Tics and Tourette syndrome: An adult perspective
ABSTRACTTourette syndrome (TS) is a disorder characterized by childhood onset multiple motor and vocal tics often accompanied by features of obsessive compulsive disorder, attention deficit hyperactivity disorder (ADHD), or other behavioral manifestations. Tics may be simple or complex, and may include motor and vocal components. Abnormal function of the basal ganglia is thought to be an important underlying cause of tics and other movement disorders. Treatment of TS requires a thorough understanding of the phenomenology of the disease for the individual patient, and should focus on symptoms that are especially troubling. Some nonpharmacologic approaches may help to improve tic severity, including conditioning techniques, relaxation training, and hypnosis. Options for pharmacotherapy include dopamine blockers and depleters, benzodiazepines, central alpha-adrenergic blockers, and botulinum toxin. Many patients require therapy for comorbid conditions such as anxiety, depression, or ADHD. In case studies and small patient series, deep brain stimulation has been shown to markedly reduce tic severity and functional impairment associated with TS. While onset is most frequently in childhood, TS should not be considered exclusively a disorder of pediatric patients. The complications and comorbidities that are encountered in children and adolescents often persist into adulthood.
PHARMACOLOGIC TREATMENT: THREE TIERS
First-tier therapies
The alpha-adrenergic blockers clonidine and guanfacine are first-tier therapies. Treatment should be initiated at a low dose and escalated gradually according to response, which is determined by the severity, and not the presence, of tics. Clonidine may be administered at a dose of 0.025 mg two or three times daily or, for maintenance, 0.1 mg three times daily; another option is 0.1, 0.2, or 0.3 mg weekly by transdermal administration. Guanfacine may be administered at a dose of 1 mg once daily. Alpha-adrenergic blockers are useful for the treatment of mild tics, and are considered first-line therapy for tic suppression. Side effects may include dry mouth, somnolence, and, rarely, blood pressure fluctuations.
Agents that affect gamma-amino butyric acid (GABA) neurotransmission have been associated with improved symptoms of tic disorders.18 For example, both clonazepam and diazepam have been reported to reduce TS symptoms.18 Both of these benzodiazepines are associated with sedation, blunting of cognition, and exacerbation of depression, however.19,20
Second-tier therapies
Second-tier therapies, consisting of neuroleptics, induce a rapid treatment response. Haloperidol may be started at a dose of 0.25 mg once daily, with a maintenance dosage of 0.5 to 3.0 mg/day. Cognitive blunting or extrapyramidal side effects are rare in patients with TS, but the potential for these side effects should be thoroughly discussed with the patient or parent/guardian before treatment. Pimozide 0.5 mg (2 to 6 mg/day for maintenance) may be associated with tremor or parkinsonian symptoms (predominantly akinesia). Risperidone 0.25 mg/day (0.5 to 4 mg/day for maintenance), olanzapine 2.5 mg/day (5 to 10 mg/day for maintenance), and quetiapine 25 mg twice daily (100 to 300 mg/day for maintenance) are associated with potential adverse effects of extrapyramidal symptoms, weight gain, and diabetes.
Third-tier therapies
Dopamine agonists (reserpine and tetrabenazine) and botulinum toxin are third-tier therapies. Reserpine, although rarely used in current clinical practice, may be administered at doses of 0.1 to 0.25 mg/day, titrating upward on the basis of clinical response. Tetrabenazine may be administered at a starting dose of 12.5 mg/day, with higher doses as needed depending on the response to treatment. Adverse effects include hypotension, sedation, extrapyramidal symptoms (predominantly parkinsonism), and depression.21
The exact mechanism by which tetrabenazine produces this suppression effect is unknown, but it is believed to be related to its effect of reversibly depleting monoamines. At least three neuronal protein classes regulate the effects of dopamine on voluntary and involuntary movement.22 The two presynaptic proteins are vesicular monoamine transporter subtype 2 (VMAT2) and dopamine transporter (DAT). Postsynaptically, dopamine activity is regulated by G-protein–linked dopamine receptors (eg, the D2 receptor). Tetrabenazine reduces the uptake of monoamines (including dopamine) into synaptic vesicles by reversibly binding to VMAT2, resulting in degradation of dopamine within axon terminals by monoamine oxidases.23 By blocking dopamine transport, tetrabenazine depletes dopamine with greater selectivity than it does other monoamines.24
The dosage of tetrabenazine for the treatment of motor disorders, particularly chorea, was established in the Huntington Study Group (HSG) clinical trial.25 In the HSG trial, a starting dose of 12.5 mg on day 1 was increased to 12.5 mg twice daily on days 2 to 7, and then by 12.5 mg/day at weekly intervals until the desired clinical effect, intolerable adverse effects, or a maximum dose of 100 mg/day was reached. Daily dosages of 37.5 mg or more are administered in three divided doses. Adverse events (reported in 70% of patients who received placebo and 91% of patients who received tetrabenazine) include sedation or somnolence, insomnia, and fatigue.21 These findings may be carried over to patients with tics.
Botulinum toxin may also help to control tics—especially dystonic tics. The premonitory symptoms of TS are usually unaffected by botulinum toxin.26 The adverse effect profile for patients with TS is similar to that of patients with dystonia or facial dyskinesia, and may include soreness, transient weakness, ptosis (if injected for eye blinking), and mild transient dysphagia (if injected into the larynx).27
MANAGING COMORBID CONDITIONS
Approximately 30% of patients with TS also have OCD.28 Treatment options include selective serotonin reuptake inhibitors at standard doses, and the tricyclic antidepressant clomipramine (25 mg once or twice daily, or 75 mg/day in sustained-release form). Trazodone, a serotonin antagonist and reuptake inhibitor that is associated with a lower incidence of anticholinergic effects, may be initiated at a dose of 50 mg/day and slowly increased to 150 to 400 mg/day depending on clinical response.
As many as 60% of patients with TS may also have ADHD.28 Methylphenidate is helpful for the treatment of ADHD and does not exacerbate tics, but it is a restricted medication. The recommended dose is 20 mg once daily, titrated upward as needed based on response. Atomoxetine carries a warning regarding increased risk of suicide. It has also been associated with an increased risk of sexual dysfunction and behavioral changes, including aggressive behaviors, agitation, and irratibility.29
