Tics in children and adolescents are a common occurrence; however, a small proportion of these disorders require pharmacologic interventions. Several limitations exist with the use of pharmacologic interventions, and hence, a more ideal multidisciplinary approach is recommenced, with emphasis on nonpharmacologic management for improved functioning, adaptation, and comorbidities. Mutual and realistic goals ensure a trustful and successful relationship between the clinician and patient. An individualized plan is recommended with the goal of limiting side effects and managing comorbid conditions as a priority before addressing the tics specifically. This article reviews medications used to treat tic disorders in children and adolescents.
Tics are patterned repetitive movements or vocalizations. They are classified as simple or complex. Simple motor tics are brief, sudden, repetitive movements involving only a few muscle groups, such as eye blinks, facial grimacing, shoulder or head jerks. Simple vocalization includes throat clearing, sniffing, barking, coughing, or grunting. Complex motor tics are coordinated patterns involving several muscle groups, such as facial grimacing with a head twist and shoulder shrug. They may seem purposeful, such as spinning and jumping. Complex vocal tics include uttering words or phrases, including coprolalia (uttering swearwords) or echolalia (repeating the words or phrases of others). Often tics are preceded by an urge or sensation in the affected muscles, commonly called a premonitory urge. Patients often describe the urge to complete the tic to get rid of this feeling. Tics are often exacerbated by anxiety or excitement and alleviated by calm and more focused activities such as playing an instrument or a video game. Tics may be present during sleep but often to a much less degree.
Typically, the onset is at school age, around 7 years, with a peak in the midteen years and a significant improvement in most by the late teens and early adulthood. About 10% of children have a progressive and disabling course that lasts into adulthood. There is a strong male preponderance. The tics are often episodic and intermittent with a waxing and waning course; also, they change in location, severity, and frequency over time. Tics are the hallmark of Tourette syndrome (TS). TS is a childhood neuropsychiatric disorder characterized by motor and vocal (phonic) tics. It often has associated behavioral comorbidities such as obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in addition to other learning disorders. Tic disorders are genetic and thought to run in families, although a specific gene locus is yet to be found.
TS was first described by a French neurologist (Gilles se la Tourette) and his student (Charcot) in 1885; they described 9 children with childhood-onset tics. It was not until the 1960s that treatment with neuroleptic medications was found favorable. This possibility also marks the shift of considering TS as a primarily psychogenic disorder to a neurologic disorder.
Pathophysiology
The pathophysiology of tics is not completely understood, although the basal ganglia, in particular the caudate nucleus and the inferior prefrontal cortex, have been implicated. Dysfunction within the cortico-striatal-thalamic-cortical circuits results in an inability to suppress unwanted movements, impulses, and behaviors. Multiple neurotransmitters are likely involved, given this large area of brain involvement. The role of dopamine has been studied in TS with specific interest. Functional neuroimaging studies suggest abnormalities in the dopaminergic systems located in the striatum and prefrontal cortex. Patients with TS have increased levels of dopamine receptors, suggesting increased uptake and release of dopamine. The sensitivity to dopamine may explain the response of dopamine receptor blockers in patients with TS.
There is some speculation as to an immune-mediated pathogenesis such as that seen in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. This hypothesis suggests an antecedent infection with group A β-hemolytic streptococci, leading to the formation of antineuronal antibodies that result in brain dysfunction. No current immune therapies are recommended in the treatment of TS.
Clinical concepts
Tic criteria including criteria for TS have been developed by the American Psychiatry Association’s Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision). TS causes marked distress or significant dysfunction in occupational, social, or other important areas of functioning; such dysfunction was thought to have a significant stigma with implications that could lead to discrimination within the workforce. There are many patients with TS who are not significantly impaired by this condition. It is important to recognize associated behavioral symptoms such as inattention, hyperactivity, impulsivity, obsessive-compulsive traits, learning disorders, and other school difficulties. Specific screening for mood-related disorders, such as depression and anxiety, are also helpful when evaluating and managing these patients.
Children and adolescents with tics or TS should otherwise have a completely normal neurologic examination; also, they should have a normal mental status examination. If the patient does not show any behavior of tics in the office, it is helpful to have the family videotape the tics to exclude other movement disorders such as myoclonus, chorea, tremor, and dystonia. A good developmental history is important to exclude underlying genetic disorders such as Down syndrome, fragile X syndrome, or autistic spectrum disorders. The physical examination (including a meticulous gait and tone assessment) should exclude dysmorphic features, neurocutaneous disorders, and signs of neurodegenerative disorders such as Kayser-Fleischer rings in the eyes diagnostic of Wilson disease, spasticity, and chorea suggestive of Huntington disease or associated disorders.
Clinical concepts
Tic criteria including criteria for TS have been developed by the American Psychiatry Association’s Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision). TS causes marked distress or significant dysfunction in occupational, social, or other important areas of functioning; such dysfunction was thought to have a significant stigma with implications that could lead to discrimination within the workforce. There are many patients with TS who are not significantly impaired by this condition. It is important to recognize associated behavioral symptoms such as inattention, hyperactivity, impulsivity, obsessive-compulsive traits, learning disorders, and other school difficulties. Specific screening for mood-related disorders, such as depression and anxiety, are also helpful when evaluating and managing these patients.
Children and adolescents with tics or TS should otherwise have a completely normal neurologic examination; also, they should have a normal mental status examination. If the patient does not show any behavior of tics in the office, it is helpful to have the family videotape the tics to exclude other movement disorders such as myoclonus, chorea, tremor, and dystonia. A good developmental history is important to exclude underlying genetic disorders such as Down syndrome, fragile X syndrome, or autistic spectrum disorders. The physical examination (including a meticulous gait and tone assessment) should exclude dysmorphic features, neurocutaneous disorders, and signs of neurodegenerative disorders such as Kayser-Fleischer rings in the eyes diagnostic of Wilson disease, spasticity, and chorea suggestive of Huntington disease or associated disorders.
Treatment
Tics often do not have any associated social or physical impairments, and hence, the greater majority of children with TS do not require any medication. Providing reassurance is encouraged, and education for families with written resources is helpful. Screening and addressing associated comorbidities are also important in the assessment and management of pediatric patients with tic disorders. The management of TS involves a multifaceted approach that includes the medical management of the frequent or disabling tics, medical and behavioral management of the coexisting behavioral symptoms, as well as educating and supporting the family. Often, a collaborative effort is needed, which includes the primary care physician, neurologist, psychiatrist, psychologist, family members, and school professionals.
Engaging classroom strategies that nurture self-esteem and self-correction is important in these patients. Behavioral counseling by an experienced psychologist is important, and beneficial behavioral techniques include conditioning techniques, competing response training, awareness training, habit reversal, relaxation training, biofeedback, and hypnosis. Often, parents and other care givers may benefit from behavioral management and discipline training with regard to the coexisting behavioral symptoms as well.
Pharmacologic treatments
Medical therapies are reserved only for tics that interfere with social interactions, school performance, or activities of daily living (ie, loss of self-esteem, peer difficulties, disruption of classroom setting, or musculoskeletal or physical discomfort). Unfortunately, there is no single medication that is helpful to all children and adolescents with tics, and conversely, no medication completely eliminates all symptoms of tic disorders. Rather, the goal of treatment is to control the tics such that the child or adolescent can encounter less embarrassment and discomfort from the tics. The treating physicians should be aware of the natural variability with waxing or waning of symptoms, placebo response, and strong influence of the environment, as well as other psychopathologies on outcome.
A comprehensive review of published studies with regard to pharmacologic therapies by Robertson and Gilbert highlight the limitations including small numbers in trials especially for children; few placebo-controlled trials; open-label trials, usually single-site studies; and the lack of pharmaceutical industry support that often funds larger trials.
According to the Tourette Syndrome Association’s Medical Advisory Board guidelines ( www.tsa-usa.org ), evidence-based studies support the use of dopamine blocking agents such as haloperidol, pimozide, and risperidone for TS. However, due to untoward side effects such as weight gain and sedation, often other agents are used first, as discussed later. A large randomized controlled trial supported the use of stimulants, specifically methylphenidate and clonidine, in children or adolescents with tics that have not worsened due to the stimulants. Clinical experience supports the use of stimulants in children with tics, especially if comorbid ADHD is present.
Emphasis should be placed on treating coexisting behavioral symptoms such as ADHD, anxiety, and obsessive-compulsive traits. The general principles of treatment are outlined in Box 1 . Tables 1–4 provide information about the different treatment agents available for tic disorders.
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Set realistic expectations at the start. Achieving a goal of modest tic suppression is realistic, and it is unlikely that complete abolishment will occur
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Address and treat significant comorbidities first
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Start at low doses, with gradual increments
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Evaluate frequently (at least monthly) for efficacy and side effects
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Use one drug at a time, as much as possible
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Seek specialist guidance once nonneuroleptic medications have failed
| Clonidine | Guanfacine | |
|---|---|---|
| Mechanism of action | α 2 -adrenergic agonist | α 2 -adrenergic agonist |
| Initial dose | 0.05 mg daily Titrate by 0.05 mg increments every 3–7 d | 0.5 mg daily Titrate every 3–14 d to an usual dose of 1.5–3.0 mg daily |
| Maximum dose | 0.4 mg daily Give in divided doses | 4 mg daily Give in 3 divided doses |
| Half-life | 8–12 h | 17 h |
| Drug interactions | Hypotensive agents Antidepressants with α 2 -antagonist properties | Hypotensive agents Antidepressants with α 2 -antagonist properties |
| Side effects | Sedation Dry mouth Headache/dizziness Constipation Orthostatic hypotension | Sedation Dry mouth Headache/dizziness Constipation |
| Precautions/warnings | Severe CV disease Caution in ESRD | Severe CV disease |
| Monitoring parameters | Blood pressure Heart rate | Blood pressure Heart rate |
| Comments | Discontinuation: titrate off to prevent withdrawal effects Taper over 1 wk to prevent rebound hypertension | More selective Less likely to have withdrawal effects |
| Atomoxetine | Baclofen | Clonazepam | |
|---|---|---|---|
| Mechanism of action | Inhibits norepinephrine reuptake | Exact mechanism unknown Inhibits monosynaptic & polysynaptic reflexes at the spinal level | Binds to BZD receptor site on GABA complex and enhances GABA activity |
| Initial dose | 0.5 mg/kg/d in 2 divided doses >70 kg: 40 mg/d | 10–15 mg daily in 3 divided doses | 0.5–12.0 mg daily Divided doses |
| Maximum dose | 1.8 mg/kg/d
| 60–80 mg daily in 3 divided doses | Same as above |
| Half-life | 5–21 h
| 2.5–4.0 h | 22–33 h |
| Drug interactions | CYP2D6 substrate MAO inhibitors (avoid concurrent use) Sympathomimetic agents CYP2D6 inhibitors/inducers | CNS depressants | CYP3A4 substrate CYP3A4 inhibitors/inducers CNS depressants |
| Side effects | Hypertension Tachycardia Insomnia Decreased appetite Headache Early morning awakenings Allergic reactions Severe liver injury (rare) | Hypotension Sedation Fatigue Dizziness Headache Rash Nausea/constipation | Ataxia Sedation Depression Concentration decreased Dizziness Change in behavior Physical dependence Psychological dependence |
| Precautions/warnings | Increased risk of suicidal ideation Avoid in patients with cardiac disease Use in hepatic dysfunction Use in CYP2D6 poor metabolizers | Patients with
| Patients with
|
| Monitoring parameters | ECG at baseline BP & HR | None noted | CBC LFTs |
| Comments | Cardiovascular assessment recommended before initiation Two divided doses: morning & late afternoon/early evening Active metabolite with equal potency | Avoid abrupt withdrawal Dose-related side effects may be minimized by slow titration Take with food or milk | Avoid abrupt discontinuation Gradually taper C-IV restriction |
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