Current Pharmacologic and Complementary Therapies for Tourette Syndrome

Release Date: January 1, 2014

Expiration Date: January 31, 2016

FACULTY:

Jeffrey Tran, PharmD Candidate 2014
University of Southern California
School of Pharmacy Intern, Pharmacy VA Learning Opportunities Residency (VALOR)
Veterans Affairs Greater Los Angeles Healthcare System
Los Angeles, California

Jennifer Turcios, PharmD Candidate 2014
Western University of Health Sciences
School of Pharmacy Intern, Pharmacy VA Learning Opportunities Residency (VALOR)
Veterans Affairs Greater Los Angeles Healthcare System
Los Angeles, California

Kristie N. Tu, PharmD, BCPS, CGP
Clinical Pharmacy Specialist, Geriatrics
Veterans Affairs Greater Los Angeles Healthcare System
North Hills, California

Janette D. Lie, PharmD, BCACP
Program Manager, Pharmacy
Education and Training Veterans Affairs Greater Los Angeles
Healthcare System
Los Angeles, California

FACULTY DISCLOSURE STATEMENTS:

Mr. Tran, Ms. Turcios, Dr. Tu, and Dr. Lie have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-14-001-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

FEE INFORMATION:

Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

Exam processing and other inquiries to:
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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists regarding Tourette syndrome and the pharmacologic and complementary therapies used to manage this disorder.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Discuss the clinical features of Tourette syndrome (TS).
  2. Describe possible etiologies associated with TS.
  3. Identify pharmacologic and complementary therapies used in the management of TS and specify the rationale for their use.
  4. Explain the role of the pharmacist in managing patients diagnosed with TS. .

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Tourette syndrome (TS) is a neurologic disorder that presents with uncontrolled, irresistible, intermittent motor and/or vocal tics.1 The CDC estimates that 3 out of every 1,000 children between the ages of 6 and 17 years have been diagnosed with TS. Males are three times more likely to be affected than females. Seventy-nine percent of children diagnosed with TS have at least one coexisting mental health, behavioral, or developmental condition, such as attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD).2

The diagnostic criteria for TS are often based on clinical features that include the presence of persistent motor and/or vocal tics for 1 year, onset of symptoms before the age of 18 years, and the absence of other medical conditions or substances that could account for the presenting signs and symptoms (TABLE 1).1 Tics in TS are classified as simple or complex (TABLE 2).1 Simple motor tics are usually short in duration, involving a small number of muscle groups, such as eye blinking, shoulder shrugging, or head jerking. In contrast, complex motor tics (e.g., bizarre gait, kicking, jumping, or writhing movements) are longer in duration and involve multiple muscle groups. Simple vocal tics arise from the contractions of the diaphragm or the oral pharynx causing repetitive throat clearing, sniffing, or grunting. Complex vocal tics include repeating one’s own words or sounds, repeating the last word or phrase heard, or vocalizing obscene words.1


tbl1


tbl2

PATHOPHYSIOLOGY

The precise etiology of TS remains unknown; however, theories involving genetic and environmental factors have been proposed. Although there is no specific genetic abnormality to which TS can be attributed, numerous studies have offered convincing evidence of its inheritability. Environmental factors, such as the possibility of an atypical autoimmune response to a streptococcal infection, may also contribute to the severity of TS.3

Tics are believed to be manifestations of abnormal function in regions of the brain responsible for motor control, such as the frontal cortex and basal ganglia.4,5 Hypertrophy of the thalamus, also responsible for regulating motor function, may play a role.

Abnormalities in various neurotransmitters have been implicated in TS as well. Increased expression of dopamine receptors and excess dopamine in the brain are thought to affect motor control.6 Noradrenergic pathways may also indirectly affect the dopaminergic pathways.7 Low serotonin and tryptophan levels have been identified in patients with behavioral disorders, including TS. More recently, several studies support the role of abnormal gamma-aminobutyric acid (GABA) receptors, the primary inhibitory neurotransmitter of the central nervous system (CNS), in the development of tics.8

TREATMENT

Pharmacologic

Currently, no universally accepted treatment guidelines exist for the management of TS. Medication regimens are often determined based upon limited scientific studies, clinician judgment, and patient preference. The goal of therapy is often directed toward managing the most troublesome symptom(s). Initiation of pharmacologic treatment is only recommended if symptoms of TS interfere with social interaction, school or job performance, or daily activities.

Although the pathophysiology is not completely understood, treatment options have been directed towards correcting the imbalances and abnormalities theorized as causing TS. The most commonly used medications include alpha-adrenergic agonist and antipsychotic agents (TABLE 3).9


tbl3

Alpha-Adrenergic Agonists: Alpha-adrenergic agonists are often recommended as first-line treatment for patients with mild-to-moderate tics due to their relatively tolerable side-effect profile and proven efficacy. Guanfacine and clonidine are commonly used medications in this drug class. These agents bind to alpha2a-adenoreceptors, decreasing sympathetic nerve impulses.10 It is postulated that reduced adrenergic impulses inhibit the overactive dopaminergic pathway responsible for the development of TS.6,7 In addition to symptomatic control in TS, the use of these medications in patients concurrently diagnosed with ADHD has been supported.11

The most common side effects of these medications include somnolence, dizziness, headache, fatigue, dry mouth, constipation, irritability, and hypotension.12,13 Although both agents are effective, guanfacine is often preferred over clonidine due to the lower incidence of somnolence and a more convenient dosing regimen. The recommended starting dosage for guanfacine is 0.25 to 0.5 mg once daily. Doses can be increased by 0.5 mg every week to achieve a maintenance dosage of 0.5 to 3 mg/day. Clonidine may be initiated at dosages of 0.025 to 0.05 mg once daily and increased by 0.05 mg/day every 3 to 7 days for a maintenance dosage of 0.1 mg/day in divided doses. Clonidine patches can be offered as an alternative to patients unable to tolerate oral medications.12-15

Typical Antipsychotics: Typical antipsychotics have a long history of use in the management of TS and are commonly used to treat severe tics. Dopamine levels are typically elevated in patients with TS. These agents block postsynaptic dopamine D2 receptors, leading to a decrease in dopamine levels.16 Efficacy appears to be proportionate to the affinity for D2 receptors. Thus, antipsychotics exhibiting strong D2 receptor blockade, such as amoxapine, haloperidol, pimozide, and fluphenazine, result in the most effective response. TS often responds to doses of psychotropic agents that are typically lower than those used for psychiatric disorders. Therefore, lower initiation doses are recommended and titration is undertaken until therapeutic effects are achieved.

In the United States, haloperidol and pimozide are the only FDA-approved medications for TS treatment.16,17 Haloperidol is initially started at doses of 0.2 to 0.5 mg and can be titrated to a usual maintenance dosage of 0.05 to 0.075 mg/kg/day in 2 to 3 divided doses.16 Pimozide can be initiated at 0.05 mg/kg at bedtime and increased every 3 days up to 0.2 mg/kg/day, not to exceed 10 mg/day. Pimozide is metabolized by CYP2D6. Patients who are slow metabolizers should not exceed doses >0.05 mg/kg/day to avoid accumulation and toxicity.17

Typical antipsychotics have been associated with significant adverse reactions. The most commonly reported include sedation, akathesia, akinesia, dry mouth, sexual dysfunction, constipation, weight gain, muscle rigidity, photophobia, and ECG changes. Additionally, patients on haloperidol may experience amenorrhea, galactorrhea, and gynecomastia, which can negatively impact adolescents and adults.16,17 It is important to note that tardive dyskinesia is an adverse reaction not as commonly seen in patients with TS; however, risk of neuroleptic malignant syndrome still exists.

Atypical Antipsychotics: Atypical antipsychotics are associated with fewer side effects than typical antipsychotics and can be an alternative treatment option. Risperidone has been used off-label in the management of TS. Risperidone acts as a serotonin (5-HT2) and dopamine (D2) receptor antagonist to regulate dopamine pathway function in the brain.18 Bruggeman et al demonstrated that risperidone compared favorably to pimozide in controlling tics.19 In addition, results of a study by Huys et al supported the use of risperidone in patients who were also diagnosed with OCD.20

Studies also support the use of olanzapine in symptomatic control of tics and management of aggression. Aripiprazole, a newer atypical antipsychotic, has also been shown to be effective in controlling tics. Few case studies have shown positive results with quetiapine and ziprasidone; thus, further studies are warranted. In general, atypical antipsychotics are associated with fewer extrapyramidal side effects, such as muscle rigidity and akinesia, but are associated with more profound metabolic effects, such as weight gain, hyperglycemia, hyperlipidemia, and hyperprolactinemia.18,20

Alternative Pharmacologic Agents: Other treatments studied in the management of tics have had varying results and often lack conclusive evidence to support widespread use. Selection of these agents may depend upon the presence of OCD and/or ADHD as a comorbidity. Some therapies investigated include botulinum toxin, baclofen, benzodiazepines, tetrabenazine, antiepileptics, selective serotonin reuptake inhibitors (SSRIs), dopamine agonists, norepinephrine reuptake inhibitors, 5-HT3 receptor antagonists, omega-3 fatty acids, nicotine, and cannabinoids (TABLE 4).


tbl4

Botulinum toxin type A has been an agent of interest in the treatment of TS. It is injected into the affected muscles to target focal motor and vocal tics. Botulinum toxin is widely known for its cosmetic benefits in reducing facial wrinkles, as well as its use in migraine headaches, bladder dysfunction caused by detrusor overactivity, and primary axillary hyperhidrosis.21 In a case report by Scott et al, a 13-year-old boy with complaints of motor and vocal tics who was unsuccessfully treated with numerous agents, including amoxapine, pimozide, guanfacine, and fluphenazine, received a local injection of 30 U of botulinum toxin to the left vocal cord. Within 2 to 3 days of receiving the injection, vocal tics were reduced by at least 75%.22

Though botulinum toxin may reduce the frequency of tics and associated urges, overall benefits are modest.23 Botulinum toxin can be considered in patients who are refractory, particularly those suffering from dystonic tics.

Baclofen is a GABA receptor agonist commonly used as a muscle relaxant. It has been studied as a potential alternative in the treatment of uncontrolled tics. Side effects, which commonly include drowsiness and sedation, are relatively lower in frequency and severity. Studies evaluating the use of baclofen have not consistently shown benefit. Roessner et al concluded that although minimal symptomatic improvements have been seen with treated patients, baclofen may be considered a therapy option.24

Benzodiazepines, such as clonazepam, are thought to reduce tics through GABA modulation. Variable success has been reported.25,26 Tolerance and addiction potential are legitimate concerns; thus, these drugs should be prescribed with caution.

Tetrabenazine is FDA-approved for the treatment of chorea (involuntary movements) of Huntington disease and works by depleting presynaptic dopamine and blocking postsynaptic dopamine receptors.27 Benefits have been seen in patients with severe tics. Though acute adverse reactions parallel those of antipsychotics, the absence of tardive dyskinesias can be an advantage.28

The antiepileptics levetiracetam and topiramate have been used recently to treat tics. These agents also enhance the transmission of GABA, leading to a decrease in tics. Although some results have shown a mean reduction in tics and improvement in behavior, not all studies have observed consistent benefits over placebo.29-31

SSRIs (e.g., clomipramine, paroxetine, fluoxetine) have rendered mixed results in the management of tics. SSRIs address the theory of low serotonin levels and may be a reasonable treatment option in patients with comorbid OCD or depression.32-35

Dopamine agonists (e.g., buspirone, ropinirole) have been investigated in the management of tics. Though counterintuitive, these agents have exhibited some treatment success. Further studies are necessary to determine the place in therapy of this class.36-39

Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) and was the first nonstimulant drug used in the treatment of ADHD. When it was studied in adolescents with ADHD and comorbid tic disorders, a reduction in tic severity was reported.40

Desipramine, a tricyclic antidepressant, also inhibits norepinephrine reuptake, thereby improving tic control. A study conducted by Spencer et al found that patients with chronic tic disorders and comorbid ADHD experienced significant reductions in the frequency of tics.41

Ondansetron, typically used as an antiemetic, is a selective 5-HT3 receptor antagonist that theoretically addresses the proposed low serotonin levels associated with TS and tics. Toren et al found significant improvement in alleviating the severity of tics in patients taking ondansetron versus placebo.42

Omega-3 fatty acids have been widely studied and used as complementary medicine in the management of various psychiatric disorders, including TS. These essential fatty acids have anti-inflammatory properties that may be helpful in tic-associated disorders related to autoimmune etiologies.43

Nicotine has been reported to possibly help with alleviating tics through its anticholinergic effects. Though isolated cases have pointed toward some improvement, more convincing evidence is required to support its use in TS.44,45

Cannabinoids have been shown to decrease the frequency and severity of tics and premonitory urges in adult patients. As expected, their use is limited by side effects such as impaired short-term memory and attention level, as well as the potential to exacerbate psychotic symptoms, such as phobic anxiety. Adequate evidence is necessary to support the use of cannabinoids in treating tics.46,47

Nonpharmacologic Treatment

While pharmacologic treatment for TS can be effective, adverse effects of some agents may be more debilitating than the tics themselves. Currently, habit reversal therapy and exposure and response prevention therapy are used in conjunction with pharmacologic treatment to minimize tics associated with TS.

Habit Reversal Therapy: Habit reversal therapy consists of a multifaceted treatment approach that includes tic recording, awareness training, competing response training, motivation enhancement, and generalization training. While there are many variations of habit reversal therapy that have been tested, it has been observed that the two key components necessary for treatment success include awareness training and competing response training. In awareness training, patients are taught to analyze the tics. Patients learn to become aware of the urges that are often sensed prior to the onset of tics. In competing response training, patients learn to develop a competing behavior, often using the same muscle set to suppress the tic.48

Exposure and Response Prevention Therapy: Exposure and response prevention therapy is another form of cognitive behavioral therapy that involves the theory of habituation, or decreased behavioral responsiveness to repeated stimuli. When used in TS, patients are exposed to the premonitory sensations that precede the motor or vocal tics and develop the ability to prevent the expression of these tics. Strategies are used to repeatedly expose the patient to the urge, thus encouraging the patient to become accustomed to the urge without having to execute the tic.48

Thalamic Deep Brain Stimulation: A newer, proposed nonpharmacologic treatment for TS involves thalamic deep brain stimulation. Porta et al followed patients with refractory TS for up to 2 years following deep brain stimulation.49 These patients reported experiencing diminished tic severity as well as decreased depression, anxiety, and OCD symptoms. Furthermore, patients who underwent deep brain stimulation exhibited no significant change in their cognitive performance when compared to their baseline. While deep brain stimulation may appear promising to selected patients, further studies are necessary to evaluate and validate the efficacy and safety of this therapy option.49

Complementary and Alternative Therapies: Some case reports have documented that acupuncture, hypnosis, dietary alterations, dental devices, and/or homeopathic remedies provide varying degrees of reduction in both the frequency and severity of tics. Although these approaches may be beneficial for some individuals, their effectiveness has not yet been confirmed in well-designed, large clinical trials.50

ROLE OF THE PHARMACIST

The role of the pharmacist in managing patients with TS is to educate these individuals and their families about the various treatment options that are available. Ensuring that patients are appropriately educated on their medications will optimize their adherence, resulting in therapeutic efficacy. Through individualized counseling, pharmacists can actively participate with patients in maximizing symptom control while reducing adverse drug reactions. Pharmacists can also partner with patients to identify issues regarding therapy that warrant discussion with their provider. Fostering a trusting pharmacist-patient relationship will facilitate open lines of communication between patient, pharmacist, and physician, resulting in the best patient care outcomes. For additional resources, please refer to the TABLE 5.


tbl5

CONCLUSION

Tourette syndrome is a condition that remains poorly understood. Since the exact mechanism of TS is unclear, establishing a regimen that balances the reduction of debilitating symptoms with minimal adverse effects can be challenging. Pharmacotherapy should only be considered when symptoms interfere with the patient’s social interactions and school or job performance. No single treatment is effective for all patients. In addition, some patients are refractory to a combination of medications. Nonpharmacologic therapies appear to be helpful in the management of TS. With continued research of new and viable treatment options, there is hope that patients living with TS will one day find promising therapies that offer a cure.


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