A case series of patients with tourette's syndrome in the united kingdom treated with aripiprazole

Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
Published online in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hup.798 A case series of patients with Tourette’s Syndrome in theUnited Kingdom treated with aripiprazole Lisa Davies, Jeremy S. Stern, Niruj Agrawal and Mary M. Robertson* St George’s Hospital, Department of Neurology, Atkinson Morley Wing, Blackshaw Rd, London, SW17-0QT, UK Objective These cases illustrate that a new neuroleptic, aripiprazole, may be an effective treatment for the motor and vocaltics of Tourette Syndrome (TS), even in younger people.
Method A case series of 11 consecutive patients with TS (age range 7–50 years; M ¼ 7) who were felt to requireneuroleptic medication, were treated with aripiprazole, the majority of whom had been refractory to treatment with otherneuroleptics, and in one case, Habit Reversal Training as well.
Results Ten out of the 11 patients who were treated with aripiprazole improved, although to differing degrees. The onlyindividual who showed no response was treated for only 1 month with a low dose (5 mg). Eight of the patients had beentreated with many typical and atypical neuroleptics without success, and which had also given unacceptable side effects,resulting in them being unable to function at times. One was also unresponsive to previous Habit Reversal Training. Theresponse to aripiprazole was dramatic and quick in five patients; in the rest (5/10) the response was less dramatic. In themajority of patients, response was sustained. The successful aripiprazole doses were between 10–20 mg daily. Side effectswere mild and transient. This, to the best of our knowledge, is the first case series of patients with TS successfully treated witharipiprazole in the United Kingdom, and one of the few to date in the English Scientific literature. Our patients are also thefirst cases reported, in which the patients were assessed and whose improvement was monitored using standardised schedulesand rating scales, such as the Yale Global Tic Severity Rating Scale and MOVES. Aripiprazole was licensed for use inpatients with schizophrenia in the European Union in June 2004. We discuss possible reasons for these dramatic andidiosyncratic responses to aripiprazole.
Conclusion We suggest that aripiprazole may well be useful for individuals with TS as response to it is often quick,dramatic, sustained and with few generally mild and transient side effects. Copyright # 2006 John Wiley & Sons, Ltd.
key words — Tourette Syndrome; treatment; aripiprazole individual him/her self has just said), coprolalia(inappropriate and involuntary use of swear words) Tourette Syndrome (TS) is characterised by multiple and self-injurious behaviours (SIB). In addition, many motor and one or more vocal tics and lasting longer patients have additional co-morbid disorders and than a year (World Health Organization, 1992; psychopathology including attention deficit hyperac- American Psychiatric Association, 2000). The age tivity disorder (ADHD), obsessive-compulsive dis- at onset of motor tics is usually around the 5–7 years, order (OCD, obsessive-compulsive behaviours (OCB) with vocal tics starting somewhat later. Tics may be and depression. TS is now recognised to be more simple or complex. Apart from the motor and vocal common than was previously reported with prevalence (phonic) tics, patients may have echolalia (copying figures of between 0.4% and 1.76% of youngsters what other people say), palilalia (repeating what the between the ages of 5 and 18 years. The prognosis isbetter than was once thought, with many individualsimproving substantially by the age of 18 years. The * Correspondence to: M. M. Robertson, St George’s Hospital, aetiopathology includes genetic influences, pre- and Department of Neurology, Atkinson Morley Wing, Blackshaw peri- natal difficulties, and proposed more recently, an Rd, London, SW17-0QT, UK. Tel: 0207 679 9460. Fax: 0207679 9426. E-mail: Profmmr@aol.com association with some infections (e.g. streptococcus) Copyright # 2006 John Wiley & Sons, Ltd.
via neuroimmunological mechanisms and molecular range of the nine patients was 7–50 years and seven mimicry. Management includes reassurance, expla- were male. All 11 patients were initially assessed, and nation, psycho-education, and more recently, beha- histories obtained, using a semi-structured interview, vioural methods such as Habit Reversal Training the National Hospital Interview Schedule for Gilles de (HRT) and medications. Treatment of the motor and la Tourette Syndrome (NHIS; Robertson and Eapen, vocal tics is more complex than once thought, but even 1996) and current initial tic severity was measured today, the typical and atypical neuroleptics form the using both the physician rated Yale Global Tic mainstay of treatment of motor and vocal tics in Severity Rating Scale [YGTSS], Leckman et al., adults. Double-blind trials have demonstrated that the 1989) and the self-rated MOVES Scale (Gaffney et al., typical neuroleptics including haloperidol pimozide, 1994), the latter both before and after treatment with sulpiride and tiapride are better than placebo. Atypical aripiprazole. The lifetime severity symptom scale, neuroleptics, which have been used successfully, rated by a physician, the Diagnostic Confidence Index include risperidone, olanzapine and quetiapine. Many ([DCI], Robertson et al., 1999), was also employed.
other medications have been used including clonidine All patients gave written consent for the publication.
and botulinum toxin for vocal tics (Robertson, 2000,2004).
Aripiprazole acts predominantly as a partial agonist at dopamine D2 and Serotonin 5-HT-1A receptors and an antagonist at Serotonin 5-HT-2A receptors (DeLeon et al., 2004). It is available in oral tablets, is well The first patient, Ms A (no. 1 on Table 1) was referred absorbed, and elimination is primarily through hepatic to us for expert management. She is 33 years old, right metabolism. It became licensed for use in patients handed and a night care assistant looking after elderly with schizophrenia in the European Union in June people with dementia, having been in the same post for 2004. Aripiprazole has been widely used in the treatment of patients with schizophrenia in the United The first symptoms were vocal tics (a sound similar States of America, Mexico, Australia, Brazil and to hiccupping/grunting), at the age of 5. At about Korea. It is well tolerated and side effects greater than 7 years of age she had bad arm tics, which lasted about placebo in double-blind trials include insomnia, 2 weeks but was then relatively well until the age of tremor, nausea, vomiting and akathisia, usually mild 16 years. She had obsessionality from the age of 7, to moderate and transient. No specific blood which on DSM criteria, seems to have progressed from monitoring is required with aripiprazole (Travis OCB to OCD over the years. At the age of 16 years, she started to develop further tics and involuntary Only a few cases of the successful use of noises and was diagnosed as having TS at the age of aripiprazole in patients with TS have been documen- 25, having suffered substantially up until that point.
ted in the literature. We report the first in the United Over the last 13 years she has not improved, and if Kingdom, and also the first two patients whose anything, was better off about 8 years ago compared to improvement was monitored using standardised rating the present time when she first consulted us. Her tics scales, to the best of our knowledge. After our success are present on a daily basis, worsened by stress, and with these two patients, we treated nine others who improved with alcohol. Her tics are briefly suppres- presented at our dedicated TS clinic and who were sible and suggestible, and she has premonitory thought to require neuroleptics (children who have TS sensations. The most noticeable feature is a very and ADHD are usually given clonidine initially frequent loud hiccupping/‘grunting’ tic. There are no echo-phenomenon, palilalia nor copropraxia, but shedoes have some mild coprolalia (muttering of swearwords under her breath). In addition, she was noted to talk in two different personae. During her two Two initial cases were treated with ariprazole and pregnancies, the tics recovered significantly despite responded dramatically and well (see case reports, and in the Table 1, no. 1,2). We therefore decided to treat Ms A’s birth was complicated as her mother had to nine other patients who presented consecutively to the be induced because of mild maternal hypertension and clinic, who (7/9) had been refractory to other the infant had shoulder dystosia, but she was born a treatments (see Table 1) and in whom we thought normal vaginal delivery, weighing 8 pounds. She was that a neuroleptic was the treatment of choice. The age breast fed for 8 months. Her milestones were normal; Copyright # 2006 John Wiley & Sons, Ltd.
Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
Copyright # 2006 John Wiley & Sons, Ltd.
Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
she was described as a ‘clingy baby’. She stopped several siblings: a sister has epilepsy, a brother has attending a nursery school because of an ear infection speech difficulties, a brother is reported to have several and after starting school, became ‘mute’ for a month.
diagnoses including TS, possible psychosis, alcohol- She suffered with dyslexia. She initially went to a ism, drug abuse and aggression. Maternal grand- private school, afterwards attending a mainstream state school, but required extra help with English. She Ms A’s mental state and neurological examinations hated school and left with no examinations at the age were normal apart from her tics. The following motor of 16 years. As a youngster she had temper tantrums.
tics were observed at interview: scalp movements, She had various unskilled jobs but latterly has been a frowning, eyebrow raising, blinking, a nasal twitch, care assistant in the same post for 13 years. There is no head nodding, shoulder shrugging, and a whole body forensic history. She takes no illicit drugs and drinks jump. Vocalisations, which were heard at interview about 14 units a week. She smokes one packet of included throat clearing and very frequent, almost tobacco a week and it helps her TS symptoms. She constant hiccupping/grunting. Ms A muttered under tried the nicotine patch, but it did not help, and she her breath, but there was no actual coprolalia heard.
Ms A’s MOVES score was 17/60, the YGTSS was Ms A’s symptoms began getting steadily worse 94%, and the Diagnostic Confidence Index was 81%.
from the age of 20 years. Ms A was previously been She was moderately to severely affected at the time of treated for her TS symptoms with haloperidol, the consultation. We also diagnosed OCD so sulpiride, amisulpiride, risperidone, olanzapine, nic- recommended that she continue with the citalopram otine patch and possibly tetrabenazine. None of these 40 mgm daily which she was taking. We also medications helped her symptoms, and gave her recommended cognitive behavioural therapy (CBT).
unacceptable side effects such as sedation and We suggested that she stop the olanzapine she had excessive sleep. Sulpiride made her so withdrawn been taking, as this was of minimal benefit for her tic and dopey that she was unable to go to work. At the symptomatology. As she had been on many medi- age of 24 years she received HRT from a psychologist cations and also had had no success with HRT, she was without success. She has two children, B, a boy of 3, keen to try further medication, particularly wanting to and C, a girl of 6 who are in good health with no try something new which she had not used before, we neuropsychiatric disorders or symptoms.
chose aripiprazole and prescribed 15 mg a day.
The only medical history of note was that she had We saw her again 3 months later and her tics had repetitive throat infections as a youngster and thus at the dramatically improved, after 2–3 weeks of her having age of 11 years, had a tonsillectomy. In addition we taken aripiprazole, especially her noises and whole diagnosed childhood OCB and ADHD (inattentive body jerking. She had mild transient nausea and type), and dyslexia. She also had two depressive blurred vision as the only side effects. In addition, her illnesses in the past. She was given citalopram and scores on the MOVES reduced from 17/60 to 13/60, improved, but relapsed after non-compliance, and was and her YGTSS went from 94% to 10%. She ascribed compliant for 6 years. There was never ever any her dramatic improvement to aripiprazole. She evidence of an eating disorder (despite her buying food remained on citalopram. The main problem with excessively as part of her compulsive spending sprees).
Ms A at her second visit was the compulsive spending, As a child there had been no evidence of oppositional which had become significant. We thus recommended defiant disorder (ODD) or conduct disorder (CD).
that her citalopram be increased from 40 mg up to The family history is as follows: Ms A’s parents 50 mg for a couple of weeks, before increasing it were separated when the patient was 24. Her father further to 60 mg. We also re-referred her for CBT as died at 72 of Barrett’s disease. Mother, has epilepsy this had not materialised. We saw her a third time. She (‘petit mal with grand mal tendencies’) which has was briefly non-compliant during a holiday, her been treated successfully with phenobarbitone for symptoms worsened, but they improved again after many years; she also had a ‘nervous breakdown’ restarting aripiprazole and remained improved after 16 6 weeks after the birth of one of her children and was weeks’ follow-up, with no side effects at present treated with sodium amytal, which she has remained on ever since. We diagnosed her as having OCB witharithmomania (fascination with numbers) and touch- ing things twice. She also has spending sprees with acompulsive flavour, similar to her daughter. Maternal The second case is Ms B, a 12 year old girl (no. 2 on grandmother also probably had OCB. Our patient has Table 1) who was referred to us for expert management, Copyright # 2006 John Wiley & Sons, Ltd.
Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
particularly as she had been refractory to many Examination of her mental state was normal apart traditional medications and had had prolonged periods from severe TS with an area of excoriation on the left off school because of her severe tic symptomatology.
side of her neck from severe tics and she complained Her tics started at the age of 7 years. Her first tics were of poor sleep because of tics. Neurological and eye blinking and staring, and since then she has had a physical examinations were normal except for mild wide variety of typical TS tics, which have waxed and ‘disco-ordination’. Eleven tics were seen at interview, waned over time. She had been treated unsuccessfully although she had a total of at least 52. Those at with adequate doses of pimozide, sulpiride, risperidone, interview included eyebrow raising, blinking, eyes clonidine and ziprasidone. She and her parents did not looking down, eyes looking sideways, mouth to the feel any of these medications helped her tics, and there side, smiling, facial grimacing, hair out of the eyes had always been a problem with side effects, or, in the flick, shoulder shrugging, arm extension, hand flicking case of ziprasidone, the risk of potential side effects (the and an orchestrated sequence of smiling, shoulder possible effects of QT prolongation). She had not been shrug, arm extension and hand movements. We heard taking any medication for 2 months prior to the first visit throat clearing and sniffing but she had 11 other vocal to us. While she was taking risperidone she was said to tics in total. She gave a clear history of self-injurious have had a Transient Ischaemic Attack (TIA), during behaviours (slapping) but this could well be a complex which she became weak down her right side, with tic. Of note is that she had a history of frequent throat slurred speech for approximately 3 days: the risperidone infections although none confirmed streptococcal had been recently increased to 4 mg. She was growth. The MOVES score at her initial assessment investigated, with results showing normal MRI neuro- was 16/60, the Diagnostic Confidence Index was 85% We diagnosed coprolalia in that she made a ‘fuh’ We suggested aripiprazole 5 mg initially, followed sound involuntarily. There was no neither copropraxia by 10 mg daily and when seen again 5 months later for nor echo- phenomenon nor palilalia. She did, however, follow-up, she and her family were delighted with her have SIB and slapped herself. She also had a dramatic response to aripiprazole. She commenced compulsion to slap her younger brother, as well as aripiprazole at 5 mg and had a minimally good touch the cooker and had burnt herself by doing this.
response. However, 4 days after her first 10 mgm dose She had also broken a glass on her head and on her she made a dramatic response. She had attended teeth in the past. Her tics could be suppressed, but with school almost every day for the last 3 months since her subsequent rebound, and they tend to be worse with commencement of the aripiprazole. She was coping at stress. She suffered both a lot of pain in her back and school and enjoying it. She had experienced a few soreness of her skin around the neck, as a result of the minor side effects (nausea, tiredness, some shortness tics, and therefore regularly took many analgesics for of breath), but as she had responded so well to the this every day. In the past she has also suffered tongue medication, these posed no great problems to her. Her MOVES score reduced from 16/60 at her first visit to Ms B was born weighing well over 9 lbs, 10 days 7/60 at follow-up. Apart from a few minor tics, her post-mature, but with no other associated problems.
mental state examination was normal.
She walked and talked by around her first birthday.
The major problem with her at our first interview was that she had severe tics and in the last 4 years she hadconsequently missed approximately two and a half The details of the other nine TS patients (age 7–50 years of schooling because of her TS symptoms. There years) treated with aripiprazole (for between 1 and 10 was no evidence of any comorbidity such as OCD, months) are presented in the Table 1. All but one responded to aripiprazole, though to varying degrees.
She has four male siblings aged 14, 8, 6 and 2. Her Five had dramatic responses (cases nos. 1, 2, 4, 8, 9); 6-year old brother had mild TS and possible ADHD.
four had a response of 20% or less. One patient (no. 8) Her mother exhibited mild tics around the mouth and not only responded with regards to their tics (80%), eyes and also describes arithmomania. She also had but her OCD reduced by half. One (no. 11) did not had some panic attacks approximately 15 or 16 years respond. This was likely, as he had only been taking before. Her mother’s sister was diagnosed as having 5 mg for 1 month. In all patients, side effects were OCD. She had two maternal cousins, one with minimal and transient, but occurred in all patients; Asperger’s syndrome and one with autism. A maternal sedation and tiredness were the most common side effects. The chest pain of Patient Number 3 was Copyright # 2006 John Wiley & Sons, Ltd.
Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
investigated with a full cardio-vascular work-up and One of the first reports was that of Hounie et al.
no abnormalities were found. In addition, this patient (2004) in Brazil who reported, in Portuguese, the case had his medication discontinued with the pain and of a 20 year old man with TS who had previously been only recently restarted aripiprazole after the investi- treated with haloperidol, pimozide, trifluoperazine, gations were completed, which may account for his sulpiride, olanzapine, quetiapine, ziprazidone, cloni- MOVES score (18 > 31). In addition Patient number 6 dine, botulinum toxin, pergolide, nicotine, clonaze- discontinued his medication (because of excessive pam and reserpine. With the addition of aripiprazole OCD and misattributing ongoing anxiety symptoms to 15 mg daily to his regime of sertraline and olanzapine, the aripiprazole) and thus his MOVES score increased (6 > 11). After reassurance, he recommenced the Hood et al. (2004) reported the successful treatment of severe SIB in the context of TS and OCD in a 16-year old adolescent girl. She had been treated withmany agents including clonidine, olanzapine, quetia- pine and paroxetine, and in the Emergency Depart- We report 10/11 patients with TS of whom 9/11 had ment yet others including lorazepam, morphine, been refractory to other treatments and who responded benztropine, diphenhydramine, chlorpromazine and well and often dramatically to aripiprazole 10–20 mg clomipramine. As an in-patient she received citalo- pram, clomipramine, clonazepam and risperidone.
We report in detail our first case, a 33-year old Risperidone was discontinued because of galactor- woman with TS who was refractory to treatment with rhoea and aripiprazole 10 mgm added. Without many neuroleptics and HRT, and who finally improved risperidone the OCD symptoms worsened and so it dramatically with aripiprazole 15 mg daily. We also was recommenced. Psychological treatment was also report in detail our second case, a 12-year old girl instituted. On that regime she improved.
refractory to treatment with many neuroleptics and Dehnig et al., 2005 documented the case of a 19- who, because of her TS symptoms had missed an year old woman with TS who had had symptoms since enormous amount of school. She improved dramatic- the age of 6 years. She also had marked SIB. She had ally on aripiprazole 10 mg daily. We also report on been treated with tiapride, sulpiride, amisulpiride, nine other patients with TS who were treated with pimozide and ziprasidone, but was vulnerable to side aripiprazole (10–20 mg daily) for 1 to 10 months.
effects with all of these. She was therefore treated with These are the first communication of the use of aripiprazole 10 mg daily and after 2 weeks was nearly aripiprazole in individuals with TS in the United tic free for the first time in 13 years, and experienced Kingdom. These are also the first cases whose no side effects. She was so well that she began working dramatic response to aripiprazole was assessed using standardised measures such as the YGTSS in the first Kastrup et al. (2005) documented two cases with TS two patients and the MOVES at follow-up. In some successfully treated with aripiprazole 15 mg daily.
instances (2/10) the MOVES scores did not go down Neither experienced serious side effects. The first was (indicative of improvement) as expected, and indeed a 33 year old male who had been treated unsuccess- increased, despite subjective improvement; in both fully with pimozide, tiapride and haloperidol, which instances the patients’ medication had been discon- had to be discontinued because of side effects. Within tinued and restarted. This may also however, illustrate 2 weeks of commencing aripiprazole, his symptoms the possible difficulties in using only a self-rated scale had almost disappeared and he was stable at 16 weeks to assess improvement. In addition, it may be worth follow-up. The second patient was a 48-year old man noting that Patients 3 and 6 in our series received more who had TS with complex SIB who refused to take than usual counseling about the new medication and in medications because of the risk of side effects. Within particular the possible side-effects; this may be 2 weeks of taking aripiprazole his motor tics almost important when new medications are used as the completely disappeared and he remained stable at 16 Internet, BNF and other consultation resources, will not yet be informative about newer drugs.
Murphy et al. (2005) then reported the successful To the best of our knowledge there have been only use of aripiprazole in six youths with TS and OCD five published single case reports of the successful use of aripiprazole in patients with tics or TS to date. A Thus, in these 22 cases with TS (11 from the literature case series of six youths was published in late 2005 and our 11), who have received aripiprazole, there was in general a dramatic and long-lasting relief from tics, in Copyright # 2006 John Wiley & Sons, Ltd.
Hum Psychopharmacol Clin Exp 2006; 21: 447–453.
many cases bringing tic relief for the first time in years.
Gaffney GR, Sieg K, Hellings J. 1994. The MOVES: a self-rating Side effects were common, but mild and transient. The scale for Tourette’s syndrome. Journal of Child and Adolescent optimal does was between 10 and 20 mg.
Hood KK, Lourival B-N, Beasley PJ, et al. 2004. Case Study: Severe self-injurious behavior in comorbid Tourette’s Disorder and OCD.
Journal of the American Academy of Child and Adolescent Hounie A, De Mathis A, Santos S, Mercandante MT. 2004. Aripi- In conclusion, we suggest that our patients add to the prazol e syndrome de Tourette. Revista Brasileira de Psiquiatria literature suggesting that aripiprazole may well be a useful medication for treating patients with TS as it is Kastrup A, Schlotter W, Plewnia C, Bartels M. 2005. Treatment of well tolerated and only has mild transient side effects. It tics in Tourette syndrome with aripiprazole. Journal of ClinicalPsychopharmacology 25: 94–96.
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mixed characteristics of aripiprazole as an atypical Robertson MM. 2000. Invited Review. Tourette Syndrome, associ- agent may be particularly effective in some cases, and ated conditions and the complexities of treatment. Brain 123: may include an action at pre-synaptic D2 receptors as Robertson MM. 2004. The Gilles de la Tourette syndrome: an has been suggested for low-dose conventional agonists.
Clearly, further cases should be treated and if possible a Robertson MM. 2006. Tourette Syndrome Attention Deficit hyper- double blind trial against placebo or a head to head activity disorder and Tourette syndrome: the relationship and double blind trial against established neuroleptics such treatment implications. A commentary. European Child andAdolescent Psychiatry Robertson MM, Eapen V. 1996. The National Hospital Interview Schedule for the assessment of Gilles de la Tourette Syndrome.
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Hum Psychopharmacol Clin Exp 2006; 21: 447–453.

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