Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Treatment of psychiatric disturbances in common

hyperkinetic movement disorders

Isabella Berardelli, Massimo Pasquini, Antonella Conte, Matteo Bologna,

Alfredo Berardelli & Giovanni Fabbrini

To cite this article: Isabella Berardelli, Massimo Pasquini, Antonella Conte, Matteo Bologna,
Alfredo Berardelli & Giovanni Fabbrini (2018): Treatment of psychiatric disturbances in
common hyperkinetic movement disorders, Expert Review of Neurotherapeutics, DOI:
10.1080/14737175.2019.1555475

To link to this article: https://doi.org/10.1080/14737175.2019.1555475

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Publisher: Taylor & Francis

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2019.1555475
Treatment of psychiatric disturbances in common hyperkinetic movement disorders

Isabella Berardelli1, Massimo Pasquini2, Antonella Conte2-3, Matteo Bologna2-3, Alfredo Berardelli2-

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, Giovanni Fabbrini2-3

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1) Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention

Center, Sant’Andrea Hospital, Sapienza University of Rome;

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2) Department of Human Neurosciences, Sapienza University of Rome, Rome;
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3) 3 IRCCS Neuromed.
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Isabella Berardelli: Isabella.berardelli@uniroma1.it

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Massimo Pasquini: Massimo.pasquini@uniroma1.it

Antonella Conte: Antonella.conte@uniroma1.it

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Matteo Bologna: matteo.bologna@uniroma1.it

Alfredo Berardelli: alfredo.berardelli@uniroma1.it

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Giovanni Fabbrini: Giovanni.fabbrini@uniroma1.it

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Correspondence to

Giovanni Fabbrini,

Department of Human Neurosciences,

Sapienza University of Rome,

Viale dell'Università, 30
00185 Rome Italy.

tel and fax +390649914074

giovanni.fabbrini@uniroma1.it

Abstract

Introduction: This paper reviews studies that have assessed the treatment of psychiatric

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disturbances in dystonia, tic disorders, Tourette syndrome, Huntington’s disease and essential

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tremor.

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Areas covered: We searched for papers in English in Pubmed using the following keywords:

blepharospasm, cervical dystonia, arm dystonia, laryngeal dystonia, spasmodic dysphonia, tic

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disorders, Tourette syndrome, Huntington’s chorea, essential tremor, depression, anxiety,

obsessive compulsive disorders, attention deficit hyperactivity disorders, psychosis, apathy.

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Expert commentary: Although psychiatric disturbances are frequent in hyperkinetic movement

disorders, few controlled studies have assessed the treatment of psychiatric disturbances in such
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disorders. In dystonia, none of the controlled studies conducted to date have demonstrated the

efficacy of drug treatment for depression or anxiety. In TS, controlled studies have demonstrated
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the usefulness of drug treatment on obsessive compulsive disorders and attention deficit

hyperactivity disorders. Behavioral interventions may also play a role. No controlled studies have
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been conducted on HD nor have any studies addressed the treatment of psychiatric disturbances
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in ET. We conclude that there is the need of controlled studies to better evaluate pharmacological

and non-pharmacological treatment of psychiatric disturbances in hyperkinetic movement

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disorders.

Keywords:

Dystonia, Tourette syndrome, tic, Huntington disease, essential tremor, depression, anxiety,

obsessive compulsive disorders, attention deficit hyperactivity disorder, psychosis

1.Introduction
Hyperkinetic movement disorders are a heterogeneous group of neurological diseases

characterized by the presence of involuntary movements and of other motor abnormalities (1 ).

These conditions include dystonia, tics and Tourette syndrome (TS), Huntington’s disease (HD)

and essential tremor (ET). In addition to motor symptoms, patients affected by hyperkinetic

movement disorders also display non-motor symptoms, including psychiatric disturbances

(2,3,4,5), which are associated with a worse quality of life and greater disability (4,6,7,8). Given the

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relevance of psychiatric disturbances in these conditions, it is necessary that the most effective

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pharmacological and non-pharmacological treatments be identified and that these conditions be

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treated. In this paper we reviewed studies designed to assess the treatment of psychiatric

disturbances frequently associated with the most common hyperkinetic movement disorders, i.e.

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dystonia, tics and TS, HD and ET. For the purposes of this paper, we first summarized the main

psychiatric disturbances found in each clinical condition, and then we described the
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pharmacological and non-pharmacological treatments available for these conditions.
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2. Methods

We analyzed papers in English in Pubmed using the following keywords: blepharospasm, cervical
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dystonia, arm dystonia, laryngeal dystonia, spasmodic dysphonia, tic disorders, Tourette

syndrome, Huntington’s chorea, essential tremor, depression, anxiety, obsessive compulsive

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disorders, attention deficit hyperactivity disorders, psychosis and apathy. We evaluated papers in
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which the treatment of psychiatric disturbances was either the primary endpoint of the study or an

indirect aim. Owing to relative lack of controlled studies, we also analyzed the results of open
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studies and case series. Review papers containing experts’ opinions were also considered.

3.Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions

that cause abnormal movements and postures. Dystonia may be classified according to age at

onset, affected segment or presence of other neurological or systemic conditions (9). In adults,

focal dystonia affecting a single body part is the most frequent form of dystonia and is classified as
cervical dystonia (CD), blepharospasm (BSP) and oromandibular dystonias (cranial dystonias),

arm dystonia or laryngeal dystonia (10,11). Psychiatric disorders may be present in all these

dystonias (12,13,14,15,16). CD patients have a high lifetime risk of depression (from 15% to

53.4%) (15,17) and suffer from depressive disorders more frequently than healthy controls (13).

Depressive symptoms are a strong predictor of low quality of life (14) and disability (6). Anxiety

disorders, including social phobia, agoraphobia and panic disorder, are also present in CD (15).

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BSP patients also suffer from mood disorders more frequently than normal subjects (13). The

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frequency and type of psychiatric comorbidities in rarer forms, such as laryngeal dystonia and arm

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dystonia, are not yet fully clear (18,19). The observation that the severity of psychiatric

disturbances does not correlate with the severity of dystonia (2), that psychiatric disorders often

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precede the onset of motor symptoms and that psychiatric disorders persist 5 years after a

reduction in the severity of the motor dysfunction (20) suggest that psychiatric disorders may, at
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least in CD patients, be part of the clinical spectrum of the disease. Finally depression and subtle

sleep quality impairment have been reported in several cohorts of patients with the dopa-
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responsive-dystonia (21).

3.1Treatment of psychiatric disturbances in dystonia

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3.1.1 Pharmacological treatment. Very few studies are available on the effect of pharmacological

treatment for psychiatric symptoms in patients with dystonia (Table 1). In a crossover randomized
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controlled study (RCT), 50 CD adult patients were treated with escitalopram (10 mg) or placebo
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(22). The primary end point in this study was the proportion of patients in whom an improvement of

at least 1 point was observed on the CGI scale for jerks/tremor, whereas the secondary endpoints
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of the study were the proportion of patients with psychiatric comorbidity and the change on the CGI

scale in the severity of psychiatric symptoms. Approximately 40% of the patients included in the

study were diagnosed with psychiatric symptoms (anxiety disorders in particular) according to

standard diagnostic criteria. Both escitalopram and placebo improved psychiatric symptoms and

the quality of life with no differences being observed between the two treatments. The overall

improvement induced in patients by either treatment was considered to be smaller than that

induced by either Botulinum Toxin type A (BTX-A) or placebo (22). An improvement in psychiatric
symptoms was reported after treatment with BTX-A in patients with CD. When Slawek et al. (23)

compared 101 patients with CD with 80 healthy subjects, they reported that depressive symptoms

measured by means of the MADRS score improved significantly from baseline to 4 weeks after

BTX-A injection (from 21.9 ± 8.7 to 16.9 ± 9; p<0.01). In the study conducted by Barrahona et al.

(24), anxiety, somatization and phobia scores, though not the Y-BOCS scores, were lower in BTX-

A-treated patients than in non BonTA-treated patients. In a retrospective observational study in

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which the main endpoint was the severity of motor dysfunction, gabapentin at a dose of 50 mg/

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kg/day improved motor symptoms as well as mood and sleep quality in 69 children affected by

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various forms of severe dystonias (25).

Non-pharmacological treatment. There are only two case reports on the effects of behavioural

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treatment on psychiatric disturbances in patients with dystonia: in one, behavioural therapy that

focused on catastrophic thoughts and abnormal illness beliefs was effective in one CD patient, in
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whom the improvement persisted at the 6-month follow-up (26); in another, progressive relaxation,

positive practice and visual feedback improved behavioural and physiological (depression and
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anxiety) symptoms in one CD patient, in whom the improvement persisted at the 2-year follow-up

(27).
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3.1.3 Surgical treatment. Deep-Brain Stimulation of the internal segment of the globus pallidum is

an established treatment for motor symptoms in dystonia (28); concerns that this treatment may be
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associated with a worsening in depressive symptoms in dystonia patients was ruled out by a recent
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study by De Gusmao et al. (29), who found that the severity of depressive symptoms assessed by

means of the BDI was similar before and after a follow-up of approximately 1 year in dystonia
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patients treated with deep-brain stimulation.

4. Tic disorders and Tourette syndrome

Tics are spontaneous, brief, repetitive and stereotyped involuntary muscle contractions that occur

on a background of normal activity. Tics may be motor or phonic, are often preceded by a

sensation or urge to execute the tic and are accompanied by transient relief once they have been

performed (30). Gilles de la Tourette Syndrome (TS) is characterized by the presence of two or

more motor tics and at least one phonic tic with onset <18 years of age; tics in this syndrome occur
many times a day nearly every day, and last longer than one year (31). In addition to motor

symptoms, patients with chronic tics, particularly those with TS, often exhibit psychiatric

disturbances. These disturbances include obsessive-compulsive disorder (OCD), which may be

present in up to 72% of individuals, attention deficit hyperactivity disorder (ADHD), which may be

observed in up to 50% of children and adolescents with TS depression, anxiety, impulse control

disorders, sleep disturbances, conduct disorder, rage attacks, oppositional defiant disorder and

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self-injurious behaviour (3, 32,33,34,35).

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4.1 Pharmacological Treatment

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4.1.1 Obsessive compulsive disorders (OCD), depression and anxiety: when George et al. (36)

randomized 11 TS patients with OCD and TS to sulpiride or fluvoxamine in a 14-week cross-over

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trial, they observed that sulpiride monotherapy reduced tics but not obsessive-compulsive

symptoms, whereas fluvoxamine was more effective in reducing obsessive-compulsive symptoms

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than tics. The possible efficacy of risperidone on OCD symptoms in TS was first reported in one

case report (37) and subsequently in two controlled studies. In a 12-week, multicenter, double-
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blind, parallel-group study of 50 TS patients (age range 11 to 50 years), 26 patients were treated

with risperidone (mean daily dose = 3.8 mg) and 24 with pimozide (mean daily dose = 2.9 mg).
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While both treatments reduced the severity of motor and phonic tics, OCD improved in the

risperidone-treated group alone (38). Risperidone was compared with clonidine in a double-blind,
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8-week pilot study for the treatment of tics and coexisting obsessive-compulsive symptoms in 21
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TS patients aged 7 to 17 years (39). Among subjects with comorbid OCD symptoms, 63% of those

in the risperidone group and 33% of those in the clonidine group responded to treatment. In a 6-
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week open-label trial conducted on 18 adult TS patients, aripiprazole given at a mean daily dose of

15mg /day improved both tics and OCD features, though not anxiety or depression (40). Few

studies have evaluated the efficacy of SSRI on OCD in TS patients. Fluoxetine at a dose of 10 to

40 mg given for 20 weeks improved obsessions and compulsions in 10 children affected by TS

(41). In two case reports, clomipramine was shown to effectively treat OCD in TS (42,43). Finally,

SSRI and tricyclic antidepressants were reported to be effective for the treatment of depressive

symptoms in TS, although no randomized controlled trials have yet been conducted (31).
Pharmacological treatments of OCD, depression and anxiety in tic and TS is summarized in table

2.

4.1.2. Attention deficit hyperactivity disorder (ADHD). TS and ADHD frequently coexist in pediatric

patients and adolescents. The efficacy of the alpha-2 agonists clonidine and guanfacine on ADHD

and tics has been assessed in a limited number of controlled studies (44). Alpha-2 agonists

significantly improve both the severity of tics and ADHD (45), though adverse effects, including

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sedation, dry mouth, headache, postural hypotension, dizziness and hypertensive crises due to

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sudden discontinuation, represent a significant limitation of such agonists. Clinical studies have

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shown that stimulants such as methylphenidate are useful in children with TS and ADHD. Although

early studies with methylphenidate showed that this drug may exacerbate the severity of tics

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(,46,47,48), a multicentre, randomized, double-blind clinical trial on 136 children with ADHD and

chronic tic disorder randomly assigned to receive clonidine, methylphenidate, combined clonidine
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and methylphenidate or placebo, showed that the combination of methylphenidate and clonidine is

effective for ADHD in children with comorbid tics and does not worsen the tics (49). Several studies
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have focused on the safety and efficacy of the noradrenergic reuptake inhibitor atomoxetine as a

means of reducing the severity of both tics and ADHD. In a double-blind controlled trial, Allen et al.
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(50) assessed the efficacy of atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks in 72

patients with either TS or chronic tic disorder associated with ADHD. Atomoxetine treatment was
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associated with a greater reduction in tic severity in the ADHD Rating Scale total score and in the
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CGI severity of ADHD/psychiatric symptoms scale score than placebo treatment. Spencer et al.

(51) also reported an improvement in ADHD symptoms in the 61 patients treated with atomoxetine
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(0.5-1.5 mg/kg/day) compared with 56 patients treated with placebo. Gilbert et al. (52) correlated

the improvement induced by atomoxetine treatment with changes in cortical inhibition as tested by

mean of transcranial magnetic stimulation. Other pharmacological treatments for ADHD symptoms

in TS have included the tricyclic antidepressant (TCA) desipramine, which was more effective than

clonidine in a controlled study performed on 33 children with ADHD and TS (53). Spencer et al.

(54) studied 41 children and adolescents with CTD and TS and comorbid ADHD in a 6-week,

double-blind, placebo-controlled trial designed to compare desipramine with placebo. Desipramine

significantly reduced the core symptoms of ADHD (ADHD Rating Scale), while no differences

emerged between desipramine and placebo in the treatment of inattentive behaviour and

hyperactive/impulsive symptoms (P<.001 for both). Aripiprazole has yielded encouraging results

for the treatment of ADHD in TS. Masi et al.(55) reported that aripiprazole administered at a mean

dose of 10.0 ± 4.8 mg/day to 28 patients with TS and co-morbid ADHD led to a 42.5% reduction in

motor tics, 47.9% reduction in phonic tics, 32.3% reduction in overall tic impairment (YGTSS score)

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and an improved ADHD-RS-IV score (ADHD-Rating Scale). In a prospective uncontrolled open-

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label study on 44 TS patients, Gerasch et al. (40) also found that aripiprazole significantly

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improved OCD, depression, anxiety and ADHD symptoms. Aripiprazole may therefore be

considered a therapeutic option to reduce the severity of both tics and ADHD symptoms in TS

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patients (56). The pharmacological treatment ADHD in tic disorders and TS is summarized in table

2.
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4.1.3 Behavioural treatment on tics and psychiatric disorders. Cognitive behavioural therapy (CBT)

helps patients understand thoughts and feelings that influence behaviours causing psychological
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and psychiatric symptoms (57). In a 16-week RCT conducted on children and adolescents affected

by OCD both with and without tics, March et al. (58) evaluated whether the presence of motor tics
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predicts a poorer or better outcome following sertraline and CBT treatment. In the 22 patients with

OCD and a comorbid tic disorder studied, sertraline at a dose ranging from 100 to 200 mg/day was
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not found to improve OCD symptoms more effectively than placebo, whereas CBT treatment plus
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sertraline was more effective than placebo. Similar results were obtained in a trial conducted on a

sample of 23 adolescents (59). O’Connor et al. (60) studied the efficacy of CBT alone and of CBT
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associated with pharmacological treatment on tic severity as well as on anxiety and depression in

76 TS patients. CBT reduced the severity of tic and depressive symptoms (assessed by means of

the BDI) when administered both alone and in association with medical treatment, and improved

anxiety (measured by means of the BAI) only when administered on its own. Comprehensive

behaviour intervention for tics (CBIT) is another type of behavioural therapy that was developed

specifically for patients with tics and that teaches people to become aware of their own behaviour

and helps those people change their behaviour using a systematic approach. Woods et al. (61)
studied the effect of CBIT on secondary psychiatric symptoms and psychosocial functioning in 126

TS children in the acute phase. The authors then performed behaviour therapy at 3- and 6-month

follow-up visits in the responders to the acute-phase behaviour treatment. At 6 months post-

treatment, those patients who had responded to acute-phase behaviour treatment exhibited

reduced anxiety, reduced disruptive behaviour and reduced family strain as well as improved social

functioning. Other behavioral treatments are widely used in TS to improve the severity of tics. The

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effect of these treatments on psychiatric comorbidities may be inferred indirectly by measuring the

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improvement in well-being and social functioning. Habit reversal therapy (HRT) is the most widely

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used behavioural treatment for tic disorders. Several studies have confirmed the usefulness of

HRT in the treatment of tics in adults (62,63,64,65,66), children and adolescents (66,67), even by

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means of remote, real-time treatment delivery using a voice over internet protocol (68). Some

studies have demonstrated that the improvement in tics induced by HRT is associated with an
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improvement in life-satisfaction and psychosocial functioning. When Deckersbach et al. (69)

studied 30 adult outpatients with TS, they found that while both HRT and supportive psychotherapy
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improved life-satisfaction and psychosocial functioning, HRT alone reduced the severity of tics.

This beneficial effect persisted at the 6-month follow-up visit. Exposure and response prevention
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(ERP), (70,71,72), relaxation training (RT) (73), mindfulness-based stress reduction (74) and

neurofeedback, tension reduction and autonomic modulation and neurofeedback are alternative
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methods that may affect tic severity by calming a person’s emotional state (75,76,77). The effect of
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these approaches on psychiatric disturbances in TS has not yet been investigated in controlled

trials. Behavioral treatments for chronic tic disorders and TS are summarized in table 3.
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5. Huntington’s disease

HD patients may exhibit a range of movement disorders that include chorea, which is by far the

most frequent motor manifestation, parkinsonism (characteristic of juvenile HD), ataxia, dystonia,

bruxism, myoclonus, tics and tourettism (78). The psychiatric, behavioral and cognitive

manifestations of this disease are also very frequent and disabling. Behavioral disturbances,

particularly depression, affect carriers of the HD mutation even before any motor symptoms
become manifest. Depression is present in approximately 15% of such patients; suicidal ideation is

a frequent finding in patients with HD, with the suicide rate being estimated to be five to ten times

higher than that in the general population. Apathy, which occurs in approximately 33% of patients,

and irritability and aggression, which occur in approximately 15% of patients, are among the most

disabling clinical features of this disease and lead to intense distress for both relatives and

caregivers. Obsessive compulsive behaviors, particularly checking, cleanliness and compulsive

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rituals, are observed in approximately 25% of HD subjects (79). Lastly, psychosis may be observed

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in HD patients, albeit less frequently than other symptoms.

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5.1 Pharmacological treatment of psychiatric disturbances in Huntington’s disease

5.1.1 Depression. Drugs used in the treatment of depression in HD include SSRI (citalopram,

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venlafaxine, fluoxetine) as well as atomoxetine, modafinil and lithium (80). In an open-label, short-

lasting clinical study on 26 HD patients with major depression, venlafaxine at a daily dose of 150
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mg improved depressive symptoms (81). Lithium reduced the level of suicidality as measured by

means of the brief psychiatric rating scale in 3 HD patients (82). One RCT based on the
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noradrenaline reuptake inhibitor atomoxetine did not reveal any significant changes in the global

severity index, though data on individual domains such as depressed mood were not presented
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(83). In another RCT on 36 HD patients in which the primary endpoint was the effect on executive

functions, citalopram treatment was associated with a slight reduction in the HAM-D total score
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(84). In a small case series of 3 HD patients, depressive symptoms improved following

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administration of low-dose aripiprazole (85), an effect that might be due to the dopaminergic and

serotonergic actions of aripiprazole when prescribed at low dosages. Severe depression and
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suicidal ideation were controlled by mirtazapine in one patient (86).

5.1.2. Apathy. Apathy is another significant symptom in HD. In a double-blind, 10-week,

multicentre, placebo-controlled trial conducted on 40 HD patients, apathy scores improved in both

the bupropion- (given at 150-300 mg per day for 10 weeks) and placebo-treated patients (87).

5.1.3. Aggressivity, psychosis, obsessive compulsive disorder. The treatment of irritability and

aggression, which are among the most disabling features of HD, is mainly based on the opinions of

experts, who recommend the use of dopamine receptor blocking agents (88). When olanzapine
was given to 11 HD patients in an open-label study for 6 months at a daily dose of 5 mg, it

improved depression, anxiety, irritability and obsessions (89). Olanzapine and risperidone are the

most commonly prescribed atypical antipsychotic drugs. Case series have demonstrated the

efficacy of quetiapine (90), risperidone (91,92) and aripiprazole (93), but evidence-based data are

still lacking. Case reports suggest that the SSRIs fluoxetine, paroxetine, and sertraline (94,95,96)

may be useful in cases of obsessive-compulsive symptoms in HD, and that sertraline and

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buspirone may help to control irritability and aggressive behavior (97,98,99,100). Mood stabilizers,

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such as anticonvulsants and benzodiazepines, may also be used as adjunctive medications

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(101,102). Finally, in a retrospective, chart review study, Duff et al. (103) reported that risperidone

improved psychiatric symptoms in 17 HD patients. Unfortunately, the study by Duff et al. did not

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provide the subscores of the main questionnaire used. There may be differences in the treatment

of psychiatric disturbances in HD across different countries. For example, an international survey

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of experts revealed that antipsychotics are more frequently used for mild symptoms in Europe,

whereas SSRIs tend to be preferred in North America and Australia (104). Pharmacological
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treatment of neuropsychiatric disturbances in HD is summarized in table 4.

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6. Essential tremor

Essential tremor (ET) is characterized by a bilateral upper limb action tremor of at least 3 years’
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duration with or without tremor in other locations (e.g. head, voice or lower limbs) that is not
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associated with other neurological signs or movement disorders (105). A positive family history is

often reported in ET patients.

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Psychiatric disorders are frequently observed in ET. Louis et al. (8) found that the frequency

of depression was twice as high in ET patients as in healthy controls , while Fabbrini et al. (106)

reported that depressive disorders diagnosed using standardized scales were present in 54% of

ET patients. Depression in ET is associated with high levels of psychological suffering (107) and

with an increase in embarrassment levels (108). Social phobia and other anxiety disturbances are

also frequent in ET patients (up to 50% of cases in some studies) as well personality disturbances

(109,110). Most studies report that the severity of depressive symptoms does not correlate with the
severity of tremor, thereby suggesting that depression in ET does not represent a psychological

reaction to tremor but may be part of the clinical spectrum of the disorder (111). Unlike depression,

social phobia correlates with the severity of tremor (112) and may therefore be considered as a

reactive process to the disease.

6.1 Treatment of psychiatric disturbances in essential tremor

Drugs used for the treatment of tremor include beta-blockers, benzodiazepines (particularly

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clonazepam and alprazolam), anticonvulsants (topiramate, primidone), antidepressants

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(mirtazapine) and, less commonly, antipsychotics (clozapine, olanzapine, quetiapine) (113).

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Severe cases of ET can also be treated by means of surgical procedures such as deep-brain

stimulation or thalamotomy (114). The primary endpoint in all the studies reviewed was the effect

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of drug treatment on the severity of tremor. Whether drugs used for the treatment of tremor also

improve anxiety and depression has not been extensively studied. We did not find any studies on
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the behavioral treatment of psychiatric disturbances in ET patients.
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7. Discussion

In the present paper, we reviewed studies that investigated the treatment of psychiatric
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disturbances in hyperkinetic movement disorders, i.e. dystonia, tics, TS, HD and ET.

In focal dystonia, only one short-term RCT study compared the efficacy of a SSRI
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(escitalopram) with that of placebo in improving dystonia and tremor in CD patients. The effect of
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escitalopram and placebo on the severity of psychiatric symptoms in that study was a secondary

endpoint and no differences were recorded between the two treatments (22). Studies with a longer
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follow-up and higher doses are needed to ascertain whether escitalopram or other drugs may

alleviate depression and anxiety in CD patients. The results of one open-label study suggest that

BTX-A treatment may improve CD depressive symptoms as well as motor function (22), though

this finding warrants confirmation in controlled trials. The observation that BTX-A injections in the

glabellar frown lines improved depression suggests that the BTX-A induced improvement in

depressive symptoms is independent of any improvement in motor function (115,116,117). Further

studies are needed to shed light on the possible mechanisms underlying this effect. Two case
reports suggest that behavioural therapies in patients affected by dystonia may be associated with

an improvement in psychiatric disturbances (28,29), though controlled trials are needed to

determine whether individual or group CBT, or other behavioural therapies, may be used to

effectively treat dystonias. According to Bernstein et al. (118), behavioural treatments focused on

physical and emotional well-being, action planning and problem solving, education to manage

anxiety symptoms through cognitive restricting and relaxation practice all deserve to be

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investigated further in controlled trials. This approach may prove particularly useful in CD, a

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condition that is also associated with changes in body perception, a sense of shame and reduced

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social functioning.

In TS, atypical antipsychotics may be a reasonable choice when OCD is the main comorbid

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condition. Risperidone has been shown to be effective in controlled studies (38,39), while the use

of aripiprazole has yielded encouraging data, though the latter finding is based on a single open-
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label trial (40). The usefulness of SSRIs on OCD in TS needs to be studied in more depth as only

one open study with fluoxetine has yielded encouraging results (41). Double-blind controlled
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studies have shown that three classes of drugs have a positive effect on ADHD in TS; these three

classes comprise alpha-2 agonists (clonidine, guanfacine), stimulants (methylphenidate) and

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neorepinephrine reuptake inhibitors (atomoxetine) (44,45,46,47,48,49,50,51,52,119,120,121).

Controlled studies have also shown that none of the aforementioned drugs worsen the severity of
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tics (49). Preliminary data suggest that desipramine and aripiprazole may be considered as
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alternative pharmacological treatments in TS patients with ADHD (53,54,55). As tardive

dyskinesias and parkinsonism may be associated with the use of dopamine-receptor blocking
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drugs, particularly in older patients, although not in children, the use of neuroleptics should, if

possible, be limited. Behavioural treatments have been designed mainly to treat primary psychiatric

disorders such as phobias, addictions, depression, obsessive-compulsive disorder and anxiety.

When used in TS, behavioral treatments are associated with fewer adverse events than

pharmacological treatments. However, few studies have assessed how behavioral therapies affect

psychiatric symptoms in TS, with most having been designed to assess the effect of these

treatments on tic severity. Behavioural treatments used in chronic tic disorders and TS include
standard CBT, habit reversal training (HRT), CBIT, exposure and response prevention (ERP),

contingency management (CM), relaxation training (RT) and autonomic modulation and

neurofeedback. According to existing guidelines, HRT/CBIT and ERP are considered as first-line

behavioural treatments, while CM, function-based interventions (FBI) and RT are considered as

second-line therapies or add-on behavioural treatments. One limitation of behavioral treatments in

TS, particularly in young patients (children and adolescents) is that they require motivation,

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attention, compliance and, in some cases, economic support.

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It has been suggested that the treatment of tic and psychiatric comorbidities in TS should

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be based on a combination of drugs, psycho-education and behavioral therapy (122). It is also

important to bear in mind that psychosocial factors may modulate the severity of TS regardless of

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treatment. Although both psychotherapy and pharmacological therapies are used as first-line

treatments in patients with TS and tic disorders, these two approaches have not yet been
an
compared in controlled studies and there are no data are available on which type of treatment

should be tried first. Drugs may be required in children and adolescents when the presence of
M

psychiatric disturbances (OCD and ADHD) are detrimental to the overall functioning of the patient.

In such cases, an improvement in OCD and ADHD may lead to a reduction in stress and,
ed

consequently, to an improvement in the severity and frequency of tics (123,124). In TS, there is a

lack of rigorously controlled studies on the effect of behavioral therapies on neuropsychiatric

pt

symptoms as well as of controlled studies on depression, anxiety and agitation.

ce

When reviewing studies that have investigated the treatment of psychiatric disturbances in

HD, we found that the number of controlled trials is limited and that the management of psychiatric
Ac

disturbances in HD is almost exclusively based on personal experience and recommendations by

experts (125,126). In an evidence-based review, Bonelli et al. (127) found that in HD there is little

evidence of the usefulness of amitryptiline and mirtazapine for depression, of risperidone for

psychosis, and of olanzapine, haloperidol and buspirone for behavioral symptoms. More recently,

in a systematic review on the treatment of depression in HD, Molton et al. (80) concluded that

studies on the treatment of depression in HD were not of adequate duration, size or outcome. The

treatment of depression in HD is important owing to the increased suicidality risk in patients with
this disorder. Depression in HD may also be underdiagnosed and undertreated, as suggested by

the findings of the Registry study, which showed that only 54.9% of all HD patients with moderate

to severe depressive symptoms used antidepressants. For example, although antipsychotics are

used for the treatment of aggression and irritability, which are two disruptive symptoms in HD

(128), no RCT has yet assessed the effect of these drugs in HD patients. It should also be borne in

mind that drugs used to treat neuropsychiatric disturbances in HD are often used off label.

t
Comprehensive treatment, administered by the caring physician, rehabilitation therapists, nurses,

ip
psychologists, genetic counselors, social workers and other health care providers, should be

cr
provided for HD patients in both the pre-symptomatic and symptomatic phases of the disease

(129).

us
Both depression and anxiety are frequent disorders in ET patients and should be routinely

evaluated. These symptoms contribute significantly to a low quality of life, social embarrassment
an
and overall disability (5,8,106,107,108,109,110,111,112). Notwithstanding the high proportion of

ET patients with depression and anxiety disturbances, no studies have yet addressed the
M

treatment of these problems in such patients. Some drugs used in ET, such as clonazepam and

barbiturates, are reported to have anxiolytic properties that reduce the anxiety associated with
ed

tremor, though this issue has not yet been assessed in a controlled study (113). Although ET is

considered the most frequent movement disorder encountered in clinical practice, no controlled
pt

studies have yet been conducted on the treatment of anxiety and depression in patients with this
ce

disorder. Future studies are needed to shed light on these two symptoms that are often associated

with ET.
Ac

8. Expert commentary

Psychiatric disturbances worsen the quality of life and impair social functions in patients with

dystonia, chronic tics, TS, HD and ET. However, the data available on the treatment of psychiatric

disturbances in these conditions are scanty. One RCT conducted on CD, in which the treatment of

psychiatric disturbances was not the main outcome measure, did not reveal any differences
between escitalopram and placebo. Comorbid OCD and ADHD in TS benefit from atypical

antipsychotics and alpha agonists, stimulants and norepinephrine reuptake inhibitors. Whether

behavioral interventions, which reduce tic severity in TS, may also be useful in the treatment of

OCD, ADHD, depression, anxiety and other psychiatric disturbances in TS is unclear. In HD,

psychiatric disturbances are usually treated according to the doctor’s experience. Bupropion may

be useful for apathy while antipsychotics are widely used for aggressivity and psychosis, whereas

t
no clear indications are available for the treatment of depression. No studies have been conducted

ip
on the treatment of neuropsychiatric symptoms in ET patients. Since the studies reviewed here

cr
indicate that the presence and severity of psychiatric disturbances are often unrelated to the

severity of motor dysfunction, psychiatric disturbances in each of these conditions should be

us
treated independently from the hyperkinetic disorder.
an
9. Five-year view

Evaluation of psychiatric abnormalities should become a significant part of the clinical assessment
M

in patients with hyperkinetic movement disorders. It is important that the diagnosis be based on

standardized instruments and that the severity of psychiatric disturbances be measured by means
ed

of ad hoc rating scales. In dystonia patients with a comorbid psychiatric condition, controlled

studies should be designed to investigate the effect of different treatments (pharmacological and
pt

non-pharmacological) for the treatment of anxiety and depression. BTX-A in dystonia may be
ce

associated with an improvement in psychiatric symptoms, but whether this improvement is

secondary to the improvement in motor symptoms or to some other effect is not yet clear and
Ac

warrants further investigation. In TS, the effect of different behavioral approaches should be

compared in studies whose primary endpoint is the treatment of the psychiatric comorbidity. In HD,

more thorough studies are needed to shed light on the best approach to the treatment of both

depression and the increased risk of suicide in such patients. In ET, pharmacological trials and

behavioral treatments such as symptom-based psychotherapy may prove useful as a means of

reducing the burden of anxiety and embarrassment, which are common symptoms in these
patients. Lastly, studies are needed to determine whether DBS may be effective for the treatment

of psychiatric disturbances in hyperkinetic movement disorders.

Key issues

• Psychiatric disturbances are frequent in patients with hyperkinetic movement disorders and

worsen the quality of life and overall disability in such patients.

t
• In dystonia, depression and anxiety are particularly frequent in CD and BPS patients. Only

ip
one RCT trial has evaluated the usefulness of citalopram on psychiatric symptoms in CD.

cr
• In TS, the treatment of comorbid ADHD is based on the use of alpha-2 agonists,

psychostimulants and noradrenergic reuptake inhibitors. Treatment of comorbid OCD may

us
benefit from risperidone and aripiprazole. Several behavioral treatments are available in

TS, though how these treatments impact on psychiatric abnormalities has not yet been fully
an
understood.

• In HD, treatment of aggressive behaviour and psychosis is generally based on

M

antipsychotics and follows the rules for the treatment of these conditions in the general

population. Depression and apathy are frequent in HD but probably undertreated.

ed

• In ET, no studies have yet fully assessed depression and anxiety that are frequently

associated with this disorder.

pt
ce

Funding

This paper was not funded.

Ac

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in the

manuscript. This includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to
disclose.

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Table 1: Pharmacological treatment of psychiatric disturbances in dystonia

Study Patients Treatment Study Design Primary Effects on reducing

characteristics Endpoint psychiatric symptoms
Zoons et al (22) 50 CD Escitalopram Crossover Dystonia Escitalopram equal to
vs Placebo RCT placebo

t
rip
Liow et al (25) 69 children Gabapentin Open label Motor Gabapentin improved
with severe symptoms, mood and sleep
dystonia mood and

c
sleep

us
Slawek et al (23) 101 CD and BTX-A 4-weeks Depression BTX-A improved
80 Healthy case control depression symptoms
subjects

an
CD= cervical dystonia; BTX-A= botulinum toxin type A

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d
te
c ep
Ac
Table 2: Pharmacological treatment of psychiatric disturbances in Tourette syndrome

Study Patients Treatment Study Primary Effects on psychiatric

t
characteristics Design Endpoint symptoms

rip
George et al (36) 11 TS + OCD Sulpiride vs 14 week OCD Fluvoxamine more effective
Fluvoxamine cross-over symptoms than Sulpiride
trial
Bruggeman et al 50 TS + OCD Risperidone vs 12 week OCD Risperidone more effective

c
(38) Pimozide double blind symptoms than Pimozide on OCD

us
parallel symptoms
group
Gaffney et al, (39) 21 TS + OCD + Risperidone vs 8 weks, Tic severity, similar efficacy of clonidine

an
ADHD Clonidine double blind OCD and risperidone on tic and
symtpoms OCD symptoms
Gerash et al (40) 18 TS + OCD Aripiprazole 6-weeks OCD Aripiprazole improved both
Open label symptoms tics and OCD symptoms

M
trial
Riddle et al (41) 10 TS +OCD Fluoxetine 20-weeks OCD Fluoxetine improved OCD
Open label symptoms symptoms

d
Trial
Castellanos et al 20 TS + ADHD Methylphenidate + 9-weeks Tic severity The combination of
(46) Clonidine te Crossover
RCT
methylphenidate and
clonidine is effective for
ep
ADHD
Scahill et al (45) 34 tic + ADHD Guanfacine vs 8 weeks ADHD guanfacine mean
placebo double blind improvement of 37%
teacher-rated ADHD Rating
c

Scale, compared to 8%
Ac

improvement for placebo.

Erenberg et al (47) 71 TS children + Immediate release double blind ADHD improvement in ADHD,
ADHD methylphenidate vs vs placebo oppositional defiant
placebo disorder, and peer
aggression behaviors.

Allen et al (50) 72 TS/CTD + Atomoxetine 18-weeks ADHD Atomoxetine improved ADH

 ADHD RCT symptoms
Spencer et al (51) 56 TS + ADHD Atomoxetine 18- weeks ADHD Atomoxetine improved ADH
RCT symptoms
Spencer et al (54) 41 TS/CTD + Desipramine 6-weeks ADHD Desipramine equal to
ADHD RCT placebo
Masi et al (55) 28 TS + ADHD Aripiprazole 12-weeks Tic severity Aripiprazole improved
Open label and ADHD ADHS symptoms
Tourette syndrome 136 children Clonidine alone, multicenter, ADHD ADHD improved

t
rip
study group (49) with TS, chronic methylphenidate randomized Tic severity significantly with clonidine
tic disorder and alone, clonidine + , double- alone and methylphenidate
ADHD methylphenidate, blind clinical alone. Clonidine +
placebo trial methylphenidate best

c
results when compared

us
with placebo. Worsening of
tics did not differ between
treatments.
Gerasch et al (40) 44 TS+ OCD + Aripiprazole 6-weeks OCD+ Aripiprazole improved

an
Depression+ Open label Depression+ OCD, depression and
ADHD ADHD ADHD symptoms

M
TS: Tourette syndrome; OCD: obsessive compulsive disorder; CTD: chronic tic disorder;
ADHD: attention deficit hyperactivity disorder

d
te
c ep
Ac
Table 3: Behavioral treatments in chronic tic disorders and Tourette syndrome

Study Patients characteristics Treatment Study Design Results

t
rip
76 TS patients divided in
O’Connor et al (60) Reduction of tics severity;
medicated and non-
CBT Controlled trial improvement in anxiety and
medicated group.
depressive symptoms

c
Randomized Reduction of tics and severity
Wilhelm et al (65) 122 TS patients

us
CBIT controlled trial of psychopathology
A waiting-list
Reduction of the severity of the
Azrin et al (62) 10 TS patients HRT control group
tics
comparison

an
Reduction of the severity of the
HRT
tics. Improvement in life-
30 TS patients Supportive Controlled trial
Deckersbach et al (69) satisfaction and psychosocial
therapy

M
functioning
HRT reduction of the severity of the
Randomized
Yates et al (66) 33 patients with TS or CTD Educational tics, improvement on quality of
controlled trial

d
sessions life
ER reduction of the severity of the
Verdellen et al (70) 43 TS patients Controlled trial
te
HR
CBT,
tics
OCD
Tic severity
ep
sertraline
In patients with a comorbid tic
March et al. (58) 112 pz with OCD and TS CBT + Controlled trial
disorder sertraline + CBT
sertraline,
better than CBT alone; CBT
placebo
c

alone better than placebo

Ac
Table 4: Pharmacological treatment of psychiatric disturbances in Huntington disease

Study Patients Treatment Study Design Primary Effects on reducing

characteristics Endpoint psychiatric symptoms
Holl et al 26 HD+ Major Venlafaxine Open label Depression Venlafaxine improved
(81) Depression depressive symptoms
Beglinger et 20 HD Atomoxetine 10-weeks RCT Neuropsycho Atomoxetine equal to
al (83) 80HS logical placebo

t
symptoms

rip
Beglinger et 36 HD Citalopram RCT Executive Citalopram equal to
al (84) functions placebo on executive
functions but improved

c
depressive symptoms

us
Gelderblom 40 HD Bupropion vs placebo Crossover Apathy Bupropion ineffective on
et al (87) RCT apathy
Squitieri et al 11 HD olanzapine 6-months open Motor Olanzapine improved
(89) label symptoms anxiety, irritability, and

an
obsessions

M
d
te
c ep
Ac