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UntitledMEDICATIONS AND TOURETTE’S DISORDER:
COMBINED PHARMACOTHERAPY AND DRUG INTERACTIONS
Barbara Coffey, M.D., Cheston Berlin, M.D., Alan Naarden, M.D.
Tourette Syndrome (TS) or Tourette’s Disorder (DSM IV) is a complex neuropsychiatricdisorder characterized by a changing pattern of motor and vocal tics that begin in childhood. Many individuals with Tourette Syndrome have associated non-tic symptoms such ashyperactivity, distractibility, impulsivity, obsessions and compulsions, anxiety, depression, andanger control. These associated symptoms may occur in patterns of frequency or intensitycharacteristic of an additional comorbid (coexisting) disorder such as Attention DeficitHyperactivity Disorder (ADHD), Obsessive Compulsive Disorder (OCD), or OppositionalDefiant Disorder (ODD). Whether these problems are an integral part of Tourette Disorder orare separate problems is under investigation. They may result in difficulties in school, in thework place and with social adjustment. Frequently these associated problems or comorbiddisorders are a source of more distress or impairment to the individual with TS than the tics. Notall patients with tics meet the formal diagnostic criteria for Tourette Syndrome but the tics maystill have significant intensity to warrant treatment. Medication Treatment: General Indications
Medication treatment can be beneficial in both reducing the tics and the behavioral andemotional problems in the individual with Tourette’s Disorder or other tic disorders. Whensymptoms are mild, treatment may include only support, education and monitoring. Forsymptoms that produce significant distress or impairment, medication treatment may beindicated. Currently there are a variety of medications available for the treatment of tics and thenon-tic symptoms. There is no single medication, which is helpful to all individuals with tics orTourette Syndrome. Tics are often mild and will frequently at least partially remit in manyindividuals, particularly as they go through adolescence. Often it is the behavioral andemotional features that cause the most difficulty for the child.
Tic symptoms that cause interference in the child’s functioning or cause significant distress aretargets for medication treatment with the goal of reducing tic severity and frequency. Forindividuals with mild to moderate tics, specific medications effective for tic reduction includeclonidine (Catapres) or guanfacine (Tenex). For individuals with moderate to severe tics, thenewer atypical neuroleptics such as risperidone (Risperdal) or older traditional neuroleptics suchas haloperidol (Haldol) may be indicated. The decision to use medication should take intoaccount a variety of factors in addition to tic severity such as the child’s age, medical history andpast history of response to medication. Typically one medication can be used over period ofseveral months or longer until the tics have abated.
For many individuals, the primary symptoms requiring treatment may be behavioral oremotional, such as hyperactivity, impulsivity or obsessions and compulsions. Medications thattarget the non-tic symptoms such as antiobsessionals (selective serotonin reuptake inhibitors or SSRIs) or medications for Attention Deficit Hyperactivity Disorder such as methylphenidate(Ritalin), dextroamphetamine (Dexedrine, Addreall), or atomoxetine (Strattera) may beindicated. These medications may or may not have direct effects on the tics, in addition to theeffects on the behavioral or emotional symptoms.
Monotherapy or Targeted Combined Pharmacotherapy
If the major symptoms include both tics and behavioral or emotional difficulties, medicationmay be effective to address both sets of symptoms. The first option is called monotherapy whenjust one medication is used to address two or more problems; this strategy is recommended ifpossible as a first choice since it is easiest to use and may have the best compliance. Thephysician may start with one agent that can address both the tics and the non-tic symptoms suchas clonidine for tics and ADHD or clonazepam (Klonopin) for tics and moderate to severeanxiety.
If monotherapy is not possible or has not been effective individuals may require the use of two(or more) medications simultaneously to control both tics and behavioral or emotionalsymptoms. This approach is called targeted combined pharmacotherapy, referring to the careful,judicious use of more than one medication simultaneously. Although this is a more complicatedapproach, it has several advantages including 1) using lower doses of each medication, reducingthe likelihood of side effects associated with higher doses of single agents and 2) potentialaugmentation or synergism (booster effects) of combination therapy. Given the increasingrecognition of the prevalence and clinical significance of the comorbid problems in individualswith TS, this approach is becoming more frequent in its use.
The combined use of haloperidol (Haldol) and fluoxetine (Prozac) would be an example of acombination used to control both tics and obsessive-compulsive behaviors. Another example isthe combination of clonidine (Catapres) and dextroamphetamine (Dexedrine) to reduce both ticsand symptoms of Attention Deficit Hyperactivity Disorder.
Less frequently, more than two medications can be used in the treatment of tics and thecomorbid problems. This is a more complicated approach since the likelihood of interactionsbetween the medications increases as the number of medications used together increases.
Medication Interactions: Prescribed Agents
Potential interactions between two or more medications prescribed simultaneously need to betaken into account when the decision is made to use targeted combined pharmacotherapy. Theseinteractions include those between the prescribed medications and those that may occur whennon-prescribed (“over the counter”) medications are used. All medications are metabolized orbroken down by a system of enzymes in the liver and distributed to the brain where they havetheir active effects. This process if also necessary to prepare the drug for elimination from thebody. There is a considerable amount of information about these enzymes, known as thecytochrome oxidase P450 system. Medications such as the selective serotonin reuptakeinhibitors (SSRIs) can alter activity in this liver enzyme system, resulting in reduced metabolismand reduced clearance of medication. This may result in increased blood levels of medicationand/or increased side effects. There is a large variation between individuals in their response to drugs. The response maydepend on genetic and environmental factors. There may be considerable variation in theresponse of a single person to different members of the same drug class.
Medication Interactions: Non-Prescribed Agents (“Over the Counter”)
Many children with Tourette’s Syndrome and other tic disorders may receive over the countermedications to reduce symptoms of upper respiratory illness such as nasal decongestants andcough suppressants. Others may take acetaminophen (Tylenol) for muscle paints or for fever, ornonsteroidal anti-inflammatory agents (NSAIDS) such as Ibuprofen (Motrin, Advil) forheadaches or muscle pain. Antibiotics are frequently prescribed for children for ear infections orstrep throats. While these medications are generally safe for pediatric usage, some may havesignificant interactions with medications prescribed for children with TS.
The medications commonly used to treat symptoms of Tourette Syndrome are reviewed in thetables at the end of this brochure. They are listed by their general purpose, typical starting doses,common maximum dosages and common side effects. Children generally require lower dosagesof the same medications used for adults. The neuroleptic medications (e.g. Haldol [haloperidol]and Orap (Pimozide) may have uncommon side effects such as restlessness, muscle stiffness orslowness or a rare side effect known as tardive dyskinesia (TD). Symptoms of TD may beginwith twitching movements of the face and mouth, which may not disappear when the medicationis discontinued. Some medications prescribed for TS have primary indications other than the treatment ofTourette Syndrome. Catapres (clonidine), and a close relative guafacine (Tenex), have beenused to control high blood pressure. Clonazepam (Klonopin) is used in the treatment of seizuresas well as for the control of tics.
Whether generic medications are as effective as brand name medication needs to be studied. Some reports have suggested that bioavailability (availability of the medication and itsbreakdown products after oral dosing is reduced slightly for generic neuroleptics such ashaloperidol when compared to the brand Haldol. Some individuals switching to generic frombrand name products have reported experiencing no problems, but some have noted that thegenerics proved less beneficial than the brand name products. It is important that individualsreview this issue with their physicians when a medication program is being started.
The more commonly used medications for ADHD are the stimulants such as Ritalin(methylphenidate), and Dexedrine (dextroamphetamine) and Adderall (mixed amphetamines). These medications may cause an increase in tics in some TS patients. Other reports have beenunable to find an effect on tic frequency. Experience has shown, however, that thesemedications can be safely taken by some individuals with TS. For those individuals withsignificant ADHD symptoms, a cautious trial of stimulant medication may be helpful. A newmedication for ADHD is Strattera (atomoxetine), which is reported not to increase tics. There is no single TS “drug of choice”. A careful matching of the medication to the specificneeds of the individual is critical. There are no medical tests, which can predict whichmedication will work best. More than one medication, even within the same family of drugs may need to be tried before the best treatment program is found. Unfortunately, there are someindividuals who may not respond to any of the available medications, or may experienceintolerable side effects. These individuals may be candidates for other types of treatment.
Additional medications for TS are also available although they are used less commonly. Research programs are working actively to discover new and better treatment programs. Untilthat time, the currently available medications can be of help to many individuals with Tourettedisorder and other tic disorders.
Medications Used in the Treatment of Tics
Fatigue, weight gain, musclerigidity, motor tardivedyskinesia, school phobias,photosensitivity, depression,cognitive dulling Same as haloperidol, EKGchanges (QTc interval) Fatigue, sleepiness, drymouth, irritability, dizziness,headache, insomnia, hypo-ension, EKG changes Fatigue, irritability, hypo-tension, sleep disturbance Fatigue, irritability,dizziness, disinhibition Medications Used in the Treatment of TS plus ADHD
Headache, stomachache, appetite loss,insomnia, irritability,increased tics *There are delayed (extended release) acting formulations available for these drugs permittingonce daily administration.
Medications Used in the Treatment of Anxiety With or Without OCD*
Restlessness, insomnia,gastrointestinal upset, sexualdysfunction Dry mouth, blurred vision,constipation, fatigue, EKGchanges, weight gain Fatigue, insomnia,restlessness, weight gain,sexual dysfunction Dry mouth, nausea, somnolence, sexual dysfunction, insomnia *Warning Information
Health care providers should carefully monitor patients receiving antidepressants forpossible worsening of depression or suicidality, especially at the beginning of therapy orwhen the dose either increases or decreases. Although FDA has not concluded that thesedrugs cause worsening depression or suicidality, health care providers should be aware thatworsening of symptoms could be due to the underlying disease or might be a result of drugtherapy.
Heath care providers should carefully evaluate patients in whom depression persistentlyworsens, or emergent suicidality is severe, abrupt in onset, or was not part of the presentingsymptoms, to determine what intervention, including discontinuing or modifying thecurrent drug therapy, is indicated.
Anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia(severe restlessness), hypomania, and mania have been reported in adult and pediatricpatients being treated with antidepressants for major depressive disorder as well as forother indications, both psychiatric and nonpsychiatric. Although FDA has not concludedthat these symptoms are a precursor to either worsening of depression or the emergence ofsuicidal impulses, there is concern that patients who experience one or more of thesesymptoms may be at increased risk for worsening depression or suicidality. Therefore,therapy should be evaluated, and medications may need to be discontinued, whensymptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms.
If a decision is made to discontinue treatment, certain of these medications should betapered rather than stopped abruptly (see labeling for individual drug products for details).
Because antidepressants are believed to have the potential for inducing manic episodes inpatients with bipolar disorder, there is a concern about using antidepressants alone in thispopulation. Therefore, patients should be adequately screened to determine if they are atrisk for bipolar disorder before initiating antidepressant treatment so that they can beappropriately monitored during treatment. Such screening should include a detailed Use of Drugs in the Pediatric Population
Some of the drug information that families may receive when the use of medication for ticdisorder is discussed may indicate that a drug is not “approved” for children in the pediatric agegroup (usually under age 18 years). This information comes from what is called the “pediatriclabel” or “package insert”. This is information jointly agreed to by both the company and theFood and Drug Administration (FDA) to support the use of the drug as indicated. It is notunusual once a drug is on the market for it to be used in either a pediatric population or for anindication that is not in the label. An example of this is the drug clonidine, which is labeled foruse in the treatment of high blood pressure in adults. However it has found widespread use forother disorders including tic disorders and ADHD. The Committee on Drugs in the AmericanAcademy of Pediatrics is very aware of this issue and has published a useful statement entitled“The Uses of Drugs Not Described in the Package Insert” in the July 2002 issue of Pediatrics(pp. 181-183). This statement points out that any labeling of a drug is not intended to preclude aphysician from using his or her best judgment in the use of this medication. Because of rapidlyadvancing knowledge in pediatric therapeutics there can be widespread acceptance of the use ofa drug not labeled for children before the label may be changed. There has been a very activeeffort in expanding the labeled drugs for the pediatric population in the last ten years so thatchildren, their families and practitioners will have the benefit of the most up to date indications. When a certain drug is suggested for the treatment of a tic disorder or a co-morbid disorder.
There is almost always significant published research to support such a recommendation. Thechild’s physician would be in the best position to discuss this with the family.
Mount Auburn Hospital Formulary Updated 10/8/03 Generic Name Trade Name and Form Formulary Notes ALEMTUZUMAB CAMPATH 30 MG/3 ML INJ Oncologist ONLY ALTEPLASE TPA 50 MG INJ Restricted ALTEPLASE TPA 100 MG INJ Restricted AMIFOSTINE ETHYOL 500 MG INJ Oncologist ONLY Mount Auburn Hospital Formulary Updated 10/8/03 AMIKACIN AMIKIN 500 MG INJ ID