This chapter presents a comprehensive analysis of the clinical characteristics of the entire patient study sample at baseline and following treatment with the antipsychotic aripipra-zole. The presented work details clinical data related to the objectives of this thesis and reflects partial material published in peer review-journal article: Gerasch S., Kanaan A.S., Jakubovski E. and Müller-Vahl K.R. Aripiprazole improves associated comorbid Conditions in addition to Tics in adult Patients with Gilles de la Tourette Syndrome.
Frontiers in Neuroscience 2016; 10: 416 [384].
10.1 Abstract
Gilles de la Tourette Syndrome (GTS) is characterized by motor and vocal tics, as well as associated comorbid conditions that include obsessive-compulsive disorder (OCD), attention deficit/hyperactivity disorder (ADHD), depression, and anxiety. Although randomized controlled trials including a large number of patients are lacking, aripiprazole is currently considered as a first choice drug for the treatment of tics. The aim of this study was to further investigate efficacy and safety of aripiprazole in a group of drug-free, adult patients. Specifically, we investigated the influence of aripiprazole on tic severity, comorbidities, premonitory urges, and quality of life (QOL). Moreover, we were interested in the factors that influence a patient’s decision in electing for-or against-pharmacological treatment. Utilizing a prospective, uncontrolled open-label longitudinal study design, 44 patients were recruited and assessed via a number of rating scales to assess tic severity, premonitory urges, comorbidities, and QOL at baseline and during treatment with aripiprazole. Eighteen out of 44 patients elected for undergoing treatment for their tics with aripiprazole and completed follow-up assessments after 4-6 weeks. Our
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major findings were(a)aripiprazole resulted in significant reduction of tics, but did not affect premonitory urges;(b)aripiprazole significantly improved OCD and showed a trend toward improvement of other comorbidities including depression, anxiety, and ADHD;
(c) neither severity of tics, nor premonitory urges or QOL influenced patients’ decisions for or against treatment of tics with aripiprazole; instead patients with comorbid OCD tended to decide in favor of, while patients with comorbid ADHD tended to decide against tic treatment; (d) most frequently reported adverse effects were sleeping problems; (e) the patients QOL was mostly impaired by comorbid depression. Our results suggest that aripiprazole may improve associated comorbid conditions in addition to tics in patients with GTS. It can be hypothesized that these beneficial effects are related to aripiprazole’s adaptive pharmacological profile, which exhibits an influence on the dopaminergic as well as a number of other neurotransmitter systems. For the first time, our data provide evidence that a patients’ decision in undergoing treatment is also influenced by factors other than tic severity and QOL.
10.2 Introduction
Although different therapeutic strategies are currently being used to treat patients with GTS (e.g. behavioral therapy, pharmacotherapy, and surgical interventions), no currently used treatment is able to target the multiple symptoms associated with GTS. With respect to pharmacological treatment, recommendations are currently based only on a small number of controlled or uncontrolled studies, as large sample and longitudinal randomized controlled trials (RCT) have not been conducted yet [6]. Nonetheless, there is general agreement that antipsychotic agents targeting the dopaminergic system are most effective in the treatment of tics. Currently, haloperidol remains as the only antipsychotic that is formally approved for the treatment of GTS in most European countries. However, haloperidol is no longer being prescribed in Germany and most European countries, since it is associated with the emergence of significant adverse effects (e.g. extrapyramidal symptoms, sedation and weight gain) [385]. Owing to their more favorable therapeutic profile, second generation antipsychotics (e.g. risperidone, aripiprazole, sulpiride, and tiapride) have become the most common off-label substances used for the treatment of tics [6]. Specifically, aripiprazole has become the favorite neuroleptic in many centers for treating tics given its remarkable efficacy and favorable side effect profile [91].
Currently, aripiprazole is approved by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of schizophre-nia, bipolar I disorder, and manic episodes [386]. Although large RCTs are lacking, aripirazole is used for the treatment of GTS symptoms since: (a) it is better tolerated
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and causes less side effects relative to other antipsychotic drugs [170], and(b)is effective in severely affected and otherwise treatment-refractory patients. Therefore, many clini-cians classify aripiprazole as first choice medication in the treatment of tics [6]. To date, varied groups have investigated the efficacy and safety of aripiprazole in the treatment of tics in GTS. However, the majority of these studies focused on child and adolescent patients groups. In one of the largest RCTs, Ghanizadeh and Haghighi [387] investi-gated the effects aripiprazole on the treatment of tics in 60 children and adolescents with tic disorders. Aripiprazole resulted in a significant reduction of both motor and vocal tics (Yale Global Tic Severity Scale — YGTSS), as well as a significant improvement of quality of life (QOL). In general, aripiprazole was well tolerated, although some adverse effects were reported including drowsiness (25.8%) and increased appetite (25.8%). A systematic review of published literature has revealed that aripiprazole is effective in the treatment of tics in both adults and children with GTS with an adverse effect profile that seems to be safer than in other antipsychotic drugs [388].
Interestingly, studies exploring the clinical effects of aripiprazole on the treatment of psychiatric comorbidities in GTS are few in number. Investigating the influence of arip-iprazole on psychiatric comorbidities in GTS is particularly interesting given that it is, in essence, a functionally selective modulator that is able to stabilize multiple neu-rotransmitters systems, which may exhibit varying abnormalities within the different sub-classifications of GTS [171]. Thus, it may be plausible to suggest that aripiprazole may amerliorate both tics and psychiatric comorbid features including OCD, ADHD, depression, anxiety and rage attacks. Along this line, Wenzel et al. [170] reported that 5 of 100 patients exhibited improvements in depression, anxiety, and aggression follow-ing treatment with aripiprazole. Other works investigatfollow-ing the effects of aripiprazole in OCD have demonstrated that it can successfully ameliorate obsessive-compulsive symp-toms [389,390]. For ADHD, results were variable as one study showed a strong influence on reducing attention deficit scores [167], while another study reported a moderate ef-fect on a child and adolescent population [391]. In contrast, Frölich [392] investigated the influence of aripiprazole on OCD and ADHD in GTS patients and reported that aripiprazole did not significantly influence psychiatric comorbidities. In the two pub-lished controlled trials investigating the effect of aripiprazole on GTS [387,393], no data on treatment effects with respect to psychiatric symptoms were reported. Thus, given the lack of published data, the effect of aripiprazole on the treatment of GTS-related comorbidities is not currently clear.
As such, the aim of this study was to investigate the effect of aripiprazole on tics and comorbid conditions in a large group of unmedicated adult patients with GTS. Our primary goal was to investigate the effect of aripiprazole on tics, quality of life, premoni-tory urges (PU) in addition to psychiatric comorbidities (depression, OCD, anxiety, and
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ADHD). As treatment with aripiprazole was voluntary for the sample, we were able to compare clinical data between the sub-samples that elected for and against aripiprazole administration. Our hypothesis was that aripiprazole improves both tics and behavioral problems in adult and otherwise untreated patients with GTS, and that those patients tend to choose treatment with aripiprazole suffer from more severe tics and lower quality-of-life.
10.3 Methods
10.3.1 Population Sampling
Forty-four right-handed adult patients with GTS (18-65 years) were recruited from the outpatient Clinic of Psychiatry, Social Psychiatry and Psychotherapy at Hannover Med-ical School according to DSM-5 criteria [19]. Patients using any psychoactive substances underwent a four-week washout period before participation. Exclusion criteria were(a) ages below 18 or above 65 years, (b) inability to lie still in Magnet Resonance Imaging (MRI) system, (c) known MRI contraindications such as metals, tattoos, and claustro-phobia as well as pregnancy and breastfeeding. The study was approved by the ethics committees of Hannover Medical School and the University of Leipzig. All participants gave written informed consent before participating the study.
10.3.2 Clinical Assessment
All patients underwent a neuropsychiatric interview and a comprehensive clinical assess-ment battery including measureassess-ments of tics, premonitory urges; QOL, and psychiatric comorbidities (OCD, ADHD, depression, anxiety, and autism) as described in Chapter 5.
10.3.3 Statistical Analysis
Statistical analysis was performed in the Statistical Package for Social Sciences (SPSS, Version 20). Descriptive statistics were computed for all measurements. Treatment ef-fects in terms of pre/post-comparison of the tic severity and comorbidity scores were carried out using the Wilcoxon-Mann-Whitney-Test for paired samples. The baseline characteristics of patients electing for- and against-treatment with aripiprazole were compared using the Wilcoxon-Mann- Whitney-Test for independent samples. All sta-tistical tests were two-sided and the alpha value was set at 0.05. No adjustment for
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multiple comparisons was performed due to the exploratory nature of the analysis. To inspect patients’ compliance to drug intake, aripiprazole serum levels were correlated with administered oral dosage via Pearson correlation.
10.4 Results
10.4.1 Patient characteristics at baseline
Clinical data was collected from a total of 44 patients (9 Females, 39.4±12.2 years). The sample exhibited moderate tic severity (YGTSS-TTS =22.2±8.5, scale range = 3–39;
RVTRS=9.6±5.0, scale range = 0–18) and a mean comorbidity score of 1.36 (range 0-4) (Tables 10.1and10.2).
Table 10.1: Subgroup classification of the whole study sample based on comorbidities
Baseline Follow-up
Overall Untreated Treated Treated
N=15 N=26 N=18 N=18
GTS only 15 9 6 8
GTS+comorbidities 29 17 12 10
GTS+OCD 8 2 6 2
GTS+ADHD 8 8 1 1
GTS+OCD+ADHD 7 4 3 2
Others 6 3 2 5
GTS=Gilles de la Tourette Syndrome; OCD=Obsessive-Compulsive Disorder; ADHD=Attention-Deficit/Hyperactivity Disorder; N=Number of cases; Others=Patients with comorbidities that do not fulfill criteria for one of the other defined subgroups.
The others group included N = 6 for depression, N = 6 for anxiety, N = for
The comorbidities include OCD, ADHD, depression, and anxiety depression+anxiety
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Table 10.2: Clinical characteristics of the whole study sample at baseline and following treatment with aripirazole
M.I.N.I. OCD current N=6 N=9 N=7 -2
Y-BOCS 3.7±6.9 5.3±6.9 4.2±5.5 -1.1
M.I.N.I. panic current N=3 N=1 N=1 —
agoraphobia N=4 N=3 N=3 — Hyperactive-Impulsive 51.4±13.3 51.1±14.4 51.5±9.4 0.4 ADHD total 53.1±14.8 52.3±14.9 54.2±12.3 1.9 YGTSS, Yale Global Tic Severity Scale; TTS, Total Tic Score; MT, Motor Tic Score; VT, Vocal Tic Score; GS, Global Score; MRVS, Modified Rush Video-Based Tic Scale; PU, Premonitory Urge; PUTS, Premonitory Urge for Tics Scale;
OCD, Obsessive-Compulsive Disorder; M.I.N.I., International Neuropsychiatric Interview; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; OCI-R, Obsessive-Compulsive Inventory Revised; MD, Major Depression; BDI, Beck Depression In-ventory; MADRS, Montgomery Asberg Depression; GAD, Generalized Anxiety Disorder; BAI, Beck Anxiety Inventory, AQ, Autism-Spectrum-Quotient; ADHD, Attention-Deficit/Hyperactivity Disorder; CAARS, Conners Adult ADHD Rating Scale (for patients treated with aripiprazole, CAARS scores are given for N = 15/17 due to missing data), WURS-k, Wender Utah Rating Scale; DSM, Diagnostic and Statistical Manual; QoL, Quality of Life (the higher the sum, the lower the QoL); VAS, Visual Analogue Scale (the higher the sum, the higher the satisfaction). Clinical diagnosis, Diagnoses for comorbidities as defined above; N, Number of cases. *p < 0.05, **p < 0.01.
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Figure 10.5: Prevalence of comorbidities in patients that elected for- and against-treatment with aripiprazole.
indicated that: (a)aripiprazole is an effective and safe treatment for the treatment of tics as well as for comorbid OCD and possibly other comorbidities such as ADHD, depression and anxiety; (b) aripiprazole has no influence on premonitory urges; (c) patients with comorbid OCD are more likely to vote for medical treatment to reduce their of their tics when compared to those with comorbid ADHD; and(d) tic severity, premonitory urges;
QOL do not influence the patients’ decision making process.
10.5.1 Efficacy of aripiprazole on tics and premonitory urges
Our findings are in line with preliminary data demonstrating that aripiprazole results in a significant improvement of tics (according to YGTSS-TTS and RVTRS) in the majority of adult patients with GTS [168, 170, 388, 394–397]. On the other hand, aripiprazole did not result in a significant improvement of PU. To the best of our knowledge, this is the first study, investigating the effect of aripiprazole on premonitory urges in adult patients with GTS. Thus, from our results it is suggested that effective treatment of tics is possible without improvement of PU. These findings support recent clinical studies
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suggesting that premonitory urges is not as closely related to tic severity as previously assumed [398,399].
10.5.2 GTS subgroup classification
For a thorough clinical characterization of our sample, a number of clinical assessment tools were utilized to diagnose and quantify each of the commonly associated psychiatric comorbidities. Specifically, three rating scales were used for each of obsessive-compulsive, inattention/hyperactivity and depressive symptoms, while two rating scales were used for anxiety. Nevertheless, it is well known that the use of different assessments — although developed for the measurement of the same symptoms — may reflect different sides of the same disorder and therefore, may lead to inconsistent findings. In addition, it is generally accepted that patients’ self-perception may differ from professional evaluation [400] resulting in discrepant results when using self-ratings compared to examiner rating scales [401]. For example, the subtle differences of commonly used depression rating scales were pointed out by Uher et al. [239], who showed that HAMD-17, MADRS and BDI-II, while all being valid and reliable scales, reflect “internally consistent but mutually distinct estimates of depression severity”. While the MADRS is closer to the core of depression observable from the outside the BDI represents a “cognitive” dimension -which is more of an internal experience. Uher et al. [239], therefore, recommended to use these scales in a complementary fashion. Comparably, we found contrary results when using the BDI-II as a self-rating compared to the MADRS as an expert rating: while treatment with aripiprazole resulted in a decrease in mean BDI-II values, mean MADRS scores increased. A closer investigation showed that this obvious inconsistency was due to the high incidence of “sleep disturbances” (44.4%) and “internal unrest” (16.7%), which were the most frequently reported AEs during treatment with aripiprazole. While having little impact on the BDI-II score, the presence of these symptoms had a considerably high impact on the MADRS scores leading erroneously to high scores for depression.
10.5.3 Efficacy of aripiprazole on associated comorbid conditions
According to defined diagnoses, treatment with aripiprazole resulted in a significant improvement of OCD, although respective assessments for OCD demonstrated no signif-icant changes at follow-up compared to baseline. Due to the relatively small number of patients, results in other psychiatric comorbidities did not reach statistical significance.
However, treatment with aripiprazole, resulted in the remission of comorbid depression in 4 of 6 patients, of comorbid anxiety in 4 of 6 patients, and of comorbid ADHD in 1 of 4 patients. Accordingly, the mean comorbidity score decreased from 1.38 at baseline to
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1.16 at follow-up. Furthermore, pathologically autistic traits remitted in 1 of 2 patients and absolute scores (according to AQ) improved in 8 patients.
Our findings corroborate available case reports in patients with GTS reporting about beneficial effects of aripiprazole in the treatment of depression [167, 170], OCD [167, 389, 390], anxiety, self-injurious behavior [170], inattention [167], and ADHD [391], but in contrast to preliminary results by Frölich [392] who found no improvement of ADHD and OCD in children with GTS. However, in none of these studies the effect of arip-iprazole has been investigated specifically for the treatment of psychiatric comorbidities, comorbidities were not assessed by using a variety of self- and examiner-ratings, and, at least in part, data were collected retrospectively from patient records.
Furthermore, our findings in GTS are completely in line with data in patients with pure OCD, where aripiprazole has been found to be effective not only in the treatment of uncomplicated OCD [402], but even in patients resistant to treatment with selective serotonin reuptake inhibitors [403–406]. Aripiprazole has also been found helpful in the treatment of depression [407] and anxiety disorders [408,409]. It is even one of the most often prescribed medication in patients with anxiety and mood disorders [410]. In ADHD
— although often prescribed [410] — its efficacy has not been demonstrated [411].
The effective influence of aripiprazole on a number of psychiatric conditions has been suggested to be a result of its unique pharmacological profile. Specifically, aripiprazole is a functionally selective drug that exhibits an adaptive pharmacological profile that is de-pendent on the local levels of the endogenous ligands. Aripiprazole is a partial dopamine D2 agonist, a partial serotonin 5-HT1A agonist, and a 5-HT2A antagonist. Apart from its recognized influence on the dopaminergic and serotonergic systems, aripiprazole has also been shown to modulate the glutamatergic and GABAergic neurotransmitter sys-tems [171]. Therefore, it can be speculated that beneficial effects of aripiprazole on OCD, depression and anxiety in patients with GTS may be the result of its ability to selectively and adaptively stabilize multiple neurotransmitter systems.
10.5.4 Influence of aripiprazole on quality of life
Comparable to previous reports by Müller-Vahl et al. [412] and Jalenques et al. [413], we found that in adult patients with GTS both QOL and satisfaction-with-life (as assessed by GTS-QOL and GTS-QOL-VAS) are mainly impaired by depression. This was the case at baseline and also during treatment with aripiprazole. Although aripiprazole resulted in a significant improvement of tics, we only found a trend towards an improvement in patients’ QOL. This is in line with the finding that depression influences patients’ QOL more than the tics. Interestingly, we found a significant correlation between premonitory
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urges and QOL at baseline. Assuming that premonitory urges is a kind of an OCB as suggested recently [414] and against the background that it is well-known that OCD significantly impairs QOL in adult patients with GTS [412], this correlation can possibly be explained by the negative influence of OCD on patients’ QOL. The complex interplay between tics, comorbidities, and QOL is also expressed in changes in the YGTSS-GS:
this “global score” of the YGTSS is a measurement for both tic severity and overall impairment. Completely in line with all above mentioned results, after treatment with aripiprazole we found a much greater reduction of the YGTSS-GS (p=0.002) compared to the tic score of the YGTSS (YGTSS-TTS, p=0.027).
10.5.5 Adverse effects of aripiprazole
Although AEs were reported by a substantial number of patients (66.7%), most AEs were mild and/or tolerable corroborating recent data that in most adult patients with GTS aripiprazole is well tolerated [170,396]. No serious AEs occurred. 3 of 18 patients (16.7%) decided to stop treatment with aripiprazole due to AEs such as drowsiness, internal unrest, sleep disturbance, and restlessness of legs. Comparable to our data, Wenzel et al. [170] also reported about the occurrence of AEs in nearly 2/3 (59%) of their patients. However, in contrast to our results, they found drowsiness (20%) to be the most common side effect, while sleep disturbances were quite rare (9%). In this study, sleep disturbances (44.4%) followed by internal unrest (16.7%) were the most often reported AEs, while drowsiness occurred in only 11.1% of our patients. This difference might be explained by different study designs and different treatment durations (4-6 weeks in our study vs. 1-60 months in Wenzel et al. [170]. Hence, it can be assumed that in the context of a longer-term treatment, patients may tolerate drowsiness rather than internal unrest and sleep disturbances. Nonetheless, our data further support the clinical practice to start treatment with aripiprazole once daily in the morning, and to postpone intake to the evening, if significant drowsiness occurs.
10.5.6 Decision factors for treatment with aripiprazole
Our study design provided us with the possibility of investigating the factors that influ-ence patient’s decision in electing for- or against-treatment. This choice was solely based
Our study design provided us with the possibility of investigating the factors that influ-ence patient’s decision in electing for- or against-treatment. This choice was solely based