Long-term Neuroleptic Administration Research Articles

Study of autoimmune mechanisms of neuroleptics action

The authors set a goal to evaluate the severity of haloperidol catalepsy depending on the level of autoantibodies to dopamine receptors and dopamine in laboratory rats that were subjected to long-term administration of neuroleptics.

Ginkgo biloba leaf extract and alpha-tocopherol attenuate haloperidol-induced orofacial dyskinesia in rats: Possible implication of antiapoptotic mechanisms by preventing Bcl-2 decrease and Bax elevation

BackgroundTardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role. PurposeThis study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD. MethodsThirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum. ResultsWe found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio. ConclusionsThese results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.

Extended neuroleptic administration modulates NMDA-R subunit immunoexpression in the rat neocortex and diencephalon.

This study aimed to evaluate the effect of extended olanzapine, clozapine and haloperidol administration on NMDA-R subunit immunoexpression in the rat neocortex and diencephalon. To explore NR1, NR2A and NR2B subunit protein expression, densytometric analysis of immunohistochemically stained brain slices was performed. Interestingly, all neuroleptics caused a downregulation of NMDA-R subunit expression in the thalamus but increased the level of NR1 in the hypothalamus. Olanzapine upregulated hypothalamic NR2A expression, while clozapine and haloperidol decreased hypothalamic levels. We observed no significant changes in NR2B immunoreactivity. None of the studied medications had significant influence on NMDA-R subunit expression in the neocortex. Neuroleptic-induced reduction in the expression of thalamic NMDA-R subunits may play an important role in the regulation of glutamatergic transmission disorders in cortico-striato-thalamo-cortical loop in schizophrenia. A decrease in NMDA signaling in this region after long-term neuroleptic administration may also cautiously explain the incomplete effectiveness of these drugs in the therapy of schizophrenia-related cognitive disturbances.

Effects of long-term treatment with the neuroleptics haloperidol, clozapine and olanzapine on immunoexpression of NMDA receptor subunits NR1, NR2A and NR2B in the rat hippocampus.

Antagonists of the N-methyl-d-aspartate receptor (NMDA-R) are associated with symptoms of schizophrenia, leading to the hypothesis that NMDA-R hypofunction leads to the pathogenesis of disease. We evaluated the long-term effect of neuroleptic administration on the NMDA subunits via immunohistochemical analysis. Rats received olanzapine, clozapine and haloperidol before evaluation of the expression of the NR1, NR2A and NR2B subunit proteins in the hippocampal areas of the brain, via a densytometric analysis of immunoexpression in the rat hippocampus. All of the neuroleptics examined caused a decrease in the expression of the NR1 subunit, and thus, one can assume that both olanzapine, clozapine and haloperidol decreased the number of NMDA receptors in the CA1 and CA2 areas of the brain. A decrease in hippocampal glutamatergic signalling after long-term neuroleptic administration may cautiously explain the incomplete effectiveness of these drugs in the therapy of schizophrenia-related cognitive disturbances.

Tardive Tourette-Like Syndrome in a Patient Treated With Paliperidone

Tardive Tourette-Like Syndrome in a Patient Treated With Paliperidone

DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia

We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.

Rapid Response of Disabling Tardive Dyskinesia to Amantadine

To the Editor: About 20% of patients treated with standard neuroleptic drugs are affected with tardive dyskinesia (TD), and approximately 5% are expected to develop TD with each year of neuroleptic treatment.1 The majority of patients with TD have a mild disorder, but about 5%–10% suffer impairment from the dyskinesia.2 The evidence in relation to the atypical antipsychotics suggests that these drugs present a significantly lower risk for TD in comparison to first-generation antipsychotics.3 Reports suggest that the risk of TD is lowest with clozapine, followed by quetiapine.4 The severity of TD and the absolute need for neuroleptic therapy often dictate the treatment approach. Although there is no currently effective treatment for TD, amantadine has been reported to be beneficial, possibly because of its glutamatergic effects.4,5 Herein, I report a patient with disabling TD due to quetiapine that responded rapidly to amantadine. To my knowledge, this report is the first description of rapid improvement of quetiapine-induced TD by amantadine. Case report. Ms A, a 57-year-old retired librarian, was hospitalized in the fall of 2009 with long-standing history of treatment-resistant DSM-IV-TR–defined major depressive disorder, recurrent, severe episode without psychotic features. For 6 weeks, she was treated with fluoxetine (60 mg/d), duloxetine (120 mg/d), quetiapine (400 mg/d), and clonazepam (2 mg/d) and underwent bilateral electroconvulsive treatment (ECT) once per week. At this hospitalization, her 17-item Hamilton Depression Rating Scale (HDRS)6 score was 40 and her Abnormal Involuntary Movement Scale (AIMS) score was 10.7 Her blood workup for the causes of refractory depression revealed no abnormalities. Ms A denied consent for ECT. She was switched from fluoxetine to paroxetine treatment (increased to 40 mg/d), and clonazepam was increased to 3 mg/d. Quetiapine was continued as an augmenting agent and was increased to 600 mg/d. She had no change in depressive symptoms and was noted to be more anxious and agitated during the following 4 weeks (HDRS score = 38 and AIMS score = 16). Therefore, paroxetine treatment was switched to mirtazapine treatment (increased to 45 mg/d) and duloxetine treatment was switched to venlafaxine extended release treatment (increased to 300 mg/d). The patient continued to worsen over the next 3 weeks. Gradually, varieties of repeated stereotypic abnormal movement became evident. She was noted to have dyskinetic blinking, frowning, lip smacking, puckering, chewing, jaw clenching, mouth opening, and facial grimacing movements. She also had stereotypic and involuntary movements of hands and toes. These movements would aggravate when she became more anxious and would disappear while she was sleeping. She was unable to interact because her speech was broken, repetitive, and nonfluent. Ms A became incapacitated to the extent that she was not able to communicate with others and take care of her daily routine activities. Her HDRS score was 38 and AIMS score increased to 41. At that time, findings of electroencephalogram and magnetic resonance imaging of the head with and without contrast were within normal limits. Clonazepam was increased to 5 mg/d, and vitamin E 1,600 units was added. The neurology department was consulted the following week when no change in her condition was noted. They stopped vitamin E and administered amantadine 400 mg/d in 4 divided doses. Within 3 days she started to improve, and her AIMS score reduced to 18 in 5 days. Clonazepam was decreased to 1 mg 2 times daily. Then, a gradual taper of quetiapine was started at the rate of 100 mg/wk. She agreed to ECT treatments and was discharged after 2 weeks, at which time her HDRS and AIMS scores were 15 and 14, respectively. During the office follow-up, quetiapine was completely stopped in the next 4 weeks. Amantadine was then tapered gradually to 100 mg/d without any worsening of TD. She has been stable for the last year, and her AIMS score at 1-year follow-up was 12. Tardive dyskinesia is the most serious consequence of long-term neuroleptic administration, and all known approaches to its treatment are relatively unsuccessful.5 Amantadine is a commonly used drug in neurology, but psychiatrists are generally less experienced with its use. There has been very little research on the use of amantadine in TD, and the patient population studied was on treatment with typical antipsychotics only.8–14 An 18-week, double-blind, crossover study by Angus et al14 demonstrated that amantadine is significantly better than placebo in the management of TD and that there is little risk of exacerbating psychosis. Using amantadine to treat TD has produced a rapid improvement in dyskinesia without emergence of psychosis even with prolonged administration. More studies are needed to prove the utility of amantadine in atypical antipsychotic–induced TD. Meanwhile, a trial of amantadine for a short period (1–2 weeks) in a patient with debilitating TD may be useful.

Genetic association analysis of the glutathione peroxidase (GPX1) gene polymorphism (Pro197Leu) with tardive dyskinesia

A possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has previously been proposed (reviewed in [Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Progress in Neurobiology 61, 525–541.]). Long-term administration of neuroleptics alters dopaminergic turnover, which results in increased formation of reactive oxygen species (ROS). This is hypothesized to lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a possible functional polymorphism of the human glutathione peroxidase (GPX1) gene (an important antioxidant enzyme) was studied in 68 chronic treatment–refractory patients with schizophrenia. A proline (Pro) to leucine (Leu) substitution at codon 197 (Pro197Leu) in the GPX1 gene was genotyped. No significant difference in total Abnormal Involuntary Movements Scale (AIMS) scores was observed among patients in the three genotype groups. Moreover, no significant differences in genotype or allele frequencies were observed between subjects with and without TD. Our results suggest that the GPX1 gene polymorphism does not confer increased susceptibility to TD, although further studies are warranted before a conclusion can be drawn.

Tripartite relationship among P300, clinical features and brain structure in neuroleptic‐naive schizophrenia

Auditory P300 abnormalities in schizophrenia patients have been repeatedly reported by many studies. However, reported relationships among P300 abnormalities, clinical features and other biological variables, such as abnormalities in structural brain imaging, are notably discrepant. This is partially due to the inclusion of patients who have had long-term administration of neuroleptics and those from whom this treatment has been withdrawn. The present study measures event-related potentials in 13 neuroleptic-naive schizophrenia patients using an auditory oddball paradigm to clarify the relationships among P300 amplitude, clinical features and brain structure. All patients underwent computed tomography to estimate the area of the right and left frontal cortical sulci and Sylvian fissures. Clinical symptoms were assessed using the Positive And Negative Syndrome Scale. The high correlation coefficients were obtained between P300 amplitude and the anxiety/depression factor score (r = -0.77), the positive factor score (r = -0.58) and between P300 amplitude and the area ratios of the fronto-temporal region (r = -0.66). These findings show that fronto-temporal region and P300 amplitude are closely related to the earliest stage of illness even in neuroleptic-naive patients.

Reversal of Reserpine-Induced Orofacial Dyskinesia and Cognitive Dysfunction by Quercetin

Tardive dyskinesia (TD) is a serious neurological syndrome associated with long-term administration of neuroleptics to humans and experimental animals. The pathophysiology of this disabling and commonly irreversible movement disorder is still obscure. It may be caused by a loss of dopaminergic cells or may be due to free radicals as a product of high synaptic dopamine levels. Quercetin is a bioflavonoid with strong antioxidant properties. Repeated treatment with reserpine (1.0 mg/kg) on each other day for a period of 5 days (days 1, 3 and 5) significantly induced vacuous chewing movements (VCMs) and tongue protrusions (TPs) in rats. Chronic treatment with quercetin for a period of 4 weeks to reserpine-treated animals significantly and dose dependently (50 and 100 mg/kg) reduced the reserpine-induced VCMs and TPs. Reserpine-treated animals also showed poor retention of memory in elevated plus-maze task paradigm. Chronic quercetin administration significantly reversed reserpine-induced retention deficits. Biochemical analysis revealed that chronic reserpine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the brains of rats. Chronic reserpine-treated rats showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD) and catalase. Chronic administration of quercetin dose dependently (50–100 mg/kg) and significantly reduced the lipid peroxidation and restored the decreased GSH levels by chronic reserpine treatment. It also significantly reversed the reserpine-induced decrease in brain SOD and catalase levels in rats. The results of the present study clearly indicated that quercetin has a protective role against reserpine-induced orofacial dyskinesia and memory impairment. Consequently, the use of quercetin as a therapeutic agent for the treatment of TD should be considered.

Informing patients about tardive dyskinesia: A survey of clinicians' attitudes in three countries

1. IntroductionThere is a general increase in awareness amongst clinicians of the need to inform patients about therisks and benefits of treatments offered. Neuroleptic drugs have proven effectiveness in the treatmentof schizophrenia, but side effects are common and potentially serious (Johnstone, 1993). These includetardive dyskinesia (TD) an involuntary movement disorder associated with the long-term administra-tion of neuroleptics. TD has an overall prevalence of 20–25% in neuroleptic-treated patients, and ispotentially irreversible. The introduction of ‘‘atypical’’ neuroleptics in recent years may have reducedthe risk of TD, but evidence for this is currently limited (Simpson, 2000). The American PsychiatricAssociation (APA) has recommended, via two Task Force reports, regular examination of at-riskpatients for TD using the Abnormal Involuntary Movement Scale at least six monthly (APA, 1992).The APA also recommends that informed consent for neuroleptic treatment be obtained anddocumented.According to the Code of Practice of the United Kingdom Mental Health Act 1983 (Department ofHealth and the Welsh Office, 1993), consent is the ‘‘voluntary and continuing permission of thepatient to receive a particular treatment, based on an adequate knowledge of the purpose, nature, likelyeffects, and risks of that treatment, including the likelihood of its success and any alternatives to it.’’Permission given under unfair undue pressure is not consent. Ensuring valid and informed consentamongst psychiatric patients, and particularly those with a psychotic illness can be problematic. We

Genetic association analysis of neuronal nitric oxide synthase gene polymorphism with tardive dyskinesia.

Possible involvement of oxidative stress in the pathophysiology of tardive dyskinesia (TD) has been proposed. Long-term administration of neuroleptics alters dopaminergic turnover, yielding the increase of the formation of reactive oxygen species (ROS), which may lead to TD through neuronal toxicity as a consequence of oxidative stress. In the present study, the relationship between TD and a polymorphism of the neuronal nitric oxide synthase (NOS1) gene whose reaction product, nitric oxide (NO), is involved in oxidative stress was studied in 171 Japanese patients with schizophrenia, including 41 patients meeting TD criteria. The C/T polymorphism in exon 29 of the NOS1 gene was genotyped using polymerase chain reaction (PCR) amplification followed by restriction enzyme digestion. No significant difference in genotype frequencies was detected between subjects with and without TD (chi2 = 1.54, df = 2, p = 0.46). In addition, there was no difference in allele frequencies (chi2 = 0.42, df = 1, p = 0.51). These results suggest that the NOS1 gene polymorphism may not confer increased susceptibility to TD, although more investigations on other populations are warranted.

Meige's syndrome associated with neuroleptic treatment and alcohol abuse

Meige's syndrome is characterized by blepharospasm and oromandibular dystonia. A case is presented in association with long-term neuroleptic administration and alcohol abuse. This syndrome may be a variant of tardive dystonia.

The suppression of brain cold-stable microtubules in mice induces synaptic defects associated with neuroleptic-sensitive behavioral disorders.

Neurons contain abundant subsets of highly stable microtubules that resist depolymerizing conditions such as exposure to the cold. Stable microtubules are thought to be essential for neuronal development, maintenance, and function. Previous work has indicated an important role of the microtubule-associated protein STOP in the induction of microtubule cold stability. Here, we developed STOP null mice. These mice were devoid of cold-stable microtubules. In contrast to our expectations, STOP-/- mice had no detectable defects in brain anatomy but showed synaptic defects, with depleted synaptic vesicle pools and impaired synaptic plasticity, associated with severe behavioral disorders. A survey of the effects of psychotropic drugs on STOP-/- mice behavior showed a remarkable and specific effect of long-term administration of neuroleptics in alleviating these disorders. This study demonstrates that STOP is a major factor responsible for the intriguing stability properties of neuronal microtubules and is important for synaptic plasticity. Additionally, STOP-/- mice may yield a pertinent model for study of neuroleptics in illnesses such as schizophrenia, currently thought to result from synaptic defects.

Can chronic neuroleptic treatment promote sleep disturbances in elderly schizophrenic patients?

It has been proposed that sleep disturbances, especially reduced delta sleep, are related to a poor outcome in schizophrenia. To determine whether long-term treatment with neuroleptics can promote sleep disturbances by increasing the risk of a nocturnal myoclonus syndrome (NMS) (=periodic movements in sleep) related insomnia, we performed all-night polysomnography in 10 chronically ill schizophrenic patients who had been under neuroleptic therapy for a mean of 27 years. NMS-related insomnia was detected in all 10 patients. Potential pathophysiological relationships between long-term neuroleptic therapy and NMS occurrence are discussed. Our findings suggest that long-term administration of neuroleptics favours the appearance of insomnia.

Effects of chronic neuroleptic administration on the hypothalamo-pituitary-gonadal axis of male schizophrenics

1. 1. The authors investigated the effects of long-term neuroleptic administration on the hypothalamo-pituitary-gonadal (HPG) axis of regularly medicated schizophrenic male patients. 2. 2. The subjects were 56 patients who were diagnosed according to the DSM-IV criteria for schizophrenia. Each patient gave informed consent for the research involved in this study. Based on the dosages of neuroleptics, the subjects were classified into two age-matched groups: those with lower dosages (LD) and those with higher dosages (HD). 3. 3. (1) The mean level of the blood testosterone (T) in the LD group was significantly lower than that in the normal group, although the level was within normal range. There was no significant difference in the mean level of the blood T for the HD and the normal groups, or for the HD and the LD groups. (2) There was no significant difference in the mean levels of the blood luteinizing hormone between all groups. (3) Also, there was no significant difference in the mean levels of the blood follicle-stimulating hormone between the groups. (4) The mean levels of the blood prolactin in both the LD and HD groups were significantly higher than that in the normal subjects, but there was no significant difference between the LD and HD schizophrenics. 4. 4. Overall, these results seem to indicate that (i) in male patients with chronic schizophrenia, HPG function is impaired, and (ii) chronic neuroleptic medication stimulates the HPG axis in schizophrenic patients with impaired HPG function.

Addition of carbamazepine to long-term treatment with neuroleptics may induce neuroleptic malignant syndrome

Background: Carbamazepine is an anticonvulsant, but also has an anti-manic effect, and recently it has been increasingly used in combination with neuroleptics. Nevertheless, there have been very few reports on the involvement of carbamazepine in the occurrence of neuroleptic malignant syndrome (NMS). Methods: A case of NMS occurring after addition of carbamazepine to long-term neuroleptic administration is described. Results: The patient had been treated with neuroleptics for about 30 years, and NMS developed when carbamazepine (400 mg/day) was added. Conclusions: This case suggests that clinicians should consider the risk of NMS when carbamazepine is administered to patients undergoing long-term treatment with neuroleptics.

Molecular forms of somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with senile dementia of the Alzheimer type

In the cerebrospinal fluid (CSF) of 53 patients with senile dementia of the Alzheimer type (SDAT) and 12 elderly controls, we measured somatostatin (SLI) and its molecular forms: high-molecular weight form (HMV-SST), somatostatin-14 (SST-14), somatostatin-25/28 (SST-28/25), and des-ala-somatostatin (des-ala-SST) using high pressure liquid chromatography (HPLC) and a radioimmunoassay. In SDAT, SLI was significantly decreased (p < 0.05) and correlated with dementia scores (r = -0.65, p < 0.05). HPLC separation showed a marked heterogeneity of SLI in the CSF with a preponderance of SST-14 and SST-25/28. The significant loss of SST-14 (p < 0.05) in SDAT was found to be correlated with dementia scores (r = 0.65). Moreover, qualitative and quantitative changes in the molecular pattern of SLI in SDAT indicated dysregulated synthesis and/or processing of somatostatin relating to the severity of dementia. The long-term administration of neuroleptics in severe cases of SDAT caused a significant increase of SLI (p < 0.05) and influenced the ratio of HMV-SST/SST-14 and SST25/28/SST-14.

Tardive dyskinesia and ethnicity: review of the literature.

Tardive dyskinesia (TD) is a side effect of long-term neuroleptic administration. The wide variation of 2 to 51% in its reported prevalence can be attributed to the varied definitions of TD, the use of different methods of assessment, and the lack of control of independent variables. Why only certain patients develop this side effect is an intriguing question. The occurrence of TD in family members and in those persons with a family history of Parkinson's disease (PD) is suggestive of genetic vulnerability. Further support for a genetic predisposition comes from the fact that only certain strains of monkeys, such as the Cebus apella strain, have a higher propensity to develop TD than others, such as the Macaca sepciosa strain. If genetic factors play a significant role in the development of TD, then, genetically diverse ethnic groups may have a different propensity for the development of TD. One method of evaluating such a possibility is to compare its prevalence in different countries. The current literature on ethnic differences in the prevalence rates of TD is reviewed. This area of study needs further rigorous investigation.

Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements

Long-term administration of neuroleptics to rats produces a syndrome of vacuous chewing movements (VCMs). The validity of the VCM syndrome as a model for tardive dyskinesia (TD) in humans is unclear. This is due, in part, to inconsistencies between studies. Methods for rating VCMs have varied markedly and could account for the inconsistencies. The purpose of this study was to evaluate the importance of the different methods on VCM scores. The effects of habituation and length of rating sessions were examined in rats habituated for 2 min, 1 h, or several hours over 4 days, compared to unhabituated rats. Ratings with and without habituation were highly correlated, as were ratings from 2- and 5-min observation periods. Ratings from neuroleptic-treated rats in restraining tubes, however, were significantly correlated with unrestrained ratings only following several hours of habituation. Locomotor activity was not correlated with VCM scores. These results suggest that habituation to open cages is not an important factor in assessing VCMs. Use of restraining tubes, however, may alter scores. The lack of an habituation effect or of a relationship between activity and VCMs suggests that locomotor and oral behaviors are not necessarily in competition. Restraining rats to rate VCMs does not appear to be necessary and could alter the neurobiology of VCMs.