Deep brain stimulation of the subthalamic or entopeduncular nucleus attenuates vacuous chewing movements in a rodent model of tardive dyskinesia

Deep brain stimulation (DBS) has recently emerged as a potential intervention for treatment-resistant tardive dyskinesia (TD). Despite promising case reports, no consensus exists as yet regarding optimal stimulation parameters or neuroanatomical target for DBS in TD. Here we report the use of DBS in an animal model of TD. We applied DBS (100 μA) acutely to the entopeduncular nucleus (EPN) or subthalamic nucleus (STN) in rats with well established vacuous chewing movements (VCMs) induced by 12 weeks of haloperidol (HAL) treatment. Stimulation of the STN or EPN resulted in significant reductions in VCM counts at frequencies of 30, 60 or 130 Hz. In the STN DBS groups, effects were significantly more pronounced at 130 Hz than at lower frequencies, whereas at the EPN the three frequencies were equipotent. Unilateral stimulation at 130 Hz was also effective when applied to either nucleus. These results suggest that stimulation of either the EPN or STN significantly alleviates oral dyskinesias induced by chronic HAL. The chronic HAL VCM model preparation may be useful to explore mechanisms underlying DBS effects in drug-induced dyskinesias.     

Neuroleptic-induced vacuous chewing movements as an animal model of tardive dyskinesia: a study in three rat strains

Vacuous chewing movements (VCMs) in three different rat strains developed at considerably different rates after 19 weeks of continual haloperidol treatment at an average daily dose of 1.5 mg/kg. Sprague Dawley (SD) rats displayed relatively high rates of VCMs with low variability, compared to Wistar (W) and Long Evan (LE) rats. Atropine decreased but did not abolish VCMs in two of the three strains (LE>SD). After haloperidol withdrawal, VCMs remitted gradually in all strains, but least rapidly in the SD rats. In a separate group of SD rats, VCMs were rated weekly from the start of haloperidol treatment and showed considerable interindividual variability. Even after 24 weeks of continuous haloperidol, 12 out of 32 treated rats showed no VCMs at all, while 13 out of 32 had intense movements, analogous to the clinical situation in which only some patients treated with neuroleptics develop tardive dyskinesia. These results indicate that there are individual and strain differences in the development of VCMs, and suggest that there may also be genetically determined differences in the development of tardive dyskinesia.     

Molindone compared to haloperidol in a guinea-pig model of tardive dyskinesia

Molindone was compared with haloperidol in animal models of tardive dyskinesia. Treatment with molindone for 14 days at 3, 6, 20 and 40 mg/kg, enhanced the stereotyped behavioral response induced by apomorphine and increased the number of D-2 dopamine receptors in the striatum (B_max) labelled by high affinity (K_d = 40 pmol) binding or [³H]spiroperidol in the guinea-pig. Molindone at 1 mg/kg, caused no behavioral supersensitivity or change in the binding of dopamine receptors. Chronic administration of haloperidol (0.1, 0.5 and 5.0 mg/kg) also increased both the behavioral response to apomorphine and the number of dopamine receptors. Haloperidol, at 0.02 and 0.004 mg/kg, had no effect. Molindone potentiated dopaminergic activity in animal models in a similar way to other neuroleptics, suggesting that its use may also result in tardive dyskinesia.     

Dose-dependent differences in the development of reserpine-induced oral dyskinesia in rats: support for a model of tardive dyskinesia

Rats treated with reserpine develop spontaneous orofacial dyskinesia that has features similar to tardive dyskinesia (TD) in humans. In contrast to TD, however, reserpine-induced oral dyskinesia develops rapidly reaching a maximal level within 3 days at a dose of 1 mg/kg per day. The present study examined whether rats administered lower doses of reserpine would develop the oral dyskinesia at a slower rate, similar to the protracted development of TD. Rats were administered 0, 0.01, 0.05, 0.1, or 1.0 mg/kg reserpine subcutaneously every other day for 100 days. Oral dyskinesia was measured by recording the incidence of tongue protrusions for 30 min on days 1, 4, 10, 20, 40, 60, and 100. The time course of the development of reserpine-induced oral dyskinesia varied dose-dependently. The response was evident within 4 days at 1 mg/kg, within 20 days at 0.1 mg/kg, within 60 days at 0.05 mg/kg, and was not evident at 0.01 mg/kg at any time during the 100 days of treatment. The protracted development of reserpine-induced oral dyskinesia at the lower doses is consistent with TD. Doses of reserpine that produced an increase in tongue protrusions also produced a 90–95% depletion of dopamine and an increase in the ratio of dopamine metabolites to dopamine in the caudate-putamen. The disruption of dopamine neurotransmission may be involved in development of the oral dyskinesia. Furthermore, it is suggested that the 1 mg/kg dose of reserpine may induce neurochemical changes similar to that produced by long-term neuroleptic treatment, but at an accelerated rate, thereby providing a new efficient model of TD.     

Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia.

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.     

Effect of clozapine in severe tardive dyskinesia: a case report

There have been conflicting reports as to whether clozapine, an atypical antipsychotic, will suppress symptoms of tardive dyskinesia. With this in mind, the authors present the case of a 32-year-old chronically institutionalized schizophrenic who showed a remarkable improvement in both tardive dyskinesia and psychotic symptoms following an open trial of clozapine, 900 mg daily. This effect was noted to persist throughout the 15-month observation period with no breakthrough dyskinesia. The ability of clozapine to suppress tardive dyskinesia symptoms raises the possibility that clozapine, at least at the doses used in this report, might also induce the disorder. Long-term, controlled studies are required to specifically address this issue.     

Association study of the GSK-3B gene with tardive dyskinesia in European Caucasians

There is solid evidence of a genetic predisposition to tardive dyskinesia (TD) although the pathophysiological mechanisms of TD are still unclear. Nevertheless, the dopamine overactivity hypothesis of the TD etiology receives support from both pharmacological and physiological evidence. Dopaminergic signaling modulates the glycogen synthase kinase 3B (GSK-3B), a kinase that may play a critical role in the pathogenesis of neurodegenerative diseases. GSK-3B is an essential element of the apoptotic signaling cascade induced by oxidative stress, which may be involved in TD pathogenesis. We investigated whether GSK-3B polymorphisms (rs11919783, rs6805251, rs7624540, rs6438552, rs4072520, rs9878473, rs6779828 and rs3755557) selected using tagging method were associated with TD manifestation and abnormal involuntary movement severity. We evaluated 215 schizophrenia subjects from whom 169 were European Caucasians. All eight evaluated variants had their minor allele carriers consistently showing lower risk to TD and lower Abnormal Involuntary Movement Scale. The rs6805251, rs6438552 and rs9878473 variants showed a trend for association with TD in European Caucasian subjects (permuted p = 0.07). Furthermore, all tested markers showed p ≤ 0.0007 after we incorporated age as covariate in the analysis of the abnormal involuntary movement severity. Our results suggest that GSK-3B polymorphism may play a role in the genetic vulnerability to TD manifestation in schizophrenia subjects with European Caucasian background further implicating polymorphisms in the dopamine D2-like receptor signaling in this context. These findings should be read with caution particularly before independent replication.     

Oral dyskinesia in brain-damaged rats withdrawn from a neuroleptic: Implication for models of tardive dyskinesia

Rats with ablated frontal sensorimotor cortex and one with ablated sensorimotor connections to forebrain showed more vacuous chewing movements following 6-week chronic administration of a neuroleptic than did occipitally damaged rats or normal controls who were treated in the same way. The effect was still present 1 month after withdrawal. It was not clearly enhanced by subsequent treatments. Other behaviors (e.g., walking, rearing, or grooming) were not similarly affected by drug withdrawal. Additional results of terminal probes with amphetamine, apomorphine, and haloperidol are described, including movements labeled sham eating, observed only in frontal rats given apomorphine (AP). The results are interpreted in terms of a Jacksonian model of levels of brain organization; such a model may be applicable to tardive dyskinesia, seen in many schizophrenic patients who are maintained on neuroleptics for long periods.     

Mixture in the distribution of haloperidol-induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia

Spontaneous adventitious oral movements which are produced in rats by very chronic (6- month) neuroleptic treatment have some phenomenologic and pharmacologic characteristics in common with tardive dyskinesia in humans. However, since not all of the features match, this putative model has been questioned and further support is warranted. Data from several laboratories support dichotomizing these neuroleptic-induced rat oral movements into “low”or “not TD-like” movements and “high”or “TD-like” movements, similar to the division of neuroleptic-induced involuntary movements in humans. Here, we have used mixture analysis to test this proposal statistically in 185 haloperidol-treated and 127 water-treated animals. Rats from several different studies were grouped together to form these two cohorts. The haloperidol dose, route of administration, rating technique, and balanced experimental groups were held constant across all experiments. Results show that two distinct groups of rat movements are induced by very chronic haloperidol treatment (1.5 mg/kg per day). The “low” vacuous chewing movement (VCM) group of rats had an average of 3.6 VCMs/5 min, and the “high” VCM group had an average of 16.1 VCMs/5 min; the conrol group, with a median VCM rate of 2.0 VCMs/5 min, demonstrated a single distribution. These data suggest that rats, like humans, dichotomize into two groups either expressing or not expressing “high” VCM dyskinesias with very chronic haloperidol treatment. Received: 5 November 1996 / Final version: 17 June 1997     

valbenazine治疗迟发性运动障碍的疗效与安全性:Meta分析

目的系统分析valbenazine治疗迟发性运动障碍(TD)的疗效与安全性。方法计算机检索PubMed、 EBSCO、 Embase、 Cochrane Library、中国知网、万方及维普数据库,查找有关valbenazine治疗TD的随机对照临床试验(RCT),时限为建库至2018年6月。由2名研究者根据纳入与排除标准独立筛选文献,进行质量评价及数据提取。采用RevMan 5.0软件进行Meta分析及文献发表偏倚评估。结果纳入4篇RCT,文献质量评估均属高质量。纳入患者603例,其中valbenazine 40 mg·d~(-1)组192例,valbenazine 80 mg·d~(-1)组210例,安慰剂组201例。Meta分析显示,与安慰剂组相比,疗效评价指标方面,valbenazine 40、 80 mg·d~(-1)组各症状量表评分变化及反应值均有显著改善(P <0.05);安全性指标方面,valbenazine 40、 80 mg·d~(-1)组不良事件发生率与安慰剂组相比均无显著差异(P> 0.05)。结论 valbenazine治疗TD疗效确切,患者耐受性高,但仍需严格设计的、大样本、多中心临床试验予以验证。     

Dopamine transporter density in patients with tardive dyskinesia: a single photon emission computed tomography study

RATIONALE: Tardive dyskinesia occurs frequently in schizophrenic patients chronically treated with classical antipsychotic medication. It may be caused by loss of dopaminergic cells, due to free radicals as a product of high synaptic dopamine levels. OBJECTIVE: To evaluate dopamine transporter density in the striatum in patients with tardive dyskinesia. METHODS: Striatal [123I]FP-CIT binding was measured with SPECT in seven schizophrenic patients with tardive dyskinesia and eight healthy controls. RESULTS: No significant difference was found between striatal [123I]FP-CIT binding ratios in patients with tardive dyskinesia and controls. CONCLUSIONS: This preliminary study indicates no change in striatal dopamine transporter density in schizophrenic patients with tardive dyskinesia. This finding does not support the hypothesis that tardive dyskinesia is caused by dopaminergic cell loss.     

The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia

Tardive dyskinesia (TD), a serious complication of antipsychotic dopamine (DA) antagonist treatment, has been hypothesised to develop due to a dominant DA D1 relative to DA D2 receptor function. Recent genetic and pharmacological studies implicate the DA D3 receptor in TD. The present study examined the role of the DA D3 receptor in relation to the DA D1/D2 imbalance hypothesis of TD in nonhuman primates. Eight Cebus monkeys displaying mild to severe TD due to previous chronic exposure to DA D2 antagonists were acutely injected with SKF 81297 (DA D1 agonist) 0.3 and 0.6 mg/kg, pramipexole (DA D3>D2 agonist) 0.025-0.1 mg/kg, CIS-8-OH-PBZI (DA D3 agonist) 5-10 mg/kg and SB-27701-A (DA D3 antagonist) 1-5 mg/kg and rated for oral dyskinesia. SKF 81297, 0.3 and 0.6 mg/kg, exacerbated TD. Pramipexole and CIS-8-OH-PBZI reduced SKF 81297-induced TD, while SB-27701-A had no effect. When administered alone, SB-27701-A increased TD relative to placebo, while pramipexole and CIS-8-OH-PBZI had no significant effect. Pramipexole did, however, ameliorate TD in those monkeys with severe TD. These results point towards a role of the DA D3 receptor in TD, but indicate that the DA D2 receptor may also play an essential role.     

Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia.

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] = 8.25, p < .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor in the pathogenesis of TD.     

Remission of severe tardive dyskinesia in a schizophrenic patient treated with the atypical antipsychotic substance quetiapine

In a single inpatient case study, a schizophrenic patient with tardive dyskinesia after prolonged treatment with typical neuroleptics was treated with the new atypical neuroleptic quetiapine, a dibenzothiazepin-derivative. Within 2 weeks of treatment with quetiapine, symptoms of tardive dyskinesia improved; 10 weeks after starting treatment tardive dyskinesia stopped completely. Over the same period, dopamine D2 receptor occupancy decreased substantially, as measured by IBZM-SPECT after 14 and 77 days of treatment.     

短暂脑缺血诱导成年大鼠纹状体内CRMP-4的表达

AIM: To study the expression of collapsing response mediated protein-4 (CRMP-4) and nestin in the ischemic adult rat brain following transient brain ischemia. METHODS: Brain ischemia was induced by transient left middle cerebral artery occlusion (MCAO) for 60 min in adult rats. The expression of CRMP-4, nestin and bromodeoxyuridine(BrdU) was analyzed by immunohistochemical method. The co-localization of CRMP-4 and nestin or BrdU was analyzed by double staining combined with confocal laser scanning microscopy. RESULTS: CRMP-4, a marker of immature neuron, could be expressed in the ipsilateral striatum and cerebral cortex at 1st and 2nd week after the ischemia-reperfusion; nestin, a marker of neural stem cell, occurred in above regions from several hours to 2 weeks. CRMP-4 costained with nestin and with BrdU incorporation. CONCLUSION: Neural stem cells may present in the striatum and cerebral cortex of adult rat and can be triggered to differentiate into newborn neuron there by ischemic brain trauma.     

Induction of CRMP-4 in striatum of adult rat after transient brain ischemia

AIM: To study the expression of collapsing response mediated protein-4 (CRMP-4) and nestin in the ischemic adult rat brain following transient brain ischemia. METHODS: Brain ischemia was induced by transient left middle cerebral artery occlusion (MCAO) for 60 min in adult rats. The expression of CRMP-4, nestin and bromodeoxyuridine (BrdU) was analyzed by immunohistochemical method. The co-localization of CRMP-4 and nestin or BrdU was analyzed by double staining combined with confocal laser scanning microscopy. RESULTS: CRMP-4, a marker of immature neuron, could be expressed in the ipsilateral striatum and cerebral cortex at 1st and 2nd week after the ischemia-reperfusion; nestin, a marker of neural stem cell, occurred in above regions from several hours to 2 weeks. CRMP-4 costained with nestin and with BrdU incorporation. CONCLUSION: Neural stem cells may present in the striatum and cerebral cortex of adult rat and can be triggered to differentiate into newborn neuron there by ischemic brain trauma.     

CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis

The present study aimed to evaluate whether there is any association between CYP2D6 alleles and susceptibility to tardive dyskinesia in patients with schizophrenia under treatment. A meta-analysis considered case-control studies determining the distribution of genotypes for any CYP2D6 polymorphism in unrelated tardive dyskinesia cases and controls without tardive dyskinesia among patients with schizophrenia who were treated with antipsychotic agents. Loss of function alleles were grouped together in a single comparison, whereas other alleles (2 and 10) were examined separately. Data were available for eight (n=569 patients), three (n=325 patients) and four (n=556) studies evaluating the effect of the loss of function alleles, the 2 allele and the 10 allele, respectively. Summary odds ratios (ORs) suggested that loss of function alleles increased the risk of tardive dyskinesia significantly [OR=1.43, 95% confidence interval (CI) 1.06-1.93, P=0.021], whereas there was no effect for 2 and inconclusive evidence for 10 (OR=0.82, 95% CI 0.50-1.32, P=0.41 and OR=1.19, 95% CI, 0.89-1.60, P=0.24, respectively). Patients who were homozygotes for loss of function alleles (poor metabolizers) had 1.64-fold greater odds of suffering tardive dyskinesia compared to other patients with schizophrenia, but the effect was not formally significant (95% CI 0.79-3.43). For the risk conferred by loss of function alleles, large studies provided more conservative estimates of a genetic effect than smaller studies (P=0.003). CYP2D6 loss of function alleles may predispose to tardive dyskinesia in patients with schizophrenia under treatment, but bias cannot be excluded.