The treatment of tardive dyskinesia and tardive dystonia

The enthusiasm produced by the introduction of antipsychotic medication in the 1950s gave way to a certain frustration in the 1970s and 1980s. Despite the development of a large number of new drugs, little progress was made in treatment because these new agents were, in essence, therapeutically equivalent. This lack of progress was perhaps also related to an emphasis on tardive dyskinesia in the 1970s, i.e., the preoccupation with a negative effect of treatment. The reverse is taking place today. Clozapine and the other atypical antipsychotics are associated in people's minds with fewer or absent extrapyramidal symptoms and less tardive dyskinesia than the older typical agents. As a result, a certain amount of complacency exists. Tardive dyskinesia not only may be painful and disfiguring, but it also predicts poor outcome in patients with schizophrenia. Although many treatments have been tried, none have proven completely efficacious. The best treatment for tardive dyskinesia and dystonia is prevention, which is a function of medication choice. Pharmacologic interventions for tardive dyskinesia include clozapine and the other atypical antipsychotics. If typical antipsychotics must be used, they should be started at the lowest possible levels. Studies of risperidone suggest that it, too, should be used at very low doses to minimize the risk of tardive dyskinesia. It is also possible that schizophrenic patients taking atypical antipsychotics may experience fewer spontaneous dyskinesias, although further study is warranted.     

Tardive dystonia

This paper provides an overview of the phenomenology, epidemiology, and treatment of tardive dystonia. Tardive dystonia is one of the extrapyramidal syndromes that starts after long-term use of dopamine receptor antagonists. The diagnosis is based on the presence of chronic dystonia, defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. Furthermore, dystonia must develop either during or within 3 months of a course of antipsychotic treatment, and other causes such as Wilson's disease, acute dystonia, or a conversion reaction must be ruled out. Tardive dystonia occurs in about 3 percent of patients on long-term antipsychotic treatment. Some probable risk factors for tardive dystonia are younger age, male, and the presence of tardive dyskinesia. The treatment of tardive dystonia starts with an evaluation of the need for using the causative drug. If antipsychotics must be continued, a switch to an atypical antipsychotic, particularly clozapine, may be helpful. If the dystonia is relatively localized, botulinum toxin is an effective but not well-known treatment possibility. If tardive dystonia is more extensive, either dopamine-depleting drugs or high dosages of anticholinergics can be tried.     

Equivalent occupancy of dopamine D1 and D2 receptors with clozapine: differentiation from other atypical antipsychotics

OBJECTIVE: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics. METHOD: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D(1) and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone. RESULTS: Mean striatal D(1) occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). CONCLUSIONS: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.     

Adjunctive quetiapine decreases symptoms of tardive dyskinesia in a patient taking risperidone

Tardive dyskinesia is a potentially permanent and disfiguring side effect associated with the use of conventional, or first generation, antipsychotics. Quetiapine is a second generation antipsychotic with transient dopamine receptor occupancy, a property shared with clozapine. Quetiapine was administered to a patient who had persistent choreoathetoid movements that developed during treatment with conventional antipsychotics and remained unimproved during longterm treatment with risperidone. During 10 weeks of monotherapy with quetiapine, his Abnormal Involuntary Movement Scale score fell from 11 to 3. He was subsequently switched back to risperidone and his movements returned. The addition of quetiapine to his risperidone regimen once again resulted in a decrease of his tardive dyskinesia symptoms. The mechanism by which quetiapine improved tardive dyskinesia symptoms in this patient is not known, but differential treatment effects between the novel antipsychotics may exist. Controlled trials of quetiapine in the treatment of tardive dyskinesia should be pursued.     

Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia.

OBJECTIVE: Tardive dyskinesia (TD), the principal adverse effect of long-term conventional antipsychotic treatment, can be debilitating and, in many cases, persistent. We sought to explore the incidence and management of TD in the era of atypical antipsychotics because it remains an important iatrogenic adverse effect. METHODS: We conducted a review of TD incidence and management literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were obtained by searching the bibliographies of relevant references. We considered articles that contributed to the current understanding of both the incidence of TD with atypical antipsychotics and management strategies for TD. RESULTS: The incidence of TD is significantly lower with atypical, compared with typical, antipsychotics, but cases of de novo TD have been identified. Evidence suggests that atypical antipsychotic therapy ameliorates long-standing TD. This paper outlines management strategies for TD in patients with schizophrenia. CONCLUSION: The literature supports the recommendation that atypical antipsychotics should be the first antipsychotics used in patients who have experienced TD as a result of treatment with conventional antipsychotic agents. The other management strategies discussed may prove useful in certain patients.     

Atypical antipsychotics in the EPS-vulnerable patient

'Typical' antipsychotic agents can lead to a variety of extrapyramidal symptoms (EPS), including parkinsonism. The efficacy of a number of atypical antipsychotics in reducing psychosis without a detrimental effect on motor function has been studied in the group of patients most vulnerable to EPS, those who already have parkinsonian symptoms. Multiple open-label studies with clozapine strongly suggested that at low doses the drug was an effective antipsychotic and did not impair motor function. This was confirmed by two double-blind, placebo-controlled studies. A disadvantage of clozapine is that it can cause agranulocytosis and therefore patients require ongoing hematological monitoring. Studies with both risperidone and olanzapine have produced conflicting results, with some patients showing an overall improvement and others exhibiting severe deterioration of motor function. As with clozapine, multiple open-label studies with quetiapine have consistently demonstrated that it improves psychosis without impairing motor function. Double-blind trials are yet to be performed: however, the existing data, coupled with the lack of required blood monitoring, have led some experts to recommend quetiapine as the drug of choice for treatment of drug-induced psychosis in patients with parkinsonism. The atypical antipsychotics have also been tested in the largest group of EPS-vulnerable patients, the demented elderly. Results from a number of trials are described here. These data are more difficult to interpret as the number of variables is far greater than for the population with parkinsonism. However, the evidence to date indicates a generally low incidence of tardive dyskinesia with atypical antipsychotics.     

Tardive dyskinesia: eliminated, forgotten, or overshadowed?

PURPOSE OF REVIEW: The present review focuses on atypical antipsychotics and tardive dyskinesia. RECENT FINDINGS: We have known for many years that clozapine has a diminished risk of tardive dyskinesia compared with typical antipsychotics. The last decade has seen the introduction of a number of other atypical antipsychotics, allowing us to begin evaluating whether they too share this attribute. In addition, the opportunity to use these drugs as first-line treatment permits a more precise means of establishing risk. While longer-term data are required, the limited evidence available clearly indicates that the atypical antipsychotics have a decreased liability of tardive dyskinesia, approximately 1% compared with 5% for typical agents annually. Like clozapine, the other atypical antipsychotics also demonstrate antidyskinetic properties in individuals with preexisting tardive dyskinesia. The underlying mechanisms remain unclear, and without such information it is not possible to say what clinical conditions, if any, might diminish or even eliminate these advantages. SUMMARY: An update is provided regarding the atypical antipsychotics and tardive dyskinesia. This information is critical in our decision-making regarding choice of antipsychotic and optimal use in the clinical setting.     

Tardive dyskinesia in older patients

Neuroleptic-induced tardive dyskinesia, which often appears in middle-aged and older adults early in the course of treatment with low doses of conventional antipsychotics, is 5 to 6 times more prevalent in elderly than in younger patients. In addition to age, other risk factors for tardive dyskinesia include early extrapyramidal symptoms (EPS), cumulative amounts of neuroleptics, duration of neuroleptic treatment, and history of alcohol abuse and/or dependence. The atypical antipsychotics, which have a low liability for EPS, are likely to also have low potential for tardive dyskinesia, despite the paucity of controlled studies. Starting and maintenance doses of the atypical antipsychotics should generally be lower in older than in younger adults.     

Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia

Psychosis occurs commonly in patients with mood disorders and has traditionally been treated with typical antipsychotics. Exposure to typical antipsychotics poses a risk for the emergence of tardive dyskinesia. Atypical antipsychotics may have advantages over typical agents in the treatment of patients with mood disorders complicated by psychotic features. The studies of typical and atypical antipsychotics in the treatment of mood disorders were reviewed. Similarly, studies regarding the risk of tardive dyskinesia from typical and atypical agents in patients with mood disorders were surveyed. Typical and atypical antipsychotics appear to be comparably effective in the treatment of acute mania. Limited data regarding these medications in psychotic depression are available. Advantages of atypical antipsychotics include, for most agents, minimal extrapyramidal and prolactin effects, inherent thymoleptic activity, and lower rates of tardive dyskinesia. Atypical antipsychotics appear to have a number of advantages over typical agents in the treatment of patients with psychotic mood disorders.     

A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia

BACKGROUND: While the atypical antipsychotics should ultimately reduce the prevalence of tardive dyskinesia, it is likely to remain a significant clinical problem for a long time to come. No strategy has clearly emerged as the treatment of choice for tardive dyskinesia. Atypical antipsychotics have reduced propensities for producing acute extrapyramidal symptoms (EPS) and possibly tardive dyskinesia and may be effective in treating patients with established tardive dyskinesia. METHOD: This 12-month, randomized, investigator-blinded study compared the efficacy of quetiapine (N = 22) and haloperidol (N = 23) in treating patients with DSM-IV schizophrenia or schizoaffective disorder and established tardive dyskinesia. Dyskinesia was assessed using the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale scores and the Clinical Global Impression (CGI) dyskinesia scores. Other EPS, weight, serum prolactin level, and glycosylated hemoglobin level were also assessed. Subjects were enrolled in the study between April 2000 and March 2002. RESULTS: Mean endpoint doses were 400 mg/day of quetiapine and 8.5 mg/day of haloperidol. Compared with the haloperidol group, the quetiapine group showed significantly greater improvements in ESRS dyskinesia (6 and 9 months [p or= 50% symptom reduction) was greater with quetiapine than haloperidol (64% [9/14] and 37% [6/16] at 6 months; 55% [6/11] and 28% [4/14] at 12 months). Other EPS decreased significantly with quetiapine at 3 (p =.01), 6 (p =.01), and 9 (p =.002) months. Serum prolactin levels decreased with quetiapine but increased with haloperidol, differing significantly between the groups at endpoint (p =.005). No significant changes in weight or glucose metabolism were recorded in either group. CONCLUSION: Quetiapine effectively reduces the severity of tardive dyskinesia and is well tolerated in patients with established tardive dyskinesia.     

Incidence of tardive dyskinesia with typical versus atypical antipsychotics in very high risk patients.

Our aim was to study the risk of developing tardive dyskinesia in highly vulnerable patients (i.e., middle-aged and older adults with borderline dyskinesia) treated with conventional versus atypical antipsychotics.We examined the cumulative incidence of definitive tardive dyskinesia at 1, 3, and 6 months during antipsychotic treatment among 240 outpatients at least 45 years of age who had borderline tardive dyskinesia at baseline.Patients treated with conventional antipsychotics were approximately two times more likely to develop definitive tardive dyskinesia during the study period compared with those treated with atypical antipsychotics (p <.001). This difference was found despite patients in the atypical antipsychotic group being significantly older and having more severe extrapyramidal symptoms at baseline than those prescribed typical antipsychotics.Among patients at a very high risk for worsening tardive dyskinesia, the use of atypical antipsychotics was associated with a significantly lower risk of developing definitive tardive dyskinesia compared with conventional antipsychotics.     

Ziprasidone-induced tardive laryngeal dystonia: a case report

Tardive laryngeal dystonia, a rare form of dystonic syndrome, was only reported to be induced by typical antipsychotics. Here, we report one case of ziprasidone-induced tardive laryngeal dystonia in a schizophrenic female patient, who showed dysphonia, hoarseness and dyspnea after taking ziprasidone 120 mg/day for 8 months. These symptoms were significantly improved after discontinuing ziprasidone and increasing the dose of trihexyphenidyl for 1 week. Although atypical antipsychotics are associated with a lower risk of extrapyramidal symptoms, caution should be taken for any tardive dystonic movement when using these medications.     

Medication treatments for schizophrenia: translating research findings into better outcomes

The atypical or novel antipsychotics have advanced the treatment of schizophrenia, especially given their reduced extrapyramidal side effect liability. In this article, the authors examine a number of recently published or presented studies of the atypical antipsychotics, many of them post approval studies, that shed additional light on this class of medications. Clozapine stands alone as a medication for treatment-resistant schizophrenia, but the other first-line atypical agents appear to reduce relapse rates during maintenance treatment and to have less of a long-term risk for tardive dyskinesia. However, additional research is needed to distinguish the atypical antipsychotics from each other and to better understand their non-neurological side effects.     

Augmentation of antidepressants with atypical antipsychotics in non-delusional unipolar depressed patients with non-response to antidepressant-monotherapy

Objective Augmentation of antidepressants with atypical antipsychotics is used in depressive patients with non-response to antidepressants. We investigated the utility of this strategy.Methods Systematic computer-based search in the online library Pubmed for randomized placebo-controlled double-blind trials (RCT) from the years 1990 to 2011.Results We found 14 RCT about augmentation of antidepressants with atypical antipsychotics in depressive patients with non-response to antidepressants. Trials examined olanzapine, risperidone, quetiapine and aripiprazole.Conclusions Augmentation of antidepressants with atypical antipsychotics is an alternative to the augmentation with lithium in unipolar depressive patients with non-response to antidepressants. But treatment with atypical antipsychotics as opposed to placebo increases the risk of non-compliance due to side-effects of medication. Augmentation of antidepressants with atypical antipsychotics in unipolar depression is an off-label therapy in Germany except for the augmentation with extended-release quetiapine. Knowledge about treatment strategies regarding augmentation of antidepressants with atypical antipsychotics can increase the chance of a successful treatment, but interactions and side-effects should be considered.     

Treatment of generalized tardive dystonia with clozapine

Tardive dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures, associated with prolonged exposure to antipsychotics. We report a case of a 35-year-old patient with schizophrenia who developed a generalized form of tardive dystonia after switching of clozapine to risperidone treatment that persisted after switch to olanzapine and during the period while treatment with an antipsychotic was discontinued. It was successfully managed with reintroduction of clozapine. The case may represent the first report of generalized tardive dystonia while taking risperidone. The possible pathophysiological bases of the disorder are discussed. The goal of our report is to emphasize that an adequate trial of clozapine is a worthwhile option in the cases of tardive dystonia, even where discontinuation of antipsychotics was unsuccesful.     

Broad therapeutic uses of atypical antipsychotic medications.

The atypical antipsychotics have a low incidence of extrapyramidal side effects (EPS), have improved tardive dyskinesia profiles, and have a broad range of therapeutic efficacy. These agents offer important therapeutic advantages that extend beyond their initial regulatory approval in several conditions and patient groups. The use of atypical antipsychotics is most relevant in the treatment of mood disorders, where these medications are being used increasingly for acute mood stabilization and in patients who are resistant to other treatments. Similar circumstances and clinical advantages pertain to the use of atypical antipsychotics in the treatment of behavioral disturbances in patients with dementia and in the management of personality disorders-both circumstances where conventional antipsychotics were initially poorly tolerated because of EPS. The low incidence of EPS associated with atypical antipsychotics is highly beneficial in several neuropsychiatric conditions. The extent to which endocrine and metabolic dysregulations associated with atypical antipsychotics will influence antipsychotics' role remains to be determined. As therapeutic opportunities evolve and diversify, atypical antipsychotics, because of favorable adverse-effect profiles, will have enhanced patient tolerability and use in nonpsychiatric conditions.     

Diabetes, tardive dyskinesia, parkinsonism, and akathisia in schizophrenia: a retrospective study applying 1998 diabetes health care guidelines to antipsychotic use.

BACKGROUND: This study examines the links among diabetes, tardive dyskinesia (TD), and other extrapyramidal symptoms (EPS) in schizophrenia outpatients treated with typical and atypical antipsychotics. OBJECTIVES: Using a retrospective chart review, we compared 30 schizophrenia patients with diabetes mellitus (DM) with 30 schizophrenia patients, matched for age and sex, with no DM. We compared prevalence and severity of parkinsonism, akathisia, TD, dystonia, and antipsychotic type (that is, typical vs atypical). RESULTS: We found no statistically significant differences between the DM group and the non-DM group prevalence and severity of EPS, including TD. CONCLUSION: We did not find DM and TD association to be significant in the era of atypical antipsychotics, possibly because of their antidyskinetic effect.     

Beneficial effect of donepezil in the treatment of elderly patients with tardive movement disorders

BACKGROUND: Tardive dyskinesia and other delayed-onset abnormal involuntary movement disorders may occur as a result of the use of psychotropic drugs. A distinction is usually made between classic tardive dyskinesia (TD) (orobuccal-lingual-facial) and tardive dystonia, tardive tremor (TT), tardive akathisia, and other related syndromes. In spite of the development of atypical antipsychotics with fewer side effects, tardive movement disorders nevertheless continue to present a significant clinical and therapeutic challenge. Several reports have suggested that donepezil may be helpful in the treatment of TD. METHOD: A preliminary study was conducted of 7 patients (5 women and 2 men) enrolled over a period of 6 months who had been experiencing TT for a period of at least 1 year. The ages of the patients ranged from 64 to 79 years, and all patients were on stable antipsychotic therapy. Donepezil was added to their usual treatment for 8 weeks. The severity of patients' extrapyramidal symptoms was assessed using the tremor subscale of the Simpson-Angus Scale (SAS) and self-rated with a modification of the Clinical Global Impressions scale, the Subjective Clinical Improvement Impression scale. The clinical response was evaluated by comparing the rating scores at baseline prior to donepezil treatment and every 2 weeks thereafter. RESULTS: The addition of donepezil (up to 10 mg/day) was associated with a clinically significant improvement (from 37.5% to 63.6%) on the SAS tremor subscale following 4 weeks of therapy. Only 1 patient discontinued follow-up due to side effects. CONCLUSION: The results suggest that donepezil may be effective in the treatment of TT, and this finding should be evaluated further by a randomized controlled study.     

Use of antipsychotics in the treatment of depressive disorders

Summary： There is a long history of using antipsychotic medications in the treatment of depressive disorders. Atypical antipsychotics, which have fewer side effects than traditional antipsychotics, have been used as monotherapy or adjunctively with antidepressants to treat depressive disorders with or without psychotic symptoms. The antidepressant effect of atypical ant-ipsychotics involves regulation of monoamine, glutamate, gamma-aminobutyric acid （GABA）, cortisol, and neurotrophic factors. To date, the United States Food and Drug Administration （USFDA） has approved aripiprazole and quetiapine slow-release tablets as adjunctive treatment for depressive disorders, and the combination of olanzapine and fluoxetine for the treatment of treatment- resistant depression. When using atypical ant-ipsychotics in the treatment of depressed patients, clinicians need to monitor patients for the emergence of adverse effects including extrapyramidal symptoms （EPS）, weight gain, and hyperglycemia.     

Oxidative stress during treatment with first- and second-generation antipsychotics

Neurotoxicity of first-generation antipsychotics (FGAs) may be involved in lipid peroxidation, which is the pathogenesis of extrapyramidal symptoms, including tardive dyskinesia (TD). Blood samples at day 0, 7, and 21 drawn from patients taking antipsychotics were analyzed for malondialdehyde (MDA) in plasma, a marker of lipid peroxidation, by high-performance liquid chromatography. Of 115 patients enrolled, 92 patients completed the study. Most MDA levels were within normal ranges (<1.0 micromol/liter). Malondialdehyde levels in patients receiving clozapine (p = 0.002), quetiapine (p = 0.003), amisulpride (p = 0.008), and risperidone (p = 0.008) were significantly lower than within the first generation antipsychotic group. The authors conclude that lipid peroxidation is significantly higher in treatment with FGAs.