Treatment of Children and Treatment of Children and Adolescents With Tic Adolescents With Tic

DisordersDisorders

شاهرخ دکترامیری

تخصص فوقو کودک روانپزشکی

نوجوانپزشکی دانشکده دانشیار

تبریز

EpidemiologyEpidemiology

The prevalence of CTD has been The prevalence of CTD has been estimated as 0.5% to 3%,with estimated as 0.5% to 3%,with approximately 7% of school age approximately 7% of school age children having had tics in the children having had tics in the previous year.previous year.

It is estimated that the It is estimated that the prevalence of transient tics is prevalence of transient tics is approximately 5%. approximately 5%.

This figure may be an This figure may be an underestimate, given that most underestimate, given that most cases of tics are mild and may be cases of tics are mild and may be misdiagnosed or unrecognized by misdiagnosed or unrecognized by medical professionals.medical professionals.

Prevalence rates for all tics Prevalence rates for all tics (chronic or transient) range from (chronic or transient) range from 5.9% to 18% for boys and from 5.9% to 18% for boys and from 2.9% to 11% for girls.2.9% to 11% for girls.

In general, CTD have a male In general, CTD have a male preponderance, with a gender preponderance, with a gender ratio of at least 2:1 or higher.ratio of at least 2:1 or higher.

Tic disorders have been reported Tic disorders have been reported in numerous Asian, Middle in numerous Asian, Middle Eastern, and European samples. Eastern, and European samples.

Medications for CTD should be Medications for CTD should be considered for moderate to considered for moderate to severe tics causing severe severe tics causing severe impairment in quality of life impairment in quality of life or when medication or when medication responsive psychiatric responsive psychiatric comorbidities are present comorbidities are present that target both tic symptoms that target both tic symptoms and comorbid conditions. and comorbid conditions.

Large, multi-site, randomized, Large, multi-site, randomized, placebo-controlled trials for the placebo-controlled trials for the treatment of tic disorders are few treatment of tic disorders are few in number, especially in pediatric in number, especially in pediatric populations .populations .

Most medication treatment Most medication treatment studies target moderate to severe studies target moderate to severe tic severity, resulting in symptom tic severity, resulting in symptom reduction but not remission. reduction but not remission.

Despite the limited number of Despite the limited number of studies, however, medical studies, however, medical treatments for tics should have treatments for tics should have evidence-based support whenever evidence-based support whenever feasible.feasible.

The only 2 Food and Drug The only 2 Food and Drug Administration (FDA)–approved Administration (FDA)–approved medications to treat TD are medications to treat TD are haloperidolhaloperidol and and pimozidepimozide; however, ; however, most clinicians use atypical most clinicians use atypical antipsychotics before these agents.antipsychotics before these agents.

A clinician survey found that the A clinician survey found that the most common medications used most common medications used to treat tics are to treat tics are risperidonerisperidone followed by followed by clonidineclonidine then by then by aripiprazole.aripiprazole.

And another survey found And another survey found aripiprazolearipiprazole to be most commonly to be most commonly used, followed by used, followed by clonidineclonidine followed by followed by risperidonerisperidone..

α-2 Agonistsα-2 Agonists   α-Adrenergic medications have α-Adrenergic medications have

demonstrated an effect size of 0.5 demonstrated an effect size of 0.5 for the amelioration of tics.for the amelioration of tics.

Some prescribers prefer α-2 Some prescribers prefer α-2 agonists as first-line agents over agonists as first-line agents over antipsychotic medications because antipsychotic medications because of the adverse effect profile, of the adverse effect profile, which is perceived as less serious which is perceived as less serious than with antipsychotic than with antipsychotic medications. medications.

A recent meta-analysis found that A recent meta-analysis found that trials that enrolled subjects with trials that enrolled subjects with tics and ADHD demonstrated a tics and ADHD demonstrated a medium-to-large medium-to-large effect in reducing tic severity effect in reducing tic severity (0.68), whereas trials (0.68), whereas trials that excluded subjects with ADHD that excluded subjects with ADHD demonstrated only a small, demonstrated only a small, nonsignificant benefit (0.15).nonsignificant benefit (0.15).

ClonidineClonidine activates the presynaptic activates the presynaptic auto-receptors in the locus ceruleus, auto-receptors in the locus ceruleus, thereby reducing norepinephrine thereby reducing norepinephrine release that may diminish tics. release that may diminish tics.

The starting dose is 0.05 mg per day The starting dose is 0.05 mg per day with gradual increases up to 0.3 mg with gradual increases up to 0.3 mg per day to control tics often per day to control tics often administered in divided doses 3 to 4 administered in divided doses 3 to 4 times per day. The main adverse times per day. The main adverse effect limiting its use is sedation.effect limiting its use is sedation.

A transdermal patch of clonidine A transdermal patch of clonidine is available, as is a sustained is available, as is a sustained release oral formulation that was release oral formulation that was recently approved for the recently approved for the treatment of ADHD, but has not treatment of ADHD, but has not been studied for use in children been studied for use in children and adolescents with CTD.and adolescents with CTD.

Compared to clonidine, guanfacine Compared to clonidine, guanfacine appears to bind more selectively appears to bind more selectively to postsynaptic prefrontal α (2A)–to postsynaptic prefrontal α (2A)–receptors to enhance functioning receptors to enhance functioning of prefrontal cortex.of prefrontal cortex.

A double-blind, placebo-controlled A double-blind, placebo-controlled trial showed efficacy for tic trial showed efficacy for tic severity. A sustained release severity. A sustained release formulation has been approved for formulation has been approved for ADHD and trials for CTD are ADHD and trials for CTD are underway.underway.

Antipsychotic Antipsychotic MedicationsMedications  

HaloperidolHaloperidol has been shown to be has been shown to be effective in several randomized effective in several randomized controlled trials (RCTs); however, controlled trials (RCTs); however, up to 84% of patients have up to 84% of patients have experienced adverse events with experienced adverse events with roughly one-third having roughly one-third having extrapyramidal side effects.extrapyramidal side effects.

A haloperidol and pimozide A haloperidol and pimozide placebo-controlled crossover trial placebo-controlled crossover trial found pimozide to be more found pimozide to be more effective at reducing total number effective at reducing total number of tics and to be better tolerated of tics and to be better tolerated as compared with haloperidol.as compared with haloperidol.

Although much lower doses are Although much lower doses are needed when using typical or needed when using typical or atypical antipsychotics for CTD atypical antipsychotics for CTD than for bipolar or psychotic than for bipolar or psychotic disorders, a careful risk/benefit disorders, a careful risk/benefit assessment and adverse effect assessment and adverse effect monitoring are recommended.monitoring are recommended.

Concerns about adverse effects Concerns about adverse effects have led to studies with the atypical have led to studies with the atypical antipsychotics for the treatment of antipsychotics for the treatment of TD.TD.

The best studied atypical The best studied atypical antipsychotic to date is antipsychotic to date is risperidonerisperidone with 4 randomized controlled trials with 4 randomized controlled trials however only 1 of the trials was however only 1 of the trials was conducted exclusively with children conducted exclusively with children and adolescents, showing and adolescents, showing risperidone to be an effective risperidone to be an effective treatment.treatment.

Active comparator trials (clonidine Active comparator trials (clonidine and pimozide versus risperidone) and pimozide versus risperidone) found found risperidonerisperidone at least as at least as effective.effective.

In pediatric subjects, common In pediatric subjects, common adverse effects were adverse effects were weight gain weight gain and mild to moderate and mild to moderate sedationsedation. No . No clinically signficant extrapyramidal clinically signficant extrapyramidal symptoms in pediatric patients symptoms in pediatric patients were observed.were observed.

Effective doses for patients with TD Effective doses for patients with TD ranged from ranged from 1.0 to 3.5 mg 1.0 to 3.5 mg per day.per day.

In an RCT of In an RCT of ziprasidoneziprasidone, a 39% , a 39% decrease on the YGTSS scale decrease on the YGTSS scale compared to 16% for placebo was compared to 16% for placebo was observed.observed.

No differences were found in vital No differences were found in vital signs or ECG measures. Despite signs or ECG measures. Despite those results, concerns about those results, concerns about ECG changes persist. ECG changes persist.

A prospective study evaluating A prospective study evaluating ECG changes in pediatric patients ECG changes in pediatric patients taking ziprasidone for TD, OCD, or taking ziprasidone for TD, OCD, or a pervasive developmental a pervasive developmental disorder reported a mean increase disorder reported a mean increase in the in the QTcQTc interval from baseline interval from baseline to peak of 28 ± 26 milliseconds, to peak of 28 ± 26 milliseconds, leading to a recommendation of leading to a recommendation of obtaining obtaining screening ECGs screening ECGs read by read by experienced cardiologists if experienced cardiologists if considering ziprasidone treatment.considering ziprasidone treatment.

Several open-label or pilot trials Several open-label or pilot trials of of olanzapineolanzapine have been have been published and 1 double-blind published and 1 double-blind crossover with olanzapine and crossover with olanzapine and pimozide.pimozide.

Only 2 of these studies were with Only 2 of these studies were with pediatric patients.pediatric patients.

In these trials, although In these trials, although olanzapine resulted in a decrease olanzapine resulted in a decrease in both tics and aggression, there in both tics and aggression, there was a mean increase in weight of was a mean increase in weight of 9 to 12 pounds.9 to 12 pounds.

Thus, despite potential reduction Thus, despite potential reduction of tics and co-occurring of tics and co-occurring symptoms, the risk of weight gain symptoms, the risk of weight gain and metabolic effects suggests and metabolic effects suggests that that olanzapine should not be the olanzapine should not be the first line medication for CTD.first line medication for CTD.

A recent open-label trial with A recent open-label trial with aripiprazolearipiprazole found a 52% found a 52% reduction in the Korean version reduction in the Korean version of the YGTSS with 79% of patients of the YGTSS with 79% of patients reported to be “much improved” reported to be “much improved” or “very much improved” on the or “very much improved” on the CGI-I.CGI-I.

The mean dose in this study was The mean dose in this study was 9.8 mg per day; the most 9.8 mg per day; the most common adverse effects were common adverse effects were hypersomniahypersomnia (37.5%), (37.5%), nauseanausea (20.8%), and (20.8%), and headache headache (16.6%). (16.6%).

In open trials of youth with CTD, In open trials of youth with CTD, tic improvement was observed at tic improvement was observed at lower doses with mean weight lower doses with mean weight gain of 2 to 5 pounds.gain of 2 to 5 pounds.

Treatment in Context of Treatment in Context of Comorbidity Comorbidity Comorbid OCDComorbid OCD   

The efficacy of pharmacotherapy The efficacy of pharmacotherapy for OCD in pediatric populations for OCD in pediatric populations has been demonstrated in several has been demonstrated in several controlled trials with controlled trials with clomipramineclomipramine and and SSRIsSSRIs . .

Some studies suggest that the Some studies suggest that the presence of tics may yield a less presence of tics may yield a less robust response to SSRIs. robust response to SSRIs.

In a response rate analysis from a In a response rate analysis from a large pediatric paroxetine trial, the large pediatric paroxetine trial, the response rate for patients with a response rate for patients with a diagnosis of OCD only (75%) was diagnosis of OCD only (75%) was significantly greater than patients significantly greater than patients with comorbid psychopathology, with comorbid psychopathology, for example, ADHD (56%), tic for example, ADHD (56%), tic disorder (53%), and ODD (39%).disorder (53%), and ODD (39%).

Similarly, individuals with Similarly, individuals with comorbid tics in the Pediatric OCD comorbid tics in the Pediatric OCD Treatment Study (POTS) did not Treatment Study (POTS) did not respond as well to sertraline as respond as well to sertraline as did those without tics.did those without tics.

The use of an The use of an antipsychotic with antipsychotic with SSRI SSRI therapy may result in therapy may result in additional benefit for those with additional benefit for those with OCD and tics. OCD and tics.

Current recommendations for the Current recommendations for the treatment of comorbid tics and treatment of comorbid tics and OCD are to use the approprite OCD are to use the approprite agent indicated for each agent indicated for each symptom.symptom.

For example,one may combine an For example,one may combine an α-2 Agonists or atypical neurolptic α-2 Agonists or atypical neurolptic with an SSRI to target significant with an SSRI to target significant tics and OCD symptoms.tics and OCD symptoms.

Comorbid ADHD Comorbid ADHD 

Treatment of ADHD in the context Treatment of ADHD in the context of tic disorders can, at times, be of tic disorders can, at times, be challenging because of concerns challenging because of concerns of worsening tic severity.of worsening tic severity.

For children with ADHD, recent For children with ADHD, recent studies have demonstrated that studies have demonstrated that tics are not universally increased tics are not universally increased by stimulant medicationby stimulant medication . .

No differences were observed in No differences were observed in worsening of tics in children with worsening of tics in children with comorbid ADHD and a CTD taking comorbid ADHD and a CTD taking methylphenidate, clonidine, or methylphenidate, clonidine, or placebo, with about 20% in each placebo, with about 20% in each group showing an exacerbation.group showing an exacerbation.

The presence of tics did appear to The presence of tics did appear to limit the maximum dose limit the maximum dose achieved.achieved.

Current recommendations is to Current recommendations is to provide stimulant treatment for provide stimulant treatment for ADHD symptoms with comorbid ADHD symptoms with comorbid tic disorder, monitoring for the tic disorder, monitoring for the exacerbation of tics.exacerbation of tics.

Other options are the use of Other options are the use of atomoxetineatomoxetine with reported with reported benefits on tic symptoms as well benefits on tic symptoms as well as ADHD however, occasional as ADHD however, occasional reports of tics worsening exist.reports of tics worsening exist.

GuanfacineGuanfacine has been shown to has been shown to have a clinically relevant effect have a clinically relevant effect size for both ADHD and tic size for both ADHD and tic symptoms.symptoms.

TCAsTCAs have shown benefit for have shown benefit for ADHD with comorbid tics, but ADHD with comorbid tics, but cardiovascular risks likely cardiovascular risks likely outweigh the benefit of this outweigh the benefit of this option.option.

Some studies of Some studies of desipraminedesipramine have suggested potantial efficacy have suggested potantial efficacy for treatment of tics in patients for treatment of tics in patients with comorbid ADHD.with comorbid ADHD.

Comorbid Comorbid Mood/Anxiety (Non-Mood/Anxiety (Non-OCD)OCD)    This area is understudied, but This area is understudied, but

clearly many youth with TD have clearly many youth with TD have co-occurring mood and non-OCD co-occurring mood and non-OCD anxiety disorders.anxiety disorders.

Currently, the best approach is to Currently, the best approach is to use evidence based treatment for use evidence based treatment for the co-occurring mood or anxiety the co-occurring mood or anxiety disorder.disorder.

Stress and anxiety are known to Stress and anxiety are known to exacerbate tics, and the use of exacerbate tics, and the use of the SSRIs to reduce dysfunctional the SSRIs to reduce dysfunctional anxiety may indirectly serve to anxiety may indirectly serve to reduce tics.reduce tics.

Explosive/Rage Explosive/Rage SymptomsSymptoms   

Anger and rage outbursts are not Anger and rage outbursts are not uncommon among patients with uncommon among patients with tics, with a survey of clinicians tics, with a survey of clinicians estimating estimating 37% 37% of their tic of their tic patients present with anger patients present with anger control problems.control problems.

In some cases, OCD symptoms or In some cases, OCD symptoms or sensory issues (too hot, too noisy) sensory issues (too hot, too noisy) may serve as triggers, and other may serve as triggers, and other times anger is due to poor times anger is due to poor frustration tolerance.frustration tolerance.

Behavioral therapies that address Behavioral therapies that address antecedents and anger antecedents and anger management may be useful. In management may be useful. In clinic-referred tic samples, up to clinic-referred tic samples, up to 80% 80% of youth are estimated to of youth are estimated to have co-occurring disruptive have co-occurring disruptive behavior disorders.behavior disorders.

There are no controlled There are no controlled pharmacological studies in youth pharmacological studies in youth with tic disorders and with tic disorders and aggressive/anger outbursts. aggressive/anger outbursts.

Although there are preliminary Although there are preliminary data for data for olanzapineolanzapine, , aripiprazolearipiprazole and and risperidonerisperidone,in reducing ,in reducing disruptive behavior disorder disruptive behavior disorder symptoms, these findings should symptoms, these findings should be interpreted cautiously given be interpreted cautiously given significant design limitations, significant design limitations, small samples, relatively weak small samples, relatively weak effects, and risks associated with effects, and risks associated with these medications.these medications.

Deep brain stimulation, Deep brain stimulation, repetitive magnetic repetitive magnetic stimulation, special diets, and stimulation, special diets, and dietary supplements lack dietary supplements lack empirical support for the empirical support for the treatment of CTD/TD and are treatment of CTD/TD and are not recommended.not recommended.

Deep brain stimulation (DBS) is a Deep brain stimulation (DBS) is a surgical treatment approach that surgical treatment approach that may hold benefit for a few may hold benefit for a few treatment-refractory adults; treatment-refractory adults; however, few cases have been however, few cases have been reported of youth receiving DBS reported of youth receiving DBS for severe, treatment-resistant for severe, treatment-resistant tics.tics.

At this time, DBS guidelines have At this time, DBS guidelines have advised that this procedure advised that this procedure should not be conducted in should not be conducted in individuals less than 25 years of individuals less than 25 years of age outside of a research setting, age outside of a research setting, because the severity of TD often because the severity of TD often diminishes in late teen/early diminishes in late teen/early adulthood.adulthood.

An open-label study examining An open-label study examining repetitive transcranial magnetic repetitive transcranial magnetic stimulation (rTMS) in youth with stimulation (rTMS) in youth with TD has been conducted with no TD has been conducted with no reported adverse outcomes.reported adverse outcomes.

Small studies examining rTMS in Small studies examining rTMS in the treatment of adults with TD the treatment of adults with TD have shown negative results.have shown negative results.

Very few youth have received Very few youth have received rTMS and this treatment option rTMS and this treatment option should be considered preliminary should be considered preliminary until larger blinded studies have until larger blinded studies have resolved issues regarding the resolved issues regarding the safety, ethics, and long term safety, ethics, and long term impact on development.impact on development.

Notably, neurosurgery and Notably, neurosurgery and neurostimulation should be neurostimulation should be considered only in refractory considered only in refractory cases, and clinicians should cases, and clinicians should carefully weigh the risks and carefully weigh the risks and benefits for these experimental benefits for these experimental procedures before recommending procedures before recommending them for use in pediatric patients.them for use in pediatric patients.

Botulinum toxin Botulinum toxin blocks blocks acetylcholine release at the acetylcholine release at the neuromuscular junction and neuromuscular junction and produces a temporary, reversible produces a temporary, reversible diminution of muscle activity,which diminution of muscle activity,which may last weeks to months for may last weeks to months for dystonic tics.dystonic tics.

Botulinum toxin may be the most Botulinum toxin may be the most useful agent for the treatment of useful agent for the treatment of solitary, troublesome dystonias eg: solitary, troublesome dystonias eg: ear-wigglingear-wiggling tics and tics and laryngeallaryngeal tics. tics.

Many parents have found Many parents have found purported therapies (e.g., special purported therapies (e.g., special diets, supplements) via the diets, supplements) via the Internet or support groups. Internet or support groups.

Although many patients with tic Although many patients with tic disorders do use complementary disorders do use complementary and alternative medical therapies, and alternative medical therapies, support for this practice is not support for this practice is not currently at the evidence based currently at the evidence based level.level.

Some therapies, such as Some therapies, such as high-high-dose vitamin B6dose vitamin B6, have the , have the potential for adverse outcomes or potential for adverse outcomes or interactions with psychoactive interactions with psychoactive medications and are not medications and are not recommended until studied recommended until studied appropriately in children.appropriately in children.