TARDIVE DYSKINESIA - A SIDE EFFECT OF ANTIPSYCHOTIC MEDICATIONS THAT CAN BE UNDERSTOOD AND TREATED!

MadisonDoctrine Web Topic 000820T

Part I: History of Antipsychotics Movement Side Effects and Treatment of Tardive Reactions.

Antipsychotics and “EPS”
Tardive Movement Disorders
Tardive Dyskinesia seemed to be “Dopamine Supersensitivity”
The cause is not that simple
Early experience that TD is due to dopamine supersensitivity
Tardive movements may or may not normalize again
Finding a workable treatment for TD
Masking the movements plus doing something else equals treatment
When given help and time the TD can get better
Case demonstrating that there can be a change toward normal sensitivity
Not every case is so easy

Part II: Description of the Types of Tardive Phenomenon

Tardive Dyskinesia (TD)
Tardive Dystonia
Blepharospasm
Torticollis
Tardive Dysphagia (difficulty swallowing)
Tardive Step-Gait Disorder
Tardive Akathisia
Tardive Behavioral Symptoms

Part III: Dopamine Sensitivity

Variation in Sensitivity of the Dopaminergic Synapse
  Between different individuals
  Between different time periods
  Between different dopamine receptor groups in the same person

The Variations are not Predictable
A Likely Mechanism Explaining the Variations in Sensitivity of the Dopamine Receptors
Other Clinical Experience Indicating “Supersensitivity” can be Adjusted
Further Evidence that Tardive Reaction Involves Extreme Sensitivity to Levels of Dopamine and Dopamine Active Medications.
         1. Sensitivity to variation in blood levels of neuroleptic
         2. Change in total dopamine reactivity caused by addition of another
         dopamine acting medication
         3. SSRI antidepressants adding to the dopamine blocking effects of neuroleptics

PART IV: Other Pharmacological Approaches to Tardive Disorders

Atypical Antipsychotics (Clozaril, Risperdal, Seroquel, Zyprexa.)  and other Medications
Treatment with Atypical Antipsychotics
Future Treatments Using Medications which affect the Glycine/MNDA Receptor Complex
Other Treatments for TD which may have Merit but are not Used Extensively in this Clinic:
High Dose Buspirone
Reserpine and other Dopaminergic Depleter Medications
Demser (Metyrosine) or Alpha-methyl para-Tyrosine
The Use of Other Dopamine Agonists besides Amantadine

PART V: 6-point Summary of MadisonDoctrine View of the Nature of Tardive Dyskinesia

Part VI: Model and Real Cases of Treatment of Tardive Dyskinesia

PART VII: Questions and Answers Concerning Neuroleptic/Amantadine Treatment

1] If this treatment works so well, why hasn't standard medical practice accepted this treatment?
2] How should doses of neuroleptic be raised to mask the tardive movements?
3] What side effects can occur in raising the neuroleptic dose?
4] Is it necessary to stop the tardive movements completely?
5] How does one determine the dose of amantadine?
6] In what kinds of patients does the amantadine/neuroleptic combination treatment not work?

PART VIII:  References

Appendix:  Sample of Bounce Method Titration
 

 PART I: HISTORY OF ANTIPSYCHOTICS MOVEMENT SIDE EFFECTS AND TREATMENT OF TARDIVE REACTIONS 

ANTIPSYCHOTICS AND "EPS". Antipsychotic medicines (also called neuroleptics) became clinically available in the late 1950's. There were stories of immediate miraculous cures occurring in individuals who had long-standing psychotic symptoms. However, some patients receiving this medicine quickly demonstrated movement problems of stiffness, tremor, and rigidity—symptoms similar to the movement difficulties of Parkinson's Disease. This group of side effects was therefore called pseudo-Parkinsonian symptoms. [They were also called EPS (Extrapyramidal Symptoms) because they disturbed the function of the nerve pathway called the extrapyramidal system, which coordinates the movement of body muscles.] Antipsychotics block a neurotransmitter Dopamine. Blocking this chemical lowers psychotic thinking, but also lowers the efficiency of an important nerve pathway in the brain which regulates how the extrapyramidal system coordinates body movement. When antipsychotics are stopped, the normal dopamine function returns, and the EPS movement problems go away. (Parkinson's Disease is caused by a loss of Dopamine nerve cells and is generally treated by increasing the dopamine function of the remaining cells.)

TARDIVE MOVEMENT DISORDERS. It was soon discovered that some patients developed a different type of movement after being on antipsychotics for a period of time. This difficulty commonly consisted of excessive movements of the muscles of the face or arms. Since these movements occurred as a late symptom they were named "Tardive Dyskinesia” (TD). ("Tardive" means late, like the word “tardy”.) Unlike EPS, TD did not necessarily disappear when the antipsychotic was stopped. The symptoms, which sometimes may be severe and disabling, persisted for years in some individuals. TD then became a major concern relating to the use of these otherwise very effective medications.  Many patients were unable to remain on antipsychotics because they developed TD. Others were not put on them because of concern that they might develop TD. 

TARDIVE DYSKINESIA  SEEMED TO BE  "DOPAMINE SUPERSENSITIVITY ”
The most simplistic idea concerning the cause of the tardive movement disorders is derived from standard laws of neurochemical receptor mechanisms. When any receptor is deprived of chemical stimulation, it develops increased sensitivity. This can be seen as an attempt of the system to overcome the lack of stimulation. In this case, the antipsychotics have caused a lowering of stimulation of the dopamine receptors in the extrapyramidal system. The tardive movement disorder would seem to occur when the increased sensitivity "overshoots" and causes increased muscle activity.  Minute amounts of Dopamine, which in the past were not enough to stimulate the receptor mechanism, now stimulate the sensitive receptors and cause movement in the muscles. 

THE CAUSE IS NOT THAT SIMPLE.  It is clear that chemical stimuli which formerly would not have caused muscle movements do so in individuals with TD. What is not clear is the exact mechanism of this increased sensitivity. Researchers have failed to find that the receptors stay overly sensitive, or that there is more Dopamine activity, or that there are more Dopamine receptors built up on the receiving nerve, etc. This failure to find a clearly defined mechanism seems to have been a major obstacle preventing psychiatry from developing a clearly defined treatment regime. There are numerous papers looking at some dozen or so alternate neurotransmitters as a possible contributor to TD.

EARLY EXPERIENCE INDICATED THAT TARDIVE DYSKINESIA IS DUE TO DOPAMINE SUPERSENSITIVITY.  When the problem of TD first appeared, clinicians figuring that the problem was due a supersensitivity reaction in the dopaminergic system gave an increased dose of antipsychotics to overcome this supersensitivity. The movement generally went away—but only temporarily. In most patients, the system again developed increased movements—presumably from further increased sensitivity.  The relief of the movement symptoms by increasing the antipsychotic was termed "masking" the symptoms. The muscle movements were stopped, but the nerves maintained the potential for recurrence. 

TARDIVE MOVEMENTS MAY OR MAY NOT NORMALIZE AGAIN
Since giving increasing doses of antipsychotics did not prove a successful way of stopping the tardive reaction, clinicians also tried stopping the antipsychotic with the natural expectation that elimination of the medication would allow the system to move back to normal. In some cases it did, but in many cases stopping the medicine did not change the excessive movement. Some people gradually improved over time—though there was hardly ever a complete cure. In other individuals the movements persisted unchanged for years—often being disfiguring and disabling.  However, some differences were noticed—individuals who had received the antipsychotics for a short length of time or who had the tardive symptoms for a relative short length of time were more likely to have their tardive movements resolve when the antipsychotics were stopped. Therefore, at some time in the 1960's or 1970's the concept developed that since there was no direct treatment for TD, the best thing to do was to stop the antipsychotics as soon as the first symptoms were seen. This was done with the hope that the symptoms would resolve on their own.  Incredibly, the official recommendations for today are not much different. The standard advice is to stop everything and wait. But in many individuals, stopping the antipsychotic medication does not cause the system to return to its original set point and the tardive movement disturbance becomes permanent. 

Not only does such a "treatment plan" leave the patient subject to unpredictability of the tardive movement disorders, but also leaves unresolved the problem of withholding antipsychotics from individuals who may need their therapeutic benefits!

FINDING A WORKABLE TREATMENT FOR TD. When I started treating the developmentally disabled (DD) population in the early 1980’s, I encountered many young people with TD. I tried the recommended approach of stopping their antipsychotics. Catastrophe! Their movement problems became twice as bad and they developed behavioral problems—sometimes frank psychosis. A few were able to remain off antipsychotic therapy the recommended three months. Not one got better. They had been on these medications a long time. Their TD was not going to go away spontaneously. Some more specific treatment had to be found!

MASKING THE MOVEMENTS – PLUS DOING SOMETHING ELSE EQUALS TREATMENT. Noting that patients had been less symptomatic when on the antipsychotics, I conceived that masking the symptoms with antipsychotics could provide genuine benefit and give time to figure a way to deal with the problem of increased sensitivity.  I learned of the work of Doctor R. M. Allen who had theorized that the dopamine stimulating effect of the medicine amantadine might counteract the body's tendency to develop the tardive reaction to antipsychotic treatment. True, it was theoretically possible that the antipsychotic and the amantadine might simply counteract each other, but it was a chance worth taking – especially since Dr. Allen already had published a paper demonstrating positive results using the combination (1).  In practice, the use of this combination of medicines has provided a foundational therapeutic treatment for TD to which many other medications and methods can be added—allowing for at least 80 % of cases of TD to be reasonably well managed.

WHEN GIVEN HELP AND TIME THE TD CAN GET BETTER
In 1985, I published a letter to the editor in the winter edition of the Journal of Neuropsychiatry presenting the technique of treating TD using antipsychotics and amantadine. (2) The technique was stated as follows:

1. An individual identified as having TD is given an antipsychotic by increments every three days until a dose that just masks the aberrant movements is reached.
2. Amantadine is started at a dose of 100 or 200 mg per day. 
3. After a waiting period of one to six months, the daily dose of neuroleptic is gradually decreased. 

CASE DEMONSTRATING THAT THERE CAN BE A CHANGE TOWARD NORMAL SENSITIVITY IN TD. 
One case history included in this letter demonstrates a very important understanding:  When given an opportunity, the sensitivity that apparently causes tardive movement disorder may diminish and disappear. 

Case 1 told of a twenty-year-old male with Tardive Dystonia. He was placed on haloperidol at a dose of 15 mg a day plus amantadine 200 mg a day. This relieved his dystonia. His daily Haloperidol dose was then lowered on a schedule of 0.5mg every two weeks until the dose was down to 2 mg a day. (This took 13 months.) On this reduction schedule, he demonstrated no recurrence of his dystonia. At that time a decision was made to discontinue the last 2 mg abruptly. Immediately, the tardive dystonia recurred as severely as at first. When the haloperidol was restarted at the 2 mg dose and then lowered at the previous rate, it was possible to stop the haloperidol and the amantadine completely with no evidence of residual dystonia. 

This case demonstrates several important points.
1.  The body was able to readjust its sensitivity over time. (Note that it took 15 mg of haloperidol to mask the dystonia the first time, but only 2 mg to mask it a year later.) 
2.  The movement disorder recurred when the dose of haloperidol was lowered too quickly. It was not the absolute amount of medicine that caused the recurrence, rather, it was making too big a change in the dose. 
3.  The presence of amantadine seemed to prevent the system from continuing to develop increased sensitivity, but there is no absolute proof. It might be argued that the patient could have been an individual whose tardive reaction would have gone away by itself.  Even if this were the case, treatment provided instant relief rather than his having months of continued symptoms. 

NOT EVERY CASE IS SO EASY
In treating several hundred subsequent patients with TD, I have found that not many cases can be so easily resolved with eventual stopping of both the antipsychotics and amantadine. Other treatments have often been needed:

1.  A fair percentage of the patients resolved their tardive disorder but could not tolerate lower doses of antipsychotics because of psychiatric symptoms. Many of these have been on a stable dose of antipsychotics and amantadine for more than 10 years with no recurrence of their TD. More recently some such individuals have been placed on the atypical antipsychotics to treat their psychiatric symptoms since the atypicals are less likely to cause TD.
2.  Others improved their tardive symptoms but did not resolve them completely. Taking the neuroleptic higher did not further mask the movement.
3.  And when some individuals were given antipsychotics, they developed movement disorder symptoms of the EPS type in some muscle areas such as the arms, while retaining tardive movements in areas such as the mouth. Both groups 2. and 3. often required the therapeutic benefit of the atypical antipsychotic clozapine (Clozaril)
4.  A significant number of individuals did stabilize on a particular dose of antipsychotic and amantadine but then did not tolerate having the dose of the antipsychotic lowered even the smallest amount without having a breakthrough of tardive movement. Such individuals sometimes benefited when their medicine was lowered by slow titration called the "bounce method." 

 PART II: DESCRIPTION OF THE TYPES OF TARDIVE PHENOMENON 

There are various types of disorders which are caused by the tardive phenomena. All are characterized by an increase in the nerve impulses to the muscles by the extrapyramidal system.
 

TARDIVE DYSKINESIA.  Tardive Dyskinesia is the most commonly seen tardive reaction.  Its most standard feature is that of involuntary movements of the mouth, muscles, and tongue.  This is generally an asymmetrical mouth movement, a rolling protrusion of the tongue often with audible lip smacking.  (Another side effect, the dystonic straight forward thrusting of the tongue with inability to put it back in the mouth, is generally not a tardive reaction, but a pseudo-Parkinson or EPS reaction.)  Many individuals with Tardive Dyskinesia also have twisting motions of the neck, writhing, and involuntary movements of the arms and legs.  Some individuals have rubbing and scratching of the arms and legs.  These movements often are exaggerated when an individual is under stress.  Less than 5% of individuals with Tardive Dyskinesia have highly severe movements interfering with major life functions, but the oral facial movements can be very distracting and cause disfiguration of normal facial appearance.

TARDIVE DYSTONIA.  In dystonia, muscles are rigidly spastic.  It is possible to have dystonia as an extrapyramidal side effect or as a tardive phenomenon.  The most common site of Tardive Dystonia is in the back muscles.  Tardive Dystonia of the back is most commonly seen in young males.  They will be noted by their tendency to walk with one of their shoulders pointing forward and their body twisted to one side.  Sometimes the back is also rigidly straight and does not flex forward and backwards. 

BLEPHAROSPASM.  Excessive, rapid blinking of the eyes is sometimes seen as a tardive movement disorder. A significant symptom is aching and/or red inflammation of the eyes.  Most of these individuals will have tardive mouth movement, but some do not.  Otherwise the symptom is similar to another disorder called Essential Blepharospasm.

TORTICOLLIS.  It is possible to have Tardive Dystonia occurring in the neck and back muscles so that the neck and head will be twisted to one side.  (When this condition occurs spontaneously in the absence of neuroleptic treatment, it is called Essential Torticollis.)

TARDIVE DYSPHAGIA (DIFFICULTY SWALLOWING) This is not really a distinct diagnosis, but the symptomology is due to TD. It needs to be noted since it presents as a seemingly unrelated problem—that of repeated pneumonia and bronchial infections secondary to aspiration of food. 

TARDIVE STEP-GAIT DISORDER.  This is a condition that apparently is not known or described in standard medical literature.  I have talked to a few physicians who think they have seen it, but they have not identified enough patients to delineate its peculiarity.  Madison County Community Hospital Psychiatric Unit has treated more than twenty individuals who have this particular disorder.  Most of them are over 50 years old, but the disorder has been seen in individuals below the age of 30.  Tardive Step-Gait Disorder has the following characteristics: 
1. The individual has difficulty with certain types of movements associated with walking.  There is a tendency for a rapid, short stepping gait when walking is initiated (called stutter-step).
2. The individual often has difficulty turning in the opposite direction and must make a wide swing rather than being able to pivot on one foot and turn. 
3. The individual tends to have a peculiar way of sitting down.  As they approach a chair, they will tend to rush toward the chair and fall into the chair out of control. 
4. Often individuals will fall down when in the process of having any of the above normal gait problems. 
5. Many times, individuals can walk perfectly normally if they are not under stress or not thinking about walking.  Thus, an individual might get up and steal a cookie off the table, but would fall to the ground if asked to get up and walk.
6. Like patients with Parkinson gait, these individuals may be “frozen” when attempting to go from one floor surface to another or through a door. 

The majority of these individuals also have typical tardive oro-facial dyskinesia, but they also may have extrapyramidal side effect tremor of their arms and legs if on a moderate dose of neuroleptic medication.  It is probable that many individuals with this disorder exist and have been mistakenly diagnosed as having EPS secondary to neuroleptic medication, or having a gait disturbance secondary to Parkinson’s Disease. 

Because so many of these individuals get extrapyramidal side effects with low dose neuroleptic medication, the standard amantadine/neuroleptic treatment is generally not effective.  However, many individuals obtain considerable relief when placed on clozapine.  Most of these individuals will still be given amantadine and some may be on neuroleptics concomitanly.  In a few individuals, it has been possible to stop the neuroleptic medications and amantadine without recurrence.  However, most individuals who have developed Tardive Step-Gait Disorder will have some irregularity of their ability to walk even after treatment.

TARDIVE AKATHISIA. There are individuals who have the excess moving of the body similar to the pseudo-Parkinson's akathisia caused by neuroleptic effect in lowering dopamine in the extrapyramidal system.  I have seen two very extreme cases of individuals who might have been called Tardive Akathisia. One had an unstoppable drive to scratch her legs. Both of these individuals demonstrated marked improvement with neuroleptic/amantadine. But one finally was stabilized most adequately on clozapine, an atypical neuroleptic. 

TARDIVE BEHAVIORAL SYMPTOMS. During the 1980’s, there was an increased understanding about psychiatric and behavioral difficulties seen when individuals who had been treated for a long time with neuroleptics were taken off of their medications.  Some individuals developed wild psychosis and wild aggression when the medications were stopped suddenly.  Often, this was interpreted that they “needed” the medication because they were psychotic.  Other clinicians discovered that a much slower tapering of the dosage would allow some individuals to function on lower doses or even without neuroleptics.  The difficult psychiatric symptoms were a tardive withdrawal effect rather than true psychosis. In the 1980’s these tardive or withdrawal behavioral problems in the DD population was a major concern. One nationwide lecturer spent nearly half of a two-day conference discussing it.  Note:  The phenomenon of tardive behavioral problems and TD can be seen when changing individuals from typical to atypical antipsychotics. 

 PART III: DOPAMINE SENSITIVITY. 

VARIATION IN SENSITIVITY OF THE DOPAMINERGIC SYNAPSE.
There are multiple ways that the sensitivity of Dopamine reactivity can vary.

1.  BETWEEN DIFFERENT INDIVIDUALS:  It is apparent that individuals with TD in some way have a dopamine receptor mechanism that is overly sensitive. They are sensitive to very small changes both in dopamine release and in antipsychotic doses. However, the dopamine receptor mechanism is not sensitive in everyone receiving antipsychotics. Some individuals can be abruptly taken off extremely high doses of antipsychotics with no evidence of movement or behavioral withdrawal.

2.  BETWEEN DIFFERENT TIME PERIODS:  It is also possible for the same person to demonstrate variations in sensitivity over time. This situation is sometimes seen in the problem of Neuroleptic Malignant Syndrome (NMS), which is due to severe muscle dystonia caused by medication changes. Some individuals can develop  NMS with a particular change in dosage of antipsychotics on one occasion, and not have it occur with the same change on another occasion. This variability is also seen in the occurrence of withdrawal reactions in patients treated with dopamine stimulants for Parkinson’s Disease (such as levodopa) . Some patients given the standard doses of levodopa will have excess dyskinesia movements immediately after the dose and gradually move toward Parkinsonian rigidity as the dose wears out.  Dr. William Glazer of Harvard, a leading authority on TD,  states that some patients with TD also can have changes  from dyskinesia to Parkinsonian movements of the same muscles over a period of time. 

3.  BETWEEN DIFFERENT DOPAMINE RECEPTOR GROUPS IN THE SAME PERSON.  There is another mixture of Parkinsonian and Tardive movement side effects seen in the same patient. Many individuals will have tardive reactions in the face, back, and gait while having Parkinsonian rigidity (EPS) in the arms. This combination of symptoms is commonly seen in many older individuals with Tardive Step-Gait Disorder. Such individuals cannot have their tardive disorder treated with increased doses of  typical antipsychotics,  since the Parkinson movements then get worse.  Giving anticholinergic medicines for the EPS is frequently inadequate. These individuals often require treatment with atypical antipsychotics, generally clozapine. (It is noteworthy that the muscles that have TD are the ones which have a normal high resting tone such as face and back, whereas those which have EPS are the ones which have a low resting tone such as the arms.)

THE VARIATIONS ARE NOT PREDICTABLE.  There is no way to predict who will have a wide margin of safety or who will have a narrow margin of safety in their Dopamine reactivity. Therefore I have developed an oft-repeated cliché for clinicians using medications which act on Dopamine. 
“Be very gentle at the dopamine receptor, friend.”

WHAT IS A LIKELY MECHANISM THAT CAN EXPLAIN THE VARIATIONS IN SENSITIVITY OF THE DOPAMINE RECEPTORS

Built into the dopamine receptor mechanism is an intricate self-regulating mechanism, which helps control the intensity of activity of dopamine neurons. The main action of Dopamine release is to activate the Dopamine-2 receptors on the receiving neuron, but there is also stimulation of other Dopamine-2 receptors which act on the releasing neuron. These are called presynaptic receptors and act on the releasing neuron to regulate the further release of Dopamine. (This arrangement is found on other neurons using the special neurotransmitters such as Norepinephrine and Serotonin.) The apparent purpose of this feed-back mechanism is to allow the system to have the potential for instant dynamic reactivity, but also to have an instant dampening mechanism to deal with the many "false alarm" arousals that occur in the course of life. So there is a system of fine-tuning between the two differently located Dopamine-2 receptors. It is probable that the tardive reactions occur through a change of sensitivity between the presynaptic and postsynaptic receptors.

This feedback mechanism is even more complex because of the influence of other neurotransmitters. For example, on some dopamine neurons stimulation of certain Serotonin-2 (5HT2) receptors increases the reactivity of the presynaptic receptors. This causes further lowering of the amount of Dopamine released. Conversely, blocking these Serotonin-2 receptors increases Dopamine secretion. This seems to be of major significance in the action of atypical antipsychotics, since they have both Dopamine and Serotonin-2 blocking effects. 

OTHER CLINICAL EXPERIENCE INDICATING THAT THE "SUPERSENSITIVITY" CAN ADJUST OVER TIME.

Other clinicians, especially those working in with the Developmentally Disabled have reported similar experiences indicating that the tardive reactivity can diminish over time, especially if the system is allowed to change gradually. Several of these are reported below.

1]  The "Jolt and Recover" method.  One psychiatrist reported to me his method of successfully titrating down antipsychotic doses in DD individuals by lowering the dose slightly on a routine schedule every 4 weeks. "On the first week, the individual might experience behavioral and movement difficulties, but these would settle down. The medicine would be lowered again with the same cycle of events. "The staff became accustomed to having one bad week. It was worth it getting the patients off the antipsychotics." Lowering the antipsychotic by regular steps is termed "step dose" reduction. Not all individuals will show withdrawal symptoms.

2]  Henry Crabbe M.D., of New Haven, CT, reported at a NADD conference a similar titration to wean patients off of antipsychotics. However, he cleverly prevented the withdrawal behavioral symptoms that occur at the point of lowering the antipsychotic by giving a low dose of the dopamine agonist (dopamine stimulant) medication bromocriptine at that time. A low dose of bromocriptine frequently acts by stimulating the presynaptic regulator receptors far more than the activating receptors on the receiving neuron. This stimulation of the presynaptic receptors actually lowers postsynaptic dopamine stimulation balancing out the effect from lowering the antipsychotic dosage. Therefore, there are very few clinical withdrawal symptoms seen. The bromocriptine loses its effect on the presynaptic receptors after a week or so, but by that time the postsynaptic receptors have changed their reactivity. The bromocriptine can be stopped and restarted again at the time of the next titration. The withdrawal was much smoother than in the first example.

3]  Paula Beale M.D., of Detroit, MI. reported at an NADD conference an alternate method of titration, which she demonstrated in a formal study. Instead of lowering the dose of antipsychotic suddenly on a particular day, she would gradually introduce the reduction—a method which she termed the "tickle method" but which I have preferred to call the "bounce method." This method starts by giving a smaller dose of medication only a few days a week—e.g. on Mon. and Fri. On the other five days the higher dose is given. After a set time period (e.g. two weeks,) the lower dose is given more days—perhaps three or four days. Eventually the lower dose is given every day of the week, and the cycle is begun again with a new lower dose. Dr. Beale reported that such a technique produced much less behavioral and movement withdrawal side effects when compared to the standard  method of straight dosage titration. I have used this technique regularly in those patients who do not tolerate standard, "step dose" titration. 

FURTHER EVIDENCE THAT THE TARDIVE REACTION INVOLVES EXTREME SENSITIVITY TO LEVELS OF DOPAMINE AND DOPAMINE ACTIVE MEDICATIONS.

In the course of years of seeking to stabilize patients tardive reactions, I have seen multiple cases which point out the particular sensitivity that the Dopamine receptor mechanism may demonstrate:

1]  SENSITIVITY TO VARIATION IN BLOOD LEVELS OF NEUROLEPTIC.
In one case of Tardive Blepharospasm, the patient was placed on 2.5 mg of Haldol at night to mask the eye blinking reaction which had caused eye pain. Her pain was eliminated in the day, but recurred slightly in the evening, when she noted more eye blinking. Moving the Haldol to 0.5 mg in the afternoon and 2 mg at night stopped the pain in the evening.  In most individuals, the variation of neuroleptic medication in the body is not normally clinically significant, but it may be in the TD patient.

2]  CHANGE IN TOTAL DOPAMINE REACTIVITY CAUSED BY ADDITION OF ANOTHER DOPAMINE ACTING MEDICATION.
 On one occasion, a patient with TD and bipolar disorder was stabilized on a dose of haloperidol decanoate and amantadine 200 mg a day. When he became clinically depressed he was placed on a low dose of buproprion, an antidepressant which increases synaptic Dopamine by the mechanism of blocking reuptake into the presynaptic neuron. He then developed increased facial movements, indicating increased Dopamine activity. This movement resolved when the amantadine was lowered to 100 mg a day.

3]  SSRI ANTIDEPRESSANTS ADDING TO THE DOPAMINE BLOCKING EFFECTS OF ANTIPSYCHOTICS.   One patient whose TD was very difficult to treat and included Blepharospasm and Dystonia causing swallowing problems finally started stabilizing when an SSRI antidepressant was added to the regime of amantadine, typical, and atypical antipsychotics. This class of medications changes the set point of the presynaptic Dopamine receptors, thus decreasing the synaptic dopamine and improving the masking of the movements—perhaps without causing increased sensitivity.

ATYPICAL ANTIPSYCHOTICS (Clozaril, Risperdal, Seroquel, Zyprexa.)  AND OTHER MEDICATIONS

TREATMENT WITH ATYPICAL ANTIPSYCHOTICS.  Atypical antipsychotics are given this designation for several reasons – the most significant one being the diminished tendency for simply blocking dopamine-2 receptors and an increase in the property of blocking serotonin-2 receptors.  This modulates the way that dopamine-2 is blocked creating less tendency for extrapyramidal side effect and TD.  There are many individuals whose tardive movement problems have improved when placed on any of the atypical antipsychotics, but one atypical antipsychotic, clozapine, seems especially able to treat tardive disorders.  This ability can occur with the use of clozapine alone, it can occur when clozapine is used with other atypical neuroleptics, or with standard neuroleptics; and with or without the use of amantadine.  Actually, low doses of this medication seem to be adequate, sometimes 25 to 100 mg can be all that is required help reverse an individual's tardive movement disorder.  There is not much consistent clinical experience about tapering the clozapine over time.  Most individuals treated in this clinic have been placed on amantadine, but there is no absolute statement that the amantadine is necessary.  Some individuals switched from typical antipsychotics to atypical antipsychotics will demonstrate an increase in tardive movements because the masking effect of the typical antipsychotic has been removed.  In such individuals, this clinic continues the typical antipsychotic and amantadine at a standard dose and uses the atypical neuroleptic for antipsychotic purposes or to enhance the treatment of the TD. The potential benefit of Atypical Antipsychotics was presented in the article, "Treatment of Tardive Dyskinesia and Tardive Dystonia" by George M. Simpson in Supplement 4 of Volume 61, year 2000 of the Journal of Clinical Psychiatry pp. 34-44.

Since Atypical Antipsychotcs are such positive medications and (except for clozapine) have so few side effects, there seems to be no reason not to try them in all cases of TD which have significant symptoms. 

FUTURE TREATMENTS USING MEDICATIONS WHICH AFFECT THE GLYCINE/MNDA RECEPTOR COMPLEX.  There are several possible treatment regimes for stimulating this receptor mechanism. Like Atypical Antipsychotics, these regimes improve negative symptoms of Schizophrenia and have less tendency to cause movement disorder side effects. As these regimes become standardized, there will be opportunity to see if this mechanism has modulating effects  on TD.

There are two reasons why this system offers hope for treating TD. 
1. Clozapine, the most effective atypical antipsychotic in preventing movement side effects and treating TD, has been shown to have Glycine/MNDA complex stimulating effects.
2. Amantadine is a Dopamine agonist, but also has MNDA blocking effects—perhaps explaining why it seems more effective than other Dopamine agonists in preventing the increase in Dopamine sensitivity in TD patients. This property might also explain the occasional report in the literature that giving amantadine to a patient with TD will cause an immediate lowering of TD symptoms—an action not expected from its Dopamine agonist effect.

OTHER TREATMENTS FOR TARDIVE DYSKINESIA WHICH MAY HAVE MERIT BUT ARE NOT USED EXTENSIVELY IN THIS CLINIC.

HIGH DOSE BUSPIRONE.  This treatment is reported by Dr. Raymond Neppe.  His concept is that buspirone in high doses acts as a partial dopamine agonist in the same way that low doses work as a partial serotonin agonist.  This means that the buspirone stabilizes both sides of the presynaptic and the postsynaptic receptors in a way that allows for improvement of the disturbance of the receptor mechanism.  Dr. Neppe states that this is a fairly effective treatment.  It has the disadvantage of not allowing the clinician to regulate dopamine blocking versus dopamine agonism as one can in the amantadine/neuroleptic treatment.  We have experienced difficulty trying to raise the dose of buspirone to the 60 to 90 mg per day range that Dr. Neppe suggests. (Buspirone may also have benefits through its effect on serotonin.) 

RESERPINE AND OTHER DOPAMINERGIC DEPLETER MEDICATIONS.  The medication reserpine has been used to treat TD because it diminishes the amount of dopamine within the dopamine system and, thus, can lower the amount of neurotransmitter available to cause the excess stimulation which produces the dyskinesia.  Reserpine is difficult to use, however, because of side effects:  (1) from its depleting nor-epinephrine and serotonin, the most significant of these are depression, lethargy, and low blood pressure; and (2) because the depletion of dopamine by reserpine is non-specific, it may effect both the presynaptic and postsynaptic dopamine receptors, thus not allowing a specific effect necessary for controlling the tardive movements.

DEMSER (metyrosine) OR ALPHA-METHYL PARA-TYROSINE.  This medication causes depletion of dopamine and nor-epinephrine by other means than reserpine.  It is also used considerably for psychiatric treatment in Madison County Community Hospital Special Psychiatric Unit since it has fewer side effects than reserpine.  It might also be useful to help lower the amount of tardive movement in certain individual cases. 

THE USE OF OTHER DOPAMINE AGONISTS BESIDES AMANTADINE.  There are other medications which increase dopamine activity besides amantadine.  None of these are demonstrated to be as effective as amantadine, but they are worth mentioning:

Bromocriptine (Parlodel).  This medication has been the most commonly used one for increasing dopamine activity.  It may be different in its actions from amantadine since there are demonstrations that, in low doses, it tends to stimulate the presynaptic (inhibitory) receptors without stimulating the postsynaptic (excitatory) receptors.  (See the description of the work of  Dr. Henry Crabb.)

Pergolide, cabergoline, levodopa, selegiline (Eldepryl), and others have dopamine agonist activity like bromocriptine.  There is an old report that one clinician actually gave short-term levodopa to people with TD with the apparent result of changing the sensitivity across the dopaminergic synapse.  Giving the levodopa apparently was extremely uncomfortable because of the increased movements that occurred during the treatment. I know of no one currently using these medications for treatment of TD. 

Vitamin E. There have been some reports of benefits of Vitamin E (tocopherol) improving the course of TD in some patients.  The supposed benefit would be presumed to be non-specific and is certainly not predictable.  I sometimes use Vitamin E in those individuals who are very hard to stabilize. However, there are many individuals whose TD has been cured who were not treated with Vitamin E. There is a strong belief by some that Vitamin E is a proven cure for TD, and I will occasionally receive a pharmacy review recommending that the neuroleptics and amantadine be stopped and Vitamin E started.

 PART V:   SUMMARY OF MADISONDOCTRINE VIEW OF THE NATURE OF TARDIVE DYSKINESIA 

1.  Tardive Dyskinesia is a change in the normal control mechanism of voluntary skeletal muscle control by a system of nerves called the extrapyramidal system. (The main nerve pathway is called the Nigrostriatal pathway.) It occurs in some individuals who have been treated with traditional Antipsychotic medications (also called neuroleptics) This problem occurs after the patient has been on the Antipsychotic medication for a length of time. Since the reaction occurs late, the symptoms which occur are called  "tardive."

2. The main regulating neurotransmitter chemical of the extrapyramidal system is Dopamine, the same chemical that regulates the system responsible for perception of rationality and irrationality in the Mesolimbic pathway.  Neuroleptics act by blocking Dopamine’s effect on postsynaptic Dopamine receptors.

3.  As the Dopamine receptors are blocked by the neuroleptics, there is a change in the system. It becomes more sensitive—as if seeking to bring the reaction back to normal. Individuals with tardive movement disorder have developed a permanent extrasensitivity of the Dopamine nerve reactions so that there is too much muscle tone or movement.  Minute stimulations which would normally not cause any reaction now cause changes in the muscle tone. Thus the medication which initially lowers body's reaction to the Dopamine stimulation causes a reaction which increases the body's reaction to Dopamine.

4.  This supersensitivity can become fixed in the nerve pathway so that the supersensitivity will remain even after the neuroleptic is completely discontinued. Thus TD is greatly feared because it represents a potentially permanent change of the movement of the body.

5.   There is no absolutely proven mechanism for the nature of this apparent supersensitivity. It was first considered that the receptors remained overly sensitive, or that there develops an increased number of receptors—but such changes have not been found by various experiments. It is more likely that the sensitivity of the feedback loop between the postsynaptic Dopamine activating receptors and the presynaptic Dopamine regulating receptors has been changed. Since both sides have identical Dopamine receptors, standard techniques for identifying Dopamine receptor changes would not necessarily indicate a difference.

6. TD is an incorrect set point for a normal Dopamine mechanism. There is the capacity for the set point to reset. This may occur spontaneously, or it may be helped with various medication regimes which lower the severity of the symptoms and perhaps make it easier for the system to readjust. Treatment regimes which program extremely slow adjustment of medication doses seem to allow for readjustment toward a normal Dopamine sensitivity.  The most predictable regimes involve neuroleptic/amantadine combination, atypical antipsychotic (especially clozapine), and Bounce Method titration. Most individuals with significant symptoms require combination therapy. 

 PART VI: MODEL AND REAL CASES OF TREATMENT OF TD 

Model cases (Cases 1-6) are presented to guide in chemical treatment of TD:

Case 1: Patient under 40 years old on typical antipsychotics for one year begins showing TD movements of mouth.  Treatment:  Raise typical antipsychotic to mask movements and add amantadine and start slow titration after two or more months.  If necessary for psychiatric treatment, add typical antipsychotic. (Stopping all antipsychotics or switching to Atypical alone might allow for resolution of TD).

Case 2: Patient under 40 years old on typical antipsychotics for over five years and TD movements of mouth appear after dose reduction of antipsychotics.  Treatment:  Raise typical antipsychotics to mask TD, add amantadine, place on appropriate dose of atypical antipsychotic, and after over two months, titrate down by step plan or bounce method.

Case 3: Patient on typical antipsychotic for over five years and is also on benztropine for EPS tremor of arms.  Antipsychotic dose was lowered by 50% to eliminate EPS.  Severe TD movements of mouth and neck occur interfering with eating.  Treatment:  Seek to raise typical antipsychotic to mask most of TD movement, continue benztropine, add amantadine, and low dose atypical antipsychotic. Seek to stabilize medication dosage for over two months with minimal tardive movements, and attempt to titrate down by step plan or bounce method.  If unable, extend treatment for six more months, then attempt titration again.

If tardive movement is intolerable at low dose typical neuroleptic, but if EPS is intolerable at higher dose, then consider use of Clozapine.  After adding clozapine, start titration of typical neuroleptic, probably by bounce method.

Case 4: Patient 60 years old with a ten year history of Tardive Dyskinesia after titration off all antipsychotics.  Symptoms are minimal, but some cause mental discomfort.  Treatment:  Add an atypical antipsychotic (possibly risperdal) with low dose amantadine 100 mg per day.  Wait over three months to see if symptoms improve.  If not, trial of low dose typical antipsychotic to seek masking effect of her dyskinesia.  Vitamin E can be added.  If no benefit or EPS side effects occur, titrate down typical antipsychotic.  Continue atypical antipsychotic plus amantadine for a further six month trial. Clozaril could be used, but only if patient insists on seeking improvement of tardive movements.

Case 5: Patient over 40 years old presents on medium dose typical and atypical antipsychotics with a history of severe tardive movements of face with difficulty chewing and swallowing, and akathisia-like movements of arms and legs.  Patient has no history of EPS.  Raise typical antipsychotic to seek to mask most of symptoms and add amantadine.  After two to four months, if dyskinesia is still severe, add low doses of clozapine—being watchful for increased swallowing symptoms.  Maintain stability for four months, then titrate typical antipsychotic down by step or bounce method.  Titrate to approximately 50% of original dose then raise suddenly to seek to mask more of the symptoms.  Once stable, patient may not tolerate any lowering of typical antipsychotics.

Case 6: Patient over 60 years old with a three-year history of Tardive Step-Gait Disorder.  Falls when attempting to walk and has typical stutter-step movement.  Is currently on only atypical antipsychotic risperdal and has EPS movements of arms.  Add clozapine slowly with a probable maximum of 150 mg per day and add amantadine.  If tardive step-gait movements improve, seek to lower risperdal slowly by bounce method.  If risperdal can be discontinued, then clozapine may be lowered.  It is unlikely patient will be able to go completely off clozapine without recurrence of Tardive Step-Gait Disorder.

Actual Cases:
Case 7:   Patient seen at age 35-40 having been on neuroleptics for many years in an institution. After moving to community residence, his dose of Thioridazine of 200 mg. was discontinued. He presented as being very hyperactive with many extra movements, sticking tongue out, twisting head, and flapping arms.  He was placed on amantadine 100 mg BID and Loxapine 40 mg a day. The dyskinesia was masked by this dose. Within the next year, Loxitane was lowered in 5 mg steps to 25mg. There was no movement breakthrough, but 8 months later it was raised back to 30mg and another Dopamine-acting medication, Reserpine, was added to lower symptoms of psychosis.  This regime was maintained 7 years, then, loxapine was lowered to 25 mg. and reserpine stopped. Each subsequent year, loxapine has been lowered by 5 mg and is now at 10 mg a day.  No significant TD has been seen for over ten years. Occasionally mild lip smacking noted.

This case demonstrates a quick resolution of TD symptoms but a prolonged time being required to deal with the chronic dissociative psychosis typical of individuals who have a history of chronic institutionalization.

Case 8: Twenty plus female with history of post-traumatic stress disorder, dissociative hallucinations and violence. She had been in a psychiatric hospital as an early adolescent. She was on chlorpromazine 800mg a day, and demonstrated muscle twitches of mouth and tongue when talking. She was discharged on 500 mg of chlorpromazine, 2mg of haloperidol, reserpine 0.4 mg , and amantadine 100mg a day, but psychotic symptoms worsened. Chlorpromazine was raised to 700mg and reserpine to 0.6 mg a day. (She was also on mood stabilizing medications.)  She was readmitted within a year for increased bizarre rituals and weight loss, and discharged on chlorpromazine 200 mg  a day, amantadine 100 mg a day and  paroxetine 20 mg a day for depression. Again she demonstrated increased bizarre behavior requiring chlorpromazine to be raised.  Over the next eight years she has had four hospitalizations because of episodes of bizarre or aggressive behavior. She has had to remain on high dose chlorpromazine (currently 600 mg) . She is also on 15 mg olanzepine and 400 mg quetiapine a day.  She now has a few mouth movements which are hardly noticeable. 

This is a case where typical antipsychotics could not be lowered, but there was improvement of the TD after adding amantadine. However, the symptoms did not totally disappear even after starting atypical antipsychotics. 

Case 9: Individual age 60+, admitted after a recent abrupt discontinuation of fluphenazine, she then started “intense, uncontrolled movements including flailing arms, scratching body, breathing rapidly. No relief had been obtained from diphenhydramine or diazepam, but movement stopped with 5 mg IM haloperidol. She was discharged with considerable improvement on fluphenazine decanoate, 12.5mg every three weeks, and amantadine 50 mg a day. She was readmitted 2 1/2 years later because oral and injectable fluphenazine was not controlling movements. She was then discharged on 100mg amantadine and haloperidol 30 mg a day. (The high dosage being required since she apparently metabolized oral haloperidol rapidly.)  She was on 35mg haloperidol and 100 mg of amantadine when she was readmitted three years later because she was demonstrating increased facial, arm, and leg movements, and increased episodes of falling. Some of her movement disorder was determined to be EPS; so it was determined to lower the haloperidol and start clozapine.  She was discharged on haloperidol 15mg, clozapine 50mg, and amantadine 100 mg a day. Her gait was “adequate” and mouth movements were “tolerable.”  Over the next 7 years the haloperidol was titrated down and she now has few symptoms on Clozapine 25 mg bid and 50 mg. at night, but her tardive movements recurred on a lower dose of clozapine.

This case shows the benefit of neuroleptic masking of acute TD symptoms, the length of time required to stabilize a patient, and the ability of clozapine to induce readjustment of the unbalanced system which causes TD. It also shows that tardive and EPS movements can occur at the same time.  The fact that she had recurrence of TD symptoms may have been due to the relatively low dose of amantadine she was given, but there had been a concern that higher doses would cause excessive movement. 

Case 10: Seen first when over 60 years old in late 1980’s.  Had been admitted to state institution at the age of 4 because of seizures in early childhood. There was a history of falling for many years, and of tongue flicking, mouth rolling, and stutter-stepping gait and falling when she turns around. Admission antipsychotic medication-50 mg. thioridazine, was continued. After two years, the dystonic gait was diagnosed as being a tardive side effect.  Eventually she was placed on haloperidol 1.5 mg. plus 25 mg of amantadine.  She then developed increased EPS tremor of the tongue movement; falling was still a major problem. Benztropine was then started. When haloperidol was raised by steps to 3 mg over several months to seek to mask the tardive gait, an EPS dystonia of the back occurred, causing leaning to left. Over then next two years, haloperidol was lowered to 2mg. EPS was down but tardive gait was not improved. In the early 90’s clozapine 25mg was started and haloperidol discontinued. With these changes her gait improved quickly, and continued to improve as the clozapine was slowly raised to 125mg over the course of the next two years.  During this time her falling diminished markedly.  Because of her age, the clozapine was discontinued causing some recurrence in her gait problems, but not sufficient to warrant restarting the clozapine.

This was one of the early cases of Tardive Step-Gait Disorder which proved refractory to the standard typical neuroleptic/amantadine therapy and required the use of clozapine.  Typically the older patients with TD Step-Gait Disorder improve with clozapine enough to allow adequate daily function.

1] If this treatment works so well, why hasn't standard medical practice accepted this treatment?

The clinical experience with neuroleptic/amantadine treatment is done in clinical case studies only; there has been no controlled scientific investigation.  However, most controlled scientific investigations tend to last only a brief time (say, three months).  The major failure of most studies in the treatment of TD is looking for permanent change within the first three months rather than accepting a need for long-term treatment. 

2] How should doses of neuroleptic be raised to mask the tardive movements?

Doses should be raised on a fairly rapid basis.  For example, an individual who might have been taken off of all neuroleptics, but having been on 10 mg of haloperidol in the past, might be placed on 5 mg of haloperidol for three days then raised to 10 mg, 12 mg, 15 mg with an increase every three days as long as there are no side effects.  The basic principle is to raise the dose fairly rapidly until the TD is masked, add amantadine, then wait for four to twelve weeks before starting a very slow titration to allow the system to change sensitivity without symptom breakthrough. In a few cases neuroleptic doses have been given by IM or IV injection. 

3] What side effects can occur in raising the neuroleptic dose?

It is possible for individuals to develop extrapyramidal side effects (tremors, dystonia, or stiffness related to too much blocking of dopamine activity) and at the same time present TD symptoms due to too much dopamine activity.  Therefore, raising the dose of neuroleptic may cause tremor of the hands and feet and drooling while there remains TD movements of the mouth.  Sometimes, these EPS movements are treated using an anti-cholinergic such as benztropine.  However, their presence often prevents neuroleptic/amantadine combination from being an effective treatment for TD. 

4] Is it necessary to stop the tardive movements completely?

Not really.  Several individuals with severe tardive movements of their lips when treated with enough neuroleptics to allow for the limb movement to be acceptably controlled. Raising the neuroleptics to a higher dose to stop oro-facial dyskinesia did not seem worthwhile.  These individuals could then be titrated down on their neuroleptic over time and the entire system would then develop less supersensitivity.  Since TD can be treated as normal physiological phenomenon with a wrong set point,it is possible that a later raise of the neuroleptic dose can eliminate residual tardive movements that were not treated by the original treatment titration.

5] How does one determine the dose of amantadine?

Seemingly, doses of amantadine from 50 mg to 200 mg are acceptable treatment.  In theory, the higher dose of amantadine would lower the supersensitivity more rapidly; however, there is no absolute evidence that higher doses of amantadine are more effective.  Some individuals develop psychosis or develop excessive tardive movements on higher doses of amantadine and, therefore, are given only 50 mg a day (using the liquid).  In individuals who fail to tolerate reduction in the dose of the neuroleptic over time, the amantadine dose has been raised on the basis of the theory that this will increase the ability of the body to desensitize the dopamine system.  However, it is difficult to prove that higher doses of amantadine have indeed improved the rate of recovery of the TD. 

6] In what kinds of patients does the amantadine/neuroleptic combination treatment not lead to cure of TD?

There are three major classes of individuals that have failed this treatment regime. 
a]  Some individuals tolerate the raised dose of neuroleptics, allowing the tardive symptoms to be masked.  However, over the course of time, any attempt to lower the dose of neuroleptic brings out the tardive symptoms again.  I have seen some individuals who could not tolerate the lowering the haloperidol dose ¼ mg per day even when done over a six-week period by the bounce method.  Theoretically, these individuals may stay stabilized for many years at this dose with no increase or decrease of symptoms and then, surprisingly, be able to tolerate going off the neuroleptic at a much more rapid rate.  There is no absolute predictability about the change of sensitivity that occurs in the dopamine systems in individuals having Tardive Dyskinesia or other dyskinesia or other dysfunctional dopamine states.
b]  A more significant cause of failure of the amantadine/neuroleptic treatment is the inability of the patient to tolerate higher doses of neuroleptics.  The most commonly seen complication is the emergence of pseudo-Parkinson movement problems, such as tremor or stiffness of extremities.  At the same time, there remains tardive disorders of the face and spine.  This difficulty is especially seen in individuals who have Tardive Step-Gait Disorder.  Those individuals who do not tolerate too high a dose of standard neuroleptic often must be treated by placing them on atypical antipsychotics – generally clozapine.  It is possible to treat pseudo-Parkinson symptoms with an anti-cholinergic, such as benztropine.
c]  Most patients over 60 are unlikely to tolerate raised doses of neuroleptics. Clozapine is generally the most effective treatment, but it is curative in only low percent of older patients.

(1) Allen RM: Palliative Treatment of Tardive Dyskinesia with Combination of Amantadine-Neuroleptic Administration.  Biological Psychiatry, 1982; 17:719-727

(2) Ankenman RL: The Combination of Amantadine and Neuroleptics Plus Time May Cure Tardive Dyskinesia. Journal of Neuropsychiatry, Winter 1989; Vol 1, No. 1: 96-97. }

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Bounce Method Titration reduces dosage of a medication by a series of staggered reductions in an individual dose (AM, noon, PM, or night).

his form presents the schedule for the medication Haldol by a special, slow titration method. Haldol will be given 3 times a day (one mg tablets) in the schedule:

        1 mg    AM            0 mg noon          1  mg (high)   ½  mg (low)   PM         1 mg night

In the table below, the "High Dose" will be 1 mg (one tablet) and the "Low Dose" will be 1 mg (one-half tablet). At the end of this step of the titration, the Low Dose will be given every day for the PM dose. (An underlined, capital letter in the corresponding row indicates a high or low dose for the given day.)

This titration schedule will repeat every 10 weeks lowering one of the doses by ½ mg by this staggered regime. The next repetition may lower (in this case, phase out)  the PM dose, or one of the other doses.