Zotepine versus other atypical antipsychotics for schizophrenia.

BACKGROUND: In many parts of the world, particularly in industrialised countries, second generation (atypical) antipsychotic drugs have become first line treatment for people suffering from schizophrenia. The question as to whether the effects of various second generation antipsychotic drugs differ is a matter of debate. OBJECTIVES: To evaluate the effects of zotepine compared with other second generation antipsychotic drugs for people suffering from schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (November 2009), inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We included only randomised clinical controlled trials that compared zotepine with any forms of amisulpride, aripiprazole, clozapine, olanzapine, risperidone, sertindole or ziprasidone in people suffering from only schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: SS and KK extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. For continuous data, we calculated weighted mean differences (MD) again based on a random-effects model. MAIN RESULTS: We included three studies (total n=289; 2 RCTs zotepine vs clozapine; 1 RCT zotepine vs clozapine vs risperidone (at 4 mg, 8 mg doses) vs remoxipride. All studies were of limited methodological quality. When zotepine was compared with clozapine, it was clozapine that was found to be more effective in terms of global state (n=59, 1 RCT, RR No clinically significant response 8.23 CI 1.14 to 59.17). Mental state scores also favoured clozapine (n=59, 1 RCT, MD average score (BPRS total, high = poor) 6.00 CI 2.17 to 9.83) and there was less use of antiparkinson medication in the clozapine group (n=116, 2 RCTs, RR 20.96 CI 2.89 to 151.90). In the comparison of zotepine and risperidone, mental state scoring found no significant difference between the groups (vs 4 mg: n=40, 1 RCT, MD average endpoint score (BPRS total, high=poor) 1.40 CI -9.82 to 12.62; vs 8 mg: n=40, 1 RCT, MD -1.30 CI -12.95 to 10.35) and use of antiparkinson medication was equivocal (vs 4 mg: n=40, 1 RCT, MD 1.80 CI -0.64 to 4.24; vs 8 mg: n=40, 1 RCT, MD 2.50 CI -0.05 to 5.05). Finally, when zotepine was compared with remoxipride, again no effect was found for mental state (n=58, 1 RCT, MD average endpoint score (BPRS total, high=poor) 5.70 CI -4.13 to 15.53) and there was no significant difference between the two groups in terms of use of antiparkinson medication (n=49, 1 RCT, RR 0.97 CI 0.41 to 2.29).Data on important other outcomes such as other adverse events, service use or satisfaction with care, quality of life were not available. AUTHORS' CONCLUSIONS: The evidence base around zotepine is insufficient to provide firm conclusions on its absolute or relative effects. This is despite it being in use in Austria, France, Germany, Japan and the UK.

Use of atypical neuroleptics in child and adolescent psychiatry.

BACKGROUND: This article reviews the published clinical experience with atypical neuroleptics in children and adolescents. METHOD: A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug. RESULTS: We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder. CONCLUSION: The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.

Comparing the efficacy of atypical antipsychotics in open uncontrolled versus double-blind controlled trials in schizophrenia.

OBJECTIVE: Due to methodological reservations, open clinical trials investigating efficacy and tolerability of antipsychotic agents are often regarded with doubt. However, there are nearly no studies comparing findings of controlled double-blind with those of open trials. The aim of this study was to investigate whether results of open and double-blind approaches differ and thereby gain information about the validity of open trials. METHODS: After literature research, three atypical antipsychotic agents were identified for which at least three open and double-blind trials existed that met the inclusion criteria and from which either the reduction of the Brief Psychiatric Rating Scale (BPRS)- or Positive and Negative Symptom Scale (PANSS) scores or the response rate could be determined. RESULTS: There were no differences in the reduction of the BPRS- or PANSS scores or in the response rates for all three antipsychotic agents between open and double-blind trials. CONCLUSIONS: Although double-blind controlled studies are essential in the investigation of new compounds, results of methodologically well-performed open studies are valid and deserve more attention. Preceding open trials may help in the design of double-blind studies.

Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride--an 123I-IBZM single photon emission tomography (SPET) study.

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D2 receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have used 123I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D2 receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone (n = 6) or remoxipride (n = 4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D2 receptor binding database of patients treated with clozapine (n = 10) and classical antipsychotics (n = 10). Patients on risperidone and remoxipride had high levels of D2 receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine, P < 0.005; remoxipride versus clozapine, P < 0.025). These results suggest high levels of striatal D2 receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D2 antagonism as the explanation for the low incidence of EPS associated with these drugs.

Tolerability of remoxipride in the long term treatment of schizophrenia. An overview.

506 patients with schizophrenia, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria, were included in a long term treatment programme with remoxipride, a selective dopamine (D2)-receptor antagonist. This overview includes pooled data from all patients who have been treated long term with remoxipride in clinical trials, focusing on patients treated for more than 6 months (n = 283). Remoxipride was administered in daily doses of 75 to 600mg. The assessment tools were Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Simpson and Angus scale, Abnormal Involuntary Movements Scale (AIMS) for abnormal involuntary movements, adverse events/symptoms using a 26-item checklist, clinical chemistry, and haematology and cardiovascular investigations. The majority of patients had a long duration of illness (median 11 years). 67% of patients (340/506) withdrew from treatment before 12 months and 44% (223/506) stopped treatment before 6 months. The median BPRS total score decreased during the first 3 months from 23 to 12, and this level of improvement was maintained throughout the 12-month period. Treatment-emergent adverse events reported by more than 5% of the patients were insomnia, tiredness, drowsiness and tremor in the group treated for 6 to 12 months. No symptoms, including checklist extrapyramidal symptoms (EPS), were reported by more than 5% of patients treated for 12 months. Low frequencies of EPS according to the Simpson and Angus scale were seen in patients treated for more than 6 months (n = 147). A small but statistically significant reduction of the mean total AIMS score from baseline to last rating was observed. There were infrequent changes in heart rate, resting diastolic blood pressure and electrocardiogram (ECG). Clinical chemistry and haematology data showed no evidence of clinically significant changes over time during the 12 months of treatment. Among 506 patients, 7 suicides and 7 suicide attempts occurred during the study period. Other serious adverse events were abnormal liver function test (2 cases), gastrointestinal, urinary retention, status epilepticus (psychotic polydipsia), granulocytopenia (1 each) and myocardial infarction (5 cases). Remoxipride is of potential value as a drug which is both effective and well tolerated in the long term management of patients with schizophrenia.

Remoxipride in the treatment of psychoses.

In Sweden the atypical neuroleptic drug remoxipride has now been used in routine treatment of psychoses for almost two years. Over 7,000 patients have been treated. During that time both advantages and problems, foreseen and unforeseen, have been encountered. This paper is based on clinical experiences and the discussion is illustrated by five short case-histories. The most important points of the discussion are: As expected, remoxipride seems to produce less extrapyramidal side-effects than traditional neuroleptics. Patients experience less, if any, impairment in cognitive functioning than with traditional neuroleptics. Patients experience less inhibition of feelings and emotions than with traditional neuroleptics, which most often is of great positive value but may also create problems when feelings and emotions get overwhelming and difficult to handle. It is very important that patients get adequate psychological support and attention from the psychiatric team when changing from a traditional neuroleptic drug to remoxipride.

Neuroleptic malignant syndrome during remoxipride treatment. A case report.

Neuroleptic malignant syndrome (NMS) is a rare, life-threatening complication of neuroleptic treatment. The authors describe a case of NMS during treatment with a new atypical neuroleptic, remoxipride. To their knowledge, there are no previously reported cases.

Remoxipride in Parkinson's disease: differential response in patients with dyskinesias fluctuations versus psychosis.

Remoxipride is a novel substituted benzamide that more effectively blocks mesolimbic than striatal D2 dopamine receptors. We used remoxipride in the management of nine patients with Parkinson's disease (PD) who were experiencing visual hallucinations due to dopaminergic therapy. Remoxipride was begun in a dose of 25 mg three times daily and gradually increased to 75-225 mg/d (mean 161 mg). The psychiatric status improved in eight patients. Little or no change in the severity of parkinsonism was noted in five, a mild increase in two, and a moderate increase in two. Because one patient with moderately severe levodopa-induced dyskinesias experienced a reduction in the abnormal movements without a substantial increase in parkinsonism, we began a trial of remoxipride for disabling peak-dose dyskinesias. The trial was abandoned after every one of the first four patients entered experienced an immediate, severe, and prolonged increase in off periods with single 10- to 25-mg doses. This striking differential response to an atypical neuroleptic with weak striatal D2 antagonist properties indicates that different states of postsynaptic dopamine receptor sensitivity or synaptic dopamine levels may be associated with various disease- and treatment-related problems found in late-stage PD.

The treatment of negative symptoms: a clinical and methodological study.

The primary objective of this study was to evaluate the efficacy, safety and tolerability of remoxipride (controlled release) versus haloperidol in patients with negative symptoms. The study comprised a multicentre, randomised, double-blind, parallel-group clinical trial. Two hundred and five patients were randomised to either remoxipride or haloperidol. Patients eligible for this study were aged 18-65 years, met the DSM-III-R diagnosis for chronic schizophrenia and the Positive and Negative Symptoms Scale (PANSS) criteria for predominant negative symptoms. There was a statistically significant reduction in the PANSS scores of at least 20% from baseline to last rating for 39 remoxipride (49.4%) and 45 haloperidol (47.6%) treated patients. There were no statistical differences found between the two treatment groups with respect to improvement of negative symptoms and adverse events. The PANSS data suggest that both remoxipride and haloperidol improve the cluster of negative symptoms concerned with social functioning. In addition, the design of the study provides a methodology that is appropriate to the study of primary negative symptoms in schizophrenia.

Separate measures of ethanol seeking and drinking in the rat: effects of remoxipride.

Remoxipride, a dopamine D(2) antagonist, decreases responding that results in the presentation of small amounts (approximately 0.1 ml) of ethanol in limited-access paradigms. This type of operant response is a combined appetitive/consummatory response that is differentially affected by changing stimulus properties of consumed ethanol (i.e., taste, pharmacology) over the course of the session. In the present experimental design, ethanol-directed appetitive and consummatory responses were procedurally separated to investigate the specific effects of remoxipride on these distinct behaviors. Male Long-Evans rats were trained to make a series of lever-press responses once each day that resulted in access to a sipper tube spout containing 10% ethanol for 20 min. Three doses of remoxipride were tested: 5.0, 10.0, and 15.0 mg/kg (-30 min, i.p.). In Experiment 1, a response requirement of 20 was used, and both reinforced and nonreinforced sessions were examined. In nonreinforced sessions, subjects were permitted to lever press for 20 min, after which the session ended without sipper tube presentation. These sessions were conducted to remove the possibility that limiting responding might obscure a drug effect on the seeking response. In Experiment 2, a low response requirement (4) was used to investigate the effects of remoxipride on ethanol intake. Average baseline ethanol intake (Experiment 1) was 0.69 g/kg, with blood ethanol concentrations at the end of the session at 64 mg%. At all doses tested, remoxipride had no effect on the measures of ethanol consumption (e.g., total intake, lick latency, lick rate) in either experiment. However, remoxipride dose dependently decreased the number of appetitive responses made, while having no effect on response latency or rate, during both reinforced and nonreinforced sessions in Experiment 1. In these experiments, the systemic antagonism of the dopamine D(2) receptor decreased ethanol seeking without causing a general impairment of motor function. The procedural separation of seeking and intake responses revealed that appetitive responding was more sensitive than consummatory responding to remoxipride treatment.

[Involvement of sigma receptors in schizophrenic syndromes. Pathophysiological approach]. / Implication des récepteurs sigma dans les syndromes schizophréniques. Approche physiopathologique.

Sigma ligands have been identified as psychotomimetic agents unrelated to opioids. A number of neuroleptics possess moderate to high affinity for sigma binding sites, raising the possibility that sigma receptors mediate some of the antipsychotic effects of neuroleptics. In addition, sigma binding sites have been reported to be reduced in the temporal cortex and in the hippocampus of schizophrenic patients. This hypothesis is further supported by the use of the sigma ligands rimcazole, BMY-14802 and remoxipride as effective antipsychotic agents. The present report, reviewing briefly the physiological effects of sigma ligands, suggests that their antipsychotic properties are related to modulation of NMDA receptors. Thus, the use of sigma ligands may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment.

[Determination of remoxipride in cadaver blood using high pressure liquid chromatography]. / Bestimmung von Remoxiprid in Leichenblut mittels Hochdruckflüssigkeitschromatographie.

The suitability of high pressure liquid chromatography (HPLC) for determining remoxipride levels in cadaver blood was tested in a case of possible remoxipride intoxication. Level in our case was found to be lower than in cases of remoxipride poisoning described in the literature. The procedure developed for using HPLC to measure remoxipride levels in cadaver blood is described in detail. Using this method a distinction could be made between remoxipride and sulpiride.

[New psychopharmacologic alternatives in treatment of schizophrenia]. / Nouvelles alternatives psychopharmacologiques au traitement de la schizophrénie.

Clozapine, risperidone and remoxipride are three neuroleptics that represent an interesting alternative in the psychopharmacological treatment of schizophrenia. Pharmacodynamic and pharmacokinetic properties, efficacy, dosages as well as the indication of these three substances are studied. In certain particular situations, a complementary treatment is of important therapeutic use, the addition of benzodiazepines, lithium, carbamazepine or beta-blockers are discussed.

A long-term study of remoxipride in chronic schizophrenic patients.

The purpose of this study was to assess the tolerability and efficacy of 150-600 mg remoxipride (predominantly a DA2 receptor antagonist) in an open long-term (1 year) multicentre trial in chronic schizophrenic patients. The mean duration of illness before entering the study was 21 years and the pre-study neuroleptic dosage in chlorpromazine equivalents was 930 mg/day. The clinical efficacy was measured with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. The adverse events were recorded by a 26-item Adverse Symptom Checklist and by the Abnormal Involuntary Movements Scale. Forty-five patients were included in the study. The mean daily dose of remoxipride during the last week of treatment was 378 mg. Eighty percent (36 patients) withdrew prematurely (< 1 year). The main reasons for withdrawal were: ineffectiveness (n = 15), treatment refusal (n = 12) and adverse events (n = 8). The most frequently reported adverse events were insomnia (n = 20) and tiredness (n = 7), whereas only a few (n = 6) extrapyramidal symptoms were reported. There was no relationship between remoxipride plasma concentration and clinical efficacy nor was any relationship found between the ratio of pretrial chlorpromazine equivalent to last remoxipride dose and the therapeutic effect. Remoxipride alone seemed to have an insufficient neuroleptic efficacy in these chronic and treatment-resistant schizophrenic patients but was well tolerated.

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile.

The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(-) and FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.

High sensitivity determination of the remoxipride hydroquinone metabolite NCQ-344 in plasma by coupled column reversed-phase liquid chromatography and electrochemical detection.

An HPLC method for the determination of NCQ-344, a remoxipride metabolite with a hydroquinone structure, in human plasma is described. Special precautions for the sampling were necessary as the compound rapidly decomposes. An efficient clean-up of the plasma samples was necessary to make use of the inherent sensitivity of the electrochemical detector. This was accomplished by a fast and simple liquid-liquid extraction at pH 7.05 combined with further cleaning on-line by using a short cyanopropyl column as the first column in a column switching system. A heart-cut from the cyanopropyl column containing the NCQ-344 fraction was then injected onto the analytical octadecyl silica column and NCQ-344 was detected at an oxidation potential of 0.70 V. The absolute recovery was > 95% and concentrations down to 0.10 nM could be determined with acceptable precision. The NCQ-344 levels in a limited number of samples from patients given remoxipride were found to be between 0.10 and 1 nM. The remoxipride concentrations in the same samples were 5,000-20,000 nM.

Overcoming the neuroleptic-induced deficit syndrome: clinical observations with remoxipride.

Remoxipride is a selective dopamine D2 antagonist with virtually no activity on other transmitter receptors. It antagonizes dopamine agonists within a wide dose range in animals when it does not cause sedation or akinesia. Clinical studies with remoxipride have demonstrated antipsychotic efficacy apparently equal to classical neuroleptics in short- and long-term treatment of schizophrenia. Remoxipride has a low extrapyramidal syndrome (EPS) profile, and it is generally well tolerated. In clinical practice remoxipride has been reported to differ from classical neuroleptics with regard to subjective side effects. On switching to remoxipride, patients report improvement in cognitive, conative, affective and emotional functions. In many cases the reports are supported by family members and/or caregivers. Although anecdotal, such reports are in line with the low EPS profile of remoxipride and its weak sedative properties. It may indicate that remoxipride does not elicit the neuroleptic-induced deficit syndrome, commonly experienced with classical neuroleptics, or that remoxipride improves the deficit syndrome (or primary negative symptoms) of schizophrenia. These and other hypotheses need to be confirmed by formal clinical studies.

Remoxipride in the treatment of levodopa-induced psychosis.

Levodopa-induced psychotic symptoms frequently complicate the management of patients with Parkinson's disease (PD). We examined the efficacy and tolerability of a novel antipsychotic, remoxipride, in this population. This was a 7-week, open-label pilot evaluation of patients with moderate to severe PD and levodopa-induced psychotic symptoms of at least 2 months' duration. The patients were recruited at the Movement Disorders Clinic, The Toronto Hospital, a tertiary referral center. After 1 week of baseline observation, the patients received remoxipride, 25 mg, three times a day orally, with the dose increasing by 25 to 50 mg each week as tolerated. The outcome measures included the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impressions (CGI) scale, and the United Parkinson's Disease Rating Scale. Adverse symptoms were elicited by an open-ended questionnaire and a symptom checklist. Six men and three women aged 69.3 +/- 9 years received remoxipride 147 +/- 57 mg/day. Total BPRS score decreased modestly in eight of nine subjects, and there was a statistically significant improvement of mental status as indicated by the CGI scale score, which decreased from 3.8 +/- 0.4 at baseline to 2.4 +/- 1.3 at last rating (p < 0.05; Wilcoxon signed rank test). The motor performance deteriorated somewhat in two subjects, whereas the rest showed no appreciable change. The most common adverse effects included tremor, rigidity, akathisia, and hypersalivation. Remoxipride treatment reduced psychotic symptoms in eight of nine subjects while having no appreciable effect on the parkinsonian status of seven of nine subjects.