Analgesia and pain: Dual effect of dopamine on the peripheral nociceptive system is dependent on D2-or D1-like receptor activation.

In this study, a pharmacological approach, together with the paw pressure test, was used to investigate the role of dopamine and its receptors in the peripheral processing of the nociceptive response in mice. Initially, the administration of dopamine (5, 20, and 80 ng/paw) in the hind paw of male Swiss mice (30-40 g) promoted antinociceptive effects in a dose-dependent manner. This was considered a peripheral effect, as it did not produce changes in the nociceptive threshold of the contralateral paw. The D2, D3, and D4 dopamine receptor antagonists remoxipride (4 µg/paw), U99194 (16 µg/paw), and L-745,870 (16 µg/paw), respectively, reversed the dopamine-mediated antinociception in mice with PGE2-induced hyperalgesia. The D1 and D5 dopamine receptor antagonists SKF 83566 (2 µg/paw) and SCH 23390 (1.6 µg/paw), respectively, did not alter dopamine antinociception. In contrast, dopamine at higher doses (0.1, 1, and 10 µg/paw) caused hyperalgesia in the animals, and the D1 and D5 receptor antagonists reversed this pronociceptive effect (10 µg/paw), whereas the D2 receptor antagonist remoxipride did not. Our data suggest that dopamine has a dual effect that depends on the dose, as it causes peripheral antinociceptive effects at small doses via the activation of D2-like receptors and nociceptive effects at higher doses via the activation of D1-like receptors.

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.

Differences among conventional, atypical and novel putative D(2)/5-HT(1A) antipsychotics on catalepsy-associated behaviour in cynomolgus monkeys.

Typical antipsychotics such as haloperidol exert their therapeutic effects via blockade of dopamine (DA) D(2) receptors, leading to extrapyramidal symptoms (EPS) in humans and catalepsy in rodents. In contrast, atypical antipsychotics and new generation D(2)/5-HT(1A) antipsychotics have low cataleptogenic potential. However, there has been no systematic comparative study on the effects of these different classes of antipsychotics in non-human primates, a species displaying a more sophisticated repertoire of behavioural/motor activity than rats. Once weekly, six young adult female non-haloperidol-sensitised cynomolgus monkeys were treated i.m. with a test compound and videotaped to score catalepsy-associated behaviour (CAB: static postures, unusual positions and crouching). Haloperidol, risperidone, olanzapine, nemonapride and remoxipride induced, to different extents, an increase in unusual positions (a response akin to dystonia), some crouching and static postures. In contrast, clozapine, quetiapine, ziprasidone and aripiprazole produced much lower or no unusual positions; clozapine also produced marked increases in static postures and crouching. Among novel D(2)/5-HT(1A) antipsychotics, SLV313 and F15063 augmented the number of unusual positions, albeit at doses 16-63 times higher than those of haloperidol for approximately the same score. SSR181507 and bifeprunox produced moderate static postures, little crouching and negligible unusual positions. These data provide the first comparative analysis in cynomolgus monkeys of EPS liability of conventional, atypical and novel D(2)/5-HT(1A) antipsychotics. They indicate that the latter are less prone than haloperidol to produce CAB, and provide a basis for comparison with rodent catalepsy studies.

Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils.

Remoxipride is an atypical antipsychotic displaying selective binding to the dopamine D2 receptor. Several cases of aplastic anemia led to the withdrawal of remoxipride from the market in December 1993. The remoxipride metabolite NCQ-344 is a hydroquinone while the structural isomer NCQ-436 is a catechol, both of which have been suggested to be capable of forming a reactive para- and ortho-quinone, respectively. Recently, these two remoxipride metabolites were shown to induce apoptosis in human bone marrow progenitor cells. Furthermore, NCQ-344 also caused necrosis of these cells unlike NCQ-436. Although NCQ-344 has been detected in plasma of humans dosed with remoxipride, to date, no experimental evidence for the formation of the corresponding para-quinone has been obtained. Here, we report the detection of three glutathione (GSH) conjugates of NCQ-344 in vitro that were formed following a chemical reaction and characterized by tandem mass spectrometry and for a cyclized conjugate additionally with derivatization and deuterium exchange. In contrast, NCQ-436 did not form a GSH conjugate. Hypochlorous acid oxidized NCQ-344 to the para-quinone while NCQ-436 was resistant to oxidation. Upon incubation with NCQ-344, stimulated human neutrophils produced from 2- to 5-fold greater amounts of glutathione conjugates than unstimulated neutrophils. Ab initio calculations on these remoxipride metabolites indicated that the reaction leading to the respective quinone was spontaneous for the para-quinone (e.g., from NCQ-344) while ortho-quinone (e.g., from NCQ-436) formation was not. These results demonstrate that NCQ-344 is capable of facile formation of a reactive para-quinone capable of reacting with GSH and may rationalize previous findings regarding the biological effects observed in vitro with these two remoxipride metabolites.

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.

Quality of life and response of negative symptoms in schizophrenia to haloperidol and the atypical antipsychotic remoxipride. The Canadian Remoxipride Group.

In a large, multicenter, double-blind study of the effect of haloperidol and the atypical antipsychotic remoxipride on improvement of negative symptoms in schizophrenia, quality of life was also assessed using a modified version of the Sickness Impact Profile (SIP). Compared with previous studies, this study had a longer duration (28 weeks), and the dose of the comparator, haloperidol, was much lower. At the end of the study, compared with the baseline, both treatment groups reported comparable improvement in negative symptoms as defined by the protocol (at least 20% improvement). Similarly, both groups showed comparable changes on global and multidimensional self-assessments of quality of life. All the subfactors of the modified version of the SIP were similar in both groups, except for the subfactor that relates to alertness behavior, which possibly reflects remoxipride's lack of any sedating properties compared with haloperidol. This study presents an approach for inclusion of quality of life as an outcome measure in the design of clinical trials of new antipsychotic medications.

[Difference in prolaction response of schizophrenic patients to equivalent doses of haloperidol, remoxipride and sulpiride].

Clinically, most of the schizophrenics usually are treated with neuroleptics. This kind of medicine increases the prolactin level in serum that causes sexual dysfunction. In this study, 27 schizophrenics were divided into three groups. After discontinuation of taking the prior medicine for more than two weeks, subjects were treated respectively with fixed doses of haloperidol (20 mg), remoxipride (450 mg), and sulpiride (1800 mg). During hospitalization, an assigned senior resident used Nancy O. Andresen's Scale for the assessment of Positive Symptoms (SAPS) and Negative Symptoms (SANS) as tools to categorize schizophrenic subjects into subtypes, and another senior resident evaluated the effectiveness of the treatment once a week with the Brief Psychiatric Rating Scale (BPRS). Prolactin level in serum was monitored weekly with fluorescent assay. The Generalized Estimating Equation-I was utilized to analyze the data. The results show that all of the three medicines cause elevation of prolactin level in serum, and sulpiride causes the highest elevation of prolactin level in this study. There is no difference between the subtype of schizophrenia and prolactin reaction. There is also no correlation between the degree of elevation in prolactin and the effectiveness of treatment. However, there is a statistically significant difference in the serum levels between genders. After being treated with antipsychotics, female patients are more likely than male patients to have an elevated prolactin serum level. In conclusion, this study suggests that physicians should be more cautious while treating female psychotic patients with sulpiride.

An atypical neuroleptic drug in the treatment of behavioural disturbances and psychotic symptoms in elderly people.

The present study is a retrospective study of remoxipride therapy. A total of 103 patients, 65 years or older, with a DSM-III-R diagnosis of dementia or delirium, were included. They had all been treated with remoxipride because of psychotic symptoms or behavioural disturbances. The dose range of remoxipride was 50-300 mg, the median dose being 75 mg. The clinical effect was rated as good in two thirds of the patients, and side-effects were noted in one fourth. When psychomotor hyperactivity was the dominating problem, a good effect was rated in 81% of the patients. Side-effects were few and mild, the most common being tiredness; only 5 patients showed extrapyramidal symptoms.

Remoxipride versus haloperidol in healthy volunteers: psychometric performance and subjective tolerance profiles.

The aim of the present study was to evaluate the psychometric effects of equivalent clinical doses of remoxipride and haloperidol in comparison with placebo in healthy volunteers. In a double-blind design, either 3 mg haloperidol, 150 mg remoxipride, or placebo were administered to 36 healthy male volunteers ranging in age from 19 to 39 years. Performance was assessed using time estimation, critical flicker fusion, and choice reaction time tasks. In addition, self-ratings on subjective well-being were obtained. In healthy subjects, an acute dose of 3 mg haloperidol caused more severe alteration in cognitive functioning, cortical arousal, and psychomotor performance than a clinically equipotent dose of 150 mg remoxipride. Also, self-rating scales showed that subjective tolerance of remoxipride was partly superior to haloperidol. In general, the results of this study strongly suggest a difference between the psychometric profiles of remoxipride and haloperidol. This difference may be essential for maintaining a high level of compliance, especially in the long-term treatment of psychotic patients.

The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia.

A double-blind, randomized study of parallel group design comparing remoxipride and thioridazine (dose range 150-600 mg/day of either drug) was undertaken at 11 Australian centres. A total of 144 patients (remoxipride = 73, thioridazine = 71) with DSM-III-R schizophrenia or schizophreniform disorder commenced the study, and 89 patients (remoxipride = 45, thioridazine = 44) completed the 6 weeks of the trial. The mean daily doses at last rating were 404 mg (remoxipride) and 378 mg (thioridazine). Initial Brief Psychiatric Rating Scale scores decreased by a mean 8.7 points in both remoxipride and thioridazine groups. Equivalent treatment responses were also confirmed by Clinical Global Impression. During the study, sedatives or hypnotics were needed by 68% of the remoxipride patients and 51% of the thioridazine patients. Thioridazine was associated with more postural hypotension, drowsiness, increased sleep, headache, dizziness on rising, dry mouth, sexual dysfunction and weight gain, while remoxipride patients reported more insomnia. There were no differences between remoxipride and thioridazine on dystonia, hypokinesia, dyskinesia, rigidity and akathisia. The results indicate that remoxipride has similar antipsychotic efficacy to thioridazine but causes fewer side effects.

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.

Symptomatic relief from treatment-induced psychosis in Parkinson's disease: an open-label pilot study with remoxipride.

Current treatment strategies for levodopa-induced psychosis in Parkinson's disease have had limited success. Remoxipride, a selective D2 receptor antagonist, was administered in an open label pilot study to seven parkinsonian patients exhibiting thought disorder. Symptoms improved significantly in six patients after treatment durations of 1-6 months and cleared completely in two individuals. One patient (at age 90 the oldest in the group) could not tolerate the compound due to significant motor deterioration, and the drug had to be discontinued after 1 week. In all remaining patients, no motor complications appeared, and therapeutic effects of remoxipride continued for up to 3 months after treatment cessation and have lasted for 2 years now in one individual. Further study of this compound in the context of treatment-induced psychosis in Parkinson's disease appears to be warranted.

[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.

The tolerability and efficacy of the atypical neuroleptic remoxipride compared with clozapine and haloperidol in acute schizophrenia.

Remoxipride and clozapine are new neuroleptics that are thought to be superior to the substances in use by their efficacy and tolerance. At the University Clinic of Psychiatry in Düsseldorf a double-blind study with 54 patients diagnosed as schizophrenic in accordance with DSM-III was conducted to record the influence of the neuroleptics remoxipride, clozapine and haloperidol on schizophrenic psychosis. The schizophrenic symptoms were rated by the AMDP-system (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie), Brief Psychiatric Rating Scale and the Clinical Global Impression on days 0, 7, 14, 21 and 28 of treatment to evaluate the degree of change in psychopathology. The tolerance of the neuroleptic treatment was checked by the doctor's overall impression and the somatic findings of the AMDP-system. All 3 neuroleptics reduced the schizophrenic symptoms to a similar degree but showed differentiation as to their side effects.

Psychomotor impairment and cognitive disturbances induced by neuroleptics.

Reviews of the literature have failed to demonstrate any consistent effects of typical or atypical neuroleptics on psychomotor or cognitive function in schizophrenic patients. Better methods and study designs are required, and healthy volunteer studies are necessary to control for variables due to schizophrenic psychopathology. Eye movements are a sensitive, reliable and relatively pure measure of attention and arousal. Two volunteer studies of the effects of single doses of haloperidol (2,4 and 6 mg), chlorpromazine (50 mg) and remoxipride (100 and 150 mg) on saccadic and smooth pursuit eye movements are described. All drugs impaired both eye movement measures, but the doses used were not clinically equivalent. No available test is yet able to distinguish between benzodiazepines and neuroleptics.

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.