Clinical Psychopharmacology Seminar 1996-1997
Paul J. Perry, Ph.D., Bruce Alexander, Pharm.D., Vicki L.
Ellingrod, Pharm.D.
Peer Review Status: None
CLINICAL PRESENTATION
The term "tardive" or late dyskinesia was introduced in 1964 and refers to an iatrogenic disease associated with neuroleptic drug use (American College of Neuropsychopharmacology FDA Task Force 1973, Fann and Lake 1976).
Tardive dyskinesia (TD) is a syndrome of hyperkinetic involuntary movements characterized by a mix of orofacial dyskinesia, tics, chorea and/or athetosis (American College of Neuropsychopharmacology FDA Task Force, 1973). Orofacial dyskinesia is the most characteristic feature of TD. It is slow in onset, which may begin as mild tongue movements, followed by exaggerated movements of the tongue and lips. Bulging of the cheeks, chewing movements, blinking, blepharospasm, grimacing, and arching of the eyebrows also occur. Movements of the extremities and trunk are also noted in some patients. These include choreoathetoid-like movements of the fingers, hands, arms, and feet. Truncal involvement may produce rocking and swaying and rotational pelvic movements.
Late-appearing dystonias involving the neck and trunk have been reported. Recently these cases have been referred to as "tardive dystonia." (Tarsy 1983). "Tardive akathisia" has been suggested to occur concurrently with the typical movements of TD (Tarsy 1983).
TD occasionally interferes with manual dexterity and eating. Diaphragmatic involvement produces grunting, difficulty in speaking, and, sometimes, in breathing.
Usually TD appears while patients are taking neuroleptics, although movements often appear for the first time or increase following a dose reduction or discontinuation of the drug.
Movements in TD may worsen with emotional stress, volitional motor activity, and attempts to inhibit portions of the dyskinesia. On the other hand, movements decrease with sedation and disappear during sleep. Thus patients should be evaluated at least several hours after awakening since TD ratings cycle. When the patient is awake they are worse in the afternoon and least severe just after the patient has awoken in the morning (Hyde et al 1995).
DIFFERENTIAL DIAGNOSIS
The only drug other than neuroleptics that regularly produces dyskinesia is L-DOPA, in patients receiving the drug for the treatment of Parkinson's. L-DOPA actually can improve neuroleptic-induced TD. However, reports have associated TD with reserpine, tetrabenazine, metoclopramide, tricyclic antidepressants, benztropine, phenytoin, and amphetamines. Depending upon the type of onset, a differential diagnosis might include Sydenham's chorea, Huntington's chorea, congenital torsion dystonia, hysteria, and the stereotyped behavior or mannerism of schizophrenia (American College of Neuropsychopharmacology FDA Task Force, 1973).
CLASSIFICATION
The following classification of TD has been suggested to help study the epidemiology, etiology, and treatment of TD patients (Schooler and Kane 1982):
Gureje (1988) examined 57 neuroleptic treated schizophrenic patients aged less than 60 years (mean = 37.5 years) with TD. These patients underwent neurophysiologic testing and AIMS rating. Three dependent variables were generated, two for oro-facial and one for limb-truncal TD. The variables were examined using multiple logistic regression in a stepwise fashion with 21 demographic, treatment, and physiological variables. Oro-facial symptoms were negatively associated with positive symptoms while limb-truncal symptoms were negatively associated with the AP dose on the day of examination. This indicates that resolution of positive symptoms through an AP dose increase results in a worsening of oro-facial TD. Conversely, limb-truncal TD appear to resolve with an increase in daily dose of neuroleptic.
EPIDEMIOLOGY
Miller et al (1995) conducted a 10 year follow-up study of 254 chronically institutionalized psychiatric inpatients. The patients were examined in 1982 for TD and then re-examined in 1992. The prevalence rate increased from 3.1% (8/254) to 12.2% (31/254). Three of the 8 patients with TD in 1982 had it remit. Thus there were 26 new TD cases in the 254 cases or a new TD rate of !% per year.
The prevalence of TD reported in the literature ranges from 0.5% to 65% (Gerlach and Casey 1988, Casey and Hansen 1984, Tepper and Haas 1979). The variability in prevalence rates is attributed to differences in the patient population heterogenicity (age, neuroleptics used, presence or absence of antiparkinsonian agents), TD definition, and research design. An estimate of the true TD prevalence figures requires a baseline prevalence rate for spontaneous dyskinesia, which is clinically similar to TD but arises independently of neuroleptic treatment, especially in elderly patients (Gerlach and Casey 1988). Casey and Hansen (1984) compiled the findings of 18 clinical TD studies. They estimated the spontaneous dyskinesia rate at 5.9% (5900 patients) and the total dyskinesia rate at 19.8% (7200 patients). Thus the net rate or true TD prevalence rate is 13.9%.
RISK FACTORS
Age
Advancing age is the most consistent risk factor capable of predicting TD. By examining pooled epidemiological data, Smith and Baldessarini (1980) found a strong linear relationship between age and both the prevalence and severity of TD. Additionally, they found that TD occurring in patients < 60 years of age was over three times more likely to remit spontaneously. Gureje (1988) was able to confirm previous reports that indicated an age related incidence of oro-facial and limb-truncal TD. Older patients appear to exhibit more oro-facial symptoms while younger patients more limb-truncal symptoms.
Duration of Neuroleptic Treatment
TD is usually first recognized after several years of neuroleptic treatment, but onset within three months has been reported in geropsychiatric patients (Sweet et al 1995). Two studies that have examined this question have concluded that a duration of neuroleptic treatment of greater than 5 (Chouinard et al 1988). or 6 (Morgenstern 1987) years is a legitimate risk factor in the occurrence of TD. However this risk factor is confounded by age. Sweet et al (1995) examined 386 consecutively admitted geropsychiatric patients (mean = 75 yo, 60-100 yo) for evidence of TD. Of these, 234 had been exposed to neuroleptics. The TD rate for the unexposed patients was 10% (15/152). The TD rate for the exposed patients was a function of duration of neuroleptic use. The prevalence of TD was 16% for patients with < 3 months of exposure, 29% for 3 to 12 months, 30% for 1 to 10 years, and 41% for greater than 10 years of exposure. Since age is the strongest risk factor for the development of TD, this study demonstrated that duration of exposure was the second most important risk factor for TD occurrence.
Diagnosis
There have been reports involving schizophrenic patients that have suggested that both a positive family history of affective disorder and the presence of depressive symptoms were markers for an increased likelihood of patients developing TD as well as neuroleptic-induced parkinsonism. Attempts to replicate these findings have either not been successful or not repeated (Barnes 1987).
Additionally, it is hypothesized that schizophrenia might be associated with a tendency to develop abnormal involuntary movements and the neuroleptics accelerate and exacerbate this process. This is especially true in patients whose illness is characterized by an excessive number of negative symptoms (blunting of affect, social and emotional withdrawal, psychomotor retardation, self-neglect, and muteness). Interestingly, it has been observed that these patients tend to have a poor prognosis and be drug-therapy resistant (Barnes 1987).
Following six years of exposure to neuroleptic drugs, patients with affective or schizoaffective illness demonstrated a 26% TD rate contrasted to 18% in schizophrenic patients. It may be that neuroleptics when combined with affective disorder treatments such as ECT, lithium, and tricyclic antidepressants may produce a greater risk of developing TD (Barnes 1987).
Studies conducted in the 1960's found TD to be more prevalent in patients with organic brain syndromes than those with schizophrenia (Barnes 1987). Today, this finding still remains true. Yassa et al (1984), after assessing TD risk in over 300 patients treated with neuroleptics, found that OBS patients (mental retardation with psychosis, alcoholism, epilepsy with psychosis) demonstrated a significantly higher prevalence rate for TD than did those with schizophrenia (Smith and Baldessarini 1980).
Neuroleptic Class
Of 13 studies, none indicated a higher or lower occurrence of TD with any neuroleptic or class of neuroleptic (Tepper and Haas 1979). Cseransky et al (1981) reported a positive relationship between fluphenazine decanoate and total neuroleptic dose. The authors concluded that long-acting injectable neuroleptics may carry a greater risk for TD than other neuroleptics. However, primate studies do suggest that the stronger D2 antagonist neuroleptics (haloperidol, fluphenazine, flupenthixol) carry a greater risk for TD development than the weaker D2 antagonists (clozapine, thioridazine, chlorprothixene) (Barnes 1987). At least with respect to clozapine this seems to be true (Small et al 1987, Lieberman et al 1991).
History of Extrapyramidal Reactions and Anticholinergic Agents
Six studies addressed the relationship of early onset neuroleptic-induced EPS (dystonia, akathisia, and/or pseudoparkinsonism) and TD. Three studies demonstrated no association, two showed a relationship, and one was inconclusive (Tepper and Haas 1979). Additionally, the use of anticholinergic agents has been postulated to increase the prevalence of developing TD. However, three studies found anticholinergics were not associated with an increased incidence of TD (Tepper and Haas 1979). Thus the question arises is the risk factor the predisposition to early EPS or the treatment of the early EPS with the anticholinergic drugs. Kane et al (1988) after examining this question have noted that patients with clinically significant neuroleptic-induced drug-induced parkinsonism have a two-fold greater risk of developing TD than patients without such a history. Obviously the former patients are more likely to receive anticholinergic drugs. This observation leads to the false conclusion that the administration of anticholinergic drugs increases the risk for developing TD. Thus the predisposition to drug-induced parkinsonism is the risk factor not the anticholinergic drugs.
Dose of Neuroleptic
Four studies reviewed showed a positive relationship between dose and TD, while seven were unable to detect a relationship (Tepper and Haas 1979). However, the neuroleptic being administered at the time of observation can mask TD, especially the stronger D2 antagonist agents if the dose has recently been increased (Branchey et al 1982).
"Drug Holidays"
It has been suggested that TD prevalence may be decreased with drug-free periods or "drug vacations (Crane 1973). Jus et al (1976) found this to be true for piperazine phenothiazines and/or butyrophenones but not other classes of neuroleptics. A study by Jeste et al (1979) in a small number of patients suggested drug holidays were associated with persistent dyskinesias. However, these patients received larger doses of neuroleptics and for a longer period of time, overall, than the comparison group. It should be remembered when discontinuing the neuroleptic initially one observes either improvement or worsening which is later followed by slow improvement.
Family History
Yassa and Ananth (1981) suggest that if one member of a family develops TD, it is likely other members exposed to chronic neuroleptic treatment will develop it as well.
Electroconvulsive Therapy
Five of six studies found no association between prior ECT exposure and predisposition to TD (Tepper and Haas 1979).
Sex
Twelve of seventeen studies found a higher proportion of TD in females, while five did not find an association (Barnes 1987). It should be noted in several of the populations studied, females were somewhat older than males.
Glazer et al (1981) investigated the relationship between serum prolactin levels and severity of tardive dyskinesia. Postmenopausal women with severe TD had higher prolactin levels than women with mild TD and men with or without TD. The authors speculated that persistent hyperprolactinemia and lowered estrogen levels from menopause in a subgroup of women may aggravate their TD.
Smoking
Three different groups have demonstrated that smoking increases the risk of TD (Kirch 1988). It is postulated that nicotine decreases striatal DA turnover (MHPG production) and decreases the amount of catecholamines that are metabolized thereby resulting in increased free radical production which can damage DA neurons.
Summary
Elderly female patients appear to be at higher risk of developing TD. Also, they appear to have a much poorer prognosis for eventual remission following discontinuation of the offending drug. Additional, strong risk variables include neuroleptic-induced drug-induced parkinsonism and a duration of chronic neuroleptic treatment of greater than 3 months.
PATHOPHYSIOLOGIC MECHANISMS UNDERLYING NEUROLEPTIC - INDUCED MOVEMENT DISORDERS
There are three major classifications for EPS. These include initial EPS, tardive EPS, and age and disease related EPS (Gerlach 1985).
Initial EPS
This group consists of dystonic reactions, pseudoparkinsonism, and hyperkinetic movement disorders, i.e., initial dyskinesia (ID) and akathisia. These symptoms may occur individually or simultaneously. They have been directly related to the dopamine antagonist activity of the Neuroleptics. Because they improve with a decrease in dose and are aggravated by an increase in dose, they are considered as AP intoxications. Following AP withdrawal they resolve quickly in some cases (7-10 days), but in other cases they are prolonged and diminish slowly over several months, and in a few cases they appear to be irreversible.
Tardive EPS
This group of syndromes develops during or following prolonged AP treatment and consists primarily of tardive dyskinesia (TD). In some cases, tardive akathisia which is indistinguishable from initial akathisia and tardive dystonia may occur.
Age- and disease-related EPS
Dystonia, parkinsonism, and hyperkinesia all occur in elderly, untreated people. The spontaneous (senile) oral dyskinesia cannot be distinguished from TD in elderly patients, just as parkinsonism cannot be differentiated from AP-induced parkinsonism. Senile dystonia and akathisia are relatively rare, although they have been described in a few cases. Historically, prior to the use of neuroleptic drugs, schizophrenic symptomatology could include various types of hyperkinetic, stereotypic movements and restlessness, which can look exactly like the AP-induced movement disorders. Schizophrenic akinesia and catatonic symptoms may similarly resemble parkinsonian and dystonic symptoms.
Traditionally, initial and tardive EPS are regarded as opposite movement disorders, i.e., the initial EPS resulting from DA hypoactivity while tardive EPS resulting from DA hyperactivity in the CNS. This view of EPS is too simple and inconsistent an explanation for initial and tardive EPS. ID are TD-like movements that develop in about 15-20% of AP-treated patients, usually early in the course of AP treatment. The syndrome has most often been seen in young patients and has a widespread and varied localization including the extremities and the trunk, whereas TD preferentially occurs in elderly patients and is confined to the oral region. This apparently different localization of ID and TD may, however, be a age-related difference rather than being related to the late versus early stage in the treatment course. It is well known that hyperkinetic movements, including withdrawal TD in younger patients, are mainly confined to the extremities, whereas a rising tendency to oral preponderance of hyperkinesia is seen with increasing age, both for TD and for L-dopa-induced hyperkinesia in Parkinson's disease. In some cases, however, ID occurs solely in the oral region, and in such cases it is impossible to distinguish it from TD.
At one time is was thought that ID and TD could be distinguished by discontinuation of the AP treatment after which TD would temporarily become worse and later diminish, while ID would resolve relatively quickly. However, recent observations suggest that in some cases ID diminishes slowly over months or remains irreversible, like TD. This means that ID and TD can be indistinguishable and may be one and the same phenomenon. If these results can be confirmed it might be necessary to change the terminology.
This overlap between ID- and TD-EPS poses the clinician an insoluble problem. The hyperkinetic movements may be very severe and disturbing, but any antidopaminergic treatment may eventually worsen the symptoms and perhneuroleptics add a severe akathisia. Clinical observations suggest that the hyperkinetic EPS, akathisia, ID, and TD are closely related symptoms, often overlapping and sometimes phenomenologically indistinguishable. Thus this clinical observation suggests that the underlying pathogenetic mechanisms may be partly the same.
The Hypersensitivity Theory
Traditional Neuroleptics block postsynaptic D2 receptors, leading to an increased dopamine turnover. Clinically, this appears to be related to parkinsonism. During long-term AP treatment, various phenomena of adaptation occur: the DA receptor blockade leads to a dopaminergic hypersensitivity, which can be shown by an increased DA receptor sensitivity. However, several observations suggest that there is no clear correlation between TD and DA hypersensitivity:
These observations indicate that the DA hypersensitivity theory cannot fully explain the pathophysiology of TD. Therefore, other possibilities should be considered.
Dopamine/GABA TD Hypothesis
During recent years, the knowledge about various neurotransmitters and their interactions in the brain has increased rapidly. One of the most interesting aspects in relation to TD is the observation of distinct types of DA receptors and GABA neurons. Regarding the interaction of DA and GABA neurotransmitters and receptors in the brain there seem to be two types of GABA receptors enervated by DA. One type (from the anterior part of the striatum to the globus pallidus, lateral segment) is inhibited by DA, while another type (from the posterior part of the striatum to zona reticulata of substantia nigra and to globus pallidus, median segment) is excited by DA. Since the Neuroleptics block these effects, GABA neurons projecting to the lateral segment of globus pallidus are facilitated, while the GABA neurons projecting to substantia nigra and medial globus pallidus are inhibited. From animal studies using intracerebral injection technique it is known that increased GABA activity in lateral globus pallidus induces parkinsonism in animals, while the decreased GABA function in the medial segment of the globus pallidus and in reticular zone of the substantia nigra seems to be associated with hyperkinetic movements. The last observation mentioned is in agreement with that of a decreased glutamic acid decarboxylase (a GABA-synthesizing enzyme) activity in substantia nigra and in the median pallidal segment in postmortem brains from Cebus monkeys with persistent dyskinesias.
These observations clearly suggest that a DA receptor blockade has distinct behavioral effects depending on the localization of the DA receptors in the brain. Blockade of some DA receptors leads to hyperkinetic disturbances, while blockade of others results in decreased mobility.
From a clinical point of view, these observations indicate that Neuroleptics might be able to induce hyperkinetic movement disturbances including akathisia, ID and TD, and at the same time, parkinsonism and dystonia. In most cases, parkinsonism and/or sedation may suppress the hyperkinetic movements at the initial stage of the treatment. Later, when tolerance has developed to parkinsonism and sedation, the hyperkinetic movements may become manifest.
The pathogenetic implication of these considerations may be the ID and TD do not have to be considered as distinct entities. It may be that both result from DA receptor blockade, merely of DA receptors sited at different points in the brain. In some cases the parkinsonism may be dominating and long standing, in other cases the hyperkinesia.
This new hypothesis does not disregard the traditional DA hypersensitivity theory. TD is probably a heterogeneous syndrome which depends on a multitude of pathogenetic mechanisms. It turns on a subtle balance between various neurotransmitters and the sensitivity of receptors of different type and localization. Furthermore, an unknown predisposition for TD is a necessary prerequisite for development of the syndrome. The DA hypersensitivity may still play a role and lower the threshold for manifestation of dyskinetic disturbances.
Serotonin-Dopamine Antagonist (SDA) TD Hypothesis
Clozapine's low affinity for D2 receptors and high affinity for 5-HT2 receptors producing a high 5-HT/D2 ratio, is hypothesized to be responsible for its improved efficacy and decreased rate of extrapyramidal side effects (Meltzer et al 1991). Figures 1 and 2 contrast the differing effects of the conventional neuroleptics and the SDA neuroleptics on the limbic and striatal areas of the brain. For the conventional neuroleptics, the antagonism of dopamine in the mesolimbic system relieves some of the symptoms of schizophrenia but at the same time, the blockade of transmission in the nigrostriatal system causes EPS. Likewise for the SDAs, antagonism of dopamine in the mesolimbic system relieves some of the symptoms of schizophrenia. However, the dopamine (D2) blockade in the nigrostriatal system is overcome by increased release of dopamine secondary to serotonin (5HT2) blockade in this area (Huttunen 1995).
Figure 1. Hypothetical mechanism of action of conventional neuroleptics.
Figure 2. Hypothetical mechanism of action of SDA neuroleptics.
The question of the pathophysiology of TD is far from solved. However, the biochemical background for various movement abnormalities has expanded enormously, and postmortem brain studies in human and monkey organs have contributed to a clarification. From a clinical point of view, the major objective is still prevention of the syndrome, and in this respect attempts to find new neuroleptics with little or no antidopaminergic effect appear to be the most promising.
PHARMACOLOGIC THERAPY
If the etiology of TD relates to chronic dopaminergic receptor site blockade and the pathophysiology relates to the denervation hypersensitivity, agents that interrupt this sequence would, theoretically, be of potential benefit. Many drugs have been tried in treating neuroleptic-induced TD. Because of differences in patient populations, study design, and doses of agents used, the results for individual agents are conflicting. All of the drugs that have attempted to treat TD using the DA hypersensitivity hypothesis as the rationale for their use have been ineffective in treating TD. Table 1 summarizes the differential pharmacology of TD (Baldessarini and Tarsy 1978, Klawans 1980). Currently we are recommending only the prophylactic use of vitamin E 1600 iU/d for patients starting on neuroleptics or in patients with TD for less than 5 years. For patients with TD for greater than 5 years we recommend discontinuation of the all typical neuroleptic medications. If the patient still requires antipsychotic medication, the atypical neuroleptic, clozapine is the only viable alternative.
Figure 3. Treatment algorithm for TD.
Amine-Depleting Agents
These agents e.g., reserpine, tetrabenazine, act by blocking the reuptake of dopamine, norepinephrine, and serotonin into the presynaptic neuronal storage vesicles, thereby depleting the brain of these substances. Studies with these agents have indicated improvement in TD but side effects have limited their use and the studies are of short duration. Short-term suppression may occur as reported with neuroleptics.
Blocker of Catecholamine Synthesis
Alpha-methyldopa studies have not demonstrated a beneficial effect on TD. AMPT, an experimental agent that inhibits tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine and norepinephrine, has shown partial reduction of dyskinesia.
Dopamine Antagonists
Formerly, TD was often treated by increasing the dose of the neuroleptic. This initially treats the pathophysiology of TD but can aggravate the pathogenesis by further denervation and subsequent hypersensitivity. Thus, the movements may decrease or disappear initially but then reappear later. This mode of treatment with the typical neuroleptic such as the phenothiazines and butyrophenones is not recommended as an unending cycle of neuroleptic dose escalation results. However, the use of the atypical neuroleptic, clozapine, may be useful in certain situations in which patients with disfiguring TD need to a neuroleptic treatment alternative. Simpson et al (1978) were the first investigators to observe the potential usefulness of clozapine in the treatment of 12 chronic schizophrenic patients with TD. The first controlled study (Caine et al 1979) that evaluated clozapine's value in the treatment of abnormal involuntary movement disorders (Huntington's, Tourette's and TD, n=12) found that only 2 patients with Huntington's experienced any benefit from clozapine. Small et al (1987) used clozapine to treat 7 patients with severe TD. A 7-week course of clozapine with a final mean dose of 269 mg/d reduced the AIMS score from 18 to 4. Lieberman et al (1991) treated 30 patients with severe TD with a mean clozapine dose of 486 mg/d for 36 months. Sixteen of the 30 patients experience > 50% decrease in their TD symptoms (Simpson Dyskinesia Scale) while 10 had a complete remission of the TD on follow-up at 100 weeks. As shown in Figure 2, it appears that switching a schizophrenic patient from a typical neuroleptic to an atypical neuroleptic such as clozapine will only partially effect the rate of spontaneous remission. If the neuroleptic is completely discontinued, the remission rate is estimated to be 60% over a 2-3 year follow-up period . However, clozapine actually accelerates the remission rate as opposed to having the patient remain on a typical neuroleptic such as chlorpromazine which ought to increase the TD rate. Clozapine treatment does not mask TD according to Lieberman's (1991) findings. TD symptoms did not re-emerge over the follow-up period. The most impressive findings suggesting a therapeutic effect for clozapine on TD were those of Gerbino et al (1980). Twenty-four TD patients were treated with clozapine in an open trial for a minimum of 4 weeks. They then followed 17 patients for a year of maintenance clozapine treatment. The average dose in the acute phase of the study was 650 mg/d. All 24 patients experienced at least a 50% decrease in their AIMS score. In the follow-up portion of the study, none of the 17 patients experienced a recurrence of TD symptoms when the clozapine was discontinued. Thus clozapine unlike typical neuroleptics does not mask TD but instead produces a sustained beneficial effect on the TD.
Blocker of Catecholamine Release
Lithium interferes with the presynaptic release of monoamines as well as having other actions on the CNS. Two studies report mild improvement in TD with lithium while two others report no improvement or exacerbation (Tepper and Haas 1979).
Cholinergic Agents
There is a well-known and accepted balance between dopamine and acetylcholine in the striatum. If TD relates to a relative increase in dopaminergic effect, then elevating the cholinergic effect would reestablish the former homeostasis, at a new level. With this theory in mind, several cholinergic agonists have administered to patients with TD.
Choline chloride and phosphatidylcholine (lecithin), which are orally bioavailable precursors of acetylcholine, have been reported to be useful in short- term studies. Lecithin may be preferred to choline because there are fewer side effects associated with it. Physostigmine cannot be given orally. Deanol was originally reported to be efficacious in the treatment of TD, but recent studies have not confirmed these findings (Gelenberg et al 1990).
GABA Agonists
Based on preclinical evidence that GABA, an inhibitory neurotransmitter in the CNS, appears to exert an inhibitory influence on nigrostriatal dopaminergic neurons, there have been several recent attempts to treat tardive dyskinesia with drugs believed to potentiate central GABA mechanisms. Thaker et al (1990) using a double-blind placebo controlled crossover design found clonazepam 2. to 4.5 mg/d for 4 weeks more effective than placebo in treating TD. TD severity decreased by an average of 37%. Patients with primarily dystonic rather than choreoatheotoid dyskinesia responded best. Although tolerance did develop to the long-term use of the drug of up to nine months, a 2-week drug holiday resulted in restoration of the anti-dyskinesia effect of the drug. Since GABA neuron inhibition cause hyperkinetics movements it is logical that a GABA agonist such as clonazepam would decrease hyperkinetic movements.
Anxiolytics
Buspirone is another anxiolytic that has been studied as a possible treatment option in TD. In a open label study, Lori et al (1993) found that in 8 patients buspirone used in dosages of up to 180 mg/day for 12 weeks produced a mean decrease of 4.4 from baseline in AIMS scores (p<0.01). Patients were started on 10 mg/day and increased by 10 mg every 3 days as tolerated. The main dose limiting adverse effects were lightheadedness, nausea, insomnia, and loose stools. The maximum dose used was either the highest dose tolerated or 180 mg/day. This dosage is different than that previously reported by Neppe (1989; 1990), where four case reports used a maximum of 240 mg/day of buspirone for the treatment of TD. Buspirone is believed to mediate it's antidyskinetic effect via either serotonergic or dopaminergic mechanisms. In addition to exerting anxiolytic effects as a partial agonist at the 5HT1A receptor, buspirone also exerts mixed agonist and antagonists effects at D2 receptors. In rats buspirone reverses the DA receptor subsensitivity induced by chronic neuroleptic administration, and it is this effect that may also occur in humans due to partial agonist effects at D2 receptors.
Anticholinergics
In a study involving 10 patients with TD of greater than a 6 month duration benztropine 2 mg IV increased dyskinetic movements in 7 patients and reduced them in the remaining three (Moores and Bowers 1980).
Beta-adrenergic-blocking agents
In a preliminary report (Wilbur and Kulik 1980) the b-adrenergic blocking agent propranolol (Inderal) in a dose of 30-60 mg/day has been shown to produce marked resolution of TD within 1 to 10 days of treatment in four patients.
Vitamin E
Lohr et al (1988), in a double-blind placebo controlled crossover study, evaluated the efficacy of vitamin E in the treatment of TD. Fifteen persistent TD patients were treated with vitamin E (week 1 = 400 iU/d, week 2 = 400 iU bid, weeks 3-4 = 400 iU tid). The mean reduction in the AIMS score with vitamin E was 43%, with seven (47%) patients showing a greater than 50% reduction in the dyskinesia.
Elkashef et al (1990) recently attempted to replicate these results using the same protocol as Lohr et al (1988) Although the results were statistically significant, they were less impressive than those of Lohr et al (1988) with a decrease in AIMS score of 21% from 8.56 to 6.75 between placebo and vitamin E. Five of the eight patients studied achieved the a priori definition of a "good response" to vitamin E, a 30% decrease in AIMS score. Shriqui et al (1992) compared vitamin E 1200 IU/day with placebo in a 6-week double-blind randomized crossover study of 27 patients with tardive dyskinesia. Vitamin E showed no differences from placebo in the treatment of tardive dyskinesia. Both treatments produced the similar AIMS ratings after six weeks of treatment. A recent NIMH study (Egan et al 1992) administered up to 1600 IU/day of vitamin E for 6 weeks in a double-blind, placebo-controlled crossover study. In the 18 patients with significant vitamin E levels, there were no significant differences between AIMS scores after receiving vitamin E and AIMS scores after receiving placebo. However, in the nine patients who had tardive dyskinesia for 5 years or less significantly lower AIMS scores after receiving vitamin E than after receiving placebo were observed. Thus vitamin E had a minor beneficial effect on tardive dyskinesia ratings in a selected group of patients who had had tardive dyskinesia for 5 years or less. In a randomized double-blind controlled study Adler et al (1993a) treated 28 patients with tardive dyskinesia with either placebo or vitamin E 1600 IU/d for 8-12 weeks. According to the AIMS ratings significantly greater improvement resulted from vitamin E (32.5% than placebo (-3.0%). A subsequent 36 week trial of Vitamin E 1600 IU/d followed by 12 weeks of placebo treatment found that although the vitamin E treatment reduced the mean AIMS scores by 21%, placebo substitution resulted in the scores returning to baseline (Adler et al 1993b).
The positive effects of vitamin E in TD are thought to be related to vitamin E's effect as a lipid soluble antioxidant. According to this theory, free radicals (highly reactive chemical species with an unpaired outermost electron), cause tissue damage leading to a lesion that results in TD. As an antioxidant, vitamin E functions as a free radical scavenger to prevent the resulting structural damage. Thus as demonstrated in the Egan (1992) study for vitamin E to be of any value it ought to be given as an adjunctive prophylactic medication when chronic maintenance neuroleptic therapy is begun
REVERSIBILITY OF TARDIVE DYSKINESIA
The older literature would lead one to conclude that in the majority of patients with TD the syndrome is permanent or irreversible. However, this is not necessarily the case. The earlier TD is diagnosed and the neuroleptic is discontinued, the better is the prognosis for reversal of the disorder. Thus, not surprising are the reports in young adults, where TD disappeared within several weeks after the early withdrawal of the drug.
Although the first report of TD by Uhrbrand the Faurbye (1960) described TD as irreversible, it was only persistent in 11 of 17 (65%) of the patients and they were only followed-up for between 4 to 22 months after discontinuing the drug. There is actually a report that describes a case of a patient whose TD reversed itself 14 years after discontinuing the neuroleptic. Itoh et al (1981) identified 19 patients with apparently irreversible TD and followed these individuals for 5 years. They observed a slow amelioration of the TD in the majority of the patients and no worsening of the TD in any of the patients. Significantly all of the patients less than 60 years old showed improvement.
In the early stages of neuroleptic withdrawal several clinical courses can be initially expected, i.e., improvement, worsening, no change, but then slow gradual reduction in the symptomatology is observed in most cases. The studies that have examined the question of whether TD is reversible or not demonstrate different findings depending on their length of follow-up. If the evaluation took place 2 to 5 years after discontinuation of the neuroleptic, 50 to 90% of patients are found to show an improvement of at least 50% on the AIMS. In conclusion, it is now accepted that TD symptoms can disappear or improve greatly in about 60% of patients during the course of 2-3 years, which reduces the group of irreversible TDs to the number of spontaneously occurring dyskinesias (Driesens 1988).
In a ten year TD outcome study, Gardos et al (1994) found that the overall prevalence of TD did not change significantly in 63 Hungarian outpatients using neuroleptics during the study period. At baseline the prevalence of TD was 30.2%, at 5 years it was 36.5%, and at 10 years of follow-up it was 31.7% . Of interest is that of the 44 patients who started the study with no TD, 72.7% showed a decrease in AIMS scores at 10 years, and 27.3% developed TD with mean AIMS scores similar to those patients with chronic TD over the last 10 years. Also, of the 19 patients at baseline who had TD, 42.1% continued to experience TD 10 years later, while 57.9% had a remission of their TD symptomatology. TD was not found to be significantly related to neuroleptic treatment or to age. The authors of this study concluded that this study provides evidence for the long term stability of TD and for the feasibility of neuroleptic maintenance therapy for chronic psychotic patients with TD.
Finally, pharmacotherapy studies done in TD are extremely difficult to interpret. This is because short-term clinical observation periods of only a few weeks or months are employed. Even if there is any improvement from the drug, usually the symptoms reappear after discontinuing the drug. This makes it extremely difficult to impossible to evaluate the long-term usefulness of any of the potentially beneficial therapies. Thus long-term treatment studies are necessary in the future to legitimately access the role of the various drugs in the treatment of TD.
PREVENTION OF TARDIVE DYSKINESIA
Gerlach and Casey (1988) recommend the following guidelines to minimize the risk of TD.
|
TABLE 1: The Differential Pharmacology of Tardive Dyskinesia | |
|
Agents that suppress tardive dyskinesia |
specific agents |
|
Dopamine antagonists |
Butyrophenones, clozapine, metoclopramide (Karp 1981), papaverine (mechanism uncertain), phenothiazines, bromocriptine, pimozide |
|
Dopamine D2 Agonists |
Buspirone |
|
Amine-depleting agents |
Reserpine, tetrabenzine |
|
Blocker of catecholamine synthesis |
Alpha-methyldopa, Alpha-methyltyrosine (AMPT) |
|
Blocker of catecholamine release |
Lithium salts |
|
Cholinergic agents |
Deanol (mechanism uncertain), physostigmine, choline and lecithin |
|
GABA agonists |
Progabide (Bartholini 1983), valproic acid (mechanism uncertain), baclofen (mechanism uncertain), iazepam, clonazepam |
|
Anticholinergic agents (Moore and Bowers 1980) |
Benztropine, trihexyphenidyl |
|
Agents with variable, negligible, or uncertain effects |
Alpha-methyldopa, Amantadine, Anticholinergics Antihistamines, Apomorphine, Barbiturates, Benzodiazepines, Methylphenidate, Penicillamine, Physostigmine, Pyridoxine (B6), Tryptophan, a-tocopherol (Vitamin E) |
|
Agents that worsen tardive dyskinesia |
Anticholinergic agents, Antiparkinson agents (e.g., benztropine), Dopamine agonists, Amphetamines, L-DOPA |
|
Newer investigational agents (peptides) (Blurn and Korczyn 1983) |
Endopioids, Substance P, Cholecystokinin, Ceruletide, Neurotensin, Cyclo-Leucine-Glycine |
REFERENCES
Adler LA, Peselow E, Rotrsen J, et al (1993a). Vitamin E treatment of tardive dyskinesia. Am J Psychiatry 150:1405-7.
Adler LA, Peselow E, Duncan E, et al (1993b). Vitamin E in tardive dyskinesia: time course of effect after placebo substitution. Psychopharmacol Bull 29:371-4.
American College of Neuropsychopharmacology--Food and Drug Administration Task Force (1973): Neurologic syndromes associated with neuroleptic drug use. N Engl J Med 289:20-3.
Baldessarini RJ, Tarsy D (1978). Tardive dyskinesia. In: Psychopharmacology: a generation of progress. Lipton MA, DiMascio A, Killiam KF, eds. New York: Raven Press 995-1004.
Barnes TRE (1987). The present status of tardive dyskinesia and akathisia in the treatment of schizophrenia. Psychiatric Dev 4:310-19.
Bartholini G (1983). GABA system, GABA receptor agonist and dyskinesia. In: Modern problems in pharmacopsychiatry. Ban TA, Pichot P, Poldinger W, eds. New York: Karger 21:143-54.
Blurn I, Korczyn AD (1983). Peptide neurotransmitters and their implications for the treatment of tardive dyskinesia. In: Modern problems in pharmacopsychiatry. Ban TA, Pichot P, Poldinger W, eds. New York: Karger 21:187-95.
Branchey MH, Branchey LB, Richardson MA (1982). Effects of neuroleptic adjustment on clinical condition and tardive dyskinesia in schizophrenic patients. Am J Psychiatry 138:608-12.
Casey DE, Hansen TE (1984). Spontaneous dyskinesia. In: Jeste DV, Wyatt RJ,, eds. Neuropsychiatric movement disorders. Washington, DC: American Psychiatric Press 68-95.
Chouinard G, Annable L, Ross-Chouinard A, et al (1988). A 5-year prospective longitudinal study of tardive dyskinesia: factors predicting appearance of new cases. J Clin Psychopharmacol 8:21S-6S.
Crane GE. Persistent dyskinesia (1973). Br J Psychiatry 122:395-7.
Cseranky JG, Grabowski K, Cevantes J, et al (1981). Fluphenazine decanoate and tardive dyskinesia: a possible association. Am J Psychiatry 138:1362-5.
Driesens F (1988). Neuroleptic medication facilitates the natural occurrence of tardive dyskinesia. A critical review. Acta-Psychiatr-Belg 88:195-205.
Egan MF, Hyde TM, Albers GW, et al (1992). Treatment of tardive dyskinesia with vitamin E. Am J Psychiatry 14(:773-7.
Elkashef AM, Ruskin PE, Bacher N, et al (1990). Vitamin E in the treatment of tardive dyskinesia. Am J Psychiatry 147:505-6.
Gardos G, Casey DE, Cole JO, et al (1994). Ten-Year outcome of tardive dyskinesia. Am J Psychiatry 151:836-841.
Gelenberg AJ, Dorer DJ, Wojcik JD, et al (1990). A crossover study of lecithin treatment of tardive dyskinesia. J Clin Psychiatry 51:149-153.
Gerbino L, Shopsin B, Collora M (1980). Clozapine in the treatment of tardive dyskinesia: an interim report. In Tardive Dyskinesia, Research and Treatment (eds, WE Fann, RC Smith, JM Davis et al),475-89. New York: SP Medical and Scientific Books.
Gerlach J (1985). Pathophysiological mechanisms underlying tardive dyskinesia. Psychopharmacology (Suppl) 2:98-103.
Gerlach J, Casey DE (1988). Tardive dyskinesia. Acta Psychiatr Scand 77:369-78.
Glazer WM, Moore DC, Bowers MB, et al (1981). Serum prolactin and tardive dyskinesia. Am J Psychiatry 138:1493-6.
Gureje O (1988). Topographic subtypes of tardive dyskinesia in schizophrenic patients aged less than 60 years: relationship to demographic, clinical, treatment, and neuropsychological variables. J Neuro Neurosurg Psychiatry 51:1525-30.
Huttunen M (1995). The evolution of the serotonin-dopamine antagonist concept. J Clin Psychopharmacol 15[suppl 1]:4S-10S.
Hyde TM, Egan MF, Brown RJ, et al (1995). Diurnal variation in tardive dyskinesia. Psychiatry Res 56:53-7.
Itoh, H (1981). Drug-induced tardive dyskinesia. In: Current developments in psychopharmacology. Essman WB, Valzelli L, eds. Jamaica, NY: Spectrum 93-126.
Jeste DV, Potkin SG, Sinha S, et al (1979). Tardive dyskinesia--reversible and persistent. Arch Gen Psychiatry 36:585-90.
Jus A, Pineau R, Lachance R, et al (1976). Epidemiology of tardive dyskinesia, part 2. Dis Nerv Syst 37:257-61.
Kane JM, Woerner M, Lieberman J (1988). Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol 8:52S-56S.
Karp JM, Perkel MS, Hersh T, et al (1981). Metoclopramide treatment of tardive dyskinesia. JAMA 246:1934-5.
Kirch DG, Alho AM, Wyatt RJ (1988). Hypothesis: a nicotine-dopamine interaction linking smoking with Parkinson's disease and tardive dyskinesia. Cellular Molecular Neurobiol 8:285-90.
Klawans HL, Goetz CG, Perlik S (1980). Tardive dyskinesia: Review and update. Am J Psychiatry 137:900-8.
Lieberman JA, Saltz BL, Johns CA, et al (1991). The effects of clozapine on tardive dyskinesia. Br J Psychiatry 158;503-10.
Lohr JB, Cadet JL, Lohr MA, et al (1988). Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms. Schizophrenia Bull 14:291-6.
Meltzer HY (1991). The mechanism of action of novel antipsychotic drugs. Schizophrenia Bull 1991;2:263-87.
Miller CH, Simioni I, Oberbauer H, et al (1995). Tardive dyskinesia prevalence rates during a ten-year follow-up. J Nerv Ment Dis 183:404-7.
Moore DC, Bowers MB (1980). Identification of a subgroup of tardive dyskinesia patients by pharmacologic probes. Am J Psychiatry 137:1202-5.
Morgenstern H, Glazer WM, Gibowski LD, et al (1987). Predictors of tardive dyskinesia: results of a cross-sectional study in an outpatient population. J Chron Dis 40:31927.
Moss LE, Neppe VM, Drevets WC (1993). Buspirone in the treatment of tardive dyskinesia. J Clin Psychopharmacol 13: 204-209.
Neppe VM (1989). High dose buspirone in a case of tardive dyskinesia (letter). Lancet 2: 8677.
Neppe VM (1990). High dose buspirone treatment in tardive dyskinesia (abstract NR269). Presented at the 143rd Annual Meeting of the American Psychiatric Association, New York.
Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia (1982). Arch Gen Psychiatry 39:486-7.
Shriqui CL, Bradwejn J, Annable L, et al (1992). Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study. Am J Psychiatry 149:391-3.
Singh MM, Nasrallah HA, Lal H, et al (1980). Treatment of tardive dyskinesia with diazepam: Indirect evidence for the involvement of limbic, possibly GABA- ergic mechanism. Brain Research Bull 5:Suppl 2, 673-80.
Small JG, Milstein V, Marhenke JD, et al (1987). Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry 48;263-7.
Smith JM, Baldessarini RJ (1980). Changes in prevalence, severity and recovery in tardive dyskinesia with age. Arch Gen Psychiatry 37:1368-73.
Sweet RA, Mulsant BH, Gupta B, et al (1995). Duration of neuroleptic treatment and prevalence of tardive dyskinesia in late life. Arch Gen Psychiatry 52:478-86.
Tarsy D (1983). History and definition of tardive dyskinesia. Clinical Neuropharmacology 6:91-9.
Tepper SJ, Haas JF (1979). Prevalence of tardive dyskinesia. J Clin Psychiatry 40:508-16.
Thaker GK, Nguyen JA, Strauss ME, et al (1990). Clonazepam treatment of tardive dyskinesia: a practical GABAmimetic strategy. Am J Psychiatry 147:445-51.
Uhrbrand L, Faurbye A (1960). Reversible and irreversible dyskinesia after treatment with perphenazine, chlorpromazine, reserpine, ECT therapy. Psychopharmacologia 1:408-18.
Wilbur R, Kulik FA (1980). Propranolol for tardive dyskinesia and EPS from neuroleptics: Possible involvement of beta-adrenergic mechanisms. Prog Neuro- Psychopharmacol 4:627-32.
Yassa R, Ananth J (1981). Familial tardive dyskinesia. Am J Psychiatry 138:1618-9.
Yassa R, Nair V, Schwartz G (1984). Tardive dyskinesia and the primary psychiatric diagnosis. Psychosomatics 25:135-8.
Next Page | Previous Page | Section Top | Title Page