Prevention Of Tardive Dyskinesia Research Articles

Tardive dyskinesia

Tardive dyskinesia (TD) is a delayed, often irreversible iatrogenic movement disorder caused by long-term use of that dopamine receptors blocking drugs. Prevention of TD is paramount, and clinicians should follow best practice recommendations for prescribing antipsychotics, as well as reduction the using of dopamine receptor blocking drugs for non-psychiatric prescriptions. Replacement of antipsychotics with lower affinity for D2 receptors drugs, addition of VMAT2 (tetrabenazine), botulinum therapy, amantadine may be effective. In detection and incurable cases, the possibility of neuromodulation of brain structures should be considered. Most methods for testing TD currently have an insufficient level of evidence, although they include recommendations from professional communities. There is a great need for new clinical trials.

Earlier Diagnosis of Tardive Dyskinesia.

Because the symptoms of tardive dyskinesia (TD) have an insidious onset and fluctuating nature, and the risk of TD associated with second-generation antipsychotic (SGA) treatment has been underestimated, it has been challenging for clinicians to make an early and accurate TD diagnosis. More patients are at risk of developing this potentially permanent, disabling condition than ever before because of the widespread use of SGAs; therefore, prevention of TD, if possible, is of utmost importance. Clinicians must use reliable screening tools and diagnostic criteria to assess patients for TD, rule out other abnormal movement conditions, and make an accurate TD diagnosis.

Tardive dyskinesia: Who gets it and why

Tardive dyskinesia (TD) is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA). Identified risk factors include the type of antipsychotic agent, being greater for those of first generation antipsychotics (FGA), the duration of illness and cumulative dose of DRBA and advanced age. Female sex and African and Caucasian ethnicity are additional potential risk factors. Because only a subset of people taking DRBA's develops TD, genetics may play a role. Susceptibility gene candidates include those involved in DRBA metabolism and the targets or receptors of DRBA's. Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme. Heparan sulfate proteoglycan 2 (HSPG 2) gene is another potential gene involved with development of TD. The pathogenesis of TD is unknown, however there are three main theories proposed: dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade, oxidative stress and maladaptive synaptic plasticity each of which is discussed further in this article.Tardive dyskinesia (TD) is a potentially permanent and disabling adverse effect from certain medications. By definition TD is the insidious onset of rhythmic, repetitive, stereotypic movements of the face, mouth and tongue, often with involvement of the trunk and extremities that occur as a result of dopamine receptor blocking agents (DRBA) [1]. The term tardive refers to the delayed onset of the disorder. The mean prevalence of TD is estimated to be 25.3% in psychiatric patients taking antipsychotics [2]. Compared to the number of people taking these drugs, TD represents a minority. TD is a potentially permanent condition; stopping the offending agent does not always alleviate the condition. Therefore, prevention of TD by avoiding DRBA's if at all possible is ideal. However, there is no apparent way to predict who will develop TD and there are some cases in which DRBA's are necessary for treatment of chronic conditions. As TD has been present since the development of DRBA's, possible risk factors for its development have been studied. Solmi et al. (2018) [3] have written a comprehensive review on this subject.

Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment.

​​ Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine. ​​​.

Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

Oxidative mechanisms and tardive dyskinesia.

Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given antipsychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena. In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.

Novel antipsychotics and extrapyramidal side effects. Theory and reality.

Novel antipsychotics are less likely to produce extra-pyramidal symptoms (EPS). The superior EPS profile of these drugs compared with that of low-potency classic antipsychotics does not seem to be associated with an antimuscarinergic effect. Several other mechanisms could account for this typical feature of novel antipsychotics, which combines a strong antipsychotic effect with low liability to produce EPS. The hypotheses are based on either the receptor affinity or the topic selectivity of the drugs, but these effects are closely interconnected and it is not possible to separate them. For clozapine treatment, its very low D occupancy could explain the absence of EPS, but this does not account for the low EPS with other novel antipsychotics. The direct topic selectivity for extrastriatal D2 receptors and different distribution of the drug in the brain is less probable. The most plausible hypotheses are based on the concept of indirect topic selectivity for extrastriatal D2 receptors, mediated by high affinity for extrastriatal D2 receptors (D3, D4), 5-HT2A antagonism, alpha1 antagonism or muscarinergic antagonism at the limbic level. The D1 and indirect GABAergic antagonisms may play a role in the prevention of tardive dyskinesia. This paper briefly outlines the hypotheses and observations and summarizes the current knowledge of the occurrence of and risk for extrapyramidal side effects with novel antipsychotics.

Estrogen receptor activation and tardive dyskinesia.

To undertake a selective review of the epidemiology, etiology, and treatment of tardive dyskinesia (TD), with emphasis on the potential influence of estrogen in its expression. Both Medline and Psycinfo databases were used to search for articles with the following key words: tardive dyskinesia, humans, animals, dopamine, estrogen, estrogen replacement therapy, antioxidants and oxidative stress. The studies reviewed here suggest that estrogen modulates dopamine-mediated behaviours and that it protects against oxidative stress-induced cell damage caused by long-term exposure to antipsychotic medication. Estrogen's multimodal role in the central nervous system may prove useful for the amelioration or prevention of TD. All the evidence suggests that a placebo-controlled, randomized trial with safer forms of estrogen should be conducted in postmenopausal women with TD.

Managing antipsychotic-induced tardive dyskinesia.

Antipsychotic-induced tardive dyskinesia is a common and clinically significant hazard of long term antipsychotic therapy. The arrival of atypical antipsychotics has markedly improved the outlook: atypical antipsychotics are emerging as effective treatments and may also reduce the prevalence and incidence of tardive dyskinesia. In mild cases, careful monitoring of tardive dyskinesia by serial Abnormal Involuntary Movements Scale (AIMS) assessments may be the appropriate course. More severe tardive dyskinesia calls for intervention in order to treat the dyskinesia. Atypical antipsychotics and tocopherol (vitamin E) are effective and generally well tolerated treatment options for tardive dyskinesia. Tardive dyskinesia variants such as tardive dystonia and tardive akathisia tend to be more severe and difficult to treat compared with typical tardive dyskinesia. Prevention of tardive dyskinesia is possible through careful selection of patients for antipsychotic therapy, use of the lowest effective antipsychotic dosages, use of atypical rather than traditional antipsychotics and concurrent tocopherol administration. The clinician can now undertake the management of tardive dyskinesia with growing confidence.

CMHC practices related to tardive dyskinesia screening and informed consent for neuroleptic drugs.

The authors conducted a national survey of community mental health centers to determine their policies and practices about screening patients for tardive dyskinesia and obtaining informed consent for use of neuroleptic drugs. Clinical directors of 235 centers in the United States, selected by geographic region and population, were surveyed through a nine-item questionnaire. Although nearly all the 160 respondents reported that they screened patients for tardive dyskinesia, only about two-fifths had formal screening policies, and about two-fifths had screening programs. The Abnormal Involuntary Movement Scale examination was used by almost two-thirds of respondents who screened patients, and about one-fifth relied on unstructured observation. Slightly more than half of respondents specified a frequency for screening examinations, at a modal interval of six months. Seventy percent used nonpsychiatric clinicians for screening. Almost three-quarters of the respondents had informed consent policies for use of neuroleptics. Urban centers tended to be more aware than rural centers of the American Psychiatric Association's tardive dyskinesia screening guidelines. They also used fewer nonmedical practitioners for screening and were more likely to obtain informed consent for neuroleptics. Despite the existence of APA guidelines and state policies and regulations about tardive dyskinesia screening, a national effort to educate clinicians about prevention of tardive dyskinesia is still needed.

Tiagabine inhibits haloperidol-induced oral dyskinesias in rats.

Chronic administration of haloperidol to male Sprague Dawley rats for 6 months at a dosage of 1.5 mg/kg/day produces oral dyskinesias in a significant percent of the treated group. This has been used as an animal model of tardive dyskinesia in several laboratories, because the rat movements display characteristics reminiscent of the human dyskinetic condition. Previously, we have reported a reduction in these haloperidol-induced oral dyskinesias with the coadministration of a direct acting GABA agonist progabide. Here, we have tested an indirect acting GABA agonist, tiagabine, coadministered with haloperidol, for its effect on the oral dyskinesias. At a dosage of 75 mg/kg/day tiagabine significantly inhibited the onset of vacuous chewing movements (VCMs), decreasing the average movement severity from 11.2 +/- 2.0 to 4.4 +/- 1.4, compared with a placebo rate of 1.3 +/- 0.5 (VCMs/5 min). These data support the proposition that an effective, potent GABAmimetic coadministered with haloperidol, will block the onset of rat oral dyskinesias. This conclusion has important implications for the treatment and prevention of tardive dyskinesia in humans.

Tardive dyskinesia: a current review

Tardive Dyskinesia (TD) is a neurological syndrome associated with long-term use of antipsychotic drug treatment (APD). Its significant prevalence (estimated 15-20%) and potential irreversibility are a major concern in psychiatry. The clinical picture is characterized by involuntary repetitive movements of choreoathetotic and dystonic nature varying in location and intensity. The individual outcome of TD is unpredictable but recent long-term studies give reason for prudent optimism. All neuroleptics are involved in the disorder, numerous risk factors have been suggested; advancing age is the only one which has a clearly definite role. Even though several hypotheses have been suggested, the pathophysiology of the disorder remains a mystery. Informed consent is discussed in this update with regard to the legal implications of the disorder. Because of lack of effective treatment, prevention of TD is essential. The present treatment of choice is gradual reduction (and ideally discontinuance) of APD treatment when possible.

Tardive Dyskinesia Litigation and the Dilemmas of Neuroleptic Treatment

The problem of liability over the occurrence of late side effects of neuroleptic treatment in mentally ill and mentally retarded patients has been underscored by four recent court decisions, in which enormous sums were awarded to plaintiffs who developed tardive dyskinesia. Four cases, Clites, Faigenbaum, Hedin, and Headley, are described in detail, and relevant issues in psychiatric malpractice are discussed. It is likely that the threat and the reality of tardive dyskinesia litigation will influence psychiatric practice in important ways. The gravity of the situation is compounded by the complexity of the medical issues, the potential numbers of litigants, and the structure of current psychiatric practice, which sometimes militates against careful adherence to established guidelines for the prevention of tardive dyskinesia.

Lithium does not interact with haloperidol in the dopaminergic pathways of the rat brain.

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

Prevention and management of tardive dyskinesia.

Because no adequate therapy is available, the prevention of tardive dyskinesia is of great importance. The disorder may be prevented by periodic evaluations of the neurologic status of patients on long-term drug treatment, followed by reducing the drug dosage or discontinuing administration. Withdrawing neuroleptics, particularly in patients with pseudoparkinsonism, may uncover latent dyskinesia. For patients already exhibiting this disorder, the use of small doses of neuroleptics may be safe, provided changes in neurological symptoms are monitored carefully.