Treatment with the new antipsychotic sertindole for late-occurring undesirable movement effects

Conventional antipsychotics are often associated with late-occurring undesirable movement effects. To gain more experience with newer antipsychotic agents, 151 patients in an acute admissions department were switched from treatment with conventional antipsychotics to sertindole between late 1996 and early 1998. Four of these patients had tardive dyskinesia, tardive dystonia and/or tardive akathisia. The effect of changing to sertindole was measured using specific rating scales for undesirable movement effects. Three of the four patients apparently recovered from the movement disorders after switching to sertindole. In one patient, sertindole monotherapy was not sufficient to reduce the movement effects, but combination treatment with tetrabenazine resulted in a greater reduction in extrapyrimidal symptoms. Because these are case reports, no direct conclusions can be drawn. However, the beneficial effect of sertindole on severe, late-occurring movement disorders, as observed in four difficult-to-treat patients, appears to be promising.     

A clinical trial of nifedipine in schizophrenia and tardive dyskinesia.

Effects of the dihydropyridine calcium channel inhibitor nifedipine on chronic schizophrenia and tardive dyskinesia were studied in an 8-week double-blind crossover trial. Four of the ten patients had tardive dyskinesia, and three of these were not receiving neuroleptics. No effects on symptoms of chronic schizophrenia were found using Psychiatric Symptom Assessment Scale ratings. In the four patients with tardive dyskinesia, an average improvement in total Abnormal Involuntary Movement Scale scores of 57% was observed. These data suggest that dihydropyridine calcium channel inhibitors may be effective in the treatment of tardive dyskinesia in schizophrenic patients.     

Familial psychosis and vulnerability to tardive dyskinesia

The demography, course of illness, cognitive dysfunction and neurological consequences of long term treatment of 11 family pairs with long history of chronic schizophrenic illness were studied. There was concordance for the presence of tardive dyskinesia in 6 pairs; each of 2 brother-brother pairs; 3 brother-sister pairs and one of mother-daughter pair. There was concordance for the absence of tardive dyskinesia in 5 pairs, each of 3 father-son pairs and 2 brother-sister pairs. In schizophrenic patients the presence or absence of tardive dyskinesia in one member of the family is a risk factor for the development of the syndrome in another member with the same psychotic illness. Those pairs with tardive dyskinesia were characterized by negative symptoms of schizophrenia and evidence of intellectual deterioration.     

Combined treatment of tardive dyskinesia with clonidine and neuroleptics: A follow-up study of three cases for three years

Three cases of tardive dyskinesia with psychotic symptoms (one presenile psychosis; two schizophrenia) were successfully treated with both clonidine and neuroleptics for 3 years. The dyskinesia abolished or reduced by clonidine returned several months after discontinuation of clonidine. During the follow-up study, it was observed that combining neuroleptics with clonidine was superior to thioridazine, levomepromazine, or sulpiride for controlling the dyskinesia. These findings suggest that noradrenergic involvement is important in tardive dyskinesia and that other subtypes of dyskinesia might exist.     

Fluperlapine in tardive dyskinesia and parkinsonism

Fluperlapine, a new clozapine-like neuroleptic drug with weak affinity for dopamine receptors, was evaluated in a blind, placebo controlled trial in 11 patients with stable hyperkinesia (ten with tardive dyskinesia (TD) and one with spontaneous dyskinesia). Drug effects during active treatment (200–600 mg/day) and during pre- and post-treatment placebo periods were determined by scoring randomly sequenced videotapes of TD and parkinsonian symptoms recorded weekly during standardized examinations. TD score was unchanged, while parkinsonism slightly decreased (P<0.05) and eye-blinking rates increased (P<0.05). Psychiatric symptoms showed no significant changes, although positive psychotic symptoms diminished in four patients. Side effects included dizziness, sedation and constipation. The effects in movement disorders found in this study may imply that fluperlapine is less liable than traditional neuroleptics to induce acute extrapyramidal side effects and tardive dyskinesia and is particularly beneficial in the treatment of patients vulnerable to neurological side-effects.     

Serotonin precursor effects in tardive dyskinesia

In an attempt to determine the role of serotoninergic mechanisms in the pathophysiology of tardive dyskinesia, the serotonin precursor 5-hydroxytryptophan (5HTP) with carbidopa, a peripheral decarboxylase inhibitor, were given in a double-blind crossover design to seven patients with longstanding tardive dyskinesia. In the five patients who completed the study, there was no change in dyskinetic movements. Most of the patients had worsening of psychotic symptoms with 5HTP. The data suggest that serotonin precursors have no therapeutic effects in tardive dyskinesia. The implications for the role of serotonin in the pathophysiology of tardive dyskinesia are discussed.Supported by the Veterans Administration and the University of Iowa Clinical Research Center     

Tardive dyskinesia and impaired glucose tolerance

The authors examined the role of impaired glucose metabolism in the pathophysiology of tardive dyskinesia in schizophrenic patients with and without persistent TD. Glucose tolerance and insulin levels were determined in 86 patients with persistent tardive dyskinesia and in 108 patients without tardive dyskinesia. Dyskinesias were assessed by the abnormal involuntary movement scale (AIMS) and extrapyramidal symptoms by the Simpson--Angus rating scale (SARS). Fasting blood glucose levels were significantly lower while the first and second hour glucose levels did not reveal any differences in patients with tardive dyskinesia compared with those without tardive dyskinesia. Insulin levels did not differ in these two groups. Our cross-sectional epidemiological study does not suggest hyperglycemia to be a risk factor for tardive dyskinesia. However, prospective long-term studies with multiple assessment points are needed to clarify the role of glucose metabolism in the development of tardive dyskinesia.     

Tardive dyskinesia after short-term treatment with oral metoclopramide in an adolescent

Case The objective of this case report is to report the development of tardive dyskinesia in an African-American adolescent male after short-term treatment with metoclopramide 10?mg orally three times daily secondary to delayed gastric emptying. The patient developed symptoms of tardive dyskinesia after 2?days of therapy with metoclopramide. Metoclopramide was discontinued and diphenhydramine 50?mg was initially administered intravenously followed with 25?mg orally every 4?hours as needed. While there are case reports of drug-induced tardive dyskinesia after intravenous administration of metoclopramide, this is to our knowledge the first report of tardive dyskinesia after short-term treatment with oral metoclopramide in an adolescent. Conclusion Awareness of the risk of development of this adverse effect even with short-term treatment with metoclopramide and in younger patients is important.     

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.     

Alprazolam reversal of reserpine-induced depression in patients with compensated tardive dyskinesia

Two patients are described who developed neuroleptic drug-induced tardive dyskinesia (TD) secondary to the treatment of schizophrenia. In both patients, neuroleptic drug discontinuation brought about a decrease in the severity of the TD and an increase in schizophrenic symptomatology. Reserpine was added for both antipsychotic coverage and reported beneficial effects in the treatment of TD. The patients' schizophrenia was controlled using reserpine 1 mg/d; the TD dissipated in one patient and decreased in the other. After about seven weeks of reserpine therapy, both patients developed depressive symptoms that required the addition or alprazolam. Within a month of the initiation of alprazolam, the depressions had cleared. Alprazolam may block reserpine-induced increases in beta-adrenergic receptors in the brain and may account for the antidepressive effects in these two patients.     

利培酮致迟发性运动障碍不良反应特点分析

目的：分析利培酮导致迟发性运动障碍不良反应的临床用药特点。方法：回顾性分析2004-2015年我院上报的10例利培酮致迟发性运动障碍的药物不良反应,分析患者的性别、年龄、体质量、原患疾病、药物剂型及剂量和发生迟发性运动障碍的潜伏期及临床表现、治疗措施及转归,探讨利培酮导致迟发性运动障碍的特点。结果：10例患者中,男女性各有5例。用药至发生迟发性运动障碍的潜伏期为13~3 505 d,其中用药后1年内发生者6例（占60.0%）。10例患者中,有5例次患者出现颈部异常表现,4例次患者出现肢体扭转,肢体姿势异常或步态异常等症状,6例次患者出现口唇舌部异常动作。10例患者中,出现不良反应后均采取减量、停用利培酮换用其他抗精神病药、密切观察或对症治疗。5例患者好转,4例虽经减量停药或对症处理,仍有后遗症。结论：利培酮所致的迟发性运动障碍临床表现以口唇舌部异常动作,颈部及肢体异常表现为主,其症状多较为严重,可能产生后遗症。另外,小剂量、短期服用利培酮也可能导致迟发性运动障碍,临床用药需谨慎。     

Amoxapine-induced tardive dyskinesia

A case report of amoxapine-induced tardive dyskinesia following discontinuation of amoxapine therapy is reported. During 68 weeks of therapy, the patient received a maximum of amoxapine 400 mg/d. Six months after amoxapine discontinuation, the patient continued to have symptoms of tardive dyskinesia. These symptoms correlate with the dopamine receptor-blocking property of amoxapine and its metabolites. We propose that amoxapine therapy be monitored for the long-term as well as the short-term adverse effects of dopamine receptor-blockade.     

A monitoring test for the liability of neuroleptic drugs to induce tardive dyskinesia

Two Cebus apella monkeys with haloperidol-induced tardive dyskinesia have been studied. Substitution of chlorpromazine, thioridazine, clozapine, melperone, or fluphenazine for the daily haloperidol administration temporarily reduced the signs of tardive dyskinesia. In a monkey with low-grade symptoms, persisting for more than 100 days after with-drawal of haloperidol, neuroleptic drugs induced a typical sequence of events: first the dyskinetic movements were abolished, but 1–3 days after administration of a single dose of a neuroleptic drug there was a rebound worsening of symptoms. It was noticed that this aggravation of symptoms corresponded in magnitude and duration to the approximate liability of each compound to induce tardive dyskinesia in man. It is therefore suggested that this animal model could be used to monitor neurological side effects in neuroleptic drugs.     

A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines

Phenothiazine administration to psychiatric patients is associated with an increase in the structural order of platelet membranes as determined by steady-state fluorescence polarization measurements with 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes (Zubenko and Cohen 1984, 1985a, b). In this study, platelet membranes prepared from a group of psychiatric patients who developed tardive dyskinesia following chronic treatment with phenothiazines exhibited a significant elevation in DPH fluorescence polarization when compared to similar preparations from an otherwise matched group of patients who had no symptoms or history of tardive dyskinesia. The distribution of polarization values obtained for the tardive dyskinesia group displayed minimal overlap with that of an unmedicated, psychiatrically-healthy control group matched for age and gender. The fluorescence polarization of DPH-labelled platelet membranes was not significantly correlated with phenothiazine daily dose or serum cholesterol concentration in the phenothiazine-treated patient groups, or with dyskinesia severity (AIMS rating) in the tardive dyskinesia group. Patient gender and the presence of an affective disorder did not significantly correlate with DPH fluorescence polarization. The potential physiological and clinical significance of these findings is discussed.     

Valbenazine granted breakthrough drug status for treating tardive dyskinesia

The chronic use and high dosing of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics predispose patients to the onset of tardive syndromes. One particular subtype, tardive dyskinesia, is characterized by rapid, repetitive, stereotypic, involuntary movements of the face, limbs or trunk. The inhibition of the vesicular monoamine transporter system, using tetrabenazine therapy, improves the severity of tardive dyskinesia. But there are also drawbacks to tetrabenazine treatment, such as a fluctuating response and the need for frequent intake due to its rapid metabolism. Clinical research on the potentially more efficacious and easier to use tetrabenazine analogs is already under way. One of them is valbenazine, the purified parent drug of the (+)-α-isomer of tetrabenazine. The FDA lowered approval hurdles for valbenazine due to a successful Phase II trial, which showed a distinctive improvement in tardive dyskinesia symptoms during valbenazine administration. This resurgence in the clinical research of tardive syndrome therapy is most welcome. This author notes that the putative long-term side effects of valbenazine should carefully be investigated in the future via naturalistic observational trials. Furthermore, valbenazine may also support the onset of symptoms, such as Parkinsonism and depression, with chronic administration, as it, to a certain extent, shares the mode of action of tetrabenazine.     

Is diltiazem effective in treating the symptoms of (tardive) dyskinesia in chronic psychiatric inpatients? A negative, double-blind, placebo-controlled trial.

Calcium channel blockers, antiarrhythmic drugs, such as verapamil and diltiazem, may decrease the symptoms of tardive dyskinesia. The efficacy and safety of administering 60 mg diltiazem hydrochloride, four times daily for a period of 3 weeks, was studied in a random, double-blind, crossover trial in which the drug was compared with placebo in 17 neuroleptic-treated, chronic psychiatric inpatients of both genders with (tardive) dyskinesia. The severity of the dyskinesia was assessed using the Abnormal Involuntary Movement Scale. Neither diltiazem nor placebo produced a significant decrease in the severity of the dyskinesia. Diltiazem did not influence the psychiatric state of the patients, nor did it have a significant effect on either the blood pressure or electrocardiographic parameters. No significant adverse drug reactions were elicited.     

Tardive dyskinesias and drugs

Although considerable controversy remains as to the etiology and pathophysiology of tardive dyskinesia, epidemiologic evidence is compelling in supporting the role of neuroleptics as a major factor in the development of this syndrome. Current evidence suggests that tardive dyskinesia is a heterogeneous condition in terms of nature of onset, phenomenology, course, and response to specific treatments or pharmacologic probes. The point prevalence of tardive dyskinesia varies widely depending on the nature of the patient population and the criterion utilized to identify a “case.” The incidence of tardive dyskine-sia among relatively young patients of varying diagnoses exposed to neuroleptics appears to be approximately 3–4% per year of cumulative neuroleptic exposure, at least for the first 6 years of such treatment. Age, vulnerability to acute extrapyramidal side effects, and a diagnosis of affective illness appear to be associated with increased risk of tardive dyskinesia development. There is clearly a need to take this aspect into consideration for new drug developments.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Extrapyramidal symptoms with atypical antipsychotics : incidence, prevention and management.

The treatment of schizophrenia changed drastically with the discovery of antipsychotic medications in the 1950s, the release of clozapine in the US in 1989 and the subsequent development of the atypical or novel antipsychotics. These newer medications differ from their conventional counterparts, primarily based on their reduced risk of extrapyramidal symptoms (EPS). EPS can be categorised as acute (dystonia, akathisia and parkinsonism) and tardive (tardive dyskinesia and tardive dystonia) syndromes. They are thought to have a significant impact on subjective tolerability and adherence with antipsychotic therapy in addition to impacting function. Unlike conventional antipsychotic medications, atypical antipsychotics have a significantly diminished risk of inducing acute EPS at recommended dose ranges. These drugs may also have a reduced risk of causing tardive dyskinesia and in some cases may have the ability to suppress pre-existing tardive dyskinesia. This paper reviews the available evidence regarding the incidence of acute EPS and tardive syndromes with atypical antipsychotic therapy. Estimates of incidence are subject to several confounds, including differing methods for detection and diagnosis of EPS, pretreatment effects and issues surrounding the administration of antipsychotic medications. The treatment of acute EPS and tardive dyskinesia now includes atypical antipsychotic therapy itself, although other adjunctive strategies such as antioxidants have also shown promise in preliminary trials. The use of atypical antipsychotics as first line therapy for the treatment of schizophrenia is based largely on their reduced risk of EPS compared with conventional antipsychotics. Nevertheless, EPS with these drugs can occur, particularly when prescribed at high doses. The EPS advantages offered by the atypical antipsychotics must be balanced against other important adverse effects, such as weight gain and diabetes mellitus, now known to be associated with these drugs.     

Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias.Part of this work was presented at the 9th C.I.N.P. Congress, Paris, July 7–12, 1974.