0.5

Range of target dose in mg/day 0.75-10

Pimozide

0.25-1

2-8

Fluphenazine Risperidone

0.5-1 0.25-0.5

0.5-12 0.5-6

3-6

Paliperidone Aripiprazole

1-2.5

5-30

Olanzapine Ziprasidone

2.5-5 5-10

2.5-30 10-40

Quetiapine Tiapride Tetrabenazine

25 50-100 12.5

75-500 100-900 50–150

Sources Budman 2014111 Roessner 20116 Singer 201019 Hartmann 2013112 Malaty 20144 Singer 201019 Budman 2014111 Budman 2014111 Singer 201019 Budman 2014111 Roessner 2013113 Guan 201365 Yamamuro 201466 Budman 2014111 Yoo 201371 Diomsina 201592 Greenaway and Elbe 2009114 Zheng 201644 Gulisano 201156 Budman 2014111 Budman 2014111 Singer 201019 Singer 201019 Budman 2014111 Malaty 20144

The ‘starting dose in mg/day’ lists the minimum and the maximum starting dose recommended in the literature listed in the column ‘sources’. The column ‘range of target dose in mg/day’ lists the minimum and the maximum target dose recommended in the literature listed in the column ‘sources’.

2.1.2 Pimozide Pimozide, a diphenylbutylpiperidine derivate, is a dopamine D2 receptor antagonist which also blocks calcium channels. It is an established drug in the treatment of tics,19 although the number of trials comparing its effectiveness to placebo or other drugs is limited.115

Update on the studies on the effectiveness of pimozide in the treatment of tics Before 2012 seven double-blind trials28,29,49,53–55,108 had proven pimozide to be effective in the treatment of tics, although slightly less effective than haloperidol.22 The effectiveness of pimozide had also been proven in two naturalistic studies31,116 and one comparative, parallel-group study.56


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11

Recent publications on the effectiveness of pimozide in patients with tic disorders has mostly been restricted to reviews/meta-analyses of older trials. Since 2012 three reviews45,47,50 including trials on the effectiveness of pimozide have been published, all giving support that pimozide is effective in reducing tics. Furthermore, a recent case series including nine patients with tics showed that pimozide improved motor timing performance.58

Characteristic adverse effects of pimozide As described in our previous review, pimozide has been generally associated with fewer adverse effects than haloperidol, although it still produces adverse effects that limit its applicability22 including EPS, dystonia, oculogyric crisis, parkinsonism, tardive dyskinesia, weight gain, hyperprolactinemia, sedation, QTc-prolongation and anxiety.108,115,116 Recent reviews on trials comparing pimozide in the treatment of tics to placebo, haloperidol or risperidone support those adverse effects, but concluded that pimozide caused EPS to a lesser extent than haloperidol and weight gain to a lesser extent than risperidone. 47,117 A recent study assessing the metabolic effects of pimozide in children with tics found increased glycaemia.85 The risk for a prolongation of the QTc was higher with pimozide than with haloperidol.

47,117

Further a case of an

exacerbation of tics in a 15-year-old boy with TS treated with pimozide has been recently reported.118 However, also in this case the natural waxing und weaning of tics needs to be considered as a potential explanation for exacerbation of the symptoms. Although rarely, also potentially serious adverse effects such as cardiac arrhythmia (torsade de pointes), cardiac arrest, neutropenia, and seizures have been described.105

2.1.3 Fluphenazine Fluphenazine, a phenothiazine derivative, is one of the oldest TA with a high-potency at dopamine D2 receptors and additional blocking activity at dopamine D1 receptors.119*. It has been used particularly in the United States for many years in the treatment of tics, although it has merely been studied systematically.6



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Update on the studies on the effectiveness of fluphenazine in the treatment of tics Up to 2012 only a few small studies have shown the effectiveness of fluphenazine in the treatment of tics.32,120,121 However, there is a recent retrospective chart review on 268 patients with TS, who were treated with fluphenazine, which supports its long-term effectiveness and safety. Marked to moderate improvement was noted in 80.5% of the patients.59

Characteristic adverse effects of fluphenazine As described in our previous review, adverse effects of fluphenazine include tardive dyskinesia, parkinsonism, neuroleptic malignant syndrome, weight gain, hyperglycemia, hyperprolactinemia, drowsiness and tachycardia.105 Also anxiety, agitation, euphoria, insomnia, confusion, headache, seizures and vision impairments may occur.105 However, fluphenazine has fewer adverse effects than haloperidol.32,122 In the above mentioned recent retrospective review59 EPS were reported by 8% (for tremor) – 23 % (for akathisia) of the patients treated with fluphenazine. Weight gain occurred in 31 % of those patients and an increase of the prolactin level was only observed in 1% of the patients.59 Drowsiness was the most common adverse effect experienced by 70 % of the patients treated with fluphenazine for their tics.

2.2 Atypical antipsychotics (AA) AA were developed in an attempt to bypass some of the typical adverse effects, mostly EPS, associated with TA. The name ‘atypical’ therefore describes the lack of the typical adverse effects of TA.123* The different mechanism of action of AA as compared to TA can be explained by its different binding to dopamine and 5-HT2 receptors, i.e. their 5-HT2A receptor antagonism (see our previous review22 for a detailed description). Treatment of tics is among the most common off-label uses of AA.124 and many publications with treatment recommendations mainly advise the use of AA rather than TA as first line treatment of tics.6,19,24,26,27


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2.2.1 Risperidone Risperidone, a benzisoxazole derivative with combined dopamine D2 receptor and 5-HT2 receptor antagonism125 is one of the most intensive studied AA for the treatment of tics.6,19,113

Update on the studies on the effectiveness of risperidone in the treatment of tics Up to 2012 several RCTs,53,54,61–63 case reports,126–129 open-label studies130–135 and retrospective studies,136–138 including small groups of patients across different ages, have proven risperidone to be effective in the treatment of tics. Between 2012 and 2017 six systematic reviews/meta-analyses33,41,45,47,50,51 including trials and one case study64 on risperidone in the treatment of tics have been published. All of these studies showed that risperidone is effective in reducing tics.33,41,45,47,50,64 Risperdione had a similar effectiveness as compared to haloperidol, tiapride, pimozide and aripiprazole51,41 and was superior as compared to placebo.50 Besides its excellent effectiveness in the treatment of pure tics, risperidone appeared to be especially beneficial for patients with comorbid obsessive-compulsive disorder as an augmentation to selective serotonin reuptake inhibitors (SSRI) for treatment refractory obsessive compulsive symptoms.47

Characteristic adverse effects of risperidone As described in our previous review, discontinuation due to adverse effects must be considered as a major problem when using risperidone to treat tics 137. Common adverse effects of risperidone include hyperprolactinemia,139–142(139,140,142*) increased appetite and weight gain,33,61,138,141,143,144* sedation141 and EPS. 135,145–147*, From studies on patients with schizophrenia we know that the increase of prolactin concentration is higher with risperidone as compared to placebo and most other antipsychotics

107

* Among children

treated with risperidone for their tics, 41 % had abnormal increases in prolactin levels.148 In the case of prepubertal children special caution needs to be taken with regard to the increase of prolactin levels, since they may not develop clinical symptoms or signs of hyperprolactinemia such as menstrual irregularity, gynecomastia or galactorrhea and since long-term effects of high prolactin on sexual,



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bone, and breast development are unknown. Therefore in prepubertal children, who show persistently highly elevated prolactin levels, a switch to antipsychotic medication that does not (or not strongly) affect prolactin (such as aripiprazole) is recommended.149* Also when used for the treatment of tics, risperidone is associated with weight gain.136,150–152 Interestingly, risperidone-related weight gain seems to reach a plateau during long-term administration, i.e. the BMI increased significantly in the first month of the treatment with risperidone and then only increased slowly over time.148 A large body of research on usage of risperidone in schizophrenia in general suggests a good EPS profile, especially in the lower dose ranges,107*,145–147* although risperidone does not completely lack the risk of inducing EPS. In fact, EPS were present in a prospective longitudinal study on the feasibility and relevance of antipsychotic safety monitoring in children with TS in 35 % of the children treated with risperidone.148 In order to avoid EPS the dose should be kept as low as possible.145*,153 Interestingly, the risk for EPS seems to be lower in individuals, who were treated with antipsychotics for TS as compared to individuals treated for other psychiatric diagnoses.154 Other common adverse effects of risperidone are fatigue, agitation, insomnia as well as anxiety and depressive symptoms 151,152 155 150.

2.2.2 Paliperidone Paliperidone, a 9-hydroxyrisperidone, is a member of the benzisoxazole derivative class of AA. It is the major active metabolite of risperidone with a slightly different receptor profile but a significantly different pharmacokinetic profile with clinically meaningful differences in the formulation, frequency of administration, pharmacokinetics and other pharmacological features.125,156–158* Paliperidone acts as an antagonist at dopamine D2 receptors, α1 and α2 adrenergic receptors, and histamine H1 receptors. It also has 5-HT2A receptor agonism but no affinity for muscarinic acetylcholine M1 receptors or β adrenergic receptors. The example of risperidone and its active metabolite 9-hydroxy risperidone, i.e. paliperidone, demonstrates how a minimal modification of the chemical structure of an agent can lead to a significantly different pharmacokinetic profile. However, the effectiveness of paliperidone in the treatment of tics has merely been studied.


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Update on the studies on the effectiveness of paliperidone in the treatment of tics Up to date, there are only two case reports including a total of four patients on the use of paliperdone in the treatment of tics: The first published result of a successful outcome of paliperidone in treatment for tics was the case-report of a 27 year old woman with TS (onset with 11 years) and comorbid schizophrenia.65 After several agents (including aripiprazole and risperidone) had not shown improvement of tics, treatment with paliperidone extended-release was started. Within 10 days of treatment her motor tics had almost disappeared.65 Furthermore a recent report on three cases of pediatric patients with TS, who were treated with paliperidone revealed a reduction of tic severity over a relatively short period of time (5 weeks).66

Characteristic adverse effects of paliperidone A large meta-analysis on the use of paliperidone in the treatment of schizophrenia shows that the adverse effects profile of paliperidone is very similar to that of risperidone including a risk for hyperprolactinemia, EPS and weight gain.107* However, the risk for weight gain appears to be lower with paliperidone as compared to risperidone, because risperidone and paliperidone differentially alter serotonergic neurotransmission, which plays an important role in the regulation of appetite.65 In the case studies on paliperidone for the treatment of tics no adverse effects65 or only mild drowsiness66 were reported.

2.2.3 Iloperidone, Asenapine and Lurasidone There are three relatively new AA for the treatment of psychiatric disorders: Iloperidone, asenapine and lurasidone. Iloperidone is a member of the piperidinyl-benzisoxazole derivative class of antipsychotic medications with mixed dopamine D2 receptor/5-HT2A receptor antagonism. Asenapine belongs to the dibenzo-oxepino pyrrole class of AA medications and strongly antagonizes dopamine D1, D2, D3 and D4 receptors, 5-HT1A, 5-HT2A and 5-HT2C receptors, α1 and α2 adrenergic receptors, and histamine H1 receptors. Lurasidone belongs to the benzisothiazol class of AA agents



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and acts as a dopamine D2, 5-HT2A and 5-HT7 receptor antagonist and as a partial agonist at 5-HT1A receptors. To the best of our knowledge no studies proving the effectiveness of those agents in the treatment of tics have been published so far. However, such studies would be desireable since studies on patiens with schizophrenia22 suggest that those agents have a good tolerability profile.

2.2.4 Aripiprazole Aripiprazole has high receptor affinity for dopamine D2 and D3 receptors and moderate affinity for dopamine D4 receptors.(159–164)* Aripiprazole also binds to 5-HT receptors and has moderate affinity for histamine and α adrenergic receptors but negligible activity at muscarinic acetylcholine receptors.(165,166)* Aripiprazole has a different mechanism of action compared to other AA167* by acting as a partial agonist at dopamine receptors. Consequently, aripiprazole does not lead to a total receptor blockade, but maintains dopamine-modulated neurotransmission although to a lesser extent.168*,184,169* The partial agonism is present on both the postsynaptic dopamine D2 receptors and the presynaptic dopamine autoreceptors.170* Possible results of the partial agonism at the postsynaptic dopamine D2 receptors are a decreased tendency for a) the upregulation of receptors and b) the development of EPS. The partial agonism at the dopamine autoreceptors decreases dopamine synthesis, release, and consequently the dopamine neurotransmission.(159,164,171–174)* Aripiprazole shows antagonism at 5-HT2A receptors and partial agonism at 5-HT1A receptors.181,(159,160,164,165,176)* The antagonism at the 5-HT2A receptors minimizes excessive dopamine blockade by increasing dopamine release, which results in a lower rate of EPSs.177* The partial agonism at the 5-HT1A receptors is associated with anxiolytic activity and is also postulated to reduce the risk for EPS.(178,179)* Partial agonistic actions at the 5-HT1A receptors might decrease tics indirectly through reduction in anxiety180* a common comorbidity in patients with tic disorders 181 Due to its effectiveness in the improvement of tics and its convenient profile of adverse effects, aripirazole has become an attractive and promising alternative in the treatment of tics.4,6,33,44,95,111


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Its rapidly growing popularity is reflected by the increase of research on its effectiveness in the treatment of tics.

Update on the studies on the effectiveness of aripiprazole in the treatment of tics Before 2012 consistent evidence for the effectiveness of aripiprazole in the treatment of tics came from case studies and case series,77,78,95,182–193 retrospective observational studies87,96,194 and open-label trials.36,38,42,56,69,79–83,94,195,196 However, controlled trials on the use of aripiprazole in patients with tics were not available. Over the last years aripiprazole then became the main focus in research on the pharmacological treatment of tics with six reviews/meta-analyses33,41,44,45,76,86 and ten additional trials

84,88–96

, i.e. that

were not included in a review, published since 2012 (see table 1). All reviews/meta-analyses33,41,44,45,76,86 as well as trials not included34,84,88–96 consistently came to the conclusion that treatment with aripiprazole is effective in reducing tics. Aripiprazole was similar effective as other dopamine-modulating agents such as haloperidol and tiapride,41,44,86 but safer with a smaller risk for EPS.44,86 In addition to the tic reducing effect, it was found that aripiprazole might also improve behavioral comorbidities such as depression, anxiety and auto-aggression95 as well as social adjustment and parental stress.90

Characteristic adverse effects of aripiprazole What already become apparent in the studies published before 2012, was now confirmed by the many trials and reviews on aripiprazole in the treatment of tics, that have been published since then: Aripiprazole seems to be well tolerated, usually leading to only mild to moderate and transient adverse effects.6,33,41,44,85,197 Those studies providing a number of patients dropping out out due to adverse effects, report relatively low discontinuation percentages from 0 up to 20.7 %.71,84,95,197 The most often reported side effects of aripiprazole are sedation,44,71,84,88,197 drowsiness,33,41,44,71,76 dizziness,35 weakness/lassitude,35 somnolence71,88 or fatigue33,88. Metabolic side effects are also frequently reported, including weight gain,35,71,81,82,84,87,117,198 increased appetite,33,35,41,71,76,81,82,84,87 as well as increased cholesterol and triglycerides85. Interestingly children



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seem to be more vulnerable too weight gain due to aripiprazole than adolescents.71 However, although weight gain is often reported aripiprazole seems to be associated with less weight gain and a lower incidence of other metabolic abnormalities than other AA, such as olanzapine.180*,199 Among the adverse effects of aripiprazole also nausea,33,35,41,71,76 loss of appetite35 and other gastrointestinal issues19 have been observed, but were usually transient, lasting approximately two weeks.33,44,80,117 Further reported adverse effect of aripiprazole are headache33,41,44,71,76 and sleep problems197,200,44,198 Potential adverse effects regarding emotions and behavior include anxiety,19,44,198 suicidal ideation and behavior, worsening of depression, hypotension and restlessness.19,198 Extrapyramidal symptoms may occur,35,87,198 but are markedly less frequent under treatment with aripiprazole than under treatment with haloperidol.44 Adverse effect concerning the QTc prolongation or blood pressure did only occur rarely23 and less frequent than compared to treatment with other antipsychotics, such as pimozide,47 ziprasidone and risperidone.33,56,71,201*

2.2.5

Olanzapine

Olanzapine, a thienobenzodiazepine202* is characterized by a high-affinity antagonism at dopamine D1, D2, D3 and D4 receptors, at 5-HT2A and 5-HT2C receptors, and at muscarinic acetylcholine and histamine H1 receptors.111 The muscarinic acetylcholine receptor antagonism can block acetylcholine binding to muscarinic receptors on the pancreatic islet, thereby inhibiting insulin release. (203,204)* Olanzapine is often listed a second line option for the pharmacological treatment of tics.

Update on the studies on the effectiveness of olanzapine in the treatment of tics There are several studies on the effectiveness of olanzapine for the treatment of tics conducted between 1998 and 2008. Those case reports,205–209 open-label studies,210–213 non-randomized57,214 and randomized46 trials have proven the effectiveness of olanzapine in the treatment of tics. Since 2012, there were two new publications on olanzapine for the treatment of tics, both systematic reviews on trials of pharmacological interventions for tics, each including one, but not the same RCTwith olanzapine. The reviews described olanzapine to be more effective than pimozide47 and similar


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effective as compared to haloperidol.45 However, one of the RCTs47 included only four patients, which is clearly insufficient.

Characteristic adverse effects of olanzapine The knowledge about the adverse effects of olanzapine in the treatment of tics has hardly changed over the last years. The most common adverse effects of olanzapine are increased appetite and weight gain,199,211*, 212,214 with mean increases of four to five kg within six to eight week,21*. A systematic review and meta-analysis including 47 studies with total of 387 children treated with olanzapine for a variety of diagnosis found that 78% of the patients experienced weight gain.215 A large meta-analysis including 212 trials on 43 049 patients with schizophrenia reports that weight gain was higher with olanzapine than with any other antipsychotics.107* In addition metabolic dysregulations may occur 199 215

, , which have also been observed independent of weight gain and changes in hunger or food

intake, suggesting that olanzapine exerts direct effects on insulin-sensitive tissues.216* Since olanzapine affects serotonergic 5HT2 receptors and increases serotonin, it may also lead to an increase in the number of platelets thereby increasing the risk for thrombosis.217* Further, adverse effects of olanzapine include sedation,47,215 electrocardiogram abnormalities215 and EPS,215 although the latter occur fewer under treatment with olanzapine as compared to haloperidol.199 The incidence of hyperprolactinemia is lower for olanzapine as compared to TA or risperidone, which is because olanzapine does not appear to block dopamine within the tubero-infundibular tract.6

2.2.6 Ziprasidone Ziprasidone is a benzylisothiazolylpiperazine. It binds to 5-HT2A receptors with high affinity and to a lesser extent also to dopamine D2 receptors. Ziprasidone also binds to 5-HT1A receptors, is an antagonist of 5-HT2C receptors, and has moderate affinity for α adrenergic receptors and histamine H1 receptors, with negligible effects at muscarinic acetylcholine M1 receptors.163* In the past various results raised the hope that ziprasidone might be an alternative treatment option for tics with a minimal to not existing risk of weight gain.(218–220)*



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Update on the studies on the effectiveness of ziprasidone in the treatment of tics Still, the base of evidence on the effectiveness in the treatment of tics is low.24 Up to 2012 there were only two RCTs in children and adolescents on ziprasidone,97,219* suggesting the agent to be effective in the treatment of tics. Since 2012, two new publication on ziprasidone in the treatment of tics are available, a meta-analysis and a review encompassing both above mentioned RCTs.45,50 They demonstrated a significant benefit of ziprasidone45,50 and stratified subgroup analysis found no significant difference in the effectiveness ziprasidone, risperidone, pimozide and haloperidol.50

Characteristic adverse effects of ziprasidone In the two existing studies on ziprasidone in the treatment of tics, transient somnolence was most commonly reported adverse effect.221,222* None of the patients included in those studies experienced EPS, akathisia, tardive dyskinesia or weight gain. Among the analyzed laboratory parameters only changes in prolactin concentrations were observed 221,222*. Based on studies including patients treated with ziprasidone for their schizophrenia a discussion has been going on about the risk of QTc-prolongation.223* Several studies report ziprasidone to be associated with a particularly high risk for prolongation of the QTc,(224–227, 107)* while other studies did not find the risk to be higher as compared to other antipsychotics.98,223*,228*,229* Nevertheless, the use of ziprasidone requires monitoring of the ECG5 and combining ziprasidone with substances known to potentially prolong the QTc, such as other antipsychotics and tricyclic anti-depressives, should be avoided.24

2.2.7 Clozapine Clozapine is a dibenzodiazepine with antagonism at dopamine D1 receptors and 5-HT2A, 5-HT2C and 5-HT3 receptors. Due to the lack of evidence for the effectiveness of clozapine in the treatment of tics, and concerns about its significant adverse effects, including agranulocytosis and metabolic syndrome, clozapine is not recommended for treatment of tics.230*


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Update on the studies on the effectiveness of clozapine in the treatment of tics Evidence for the effectiveness of clozapine in the treatment of tics remains limited and heterogeneous. Up to 2012 a successful tic-reduction under treatment with clozapine has been reported in two cases.231,232* In contrast, a placebo-controlled, double-blind, crossover study including twelve patients with abnormal movement disorders failed to prove the effectiveness of clozapine in the of tics.233 However, there is a recent case report of a 15 year old boy, suffering of tics for more than six years. Within the course of pharmacological treatment he had received a wide range of agents (eg. clonidine and risperidone) in various doses over years, when eventually a satisfactory tic control could be reached and maintained for more than one year with a combination of clozapine and quetiapine.99

Characteristic adverse effects of clozapine Knowledge about adverse effects of clozapine merely comes from studies on patients with schizophrenia. Like described in our previous review, some of the adverse effects of clozapine are potentially serious like neutropenia, agranulocytosis, myocarditis and seizures

234

*

235

*. Serious

adverse effects of clozapine have also been reported in patients treated for their movement disorders.233 Further, clozapine might cause weight gain, QTc-rolongation and sedation, 107*,236* but it is not associated with hyperprolactinemia and the risk of EPS is much lower compared to other antipsychotics. 107*,237*

2.2.8 Quetiapine Quetiapine, a dibenzothiazepine derivative, has affinity for dopamine D2, 5-HT, histamine H1 and α1 adrenergic receptors.238* Quetiapine displays antagonistic actions at 5-HT2A receptors and a high 5HT2A/dopamine D2 receptor ratio.239* Quetiapine is further a partial agonist at 5-HT1A receptors, which presumably causes its antidepressant effects.240* The evidence for the use of quetiapine in the treatment of tics is still limited and results vary.21*



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Mogwitz et al.

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Update on the studies on the effectiveness of quetiapine in the treatment of tics There are only a few case reports, retrospective surveys and open-label studies on quetiapine in the treatment of tics, with mixed results. While two open-label trials241,242 and a retrospective survey243 suggested the agent to be effective in the treatment of tics, another open-label study showed no differences in tic severity between the baseline and endpoint of the study.244 However, it was discussed that quetiapine might only be effective in reducing tics at high doses, which are not tolerable for many patients.21* Since 2012 one case report has been published that describes a 15 year old boy with a decent history of tics. After multiple trials with different agents, finally a combination of quetiapine and clozapine led to a control over the tics for more than one year (see also chapter 2.2.7).99

Characteristic adverse effects of quetiapine Although information about adverse effects of quetiapine in the treatment of tics is limited, it seems that they are milder than those of most other AA 245. A commonly observed adverse effect was sedation

242,246 247 241,244

. Results concerning weight gain

were mixed. While some studies found no significant weight-changes241,244 other reported weight gain (while laboratory parameters and serum prolactin level stayed normal).243 However, since several pediatric and adult studies on quetiapine for other indications have shown a significant risk of metabolic adverse effects, a monitoring of metabolic parameters during administration of quetiapine is suggested.21*,107* Moreover a recent study about adverse effects of quetiapine in 15 children and adolescents treated for schizophrenia or bipolar disorder in the period of 1997-2015 reports that endocrine side effects, such as hyperprolactinemia and hyperthyroidism, cardiac side effects such as tachycardia and QTc-prolongation, neurological side effects, such as seizures and cerebral hemorrhage as well as psychiatric side effects, such as hallucinations might occur.198 Since some of those adverse events are life threatening, the off-label use of quetiapine in children and adolescents gives rise to safety concerns.248*


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2.3 Benzamides 2.3.1 Tiapride Tiapride, a benzamide with low antipsychotic action, acts as a selective dopamine antagonist at dopamine D2 and D3 receptors. The body of evidence on the effectiveness of tiapride in the treatment of tics is still small.6,249 The actual use of tiapride in the treatment of tics strongly differs between countries: While it is unavailable in the US8,50 it is one of the most prescribed medications in the treatment of tics in Germany.8,249 In china there is growing interest on this agent with a variety of publications in the last few years (see table 1).

Update on the studies on the effectiveness of tiapride in the treatment of tics Over the last 35 years case reports,250 open-label trials251,252* and two placebo-controlled studies253,254 described tiapride as a useful, effective and well tolerated agent in the treatment of tics. Since 2012, four reviews/meta-analyses33,41,44,45 including trials using tiapride (as a control agent) in the treatment of tics and one such study52 not included in a review have been published (see table 1). All of these studies showed that tiapride was effective in reducing tics and that there were no differences in effectiveness between tiapride and aripiprazole33,41,44,45 or tiapride and haloperidol.52 However, after two weeks of treatment tiapride was less effective than aripiprazole and only after 12 weeks of treatment the effectiveness of both agents was comparable.69,72

Characteristic adverse effects of tiapride The recent studies described above, report only mild adverse effects of tiapride, suggesting that it is well tolerable. Tiapride is not associated with EPS, in contrast it is even used to treat medicationinduced motor symptoms.249,255* Weight gain was reported to be a common adverse effect with average increases of two-five kg, while extreme weight gain has only been observed in rare cases.249,254,256 Moderate increase of prolactin level due to treatment with tiapride followed by gynecomastia, galactorrhoea and menstrual cycle, libido and orgasm dysregulations has been reported,254 but these side effects seem to be reversible and the natural endocrine dynamics might not be touched.254,257 Sedation was reported to be a common adverse effect in patients treated with tiapride



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for their tics,249,254 but preclinical trials showed that tiapride has lower potential for sedating effects as compared to haloperidol and risperidone.255* Further adverse effects of tiapride include nausea/vomiting, drowsiness, dizziness, anxiety, loss of appetite, weakness/lassitude, dry mouth, insomnia, headache, and nocturnal enuresis.33,44

2.3.2

Sulpiride

Sulpiride is a substituted benzamide, classified as low-potency AA due to its weak, but highly selective antagonism of dopamine D2 receptors.249 It is administered quite often in Europe especially in adults,258,259 but not available in the US.260 In fact, sulpiride has been assumed to be the most commonly prescribed benzamide in the treatment of tics in Europe.26

Update on the studies on the effectiveness of sulpiride in the treatment of tics Up to 2012 evidence for the effectiveness of sulpride in the treatment of tics came from one RCT261 and two open-label studies.262,263 Those studies suggested that sulpiride has the additional ability to reduce comorbid obsessions and might therefore be a good treatment option for patients with mild to moderate tics accompanied by obsessive-compulsive disorder.259,261,262 Research efforts on sulpiride remained scarce over the last years. To the best of our knowledge, since 2012 there has been no study on sulpiride in the treatment of tics. However, there was one publication about a new pediatric rectal formulation of sulpiride that has been tested in vitro and in animal studies. The authors suggested that this formulation might be help in the management of tics in rural areas.264

Characteristic adverse effects of sulpiride Several studies using sulpiride in the treatment of tics showed that it caused less EPS than haloperidol.260,262,263 From studies on the use of sulpiride in the treatment for schizophrenia we know that the strong stimulation of prolactin-secretion causing galactorrhoea and amenorrhea can be a significant problem with sulpiride as well as increased appetite leading to weight gain.(265–267)* Weight gain was also a common adverse effect of sulpiride when used for the treatment of tics.249


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2.3.3

25

Amisulpride

Amisulpride is a substituted benzamide, chemically related to sulpiride and sultopride, which binds to dopamine D2 and D3 receptors. Successful treatment of tics with amisulpride has only been described in case reports.268*,269

Update on the studies on the effectiveness of amisulpride in the treatment of tics There are only two case reports describing a positive effect of amisulpride in the treatment of tics, one published in 1990269 and the other published in 2004.270 To the best of our knowledge no further trials have been conducted.

Characteristic adverse effects of amisulpride Due to the lack of systematic studies on the use of amisulpiride in the treatment of tics, also little is known about its adverse effects in those patients. Based on clinical experience it has been suggested that potential adverse effects include weight gain, sleep disturbances, fear, agitation, EPS, akathisia, increased salivation, drowsiness, dizziness, gastrointestinal disturbances, and hyperprolactinemia.271 A large meta-analyses on antipsychotics used in the treatment of schizophrenia reports that amisulpiride is associated with a considerable risk of QTc-prolongation.

2.4 Tetrabenazine Tetrabenazine, is a vesicular monoamine transporter (VMAT)-inhibitor272* boostering the early degradation of dopamine. Tetrabenazine works at VMAT2, which are mainly expressed in the central nervous system272*,273*, leading to a depletion of central dopamine.70 Further, tetrabenazine is blocking the presynaptic and postsynaptic dopamine receptors.274*,275* Tetrabenazine is mainly used for the treatment of chorea related to Huntington's disease, but may also be effective in various other conditions such as tardive dyskinesia, dystonia and tics.70,276*



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Update on the studies on the effectiveness of tetrabenazine in the treatment of tics Several open label277 and retrospective studies,278–282 which we descriebd in our previous review,22 suggested that tetrabenazine is effective in the treatment of tics. Since 2012 only one case study on the use of tetrabenazine in the treatment of tics52 has been published (see table 1). In this case tetrabenazine was successful in treating a secondary tic disorder caused by traumatic head injury.52

Characteristic adverse effects of tetrabenazine Parkinsonism and akathisia were common adverse effects of tetrabenazine, which occurred in up to 28.5 % of the patients treated with tetrabenazine for their movement disorders.281,283 Weight gain occured much less with tetrabenazine than with other antipsychotics.284 Sedation/drowsiness was a commonly reported adverse effect.281,283 Most importantly, depression is also amongst the more common adverse effects of tetrabenazine amd occurred in up to 19 % of the treated patients.276*,281 This adverse effect is particularly serious since it might lead to suicidal ideation.

2.5 Deutetrabenazine Deutetrabenazine, a deuterated form of tetrabenazine, was developed in order to circumvent the limitations of tetrabenazine. Deutetrabenazine is a VMAT2 inhibitor with two trideuteromethoxy groups (–OCD3) at the 9 and 10 positions instead of the two methoxy groups (–OCH3) at the corresponding positions of the parent agent. Deuterium placement at these positions debilitates metabolism and thus confers important pharmacokinetic advantages compared to tetrabenazine. Deuterium facilitates longer half-lives of the circulating active metabolites (total [α+β]-HTBZ) and lowered metabolic variability, thereby increasing the concentration over the time (area under the curve) with smaller doses and lower peak concentrations without changing the targeted pharmacology.(285–287)* Like tetrabenazine deutetrabenazine is mainly used for the treatment of chorea related to Huntington's disease, but may also be effective in various other conditions such as tardive dyskinesia, and tics.101


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Update on the studies on the effectiveness of deutetrabenazine in the treatment of tics There is one recent study on the effectiveness of deutetrabenazine in the treatment of tics.101 After 8 weeks of treatment, 76 % of the patients were ‘much improved’ or ‘very much improved’ and the tics were reduced by about 37.6%.101

Characteristic adverse effects of deutetrabenazine Deutetrabenazine produced an acceptable level of overall adverse effects.101,288 As compared to tetrabenazine, deutetrabenazine caused less EPS.101 Deutetrabenazine has no effect on the QTc.288 Sedation (i.e. drowsiness, fatigue, somnolence) was among the most common adverse effect, occurring in up to 17 % of the treated patients, although it occurred less frequent as compared to tetrabenazine.101,289* Also the incidence of depression was lower with deutetrabenazine as compared to tetrabenzine.289* The most frequent adverse effects were were fatigue, headache, irritability, somnolence, hyperhidrosis, diarrhea, and nasopharyngitis.101

2.6 Ecopipam Ecopipam, is a dopamine D1 receptor antagonist,(290–292)*, which is about 1000 fold selective for dopamine D1 versus D2 receptors as well as 100 fold selective for dopamine D1 versus 5-HT receptors.293* Pharmacologic antagonism of the dopamine D1 receptors is a relatively novel approach to achieve tic reduction. It influences the excitatory direct pathway in the basal ganglia, whereas dopamine D2 receptor modulation theoretically targets deficient inhibition of indirect pathways. Therefore, ecopipam may have a more ‘direct’ tic-suppressing activity via circuits underlying selected and habitual actions than dopamine D2 receptor antagonists, which may ‘indirectly’ suppress tics via a more broadly inhibited motor state.102

Update on the studies on the effectiveness of ecopipam in treatment of tics A first open label multicenter, non-randomized, single-arm study (18 adults) showed that ecopipam taken orally before bedtime, was able to reduce tic severity. However, there was no significant change in premonitory urges or psychiatric symptoms.102 The authors constituted the need for double-blind,



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placebo-controlled studies to further confirm the safety and effectiveness of ecopipam in the treatment of tics. Further, they suggested that certain individuals with tics might respond more selectively to one class of agents (dopamine D1 versus D2 receptor antagonists).

Characteristic adverse effects of ecopipam Since it works at dompamine D1 receptors ecopipam is not associated with EPS typically observed with dopamine D2 receptor antagonists. Ecopipam does not cause weight gain, but rather led to weight loss in obese individuals.294* No weight and no prolongation of the QTc was observed.102 Sedation was one of the most common adverse effects of ecopipam, occurring in 39% of the patients treated with ecopipam for their tics.102

2.7 Dopamine agonists Dopamine agonists, chemically divided into ergoline- and non-ergoline dopamine agonists can also be considered as an option for the treatment of tics.295 It has been hypothesized that dopamine agonists could normalize the suspected central dopamine hypersensitivity in patients with tics.

Pergolide, ropinirole and pramipexole Pergolide, an ergoline dopamine agonist, works by presynaptic inhibition of dopamine release on dopamine D1 receptors carrying GABAergic neurons. However, pergolide may cause serious adverse effects, i.e. valvular heart disease and has therefore been withdrawn from the US market.19 Two other non-ergoline dopamine agonists, ropinirole and pramipexole, have been suggested for the treatment of tics,296,297 but the evidence for their effectiveness is scarce.

Update on the studies on the effectiveness of dopamine agonists in the treatment of tics Evidence for the effectiveness of pergolide in the treatment of tics was found in one case series,298 one open-label study299 and two placebo-controlled trials300,301 (see also our previous review on the same topic22). There was one study on ropinirole showing improvement of motor symptoms of TS296 and


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one RCT on pramipexole, suggesting that it is not effective in suppressing tics297. Since 2012 no new studies on dopamine agonists in the treatment of tics have been published.

Characteristic adverse effects of dopamine agonists Like written in our previous review,22 pergolide seems to have a good tolerability and cause no serious adverse effects when used in the treatment of tics in children.300,301 The same holds true for ergoline dopamine agonists (pramipexole and ropinirole)296,297 except for the a elevated prevalence of valvular heart disease.19 However, standard echocardiography was sufficient to detect valvular heart disease in patients treated with DA agonists for their Parkinson ´s disease 302*. In a randomized control trial on pramipexole in the treatment of tics, the most frequent adverse events were headache, nausea, vomiting, myalgia and fatigue.303 In an open-label study on ropinirole, all patients completed the study without complaints about adverse effects 304.

2.8 Traditional Chinese medicine (TCM) in the treatment of tics Traditional Chinese medicine (TCM) has been widely used in the treatment of various diseases such as nervous system disease, infectious diseases, and cancer in Asian countries for thousands of years.305– 309(306,307,308*)

Particularly in China, where herbal medicine is an important option in mental

healthcare,44 it has been increasingly used in psychiatry practice.310* Empirical evidence for a potential effectiveness of a variety of herbal medicines in the treatment of tics is apparent.311,312* Three substances of TCM, Ningdong granule, 5-Ling Granule (5-LGr), and Qufeng Zhidong Recipe were particularly designed for the treatment of tics with an underlying believe that the origin of tics is a yininsufficiency in heart and liver.309,313 The exact pharmacological mechanism of the TCM substances is still unclear, but a preclinical study has shown that 5-LGr might work over reducing striatal D2 receptor affinity and the dopamine metabolite level.314 A recent study on two rat models of tics (Apomorphine (Apo)- and 3,3'-iminodipropionitrile (IDPN)-induced) found that Ningdong granule has a regulating effect on the extracellular dopamine concentration.315 Further, preclinical trials suggested that Ningdong granule improves apomorphine-induced tics in rats by suppressing the dopamine system.316,317 Besides the influence on the dopamine system the TCM substances might also exert its



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tic-reducing effect over down regulation of inflammatory processes (e.g. related to streptoccoen infection). 315

5-Ling Granule 5-LGr is a patented multiherbal product containing eleven herbal materials and was found to have an ability to suppress hyperactivity and ease fidgetiness.314,318 Particularly preclinical studies have shown a suppression of head twitching and stereotyped movement after administration of 5-LGranule in a rat model.314 Further an inhibition of amphetamine-induced hyperactivity, aggression, and irritability in mice was observed.314 Results of pilot studies suggested that 5-LGr and similar herbal preparations might be able to reduce tics.319–321 A recent RCT including 603 patients compared the effectiveness of 5-LGr, placebo and tiapride in the treatment of tics over 8 weeks. Results suggested that 5-LGr is comparable to tiapride in its potency to reducing tics with a better safety profile.318

Ningdong granule Ningdong granule is composed of eight different Chinese herbs and natural materials. Ningdong granule has been used to treat tics in China for several years.315 Clinical studies have shown that Ningdong granule is effective in the treatment of tics with little adverse effects.315 It has been suggested that Ningdong granule relieves convulsion and spasm by nourishing heart and liver yin.322 There was also one RCT on 120 patients with tics comparing the effects of Ningdong granule, of haloperidol and of Ningdong granule plus haloperidol. A significant reduction of tics by Ningdong granule was found, but Ningdong granule plus haloperidol was most effective.305

3 Summary Concerning the pharmacological treatment of tic disorders, there is consensus that it is to the best of our knowledge only symptomatic.8 The agent groups utilized are mainly AA and TA.6,323 But due to the still existing lack of studies directly comparing long-term effectiveness and safety of different pharmacological agents in the treatment of tics, every recommendation remains at least in parts


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subjective and strongly depending on the experts own experience and preference. This leads to a broad spectrum of pharmacological treatment recommendations. The huge variety of the agents used also indicates that none of them is ideal, i.e. none offers complete symptomatic relief without the risk of adverse effects.6 Some adverse effects might not have been observed in present studies, because long-term evaluations of outcomes were missing. Especially with regard to metabolic risks of antipsychotics long-term studies are very urgently needed to fully outweigh risk and benefits of treatment even in the pharmacological treatment of tic disorders.41,71 Treatment of tics with dopamine-modulating agents has started with TA, but due to their poor tolerability profile, mainly EPS, TA got more and more replaced by AA. For example, the relevance of the TA haloperidol in the treatment of tics (in the specialized TS clinic at the University of London) declined between 2002 and 2012 from being a first line agent to being used only in refractory patients.9 By now, AA are recommended as first line pharmacological treatment for tics by European, US, Canadian and Chinese guidelines.6,7,21*,27 Results from an online survey among the members of the European Society for the Study of Tourette syndrome (ESSTS) suggested that the AA risperidone was the most commonly prescribed medication for tics in 2011.107* Over the last five years aripiprazole has gained a lot in popularity and evidence on its effectiveness and safety is now catching up quickly with existing evidence on risperidone. There are several systematic reviews/meta-analyses supporting the effectiveness of aripiprazole for the treatment of tics(see chapter 2.2.4.) Currently, aripiprazole seems to be the most promising agent in the pharmacological treatment of tics, even in patients refractory to previous treatment.117,184,187 The trend towards the use of aripiprazole is reflected in the results of a recent survey we conducted among the members of the ESSTS.

+++ Figure 1 about here +++

The survey asked 45 experts working at tertiary clinical centers all across Europe about their prescription preferences. The results show a clear trend towards aripiprazole over the last 6 years. In



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fact, the favor for aripiprazole has overtaken risperidone and aripiprazole is now the most favored agent by European experts of tic disorders. The change in prescription preferences from 2011 to 2017 among the members of the ESSTS is shown in figure 2.

+++ Figure 2 about here +++

Furthermore, in Europe, also benzamides (especially tiapride) are commonly used to treat tics due to their excellent effectiveness-tolerability profile proven over decades in clinical practice while possible long-term (e.g. after 20 years) adverse effects of aripripazole are not fully known because it was only introduced in 2002.249,259 In addition, benzamides are much cheaper than aripiprazole. But, although used quite frequently, well performed studies on benzamides are an absolute scarcity, which might at least partly be due to the unavailability in the US.8 However, recently there has been great research effort in China evaluating the effectiveness and safety of tiapride or using it as direct control agent.41,44,68,72,324 In patients with tics and comorbid ADHD, treatment with α2 adrenergic receptor agonists such as clonidine or guanfacine should be considered. There is evidence suggesting that those agents have an additional effectiveness for treating comorbid ADHD symptoms, while they have only a minimal benefit in tic patients without ADHD.24,50 In patients with tics and comorbid obsessive-compulsive disorder, treatment with risperidone appeared to be especially beneficial as an augmentation to selective serotonin reuptake inhibitors (SSRI) for treatment refractory obsessive compulsive symptoms.47 Unfortunately, still haloperidol and pimozide are the only formally approved substances for the treatment of tics in Germany and the US, respectively. Therefore, the major percentage of pharmacological prescriptions for the treatment of tics must be done off-label, which might make physicians reluctant to prescribe these substances, thus withholding state-of-the-art treatment options from patients with tic disorders.8


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Overall there is no evidence suggesting that children and adults should be treated differently apart from dosage adaption.259,325* Dosage should take body weight into account and be adapted to increasing body weight during maturation.98,326* Because tic severity decreases during adolescence in nearly 75% of patients,327 treatment should be tapered off periodically to determine if the treatment is still required.21* Summing up, especially the evidence on the effectiveness and safety of aripiprazole grew rapidely over the last years, therefore this agents currently seems to be the most promising in the pharmacological treatment of tics. Furthermore, benzamides (especially tiapride) have proven their excellent effectiveness-tolerability profile over decades in European clinical practice and are therefore also highly recommended for the treatment of tics. Nevertheless, the pharmacological treatment recommendation in each individual case is always a well-thought-out compromise between personal preference and expertise based on the psychiatrists clinical experience, the knowledge of current guidelines including evidence on effectiveness, tolerability profile and individual physical condition, the regional availability, the ability of the patient to bear the costs as well as the consideration of the patient’s psychopathological profile including comorbidities.

Acknowledgements We thank our student assistant Miriam Petasch for helping with the preparation of the references and the tables as well as our colleagues from ESSTS for answering the questionnaire.

Author contributions: Sabine Mogwitz: Conception of the review, conception and design of the survey, acquisition of data, drafting of manuscript (chapters on studies on effectiveness) Judith Buse: Conception of the review, drafting of manuscript (chapters on adverse effects), critical revision Nicole Wolff: Critical revision Veit Roessner: Conception of the review, conception and design of the survey, critical revision All authors gave final approval of the version to be submitted.



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Funding Sources: Sabine Mogwitz and Judith Buse received no external funding. Nicole Wollf received consultant fees by Servier. Veit Roessner received funding for consulting and writing activities by Lilly, Novartis, and Shire Pharmaceuticals, lecture honoraria by Lilly, Novartis, Shire Pharmaceuticals and Medice Pharma, research support by Shire and Novartis, funding for clinical trials by Novartis, Shire, and Otsuka companies.

Conflict of Interest: The authors declare that no financial, personal or other relationship with other people, organizations or companies has inappropriately influenced the submitted work.


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Figures Figure1. Preferences of medication for the treatment of tics among European experts Results of a survey among members of the European Society for the Study of Tourette syndrome (ESSTS) (n=45 experts answered) questioning which medication the expert clinician would consider as first, second, third, and subsequent choices (provided there would be no contra-indication for any of the available agents and no comorbidity). Each first choice agent was weighted with 4 points, each second choice agent with 3 points, each third choice agent with 2 points, and additional agents with 1 point. The percentages indicate the weighted frequency with which the agent was recommended.

Figure2. Trends in preferences of medication for the treatment of tics among European experts Comparison of the survey results among the members of the European Society for the Study of Tourette syndrome (ESSTS) between 2011 and 2017.


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Figure1. Preferences of medication for the treatment of tics among European experts Results of a survey among members of the European Society for the Study of Tourette syndrome (ESSTS) (n=45 experts answered) questioning which medication the expert clinician would consider as first, second, third, and subsequent choices (provided there would be no contra-indication for any of the available agents and no comorbidity). Each first choice agent was weighted with 4 points, each second choice agent with 3 points, each third choice agent with 2 points, and additional agents with 1 point. The percentages indicate the weighted frequency with which the agent was recommended.

30x18mm (600 x 600 DPI)


ACS Chemical Neuroscience 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure2. Trends in preferences of medication for the treatment of tics among European experts Comparison of the survey results among the members of the European Society for the Study of Tourette syndrome (ESSTS) between 2011 and 2017.

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Faculty of Medicine Carl Gustav Carus, TU Dresden - ACS Publications

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