Aripiprazole in Children with Tourette's Disorder and Co-morbid Attention-Deficit/Hyperactivity Disorder: A 12-Week,Open-Label,Preliminary Study

Abstract

Tourette's disorder (TD) in children and adolescents is frequently co-morbid with attention-deficit/hyperactivity disorder (ADHD). Dopamine-blockers are the first line treatment for TD, whereas dopamine-agonists, such as stimulants, are the gold-standard in the treatment of ADHD. These contrasting effects supported concerns about the risk that stimulants for treating ADHD may trigger or worsen co-morbid tics. Aripiprazole, a partial dopamine agonist, acts as an antagonist at dopamine D2 receptors in hyperdopaminergic conditions and displays agonist properties under hypodopaminergic conditions. The present study describes the use of aripiprazole (10.0±4.8 mg/day) in a consecutive group of 28 patients with a primary diagnosis of TD and co-morbid ADHD, combined subtype. The Yale Global Tic Severity Scale (YGTSS) and the ADHD-Rating Scale (ADHD-RS-IV) were used as primary outcome measures and both significantly improved (p<0.001) after the treatment. Global measures of severity (Clinical Global Impressions–Severity) and of functional impairment (Children's Global Assessment Scale) also significantly improved during the treatment (p<0.001). At the YGTSS there was a reduction of 42.5%, in motor tics, of 47.9% in phonic tics (44.7% for the combined scores), and of 32.3% in tic impairment. Nineteen patients (67.9%) had a reduction of at least 50% of the YGTSS score (motor+phonic tics). The improvement at the ADHD-RS-IV score was 22.5%, 12 patients (42.8%) presented an improvement of 30%, but only 2 (7.1%) an improvement greater than 50%. Using a logistic regression model, a reduction of at least 30% in ADHD-RS-IV score was more likely to occur in the obsessive-compulsive disorder co-morbid group. Aripiprazole was well tolerated and none of the patients discontinued medication because of side effects. In summary, aripiprazole resulted in an effective treatment for TD, but it was only moderately effective on co-occurring ADHD symptomatology. Our preliminary data suggest that aripiprazole may represent a possible therapeutic option, among other possible monotherapies addressing both tics and ADHD.

Introduction

T ourette's disorder (TD) is a neurodevelopmental disorder with multiple vocal and motor tics (American Psychiatric Association 2000). TD is frequently co-morbid with other disorders involving the basal ganglia, including attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) (Palumbo et al. 1997; Grados and Mathews 2008). In a large sample of 596 subjects with TD, only 24% presented TD only, whereas 32% had TD plus OCD, 10% TD plus ADHD, and 34% TD plus both ADHD and OCD (Grados and Mathews 2008). Data from Medicaid (n=10.247.827) and privately insured youths (n=16.128.828) focusing on tic disorder diagnoses in 4–18 year-olds during a 1-year period, reported a rate of ADHD co-morbidity of 50.2% and 25.9%, respectively (Olfson et al. 2011).

Dopaminergic modulation is a crucial component in both motor and vocal tics and ADHD symptoms, but with contrasting mechanisms. Traditionally, dopamine-blockers are the first line treatment for tics and have the most compelling evidence of efficacy from controlled studies (Du et al. 2010). On the contrary, dopamine-agonists, such as stimulants, are the gold-standard in the treatment of ADHD (Kaplan and Newcorn 2011). These contrasting effects supported concerns about the risk that stimulants for treating ADHD may trigger or worsen co-morbid tics (Cohen et al. 1982; Robertson and Eapen 1992). However, several studies have shown that stimulants are quite effective in controlling ADHD even in the context of TD and they do not inevitably worsen motor or vocal tics (Tourette's Disorder Study Group 2002). A recent meta-analysis (including nine studies and 477 subjects) analyzed the relative efficacy of different medications in children with both TD and ADHD (Bloch et al. 2009). Methylphenidate resulted in the best and most rapid treatment for ADHD and it did not worsen tic severity, at least in the short term. Atomoxetine has been explored as a nonstimulant treatment for ADHD patients with co-morbid TD, with positive effects on ADHD but only mild improvements in tic symptomtology (Spencer et al. 2008). Further, some case studies reported possible recurrences of tics during or following treatment with atomoxetine (Párraga et al. 2007; Sears and Patel 2008).

Alpha-2 agonists (clonidine and guanfacine), which decrease the firing of noradrenaline neurons in locus ceruleus (Scahill 2009), can offer a combined improvement in both tic and ADHD symptoms (Bloch et al. 2009). Clonidine can be effective in both children with TD (Du et al. 2008; Hedderick et al. 2009) and ADHD (Jain et al. 2011), with possible improvements in hyperactivity, impulsiveness, and inattention in children with tic disorders. Also guanfacine significantly improves ADHD symptoms in children with tic disorders (Scahill et al. 2001). However, both clonidine and guanfacine are associated with sedation, fatigue, somnolence, and modest reductions in heart rate and blood pressure (Scahill 2009). A consensus ADHD algorithm for ADHD in TD patients, suggests starting with psychostimulants, followed by atomoxetine or clonidine/guanfacine (Pliszka et al. 2006). In addition, the possibility of a co-therapy with a stimulant and an antipsychotic should also be mentioned, even though this association may be poorly tolerated (Benjamin and Salek 2005; Hollis and Thompson 2007).

Aripiprazole is a newer antipsychotic with a specific mechanism, being a partial dopamine agonist, acting as an antagonist at dopamine D2 receptors in hyperdopaminergic conditions, and displaying agonist properties under hypodopaminergic conditions. Further, it acts as a partial agonist of 5-HT_1A receptor and antagonist of 5HT_2A receptor (Burris et al. 2002). Based on animal models, it has been proposed that the agonist effect on 5-HT_1A receptor may explain the anti-OCD properties of aripiprazole (Matsushita et al. 2005), compared to other atypical antipsychotics, whose potent 5HT_2A antagonism may even worsen OCD symptoms (Gao et al. 2006).

Efficacy and fair tolerability of aripiprazole in youths with TD is supported by several noncontrolled studies or case reports since 2005 (Yoo et al. 2007; Budman et al. 2008; Seo et al. 2008; Lyon et al. 2009; Murphy et al. 2009; Cui et al. 2010; Yoo et al. 2011). Budman et al. (2008) treated 37 patients, 8 of which (22%) discontinued treatment because of side effects (weight gain, akathisia, sedation). The remaining 29 youths, who completed the 12-week trial with a mean aripiprazole dosage of 12.3±7.5 mg/day, improved tic symptomatology (and in all but one their explosive outbursts). In Cui et al. study (2010), 72 children and adolescents participated in an 8-week, open-label trial and showed, at the end point, a 50.3% reduction at the Yale Global Tic Severity Scale (YGTSS), with improvement of behavior symptoms according to Child Behavior Checklist (Achenbach and Edelbrock 1983), and without weight gain. Finally, in a nonrandomized, parallel-group study comparing aripiprazole (n=31) (up to a maximum 20 mg/day) and haloperidol (n=17) (up to a maximum 4.5 mg/day), the two medications showed similar efficacy (rate of response 54.3% with aripiprazole, 63.4% with haloperidol) (Yoo et al. 2011). In this study, only 16% in the aripiprazole group, compared to 35.3% in the haloperidol group, discontinued treatment because of unbearable side effects. Aripiprazole as effective augmenting strategy has been explored in youths with OCD who did not respond to serotonin-selective reuptake inhibitor (SSRI), with an additional positive effect on co-morbid tic disorder (Masi et al. 2010).

Evidence supporting efficacy of aripiprazole on ADHD symptoms is more controversial. Findling and colleagues (2008) explored efficacy of aripiprazole (maximum dose 10 mg/day) in a 6-week, open-label pilot trial including 23 youths, aged 8–12 years with a primary diagnosis of ADHD (14 combined and 9 predominately inattentive subtype). A significant improvement from the baseline was found on clinical measures, ADHD-Rating Scale (ADHD-RS) (DuPaul et al. 1998), Clinical Global Impressions (CGI) (Guy 1976), and Children Global Assessment Scale (C-GAS) (Shaffer et al. 1983). Aripiprazole treatment improved both inattentive and hyperactive symptoms and overall functioning for patients with either the inattentive or the combined subtype of ADHD. Sedation was frequently reported (n=18; 78.3%), but aripiprazole did not have a negative impact on cognitive functioning (Conners' Continuous Performance Test, Reading and Math Fluency, Stroop Color and Word Test).

The present study describes the use of aripiprazole in a consecutive group of patients with a primary diagnosis of TD and co-morbid ADHD, combined subtype, who received aripiprazole for 12 weeks. Efficacy was separately assessed for tic and ADHD symptoms.

Methods

Sample

This is a study based on a clinical database of 28 consecutive patients diagnosed as having TD and co-morbid ADHD (combined subtype), referred to two different tertiary-care hospitals by other hospitals, community-based child psychiatrists or pediatricians, to assess the need for pharmacotherapy. The 28 patients were aged between 8 and 16 years (mean age 12.1±2.3 years, mean age at onset of TD 7.8±1.6 years, 26 males and 2 females). The inclusion criterion for this study was the fulfillment of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) criteria for TD and ADHD, including duration, and impairment (CGI–Severity [CGI-S] score 4 or less; C-GAS score 60 or less), based on a structured clinical interview according to DSM-IV criteria, the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS-PL) (Kaufman et al. 1997). Further, all the patients scored 30 or higher at the YGTSS (Leckman et al. 1989), and 30 or higher at the ADHD-RS-IV.

All patients with mental retardation, pervasive developmental disorders, schizophrenia, or neurological diseases (epilepsy, brain injuries, or cerebral lesions documented by magnetic resonance imaging) were excluded.

Demographic, clinical, and therapeutic features are reported in Table 1.

Table 1.

Baseline Demographic, Clinical, and Treatment Characteristics of Children and Adolescents with Gilles de la Tourette's Disorder and Co-morbid Attention-Deficit/Hyperactivity Disorder (n=28)

Males, n (%)	26 (92.9)
Age, mean (SD)	12.1 (2.4)
Age at onset of Tourette's disor., mean (SD)	7.8 (1.6)
Aripiprazole dosage, mg/day	10.0 (4.8)
Responders, Tourette's disorder, n (%)	19 (67.9)^a
Responders, ADHD, (<30%) n (%)	12 (42.8)^b
Responders, ADHD, (<50%) n (%)	2 (7.1)^c
Co-morbidity, n (%)
Generalized anxiety disorder	4 (14.3)
Panic disorder	1 (3.6)
Social phobia	4 (14.3)
Simple phobia	1 (3.6)
Obsessive-compulsive disorder	12 (42.9)
Oppositional defiant disorder	5 (17.9)
Conduct disorder	2 (7.1)
Pharmacotherapy, n (%)
SSRI	5 (17.9)
Psychotherapy, n (%)	17 (60.7)

50% Reduction of YGTSS from the baseline.

Reduction of 30% of ADHD-RS-IV.

Reduction of 50% of ADHD-RS-IV.

SD=standard deviation; ADHD=attention-deficit/hyperactivity disorder; SSRI=serotonin-selective reuptake inhibitor; YGTSS=Yale Global Tic Severity Scale; ADHD-RS=ADHD-Rating Scale.

Measures

The K-SADS-PL (Kaufman et al. 1997) was individually administered to the parents and to the patients, by child psychiatrists trained in the use of this interview. The K-SADS-PL is a structured interview according to DSM-IV, organized in such a way as to explore the presence or absence of each of the symptoms in different psychiatric syndromes.

The severity of global impairment at baseline and subsequent course during follow-up were assessed monthly by means of the CGI-S and CGI–Improvement scores (CGI-I) (Guy 1976). CGI-S Score is a single item, recorded at the baseline, that rates the severity of global symptomatology on a scale from 1 (“Normal”) to 7 (“Extremely ill”). CGI-I Score is a single item, recorded during the follow-up, that rates behavior from 1 (“Very Much Improved”) to 7 (“Very Much Worsened”). Further, global functional impairment was assessed with the C-GAS (Shaffer et al. 1983) that describes the severity of functional impairment on a scale from 0 (severe impairment) to 100 (superior functioning).

ADHD was explored using the ADHD-RS-IV, a widely used measure of efficacy in clinical trials of ADHD treatments in children and adolescents, derived from the 18 inattentive and hyperactive/impulsive diagnostic criteria for ADHD from DSM-IV (DuPaul et al. 1998).

Current tic symptomatology (vocal and phonic) was assessed with the YGTSS (Leckman et al. 1989), a semi-structured clinical interview with three summary tic scores (total motor, total phonic, total tic) and an impairment scale.

Extrapyramidal side effects were explored by using the Abnormal Involuntary Movement Scale (AIMS) (NIMH 1985).

Primary outcome measures were YGTSS and ADHD-RS-IV at the baseline and at the end point (12 weeks). Further, we considered as a response criterion for TD, a 50% reduction of YGTSS from the baseline. Given that the effect of antipsychotics on tics is well established, although the effect of aripiprazole on ADHD is only putative, both a reduction of 30% and 50% of ADHD-RS-IV were considered as response criteria, to explore both a good and a moderate effect of medication on ADHD symptomatology.

Treatments

All the 39 adolescents received aripiprazole. The titration of aripiprazole was the following. The starting dose of aripiprazole was 1.25 or 2.5 mg in the morning, with subsequent titration of 2.5 mg no more than at 5-day intervals, depending on clinical outcome and occurrence of side effects, but frequently with longer intervals, according to the clinicians' judgments, to better assess the TD response. The maximum dosage was the highest dose associated with a good tolerability and efficacy, with an upper limit of 20 mg/day.

The patients received the medication in the morning and at bedtime. When sleeping disorders were reported, medication was given in the morning and/or at lunchtime.

Five patients were drug-naïve, the other 23 had received previous treatment with antipsychotics (risperidone, pimozide, haloperidol) without significant efficacy or side effects (extrapiramidal side effects and/or weight gain and/or sedation). Five patients previously received methylphenidate, but the medication was discontinued because of worsening of tics. Two of these children also previously received atomoxetine, without improvement of ADHD symptoms and no efficacy on TD. At baseline, all patients were drug-free for at least 1 week.

Five of the 12 patients with co-morbid OCD received an SSRI during the study. Given that SSRIs are not considered an effective treatment for both TD and ADHD, we assumed that this co-therapy did not affect tic and ADHD response to aripiprazole. Seventeen patients (60.7%) were receiving a co-occurring cognitive behavioral therapy at the baseline.

Subjects and parents received detailed information on the characteristics of the assessment instruments and different treatment options; all parents gave a written informed consent, and all the patients gave their consent as well.

Statistical analyses

Descriptive analyses were used to analyze demographic and clinical characteristics of the whole sample. Chi-square analyses were performed on categorical variables and an unpaired t-test on continuous variables. Considering the large number of comparisons, p values were based on two-tailed tests with alpha=0.001, using a post-hoc Bonferroni correction. The odds ratio and 95% confidence interval (CI) were correlated using logistic regression model. The predictive significance for ADHD and TD response to treatment of the following variables was assessed: age (<11 vs. ≥11), age at onset of TD (<7 vs. ≥7), OCD co-morbidity, co-occurring psychotherapy (combined treatment).

Results

This was a sample of severely impaired patients, in terms of clinical severity (CGI-S=5.6±1.0) and functional impairment (C-GAS=42.6±8.2). The most relevant co-morbidity was with OCD (12, that is 42.9%). (Table 1)

The mean aripiprazole dosage was 10.0±4.8 mg/day (range 5–20 mg).

A comparison of baseline and end point scores shows that all the YGTSS scores (number, frequency, intensity, complexity, and interference of both motor and phonic tic) were statistically significant (p<0.001), except for the intensity of phonic tics, whose improvement did not survive Bonferroni correction. Also ADHD-RS-IV total score significantly improved during the treatment (p<0.0001). When the improvement in tic symptomatology was separately assessed for motor and phonic tics and for the impairment, the reduction of the scores was 42.5% for motor tics, 47.9% for phonic tics (44.7% for the combined scores), and 32.3% for tic impairment. The improvement of the ADHD-RS-IV score was 22.5%.

The global measures of severity (CGI-S) and of functional impairment (C-GAS) also significantly improved during the treatment. More specifically, CGI-S improved from 5.6±1.0 at the baseline (severely ill), to 2.7±.9 (mild to moderately ill) at the end of the follow-up (p<0.0001).

The rate of responders in TD according to a reduction of at least 50% of the YGTSS score (motor+phonic tics) was 67.9% (19 patients). According to a categorical measure of clinical response, 12 patients (42.8%) presented an improvement of 30% or more at the ADHD-RS-IV, but only 2 (7.1%) an improvement greater than 50%.

Using a logistic regression model, we assessed and found that a reduction of at least 30% of ADHD-RS-IV score was more likely to occur in the OCD co-morbid group (odds ratio 8.333; 95% CI 1.344–51.671, p<0.001). No significant associations occurred for age (<11 vs. ≥11), age at onset of TD (<7 vs. ≥7), and psychotherapy (combined treatment). These possible predictors were not associated with a reduction of YGTSS score of at least 50%.

Aripiprazole was well tolerated with no patients discontinuing medication because of side effects. Six patients (21.4%) experienced mild sedation, four patients (14.3%) mild to moderate agitation, prevalently in the first 2 weeks, four (14.3%) complained of mild and transient nausea, two (2.6%) of increased appetite. One patient had to reduce the aripiprazole dose at week 12 due to mild hand tremor that remitted after decrease of aripiprazole dosage from 7.5 to 5 mg/day. No other patients presented extrapyramidal symptom (EPS) according to the AIMS. No significant effects were revealed in blood parameters, prolactin levels, electrocardiogram, weight, height, blood pressure, and cardiac frequency during the follow-up period. Of note, cognitive functioning did not appear to be negatively impacted by aripiprazole treatment, based on scholastic performance reported on school records.

Discussion

ADHD symptoms are frequently under-recognized in youths with TD, especially when tics are more severe, and often undertreated with stimulants because of concerns about a possible worsening of tics. Although stimulants have not been shown to worsen tics in most people with tic disorders, they may nonetheless exacerbate tics in individual cases (Pringsheim and Steeves 2011). Antipsychotics can be effective in ameliorating tic symptomatology, but the blockade of dopaminergic transmission may further worsen the inattention symptomatology of ADHD. Alpha-adrenergic agents may be effective in improving both tic and ADHD symptoms, but they are sometimes only moderately effective in TD, compared to antipsychotics. There is still limited evidence suggesting that aripiprazole, based on its partial dopamine agonism, may be effective in the treatment of tics and it may also ameliorate ADHD symptoms.

Our data indicate that aripiprazole is effective in reducing tic symptoms, with an improvement of both motor and vocal tics, except for intensity of phonic tics. However, number, complexity, and interference of phonic tics significantly improved. The reduction of combined motor and phonic tics was 44.7%. The impairment deriving from TD was also significantly improved by aripiprazole. About two-thirds of the youths experienced a significant improvement in tic symptomatology (improvement of at least 50% of total YGTSS score).

Regarding ADHD symptomatology, aripiprazole is only moderately effective. Although the ADHD-RS-IV score significantly improved after treatment, the improvement was only 22.5%. Further, 42% of the patients presented an improvement greater than 30% at the ADHD-RS-IV, but only 7.1% of the patients showed an improvement greater than 50%. When selected predictors of clinical response were considered for TD and ADHD, only OCD co-morbidity was associated with a better response to ADHD symptoms (improvement of at least 30% of ADHD-RS-IV score). This finding may be related to the possible improvement of OCD symptoms after aripiprazole treatment (Masi et al. 2010) with secondary beneficial effects on attention. Not alternatively, the ADHD-OCD association may represent a specific pattern of co-morbidity, with greater incidence in males, an earlier onset of OCD, a greater psychosocial impairment, and a heavier co-morbidity (tic disorders, bipolar disorder, oppositional defiant disorder/conduct disorder) (Geller et al. 2002; Masi et al. 2006). The co-morbidity among ADHD, OCD, and Tourette's disorder, based on the partial overlap of neurobiological basis of these disorders (Grados and Mathews 2008) is more often characterized by a higher frequency of aggressive behavior and explosive outbursts of rage, independent of tic severity or age (Stephens and Sandor 1999), with putative sensitivity to specific treatments, such as aripiprazole.

The lower improvement in ADHD symptomatology may be partly affected by the dosage of aripiprazole, which was relatively high (10±4.8 mg/day), in order to adequately improve tic symptoms. Lower dosages may be more beneficial for ADHD symptoms, as they are associated with higher dopamine agonism. Optimal dosages for TD and ADHD may be thus different, and an accurate balance between higher and lower aripiprazole dosages may be one of the main focuses of treatment of these patients.

When the effectiveness of treatment was assessed with global measures of clinical severity and functional impairment (such as CGI-S and C-GAS), patients presented a positive response in their overall symptomatology and impairment. This is relevant, considering that aripiprazole was well tolerated in terms of both side effects and cognitive functioning. However, the short duration of the follow-up limits strong conclusions on safety, namely on weight gain or EPS, which may appear later in the course of treatment.

This study should be considered in light of several methodological limitations. First of all, our results are not based on a randomized, placebo-controlled study, but on an open study on a small sample, and this limits evaluation of response. Thus our findings should be considered preliminary. Further, there is no comparison to other active treatments of TD+ADHD, such as stimulants alone, or stimulants plus antipsychotics. Finally, the short duration of the follow-up limits conclusions of long-term efficacy and safety, particularly on EPS and weight gain. However, our findings describe an unselected sample of children and adolescents with TD and co-morbid ADHD. Clinical open studies, albeit not controlled, might represent a helpful source of information regarding the effectiveness of a treatment under more ordinary clinical conditions.

Conclusions

Our findings indicate that aripiprazole monotherapy is effective on tic symptoms, with similar improvements in both motor and phonic tics, and on functional impairment. The effective dosage of aripiprazole is relatively high (10.0±4.8 mg/day). On the contrary, the response of the symptoms of ADHD is only moderate, and it does not approach that seen with stimulants or even atomoxetine. A positive predictor of response to ADHD symptoms is the co-morbidity with OCD. At least in the first 12 weeks of treatment, aripiprazole is well tolerated, in particular on weight gain and EPS. Further research is needed to support these data with randomized, placebo-controlled studies with larger samples. Further, studies addressing the optimal dosages of aripiprazole for both tics and ADHD symptoms may indicate a more effective titration strategy.

Clinical Significance

Co-morbid ADHD in patients with TD is far from rare, and it can strongly affect the clinical picture, resulting in a more severe impairment of quality of life, psychosocial outcome, and social competence (Hoekstra et al. 2004; Roessner et al. 2007). Similarly, tics are a strong indicator of a more severe psychopathology in ADHD patients and their management should be considered a priority (Schneider et al. 2009). For this reason, both the disorders must be considered in the treatment plan, including the choice of the pharmacotherapy. A possible strategy is a combined treatment aimed at controlling TD and ADHD with distinct medications (i.e., antipsychotics for TD, stimulants for ADHD), with higher rates of efficacy, but with higher risks of side effects, particularly dyskinesias and dystonias (Benjamin and Salek 2005; Hollis and Thompson 2007). An alternative strategy is to consider a monotherapy with medications having at least a putative efficacy on both TD and ADHD (Singer 2010). Aripiprazole monotherapy may be considered as a possible option when tic disorder is the prevalent component of the clinical picture, and/or when a previous treatment with stimulants determined a worsening of tic symptomatology, and/or when alpha(2)-agonists were not effective or poorly tolerated, and/or when an OCD is co-morbid. In these situations aripiprazole may avoid the association between antipsychotics and stimulants. Finally, in patients with a good response on TD but poorer response on ADHD, aripiprazole-stimulants association may be more effective on ADHD symptoms and better tolerated than the association between stimulants and other first- or second-generation antipsychotics, with potential negative impact on cognition.

Footnotes

Disclosures

Dr. Masi, consultant for Eli Lilly, Shire, and Novartis, has received research grants from Eli Lilly and has been speaker for Eli Lilly, GlaxoSmithKline, Sanofi-Aventis, Janssen Cilag, and Astra-Zeneca. Dr. Gagliano has received research grants from Shire and has been speaker for Novartis and Shire. Dr. Pfanner has received research grants from Eli Lilly and has been speaker for Eli Lilly. Drs. Siracusano, Berloffa, Calarese, Ilardo, Magazù, and Cedro do not have disclosures to declare.

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