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Characteristics of D-1 dopamine receptors labelled by [3H]fluphenazine in homogenates of rat neostriatum.

The properties of the site labelled by [3H]fluphenazine in membranes prepared from the rat neostriatum were examined using radioligand binding methodology. Binding of [3H]fluphenazine was rapid, saturable and of high affinity (K4 = 0.4 nM). Drug displacement experiments demonstrated that the site labelled by [3H]fluphenazine possessed pharmacological characteristics consistent with those of a D-1 dopamine receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Combined electroconvulsive and neuroleptic therapy in schizophrenia refractory to neuroleptics.

The results of treatment in 13 schizophrenic patients (nine males, four females) who underwent electroconvulsive therapy (ECT) because of varying degrees of therapy resistance to neuroleptics (therapy failures, renewed and in some cases catatonic exacerbation under neuroleptic therapy, neuroleptic intolerance) are reported. The single treatments, which were carried out on average 12 times (between six and 20 times), led from very good to good remission in a period of between 10 and 7 years in nine patients. Four patients did not respond adequately: the small improvement of psychopathology on discharge correlated with unfavorable outcome. In three of these patients, the asthenic syndrome was found on admission and persisted. In patients with good remission, neuroleptics could be reduced after ECT by over 70%, and over 50% in patients with poor remission. This result confirms corresponding literature data with regard to neuroleptics. The results in this highly selected group also confirm Bleuler's 'one third rule' of remissions, also the fact that global outcome does not correlate with response to neuroleptics, as well as confirming the relevance of the psychopathological state on discharge as an outcome predictor.

Adolescent↗

Somatostatin in the cerebrospinal fluid of schizophrenic patients before and after neuroleptic drug treatment.

A radioimmunoassay procedure was used to determine levels of somatostatin-like immunoreactivity in cerebrospinal fluid obtained from 9 schizophrenic patients, 7 patients with other psychiatric disorders, and 10 nonpsychiatric surgical controls. There were no significant differences in mean somatostatin baseline levels between the schizophrenic, nonschizophrenic, and surgical patients. The concentration remained almost unaltered after 4 weeks of zuclopenthixol treatment in the schizophrenia group and following various neuroleptic, antidepressant, and anxiolytic medications in the nonschizophrenic patients despite a significant decrease of overt psychopathology assessed by the Brief Psychiatric Rating Scale.

Adult↗

Neuroleptic malignant syndrome (NMS): challenge with zuclopenthixol and follow-up--a case report.

In view of its receptor-binding profile, zuclopenthixol was used for NMS-challenge in the past 2 years. In 2 patients uneventful challenge took place. One patient showed recurrence of NMS. This occurrence may have been due to challenge shortly after the first episode had abated, and to use of a relatively high dose of zuclopenthixol. Differences in results of challenge showed no relationship with findings on follow-up: the patients who suffered recurrence had an uneventful recovery. One of the others showed a persisting organic amnestic syndrome, lasting now for more than 1.5 year, with EEG disturbances. The last patient rapidly developed tardive dyskinesia, despite the fact that he was treated with neuroleptics for a relatively short time. A hypothesis concerning these effects is presented.

Adult↗

Zuclopenthixol, a combined dopamine D1/D2 antagonist, versus haloperidol, a dopamine D2 antagonist, in tardive dyskinesia.

Animal data suggest that a D1 antagonistic component in neuroleptic drugs counteracts development of dopamine supersensitivity and of tolerance to cataleptic effect. This has led to the hypothesis that neuroleptics with D1 antagonistic activity should cause a better suppression of tardive dyskinesia (TD) and less rebound aggravation after withdrawal than pure D2 antagonists. In this study the effect of zuclopenthixol (mixed D1/D2 antagonist) and haloperidol (D2 antagonist) was evaluated in chronic psychotic patients with TD. Fifteen patients completed a randomized crossover study with blind evaluation of TD and parkinsonism. The test medications, haloperidol and zuclopenthixol, caused a significant suppression of TD and a significant increase of parkinsonism. No significant differences between haloperidol and zuclopenthixol were observed. No TD aggravation was seen. The lack of differences between the mixed D1/D2 antagonist and a D2 antagonist suggest that tolerance and DA supersensitivity play no or a minor role for development of TD.

Adult↗

Randomised clinical trial comparing oral versus depot formulations of zuclopenthixol in patients with schizophrenia and previous violence.

PURPOSE: The aim of this longitudinal study was to determine whether the depot formulation of an antipsychotic reduces violence in outpatients with schizophrenia as compared to oral administration of the same antipsychotic. METHODS: Forty-six previously violent patients with schizophrenia were randomised to receive treatment with oral or depot zuclopenthixol for 1 year. Clinicians interviewed patients at baseline and every month thereafter to assess treatment adherence. An interviewer blinded to treatment assignments interviewed an informant about any violent behaviour during the previous month. RESULTS: Violence during the follow-up year was inversely proportional to treatment adherence, better compliance, and greater reduction of positive symptoms. Lower frequency of violent acts was observed in the depot group. The level of insight at baseline was not significantly associated with violence recidivism. Regardless of route of administration, treatment non-adherence was the best predictor of violence. CONCLUSIONS: Some patients with schizophrenia and prior violent behaviour may benefit from the depot formulation of antipsychotic medication.

Administration, Oral↗

Effects of antipsychotics on prepulse inhibition of the startle response in drug-naïve schizophrenic patients.

BACKGROUND: Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. METHODS: First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. RESULTS: The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. CONCLUSIONS: The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.

Adult↗

The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol.

BACKGROUND: Most antidepressant and neuroleptic agents are metabolized by the polymorphic cytochrome P450 enzyme CYP2D6. This study evaluates the importance of the CYP2D6 genotype for the disposition of the neuroleptic agents perphenazine and zuclopenthixol. METHODS: Patients treated with neuroleptic agents (n = 36) were studied prospectively with regard to CYP2D6 genotype and neuroleptic plasma concentration during oral treatment. Because no patient provided enough samples for individual kinetic modeling, a bayesian approach was used for determination of the clearance. Population kinetic parameters for this procedure were collected from retrospective therapeutic drug monitoring data (n = 113) by use of a nonparametric approach. RESULTS: The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression). The difference in clearance between homozygous extensive metabolizers and poor metabolizers was threefold for perphenazine and twofold for zuclopenthixol. CONCLUSION: The results show that the genotype for CYP2D6 is closely related to the oral clearances of perphenazine and zuclopenthixol. If this finding can be confirmed in a larger population, genotyping may become an important tool for the dosing of these two neuroleptic agents.

Administration, Oral↗

Zuclopenthixol facilitates memory retrieval in rats: possible involvement of noradrenergic and serotonergic mechanisms.

Although disturbed memory function often coexists with psychosis, the cognitive effects of antipsychotic medications with diverse pharmacodynamic properties are rarely investigated. The neurocognitive profile of zuclopenthixol, a thioxanthene dopaminergic antagonist and a conventional neuroleptic agent, has yet to be investigated despite the effect of the drug on a variety of neurotransmitter systems involved in mediation of learning and memory processes. In this study, the effect of zuclopenthixol was tested on memory retrieval 24 h after training using an inhibitory avoidance task in rats. Acute administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) before retrieval testing increased step-through latency during the test session. The same doses of zuclopenthixol did not affect the ambulatory activity of rats in the openfield test and therefore the facilitatory effect of the drug on memory function could not be confounded with any motoric properties. This study also investigated the effect of zuclopenthixol on cortical and hippocampal monoaminergic neurotransmitters' levels together with acetylcholinesterase enzyme (AChE) activity, both of which are known to be important in control of cognitive function. Administration of zuclopenthixol (0.7 and 1.4 mg/kg i.p.) neither affected dopamine (DA) level nor AChE activity in rat cortex and hippocampus. On the other hand, the lower dose of zuclopenthixol elevated cortical norepinephrine (NE) level, while the higher dose elevated both cortical and hippocampal NE level together with hippocampal serotonin (5-HT) level. These results may suggest the involvement of adrenergic and serotonergic mechanisms in the facilitatory effect of zuclopenthixol on retrieval memory. Zuclopenthixol may therefore be a better alternative than other commonly used antipsychotic medications reported to impair cognitive function of schizophrenic patients.

Animals↗

Economic evaluation of zuclopenthixol acetate compared with injectable haloperidol in schizophrenic patients with acute psychosis.

Zuclopenthixol acetate is a rapid-acting, injectable neuroleptic drug with a duration of action that allows for administration once every 2 to 3 days, in contrast to injectable haloperidol, which may require administration more than once daily. To assess the place of zuclopenthixol acetate in the treatment of acute episodes of schizophrenia, a cost-consequence analysis was performed comparing this new medication with short-acting, injectable haloperidol. The perspective of the Quebec health care system was adopted. The study population comprised patients diagnosed with schizophrenia who experienced an acute episode of psychosis and who were treated with intramuscular (i.m.) haloperidol. The study assessed patients for 9 days after the start of treatment. The literature was the principal source of comparative data about the clinical outcomes of the two treatments. The total cost associated with zuclopenthixol acetate i.m. or haloperidol i.m. was modeled using a decision tree built around the number of i.m. injections required to achieve stabilization. To establish costs, expert panels were consulted and patients' files were reviewed for a sample of schizophrenic patients who had been hospitalized in a large psychiatric or general hospital subsequent to a visit to the emergency department and had received a short-acting i.m. neuroleptic drug. Only a direct medical records costs were considered. Because zuclopenthixol acetate was not on the market at the time of the study, the file review did not allow for a direct estimate of its related costs but did provide an account of haloperidol use. The literature shows that zuclopenthixol acetate is similar to haloperidol with respect to the control of psychotic episodes; however, zuclopenthixol acetate is associated with increased sedation and a lower incidence of extrapyramidal symptoms. Using the base-case estimate for the number of injections required for stabilization, the incremental cost of zuclopenthixol acetate 50 mg over haloperidol was $25.00 (1995 Canadian dollars) per patient at the psychiatric hospital and $21.00 per patient at the general hospital. The results were sensitive to the estimate of the number of injections and the number of minutes of nursing care required by agitated patients. Zuclopenthixol acetate resulted in cost savings over haloperidol if it permits a reduction of 25% in minutes of nursing care or if 85% of patients require 2 injections or less (45% requiring 1 injection and 40% requiring 2). However, whichever drug is used, the cost of the injectable neuroleptic represents a small fraction of the cost of care for acutely psychotic patients.

Antipsychotic Agents↗

[Chronic colonic pseudo-obstruction secondary to neuroleptics].

Colonic pseudo-obstruction is characterized by non-mechanical chronic colonic dilatation. It is an infrequent entity that can be provoked by multiple causes, among them pharmacological. We present the case of a 74-year-old female psychiatric patient who presented abdominal bloating, diarrhea, intense electrolytic alterations and marked radiographic colonic dilatation after treatment with a neuroleptic (zuclopenthixol decanoate). Organic obstruction and other causes were ruled out and the final diagnosis was chronic colonic pseudo-obstruction secondary to the use of neuroleptics. Cisapride (20 mg/8 h) produced a slight improvement in symptoms but colonic dilatation was permanent.

Aged↗

Local-global processing in early-onset schizophrenia: evidence for an impairment in shifting the spatial scale of attention.

In this study we report the results of two experiments on visual attention conducted with patients with early-onset schizophrenia. These experiments investigated the effect of irrelevant spatial-scale information upon the processing of relevant spatial-scale information, and the ability to shift the spatial scale of attention, across consecutive trials, between different levels of the hierarchical stimulus. Twelve patients with early-onset schizophrenia and matched controls performed local-global tasks under: (1) directed attention conditions with a consistency manipulation and (2) divided-attention conditions. In the directed-attention paradigm, the early-onset patients exhibited the normal patterns of global advantage and interference, and were not unduly affected by the consistency manipulation. Under divided-attention conditions, however, the early-onset patients exhibited a local-processing deficit. The source of this local processing deficit lay in the prolonged reaction time to local targets, when these had been preceded by a global target, but not when preceded by a local target. These findings suggest an impaired ability to shift the spatial scale of attention from a global to a local spatial scale in early-onset schizophrenia.

Adolescent↗

Treatment of acute mania with topiramate in hospitalized patients.

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of acute manic symptoms. Fourteen patients, admitted with an acute manic episode, were treated with topiramate. All required supplementation therapy with benzodiazepines. Nine patients received topiramate as monotherapy; four of them required zuclopenthixol acutard 100 mg/48 h intramuscularly (im) for not more than 6 days. In three treatment-resistant patients, topiramate was added to the existing therapy. Finally, in two patients topiramate was coadministered with an antipsychotic from the beginning. Patients were assessed every week for 4 weeks with the Bech and Rafaelsen Mania Scale (BRMS). Mean BRMS scores declined from 26.2 to 11.6 in the fourth week (P<.001); a significant decline (P<.001) was observed after the first week. Response rate (> or = 50% reduction of BRMS) was 61.5% (8 out of 13 patients). All patients tolerated topiramate well. Reduced appetite and weight loss was observed in four patients; however, two patients presented weight gain. These preliminary findings provide support for a modest efficacy of topiramate, especially as monotherapy, in the treatment of acute mania.

Acute Disease↗

HPLC-ESI-MS/MS determination of zuclopenthixol in a fatal intoxication during psychiatric therapy.

The first non-suicidal fatality due to intramuscular administration of Cisordinol (zuclopenthixol, ZPT) is described. A new, rapid, and sensitive method for the determination of ZPT in postmortem specimens has been developed. High performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was employed for drug confirmation and quantitation. Sample clean up was performed using a simple liquid-liquid extraction procedure. The postmortem concentration of ZPT in heart blood was 0.68 microg/ml. Furthermore, zotepine, carbamazepine, and chlorprotixene were detected in body fluids. The proposed method enables the unambiguous identification and quantitation of ZPT and other neuroleptic drugs in clinical and forensic specimens.

Adult↗

Voltammetric investigation of oxidation of zuclopenthixol and application to its determination in dosage forms and in drug dissolution studies.

The oxidative voltammetric behaviour of zuclopenthixol (ZPT) at a glassy carbon has been studied using cyclic, linear sweep and differential pulse voltammetry. Oxidation of the drug produced three pH dependent anodic steps (representing an irreversible oxidation). Using differential pulse voltammetry, the drug yielded a well-defined voltammetric response in phosphate buffer, pH 5.2 at + 0.82 V (vs. Ag/AgCl). This process could be used to determine ZPT concentrations in the range 8 x 10(-7)-2 x 10(-4) M. The method was applied, without any interferences from the excipients, to the determination of the drug in tablets and oral drops, and in drug dissolution studies.

Antipsychotic Agents↗