Tardive dyskinesia tongue movements

What Is Tardive Dyskinesia?

Tardive dyskinesia mainly causes random, involuntary movements of the face, tongue, lips, or jaw.

Tardive dyskinesia is a neurological syndrome marked by involuntary muscle movements. It’s caused by the long-term use of certain drugs.

The word “tardive” means delayed, and “dyskinesia” means abnormal movement.

Coined in 1964, the term “tardive dyskinesia” refers to the delay between the first use of the offending drug and the onset of movement symptoms.

What Causes Tardive Dyskinesia?

Tardive dyskinesia is mainly caused by the use of neuroleptic drugs.

These drugs are prescribed for psychiatric disorders (and some gastrointestinal and neurological issues) and work by blocking the body’s receptors for dopamine.

Dopamine is a neurotransmitter involved in controlling the reward and pleasure centers of the brain, but which also plays an important role in motor function, among other things.

It’s not perfectly clear why or how tardive dyskinesia symptoms begin, but they’re thought to be related to the chronic blocking of these receptors.

Neuroleptic drugs that typically cause the disorder include:

  • Amoxapine
  • Compazine or Compro (prochlorperazine)
  • Haldol (haloperidol)
  • Prolixin (fluphenazine)
  • Reglan (metoclopramide)
  • Sibelium (flunarizine)
  • Stelazine (trifluoperazine hydrochloride)
  • Thorazine or Largactil (chlorpromazine)

It usually takes many months or years to develop tardive dyskinesia from the use of neuroleptics, but the disorder can sometimes arise in just six weeks, according to the U.S. National Library of Medicine.

In rare cases, drugs including lithium, selective serotonin reuptake inhibitors (SSRIs), and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have reportedly caused tardive dyskinesia or syndromes clinically indistinguishable from it, according to a report published in July 2013 in the journal Tremor and Other Hyperkinetic Movements.

Dyskinesia may also develop in people with schizophrenia who haven’t used antipsychotic medications.

This type of dyskinesia, called spontaneous dyskinesia, may occur in up to 40 percent of people with schizophrenia who haven’t taken these drugs, according to a report published in September 2011 in the International Review of Neurobiology.

Tardive Dyskinesia Symptoms

Tardive dyskinesia mainly causes random, involuntary movements of the face, tongue, lips, or jaw, resulting in:

  • Lip smacking, puckering, or pursing
  • Tongue thrusting or protrusion
  • Grimacing
  • Repetitive chewing
  • Rapid eye blinking

In some cases, the disorder can affect the fingers, arms, legs, and trunk, causing either rapid, jerking movements or slow, writhing movements. Swaying movements associated with breathing are also possible.

AIMS Test

The symptoms of tardive dyskinesia may appear similar to those of several other movement disorders, such as Parkinson’s disease, Huntington’s disease, cerebral palsy, Tourette syndrome, and dystonia.

To detect tardive dyskinesia in people who are taking neuroleptic drugs, and to track the severity of symptoms over time, doctors refer to a tool called the Abnormal Involuntary Movement Scale (AIMS).

During an AIMS test, your doctor will gauge the involuntary movement throughout your body on a five-point scale. This includes the movement of your:

Your doctor will also assess the overall severity of your movements, whether you’re aware of them, and whether you’re in distress.

During the exam, you’ll also be asked to perform a variety of actions, such as opening your mouth, extending and flexing your arms, and walking around, among other things.

Tardive Dyskinesia Treatment

Treatment for tardive dyskinesia varies among people.

As a first step, your doctor will recommend minimizing or discontinuing use of the offending neuroleptic drug (if this is safe, given your condition). Your doctor may prescribe an alternative medication.

Some people, however, will have irreversible tardive dyskinesia even after stopping their medications.

Austedo (deutetrabenazine) and Ingrezza (valbenazine tosylate) are approved by the Food and Drug Administration specifically for the treatment of tardive dyskinesia.

Other medications can be used off-label to help treat symptoms of tardive dyskinesia, including Xenazine (tetrabenazine), benzodiazepines, Botox (botulinum toxin) injections, and Clozaril or FazaClo (clozapine).

Various other treatments have been studied for the treatment of tardive dyskinesia, but their effectiveness is unclear.

Strategies for managing drug-induced tardive dyskinesia

Fifteen years ago, Mr. L, age 40, was given a diagnosis of schizophrenia, which has been treated with haloperidol, 10 mg/d. Approximately 1 year ago, he began experiencing consistent lip smacking, a sign of tardive dyskinesia. Vitamin E was added to the treatment regimen, after which the tardive dyskinesia symptoms resolved.

A few months later, however, those symptoms returned and became worse. In addition to lip smacking, Mr. L now also describes involuntary bilateral twitching and muscle spasms in both legs.

Haloperidol and vitamin E are discontinued and Mr. L is switched to olanzapine, 20 mg/d. Although olanzapine is effective for Mr. L’s symptoms of schizophrenia, tardive dyskinesia persists, and he gains 60 pounds and develops diabetes. Olanzapine is discontinued and he begins a trial of risperidone, 4 mg/d.

While on risperidone, blood sugar control, measured by hemoglobin A1c, and insulin resistance improve, but Mr. L continues to have symptoms of tardive dyskinesia. Vitamin E is added again, but is ineffective. The treatment team switches Mr. L to clozapine but symptoms of tardive dyskinesia do not improve.

Extrapyramidal side effects are common with first-generation antipsychotics (FGA) such as haloperidol. Types of antipsychotic-induced movement disorders include dystonias, akathisias, pseudoparkinsonism, and tardive dyskinesia. Of these, tardive dyskinesia is the most concerning because it often is difficult to treat and may be irreversible.

Tardive dyskinesia involves abnormal, involuntary movements, usually involving the face and, sometimes, the limbs. Common symptoms include lip smacking, tongue protrusions, and puffing the cheeks1; severe tardive dyskinesia may affect the larynx and diaphragm, which can be life-threatening. The incidence of tardive dyskinesia is approximately 5% after the first year of FGA treatment and 1% with second-generation antipsychotics (SGAs).2 The risk increases with higher doses and longer duration of treatment, with a prevalence of 20% to 25% with long-term FGA use.3

Treatment strategies
There are no FDA-approved drugs for tardive dyskinesia (Table).4-6 The best strategy is to prevent tardive dyskinesia with judicious use of an antipsychotic. If a patient taking a FGA develops tardive dyskinesia, the first-line treatment is to switch to a SGA. Risperidone, olanzapine, quetiapine, and clozapine have a low risk of tardive dyskinesia. Newer agents, such as lurasidone, asenapine, iloperidone, and aripiprazole, might have a lower risk of tardive dyskinesia, possibly because of differences in dopamine blockage between these agents and FGAs. Clozapine is least likely to cause tardive dyskinesia, but it often is used as a last resort because of the risk of agranulocytosis and the need for frequent tests to measurewhite blood cells.1,4

Other treatments include melatonin, donepezil, vitamin B6, and vitamin E.4 These agents can reduce symptoms, but no large clinical trials have proved that the are efficacious. Last-resort treatments include suppressive treatment using FGAs several times a day, because the constant dopamine blockade may stop symptoms for a short time; this approach is not recommended because it can exacerbate symptoms of tardive dyskinesia.4

Other suppressive treatments used in severe or refractory cases include reserpineand tetrabenazine, which are used off-label and work by blocking monoamine transporters. This blockage results in a reduction in neurotransmitters such as dopamine, which have been implicated in the development of tardive dyskinesia. Compared with tetrabenazine, reserpine has a higher affinity for cells in the periphery and therefore causes side effects such as hypotension and diarrhea.7

Tetrabenazine is indicated for chorea associated with Huntington’s disease and is used off-label for treating tardive dyskinesia. Tetrabenazine is thought to work by inhibiting human vesicular monoamine transporters. Blocking these transporters prevents monoamines such as dopamine from entering synaptic vesicles.8 Because of its side-effect profile, lack of large clinical trials, and high cost, tetrabenazine is used as a last-line treatment in severe cases of tardive dyskinesia. Adverse effects include somnolence (31%), insomnia (22%), depression (19%), and akathisia (19%). Tetrabenazine carries a black-box warning for depression and suicidalityand is contraindicated in patients with untreated or inadequately treated depression or who are suicidal.8 Assessing the patient’s mental state is important when using this medication.

A review by Chen et al7 found that 9 of 11 studies had positive results for tetrabenazine treatment for tardive dyskinesia. Most of the studies were small and retrospective. The biggest prospective blinded study was a videotaped study by Ondo et al of 20 patients with tardive dyskinesia.9 At least 30 days before beginning the study patients discontinued the medication that caused their tardive dyskinesia and any treatments for tardive dyskinesia. Each patient was videotaped before starting tetrabenazine and an average of 20.3 weeks after starting the drug. Investigators’ scores showed an average of 54.2% improvement in movement scores and participants’ subjective scores reported an average of 60.4% improvement. One patient withdrew because of somnolence. The remaining 19 patients did not experience more than mild side effects and continued treatment with tetrabenazine after study completion.9

Treatment recommendations
Tardive dyskinesia is a difficult condition to treat; it is best, therefore, to prevent its onset by using the minimally effective antipsychotic dose, by preferential use of an SGA rather than a FGA, and by regular screening for tardive dyskinesia using a standardized rating scale such as the Abnormal Involuntary Movement Scale. Symptoms associated with tardive dyskinesia are more likely to resolve if caught early. If a patient develops tardive dyskinesia while taking a FGA, switching to a SGA may alleviate the symptoms.

Several medications can be used off-label to relieve symptoms, including vitamin E and tetrabenazine, which both have the most-although not considerable-literature-based support. Although some studies show benefit with tetrabenazine for tardive dyskinesia, larger clinical trials are needed to more strongly support its use. Tetrabenazine might be a good option for patients with refractory tardive dyskinesia but, given the associated risk of suicidality and depressive symptoms, careful monitoring of suicide risk is essential and may preclude its use for tardive dyskinesia in patients who are experiencing depressive symptoms.

Drug Brand Names
Aripiprazole • Abilify Lurasidone • Latuda
Asenapine • Saphris Olanzapine • Zyprexa
Clozapine • Clozaril Quetiapine • Seroquel
Donepezil • Aricept Reserpine • Serpasil
Haloperidol • Haldol Risperidone • Risperdal
Iloperidone • Fanapt Tetrabenazine • Xenazine

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

There is no standard treatment for tardive dyskinesia. Most interventions focus on adjusting the medication thought to be causing tardive dyskinesia. In many cases neuroleptic medications will be adjusted to use the lowest possible dose, or discontinued if at all possible. Stopping the medication is a gradual process, lowering the doses 10 to 25 percent every one to three months. Replacing the neuroleptic drug with other medications may help some patients. Other drugs such as tranquilizers like benzodiazepines and medicines that mimic the effect of dopamine, may also be beneficial. Symptoms of tardive dyskinesia may remain even after the medication is stopped. However, with careful management, some symptoms may improve or disappear with time.

Tardive dyskinesia symptoms may take time to develop. On some occasions symptoms do not arise until after neuroleptic drug use has been stopped. For this reason, tardive dyskinesia may be hard to diagnose. If you think you have tardive dyskinesia seek medical attention through a neurologist. For a diagnosis, doctors should evaluate the length of neuroleptic drug exposure. Exposure does not need to be consistent but should continue for three or more months of use. They should also rule out other conditions that cause movements such as Parkinson’s or Cerebral Palsy and recognize symptoms in two or more body areas.

New treatments for tardive dyskinesia have been developed and work by reversibly limiting the amount of excess dopamine. While these treatments have not been around long, they have shown great promise in clinical trials. If taking psychiatric medications, these new drug treatments for TD are meant to be taken in addition to existing medications.

Tardive Dyskinesia

Dyskinesia, also known as tardive dyskinesia (TD), is a neurological disorder often caused by the long-term use of neuroleptic drugs. Such drugs are generally prescribed for psychiatric disorders, as well as for some gastrointestinal and neurological disorders.

TD involves involuntary movements of the lips, tongue, mouth and face. These excess movements also may be experienced by people with Parkinson’s disease.

The movements can become more diffuse and can resemble generalized jitteriness, chorea or dystonias. Akithisia, a form of restlessness, is often associated with TD and manifests itself as constant fidgeting or a necessity to keep moving.

Elderly women appear to be the most susceptible to developing TD from neuroleptics.

Symptoms include movements that have continuous, repetitive and stereotyped patterns. Such movements include lip smacking, grimacing, blinking and grunting. You may also have rapid movements of the arms, legs and trunk.

With tardive dyskinesia, the first step of treatment may be to discontinue or alter the neuroleptic drug.

Injections of botulinum toxin may be the most desirable therapy. The drug weakens certain muscles and lasts several months.

Therapies may be necessary to help patients with language and movement.

Tardive Dyskinesia Treatment: Surgical Options

Deep brain stimulation (DBS) is a procedure where electrodes are placed in specific areas of the brain. The electrodes block the abnormal brain circuitry seen in patients with neurological conditions such as Parkinson’s disease, essential tremors, dystonia and dyskinesia.

DBS does not destroy the overactive cells, like other movement disorders treatments such as pallidotomy and thalamotomy surgeries. Rather, it temporarily blocks the abnormal signals and is a reversible process. In DBS, a lead is permanently implanted into your brain and connected to a generator, which is attached under the skin of your chest.

An alternative to making a lesion with an electrode is to use highly focused radiation. Two types of devices can be used to deliver stereotactic radiosurgery, namely the Gamma Knife® and the LINAC-Scalpel.

Wake Forest Baptist Multidisciplinary Approach

The treatment of movement disorders at Wake Forest Baptist is a collaborative effort between neurologists and neurosurgeons.

Quality of life is further enhanced by the participation of physical, occupational and speech therapists, and otolaryngologists who have special expertise in speech and swallowing difficulties.

University of Michigan Health System

Hyperkinetic Movement Disorders

  • Ataxia
  • Chorea
  • Dystonia
  • Hemifacial Spasm
  • Huntington’s Disease (HD)
  • Myoclonus
  • Restless Legs Syndrome
  • Tardive Dyskinesia / Tardive Dystonia
  • Tics/Tourette’s Syndrome
  • Tremor
  • Wilson’s Disease

Ataxia

The term ataxia refers to a group of progressive neurological diseases that affect coordination and balance. Ataxias are often characterized by poor coordination of hands and eye movements, speech problems and a wide-based and unsteady gait. Ataxia can result from stroke, tumor, infection, trauma or degenerative changes in the cerebellum. They are generally classified into two groups: hereditary and sporadic ataxias. Hereditary ataxias affect the cerebellum and spinal cord and are passed from one generation to the next through a defective gene. A common hereditary ataxia is Friedreich’s (recessive) ataxia. Sporadic ataxias occur spontaneously in individuals with no known family history of ataxia.

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Chorea

Chorea refers to involuntary movements that are irregular, purposeless and unpredictable in timing. Any body part may be affected. When mild, a person may look fidgety and can often incorporate the chorea into other purposeful movements. Chorea is the hallmark of an inherited disorder called Huntington’s disease.

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Dystonia

Dystonia is the third most common movement disorder, after essential tremor and Parkinson’s disease. It is characterized by sustained co-contractions of opposing muscle groups that cause twisting or repetitive movements and abnormal postures. Dystonia is classified according to the number of muscle groups affected. It may be may be focal and limited to one area (such as the face, neck, larynx/vocal cords, or limbs), or it may be generalized and affect the whole body. These conditions can be both painful and debilitating. Aside from medications, dystonias are frequently treated with Botox injections. Patients with regional and generalized dystonias and normal MRI scans may benefit from deep brain stimulation therapy. The following are examples of focal dystonias:

  • Blepharospasm is marked by involuntary contraction of the eyelid muscles. Symptoms may range from intermittent, increased frequency of blinking to constant, painful eye closure leading to functional blindness.
  • Oromandibular dystonia is characterized by forceful contractions of the lower face causing the mouth to open or close. Chewing and unusual tongue movements may also occur.
  • Laryngeal dystonia or spasmodic dysphonia is due to abnormal contraction of muscles in the voice box producing changes in the voice. Patients may have a strained-strangled quality to their voice or in some cases a whispering/breathy quality .
  • Cervical dystonia (CD) or spasmodic torticollis is marked by muscle spasms of the head and neck may be painful and cause the neck to twist into unusual positions or postures.
  • Writer’s cramp and musician’s cramp is a task-specific dystonia, meaning that it only occurs when performing certain tasks. Writer’s cramp is a contraction of hand and/or arm muscles that happens only when a patient is writing. It does not occur in other situations, such as when a patient is typing or eating. Musician’s cramp occurs only when a musician plays his/her instrument. For example, pianists may experience cramping of their hands when playing, while brass players may have cramping or contractions of their mouth muscles.

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Hemifacial Spasm

Hemifacial spasm (HFS) is characterized by involuntary contraction of facial muscles. HFS usually occurs only on one side of the face. Like blepharospasm, the frequency of contractions in hemifacial spasm may range from intermittent to frequent and constant. The unilateral blepharospasm of HFS may be particularly troublesome, interfering with routine tasks such as driving. In addition to medication, patients may respond well to treatment with Botox. HFS may be due to vascular compression of the nerves going to the muscles of the face. For these patients, surgical decompression may result in long-lasting improvement of symptoms.

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Huntington’s Disease (HD)

Huntington’s disease is a hereditary degenerative brain disorder. Its most common symptom is chorea (involuntary movements). The chorea slowly progresses and becomes more severe over time. In addition, HD slowly reduces the individual’s ability to walk, think, talk and reason. Since HD is a hereditary disorder, the diagnosis is made through gene testing of the blood. There is no cure for HD, and there is no known way to stop the progression of the disorder. The goal of treatment is to minimize complications associated with disease progression and improve the patient’s overall quality of life.

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Myoclonus

Myoclonus refers to involuntary movements that are sudden and brief. They can be classified as positive or negative. Positive myoclonus is caused by sudden muscle contractions, while negative myoclonus is caused by sudden loss of muscle contractions. In general, myoclonus cannot be suppressed and can occur in any part of the body.

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Restless Legs Syndrome

Restless legs syndrome is a disorder where patients feel uncomfortable or unpleasant sensations in the legs. These sensations occur usually in the evening, while the patient is sitting or lying down and relaxing. Patients feel like they have to move their legs to relieve the sensations, and walking generally makes the symptoms disappear. In many patients, this can lead to insomnia and excessive daytime sleepiness. This is a very common problem and can occur at any age.

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Tardive Dyskinesia / Tardive Dystonia

Tardive dyskinesia or tardive dystonia, both referred to as “TD,” refers to a wide variety of involuntary sterotypical movements caused by the prolonged use of dopamine receptor-blocking agents. The most common dopamine receptor-blocking agents are antipsychotics and anti-nausea agents. The classic form of TD refers to stereotypic movements of the mouth, where patients look like they are chewing gum. However, TD can take the form of other involuntary movements such as chorea, dystonia or tics.

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Tics/Tourette’s Syndrome (TS)

Tics are involuntary movements that are stereotyped, meaning that they tend to recur with the same or a very similar pattern in the same muscles. They most commonly involve the face, mouth, eyes, head, neck or shoulder muscles. Tics can be motor (pertaining to movement) or vocal (pertaining to speech). Tics usually vary in severity over time and worsen in times of stress.

When both motor and vocal tics are present and persist for more than one year, a diagnosis of Tourette’s syndrome (TS) is likely. TS is an inherited neurobehavioral disorder characterized by both motor and vocal tics. Many individuals with TS also may develop obsessions, compulsions, inattention and hyperactivity. TS starts in childhood.

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Tremor

Tremor is the shaking of one or more body parts and is the most common type of involuntary movement. There are many reasons for people to have tremor; many people notice tremor when they are excited or scared. However, when tremors become persistent, it may be a sign of something else.

Essential tremor (ET), also known as benign essential tremor, or familial tremor, is the most common movement disorder. It is estimated that 5 percent of people worldwide have this condition. It can affect people of any age and tends to run in families. ET is a tremor that usually affects the hands and arms but can also affect the head, voice, chin, trunk and legs. Both sides of the body tend to be equally affected. The tremor is called an action tremor, meaning that the tremor typically becomes noticeable in the arms when they are being used. Patients often report that the tremor in ET improves significantly with alcohol. First-line medical treatments for ET are beta-blockers. For patients in otherwise good health who fail to respond adequately to medication, deep brain stimulation and thalamotomy can be highly effective.

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Wilson’s Disease

Wilson’s disease (WD) is a rare inherited disorder in which patients have a problem with copper metabolism. In patients with WD, copper accumulates in the liver and then in other parts of the body, particularly the brain, eyes and kidneys. When the copper starts to accumulate in the brain, patients may experience tremor, speech problems, incoordination, dystonia gait difficulties and swallowing problems. Psychiatric disturbances such as irritability, impulsiveness, aggressiveness and mood disturbances are also common. UMHS has a research protocol for patients with Wilson’s disease.

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Two New Drugs for Tardive Dyskinesia Hit the Market

During my residency many years ago I rotated through a locked psychiatric ward, a place depicted in many movies and television shows but entirely new to me at the time. This was my first real glimpse at the people who were severely affected by thought disorders such as schizophrenia. The treatment options included antipsychotic or major tranquilizers like Thorazine and Haldol, both of which are in the dopamine antagonist D2 class of drugs. They helped control the symptoms of schizophrenia but at a high cost to the patient. This family of drugs was notorious for causing people to develop strange, involuntary movements of their tongue, face, lips, and jaw as well as what are called choreoathetoid movements of the extremities and trunk.

Those movements are collectively called tardive dyskinesia, a subgroup of dyskinesia movements typically occurring in people treated with long-term antipsychotic drugs. Tardive dyskinesia is associated with the “typical” antipsychotics like Thorazine and Haldol, but there are a number of other medications that also cause the troubling condition, including the more recently approved “atypical” antipsychotic medications, such as Clozaril, Seroquel, and Zyprexa, as well as drugs in entirely different classes such as Reglan, a drug used for GI motility disorders. Between 20% and 50% of the people who take antipsychotics on a long-term basis develop tardive dyskinesia, and the condition may persist after people stop taking the medication. Tardive dyskinesia affects people’s quality of life but it goes beyond that. The involuntary movements can interfere with speech, walking, and swallowing. Some people have a hard time breathing because of it. In severe cases, people can develop joint inflammation and lip or tongue lacerations.

The standard of care for tardive dyskinesia is to reduce the dose of the antipsychotic drug or switch to one of the atypical antipsychotics that are somewhat less likely to cause tardive dyskinesia.

Physicians have treated tardive dyskinesia in a variety of off-label ways, ranging from benzodiazepines to botulinum toxin injections (Botox) to vesicular monoamine transporter 2 (VMAT2) inhibitors such as tetrabenazine. The FDA approved tetrabenazine in 2008 as a treatment for the jerky, involuntary movements associated with Huntington’s disease—called chorea—but not for tardive dyskinesia.

But now two new treatments for tardive dyskinesia are available. Valbenazine, developed by Neurocine Biosciences, was approved in April 2017 and is being marketed under the name Ingrezza. Deutetrabenazine, brought to market by Teva, was approved a few months later and is being sold under the name Austedo. Like tetrabenazine, they are in the VMAT2 family. The mechanism of action is unclear, but it’s thought to be mediated through the reversible inhibition of VMAT2, which regulates monoamine uptake from the cytoplasm to the synaptic vesicle.

There’s a great deal of published information available on the new tardive dyskinesia drugs. In addition to the usual trove of FDA documents, the Institute for Clinical and Economic Review (ICER) in Boston published a 165-page evidence report in November. Many of the details that follow are taken from the ICER report, which is based on FDA documents.

Ingrezza’s approval was supported by several studies, but the main Phase 3 trial included 234 patients. The main Phase 3 trial of Austedo included 293 subjects. The Abnormal Involuntary Movement Scale (AIMS), a scale commonly used to evaluate the presence and severity of tardive dyskinesia, was used as the primary endpoints in these studies. The complete AIMS contains 12 items, but the Ingrezza and Austedo trials used a subset of seven items that are termed the “dyskinesia portion” of the AIMS.

In the Ingrezza trial, the primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia score at the end of Week 6. People in the Ingrezza study were given either a 40- or 80-mg dose of the drug or placebo. After the initial six-week double-blind period, subjects could be re-consented to enter the 42-week extension period where those originally randomized to receive Ingrezza continued at their then current dose and those who initially received placebo were randomized to receive either 40 mg or 80 mg of Ingrezza. The two Austedo trials tested 24- and 36-mg doses of the drug against a placebo over a 12-week period.

The results for the primary endpoint were statistically significant, but as is true with all clinical trials, the proof is in the detail.

In the Phase 3 Ingrezza study, only 121 (61%) of patients completed the entire 48-week study.

The Ingrezza and Austedo studies also included a measurement called patient global impression of change (PGIC). Unlike AIMS and other tardive dyskinesia measures, PGIC is based on patient self-reporting, not outside raters of symptoms. According to the ICER report, unpublished PGIC data on the Phase 3 Ingrezza trial that were part of a FDA review document show that, on average, the Ingrezza groups (40 mg and 80 mg) and placebo did not differ in their tardive dyskinesia symptom improvement, although a Phase 2 did show an improvement. The ICER report says that PGIC data from the Austedo trial favor the drug but the difference compared with placebo was not statistically significant.

Managed care implications

Tardive dyskinesia is without question a disturbing and disabling condition. ICER, which was scheduled to make its policy recommendation in late December after we went to press, notes that the antipsychotics are often used off-label for illnesses ranging from obsessive-compulsive disorder to insomnia. Hundreds of thousands of people might benefit from drugs that ameliorate tardive dyskinesia. And Ingrezza and Austedo did show a large enough effect on the condition using relatively objective measures to warrant FDA approval.

But let’s consider the prices. ICER pegged the wholesale acquisition cost (WAC) of a daily 80-mg dose of Ingrezza at $75,789 and the WAC for a daily 36-mg dose of Austedo at $90,071.

ICER went on to compute the cost per quality-adjusted life year (QALYs). QALYs often stir up a hornets’ nest of controversy because of all the judgments about what goes into the quality of life. The evidence base may be thin or uneven. In the case of tardive dyskinesia, there isn’t a huge amount of research to go on, and the condition may, in fact, cause more harm and distress than the current research shows. Still, QALYs are a way to organize the thinking about the price and benefits of medical intervention. ICER calculated that at the current WAC, Ingrezza would cost $752,080 per one QALY gained and Austedo, $1,100,773. Cost-effectiveness research suggests that $150,000 is a reasonable price for a QALY. To hit that threshold, Ingrezza’s annual cost would need to be $11,260, according to ICER, and Austedo’s, $9,158.

Even without all this elaborate ICER number crunching just consider the fact that these drugs reduced AIMS score modestly from roughly 10 to 7 at their higher doses and that the patient self-reported improvement was unimpressive.

I am sympathetic to people who suffer from tardive dyskinesia. But the price of Ingrezza and Austedo make me wonder the high prices charged by the pharmaceutical industry are at all sustainable.

Thomas Morrow, MD, is a retired physician executive and part-time consultant. He has been the founding medical director of five HMOs and a disease management company, a medical director at Genentech, and president of the National Association of Managed Care Physicians. You can contact him at [email protected]

Tardive Dyskinesia

What is tardive dyskinesia?

Tardive dyskinesia is a neurological syndrome caused by the long-term use of neuroleptic drugs. Neuroleptic drugs are generally prescribed for psychiatric disorders, as well as for some gastrointestinal and neurological disorders.

Tardive dyskinesia is characterized by repetitive, involuntary, purposeless movements. Features of the disorder may include grimacing, tongue protrusion, lip smacking, puckering and pursing, and rapid eye blinking. Rapid movements of the arms, legs, and trunk may also occur. Involuntary movements of the fingers may be present.

Is there any treatment for tardive dyskinesia?

Treatment is highly individualized. The first step is generally to stop or minimize the use of the neuroleptic drug, but this can be done only under close supervision of the physician.

However, for patients with a severe underlying condition this may not be a feasible option. Replacing the neuroleptic drug with substitute drugs may help some individuals.

The only approved drug treatment for tardive dyskenesia is tetrabenazine, which is usually effective but can have side effects that need to be discussed prior to starting therapy. Other drugs such as benzodiazepines, clozapine, or botulinum toxin injections also may be tried.

What is the prognosis for tardive dyskinesia?

Symptoms of tardive dyskinesia may remain long after discontinuation of neuroleptic drugs. In many cases, the symptoms stop spontaneously, but in some cases they may persist indefinitely.

What research is being done on tardive dyskinesia?

The NINDS conducts and supports a broad range of research on movement disorders including tardive dyskinesia. The goals of this research are to improve understanding of these disorders and to discover ways to treat, prevent, and, ultimately, cure them.

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274 Possible Causes for Lip Smacking

  • Absence Seizure

    Signs and symptoms of absence seizures include: Sudden stop in motion without falling Lip smacking Eyelid flutters Chewing motions Finger rubbing Small movements of both hands However, automatic movements, avoidance of eye contact and lip smacking are all common in children with autism. Keep a seizure diary of suspected absence seizures. Symptoms commonly include a vacant stare, staying still in a position, smacking the lips, fluttering of the eyelids, chewing and making small movements with both arms or the

  • Focal Onset Impaired Awareness Seizure

    During the remainder of the attack, lip-smacking and swallowing are not uncommon. The seizure may include involuntary movements called automatisms, such as lip-smacking, chewing, hand wringing, picking, and swallowing.

  • Jacksonian Seizure

    An example of a focal ( partial ) seizure would be rhythmic muscle contractions in one area of the body: lip smacking, mouth movements , drooling, head turning, eye movements Head turning Eye movements Lip smacking Mouth movements Drooling Rhythmic muscle contractions in a part of the body Abnormal numbness Tingling Crawling sensation over the

  • Focal Motor Seizure

    Patients experiencing a complex focal seizure may stare blankly into space, or experience automatisms (non-purposeful, repetitive movements such as lip smacking, blinking, The seizure usually starts with a blank stare, followed by an automatism such as lip smacking, chewing, rolling of the fingers, fidgeting or some other repetitive movement Abnormal neuronal discharges that arise in the motor area that controls mastication and salivation may be manifested by chewing, lip smacking, swallowing movements, and profuse

  • Temporal Lobe Tumor

    You’ll make repetitive, uncontrollable movements such as lip smacking, swallowing, chewing, staring, or hand rubbing.

  • Frontal Lobe Neoplasm

    A frontal lobe neoplasm might present with an array of symptoms that are collectively included in the “frontal lobe syndrome”. Personality and abrupt emotional changes (aggression, apathy, impulsive behavior), and an overall decline of the functions for which the frontal lobe is crucial – planning, judgment, attention,

  • Herpes Simplex Encephalitis

    He also had intermittent lip smacking movements, suggesting seizure activity. In the prior week, he had progressed to having slurred speech, bizarre behavior, jerking leg movements, and intermittent lip smacking. smacking movements.

  • Abdominal Epilepsy

    The automatisms of the mesiobasal temporal lobe seizures are typically less violent and are usually oro-alimentary (lip-smacking, chewing, swallowing) or gestural (fumbling

  • Postictal State

    smacking chewing. Common automatisms include lip smacking, chewing, fidgeting and walking. QUESTION If you have had a seizure, it means you have epilepsy. They may also exhibit repetitive movements, which include lip-smacking, fidgeting, or chewing. If you or someone you love is suffering from seizures, you aren’t alone.

  • Temporal Lobe Epilepsy

    Motor or movement disturbances (called automatisms) may include the following: Rhythmic muscle contractions on one side of the body or face Abnormal mouth behaviors (lip smacking They lose awareness and tend to have a motionless stare accompanied by automatisms — stereotyped, repetitive, involuntary movements such as lip smacking, chewing, picking

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