[Evaluation of prescription practices of long acting injectable risperidone in French hospitals]. / Enquête des prescriptions de rispéridone injectable à libération prolongée dans neuf centres hospitaliers du réseau PIC.

INTRODUCTION: Atypical antipsychotics or antipsychotics of second generation are still recommended by guidelines for primary use in the treatment of psychotic disorders because of their better neurologic safety and efficacy. However, they require daily dosing, thus compromising their overall efficacy whereas conventional depot neuroleptics provide constant pharmacologic treatment but induce extrapyramidal adverse effects and poor efficacy on negative symptoms. Long acting injectable risperidone (LAIR) is the first long-acting second-generation antipsychotic. Registered in October 2003 and launched in March 2005 in France thanks to Kane et al.'s and Fleischhacker et al.'s reference studies, it was supposed to provide the advantages of conventional long acting formulations of antipsychotics over those of an atypical agent. OBJECTIVES AND METHODS: The aims of this study, with the description of the prescription practices of LAIR in naturalistic conditions, were to assess the place of this new drug in psychotic medication, with the efficiency value measured by treatment discontinuation rate and analysis of the reasons for discontinuation, and to assess whether the prescriptions practices are or not in adequacy with guidelines and reglementation. In June 2005, we conducted a one-year naturalistic non-randomised open-label study in nine French psychiatric hospitals, members of the PIC network: were included all the patients who received LAIR every 2 weeks, between July 1st 2005 and November 30th 2005. RESULTS: Prescriptions of 216 patients were examined for 1 year. LAIR was used off label for 15% of the patients. Ninety-two percent of patients were hospitalized at the beginning of the treatment while 72% of the treated patients had dropped out one year after the first injection. Regarding the nature of previous antipsychotic treatments prescribed in the last three months before the first injection of LAIR: 31% patients had received a first generation antipsychotic, half of which had received a depot antipsychotic of first generation and 69% had received a second-generation antipsychotic, among which half had received oral risperidone. The principal reason noted by the clinicians for starting the new formulation was non-observance with anterior treatments. However, oral antipsychotic treatment preceding the first injection was used less than 4 weeks for one third of the patients. When this treatment was oral risperidone, average posology at the first injection was 6.7 ± 2.4 mg per day; it was 7.4 ± 2.1 mg per day for the patients who received the higher dose of LAIR (50 mg/2 weeks). So, it seems that some patients were not sufficiently stabilized by their antipsychotic before the beginning of the long acting treatment. The result was a significant rate of treatment discontinuations (53%) in the following year, principally caused by the withdrawal of the patient's consent and an insufficient response to treatment. CONCLUSION: This investigation provided the opportunity to analyze the prescriptions of a new formulation drug in routine clinical practice. It confirms the need for respecting the authorized indications and the recommendations of good use of a drug to avoid the failures of treatment and also the importance of the role of the pharmacist in recalling it to the physicians.

[Study on clozapine treatment at the Charles Perrens Hospital in Bordeaux, 15 years after its marketing]. / Enquête observationnelle de prescription de la clozapine au centre hospitalier Charles-Perrens à Bordeaux, plus de 15 ans après l'AMM en France.

INTRODUCTION: The international consensus conferences concerning schizophrenia and the authorization to market (French AMM) reserve this molecule for the treatment of resistant schizophrenia. Resistant schizophrenia, as defined by the marketing authorisation, corresponds to the absence of improvement in a patient's state despite two successive treatments with antipsychotics, or at least an atypical drug at an adequate dose for a sufficient length of time. OBJECTIVES: Our investigation compares hospital practices to the marketing authorisation and guidelines regarding resistant schizophrenia. METHODS: All clozapine prescriptions delivered by the pharmacists at the Charles Perrens Hospital were recorded during the month of February 2007. General information concerning the patient and his or her treatment were collected, based on different support teams set up in the hospital. First, the hospital administrative program was used to manage the patients. Then, the treatment establishment form, filled out by psychiatrists before the beginning of the treatment, listed all previous treatments given to the patient and indicated any inefficacy or intolerances to prior treatments. Then, a program monitored the delivery of this molecule and finally, prescriptions were recorded to describe present treatment. RESULTS: Our study consisted of 61 patients, mostly male subjects averaging 40 years of age, single, who had been under psychiatric care for about 15 years, and were, for the most part, professionally inactive. Clozapine was prescribed for schizophrenic (90%) and for bipolar patients (10%). Clozapine was also often prescribed for patients whose illness had not improved with prior treatments. The average dose was of 489 mg/day for patients considered stable, i.e., those for whom clozapine was prescribed with efficacy observed for a sufficiently long time. It was associated in 88% of all cases with another psychotropic: anxiolytic (68% of cases), normothymic (26% of cases), antidepressant (16%) and antipsychotic (42%). DISCUSSION: In practice, clozapine seems to be efficient in bipolar disorders, although the marketing authorisation does not envisage this indication. It is never prescribed first, as some recommendations indicate, even though the follow-up of certain treatments does not always seem adequate to appreciate their non-effectiveness. Seldom prescribed alone, clozapine is often associated with another antipsychotic, a practice not favoured by many experts. Our investigation thus confirms the increase in co-prescriptions, particularly in hospital, for patients who have not improved with clozapine alone, a case that is barely taken into consideration in consensus conferences. With the lack of innovative molecules, psychiatrists are prompted to associate several antipsychotics, with the risk of supporting iatrogenic medication, whereas the experts reserve the relevance of such associations because of a lack of randomised studies.

[Prescribing patterns of antipsychotics in 13 French psychiatric hospitals]. / Enquête de pratiques de prescription des antipsychotiques dans 13 centres hospitaliers du réseau PIC.

INTRODUCTION: The commercial introduction of atypical antipsychotics, called second-generation antipsychotics (SGAs), a few years ago, has led to a world-wide reappraisal of the established treatment strategies for people with psychotic or bipolar disorders. They permitted improvements in the pharmacologic management of psychiatric diseases. As compared to conventional neuroleptics or first-generation antipsychotics (FGAs), they promised better efficacy especially on negative symptoms and cognitive impairments of psychiatric diseases and, at the same time, better tolerance on neurological side effects. Now, they have shown other side effects and they have a higher acquisition cost than FGAs. OBJECTIVES AND METHODS: The aim of this paper is to describe and analyse the prescribing practices of antipsychotic drugs in French psychiatric hospitals for adult inpatients and to compare them with other surveys and guidelines. In June 2004, we conducted a one-day, cross-sectional, observational and naturalistic study in 13 hospitals, members of the PIC network. RESULTS: Two thousand one hundred and ninety-two prescriptions with antipsychotic treatment were collected. One thousand one hundred and fifty-four prescriptions (52.6%) included a SGA, but the FGAs were the most prescribed (65.8%; n=2259), principally cyamemazine (24.7%). There was one antipsychotic in 50.7% of prescriptions, two antipsychotics in 42.2%, but the second neuroleptic used was a sedative (82.6%), principally cyamemazine. Multiple antipsychotics were present in 1081 prescriptions (49.3%), with an average number of 1.57 antipsychotics. A mood stabiliser, an antidepressant, an anxiolytic and a hypnotic were coprescribed in respectively 37, 30.5, 65.1 and 41.6%. There were 2.48 psychotropic drugs associated with the principal antipsychotic; in total, with correctors of side-effects of the antipsychotics, there were 3.38 drugs per prescription. The SGAs aimed more often for psychotic (F20-F29) patients (61.9% versus 43.3% with FGAs), who were males (61.4% versus 68%), younger (42.6 years versus 44.1 years; p<0.02), with higher average daily doses, more associated with other neuroleptics (p<0.0004) and less associated with anticholinergic antiparkinsonian agents (p<10(-4)) than FGAs. Compared to other surveys, these results showed that the SGAs have become the first-line treatment for psychiatric disorders. The highest average daily doses corresponded to treatments of psychotic patients and, hence, the values might largely exceed the authorized maximum doses. Furthermore, in more than half of the cases, an FGA, generally a sedative, was associated with an SGA that did not comply with the principle of monotherapy established by the national and international guidelines; that also annulled the expected benefit of the SGAs on the awakening, cognition and the neurological tolerability of the treatment. The coprescriptions of the other psychotropic drugs to neuroleptics also remained the rule in psychiatry, showing all the complexity of pharmacological psychiatric medications. Prescriptions also included treatments for side effects of antipsychotics; even on the prescriptions including the SGAs, there was the coprescription of anticholinergic antiparkinsonian drugs, the deleterious character of which one knows on cognition. This resulted in a difficulty of understanding the prescription for the patient, associated with reduced compliance and increased risks of pharmacological side effects. The heterogeneity of the situations of crisis in psychiatric hospitals could make the strict application of guidelines' recommendations difficult. Nevertheless, the educational interventions in psychopharmacology for patients and the training campaigns for psychiatrists and nurses are necessary to improve the therapeutic management of the patient and ensure him/her optimal quality of life. CONCLUSION: This kind of survey, far too rare, was very important because it showed the routine clinical settings in which these new drugs were really used. The results showed that SGAs appeared to take the place of the FGAs used in the treatment of psychoses, particularly schizophrenia, but also in the treatment of mood disorders and they reflected actual clinical practices. Other surveys must be conducted to see whether our study confirms the general trend concerning the use of these drugs and, therefore, to reassess these prescribing practices.

[Long-acting injectable risperidone: naturalistic study in three hospitals in Aquitaine]. / La rispéridone injectable à libération prolongée: enquête d'utilisation dans trois établissements d'Aquitaine.

INTRODUCTION: Injectable risperidone is the first long-acting second-generation antipsychotic. A middle-term naturalistic study has been conducted with the first treated patients of three psychiatric hospitals in Aquitaine. METHOD: Two evaluations of these patients were performed by psychiatrists: the first before the beginning of treatment and the second after six months. Data on efficacy and tolerance of the drug were obtained from in-patients who were unstable or non-compliant with their previous treatment. Two scales were used to highlight efficacy (positive and negative syndrome scale (PANSS) and clinical global impression (CGI)). All adverse events had to be notified in a general form and AIMS was used for extrapyramidal symptoms. Patient's quality of life was auto-evaluated by TEAQV. The pain on injection was assessed by the patients on a visual analogic scale. RESULT: Patients were treated between February 4th and December 4th 2004. Among the 71 treated patients, 27 (38%) discontinued treatment before the six months, due to: lost to follow-up (11.3%), consent withdrawn (9.9%), insufficient response (7%), adverse event (2.8%) or unknown reason (7%). The results of efficacy and tolerance concern 37 patients (52%) with a mean age of 32.8 (+/-7.8) years. Patient's PANSS score was 86.6 (+/-21.4) at the beginning of treatment. Mean decrease of this score was 13.2 after six months. Efficacy of the product is shown by 40.5% of the patients who decreased more than 20% of their initial PANSS score. CGI showed a global improvement "mild" to "great" with 46% of "strongly" to "very strongly" improved patients. Adverse reactions reported are known with risperidone: extrapyramidal symptoms (29.7%), weight gain (13.5%), dry-mouth syndrome (13.5%), hypotension (8.1%), sexual disorders (5.4%) and hyperprolactinemia (2.7%). Extrapyramidal symptoms were still the most common adverse events, as in the initial evaluation. Patients claimed their quality of life was unchanged after six months in comparison with the initial evaluation. They evaluated pain at injection site as moderate (2.6/10). DISCUSSION: The results of efficacy have been compared to the results published in the two studies that made it possible to obtain marketing autorisation of the drug in USA. The PANSS results for efficacy were not statically different from the results of the two reference studies (except for negative symptoms: there was no statistical difference observed between initial and final scores in our study, probably due to the small size of the sample). This study highlights several positive aspects for long-acting injectable risperidone (innovating pharmaceutical presentation: aqueous suspension which contains microspheres, moderate pain at injection site, efficacy in 40.5% of initially unstable patients, discharge and no rehospitalisation in most patients, decrease of the use of anticholinergic products) but also shows several negative aspects (frequency of injections--every two weeks--, high percentage of treatment discontinuation, same adverse event profile as oral risperidone, no improvement in quality of life). CONCLUSION: Despite the small size of the sample, this study presents a view of the use of the drug in realistic conditions and appears to show that long-acting injectable risperidone is probably the most appropriate treatment for stable, discharged patients.

[Use of atypical antipsychotics in Charles Perrens psychiatric hospital (Bordeaux) analysis of prescribing practices for Amisulpride, Clozapine, Olanzapine and Risperidone]. / Etude des pratiques de prescription des neuroleptiques dits atypiques ou antipsychotiques atypiques au centre hospitalier Charles Perrens de Bordeaux.

UNLABELLED: The commercial introduction of atypical antipsychotics (AAP) constitutes a considerable step forward in the sense that it has led to a world-wide reappraisal of the established treatment strategies for people with psychoses (including schizophrenia and affective psychoses). They have allowed refinements in the pharmacologic management of psychoses but they have a higher acquisition cost than conventional neuroleptics. The cost of the newer AAP had a substantial effect on medical resources: the AAP account for only 43.2% of neuroleptic prescriptions, but 76.1% of medical costs associated with neuroleptic drugs, and in terms of treatment costs, a reduction (50%) was found with risperidone compared with olanzapine for a same number of treated patients. The aim of this paper was to examine the use of these drugs, to compare them and to assess their impact within the context of psychiatric hospital practice, by means of analysis of prescribing practices for amisulpride, clozapine, olanzapine and risperidone for all treated patients. We conducted an observational, naturalistic study at Charles Perrens psychiatric Hospital in Bordeaux (France) that reproduced the clinical conditions in which these new drugs are used. Four photographies of all the medical prescriptions concerning atypical antipsychotic drugs were done between October 1999 (four months after the introduction in France of the olanzapine, the last of the new antipsychotics) and June 2001 (n=682 prescriptions). The total amount of these prescriptions corresponded to 527 patients. Treatment groups were compared - first overall and after by considering 2 groups: psychotic and non-psychotic patients - through descriptive analyses of sociodemographic characteristics of patients, diagnosis, percentages of patients receiving concomitant psychotropic medication and/or receiving treatment-emergent side effects and mean dosages of AAP therapy according to concomitant medication. In the same way, we compared the four AAP through their prescribing practices'evolution during the four survey. RESULTS: AAP drugs account for 43.2% of prescriptions (and conventional neuroleptics 56.8% of them). We recorded a significant increase between the four surveys (p<0.02): 36.6% at the beginning to 47.8% at the end of the study. From the 682 collected prescriptions, 72 (10.6%) included clozapine, 130 (19.1%) amisulpride, 229 (33.6%) olanzapine and 251 (36.8%) risperidone. Sixty five percent of AAP prescriptions involved psychotic patients. A relative stability in characteristics of AAP prescriptions during the four surveys was found. So, no significant differences were observed between amisulpride, olanzapine, risperidone, in terms of age, sex, sociodemographic characteristics, unlike clozapine. However, there were statistical differences between all the AAP in the concurrent use of other neuroleptic agents (p<0.02), hypnotic drugs (p<0.006), mood stabilizer drugs (p<0.03), and anticholinergic drugs (p<0.007). Statistically, the mean dosage of amisulpride increased when a mood stabilizer drug was coprescribed (p<0.0007), but it decreased with an antidepressant drug (p<0.004) or an hypnotic drug (p<0.02); clozapine 's one decreased every time an antidepressant drug was coprescribed (p<0.02); with olanzapine, there was a significant increase every time an other neuroleptic agent (p<0.03) or an anticholinergic drug (p<0.006) was associated; then for risperidone, the mean dosage increased with the coprescription of an other neuroleptic agent (p<0.00002), an anticholinergic (p<0.00003) or an adrenolytic drug (p<0.04). The pattern of prescribing practices that emerges from our four surveys suggests that these new AAP are significantly more and more often associated with a stabilizer mood drug (p<0.009) (particularly the olanzapine) or/and an anxiolytic drug (p<0.05) (like the amisulpride in particular). Considering the four AAP globally, but more with the risperidone, the association with a neurovegetative corrector agent decreased (p<0.004) during the four surveys. Then, concerning the psychoticng the four surveys. Then, concerning the psychotic patients, the AAP were significantly more often associated with other neuroleptic agents (p<0.03), the amisulpride in particular, with anticholinergic drugs (p<0.00005), but significantly less with mood stabilizer drugs (p<0.00003) principally the amisulpride and the risperidone, with antidepressant drugs (p<0.02) particularly the risperidone. This kind of survey, however it is too much rare, is very important because it shows the clinical conditions in which these new drugs are really used. The results show that AAP appear to be the replacements of the older neuroleptics used in the treatment of psychoses, including particularly schizophrenia, but also in the treatment of mood disorders, and they reflect actual clinical practices. Other surveys must be achieved to see if our study confirms the general trend concerning the use of these drugs and so as to reassess these prescribing practices.

[Medico-economic study of Léponex (clozapine) in the Bordeaux Charles Perrens Hospital Center]. / Etude médico-économique du Léponex (clozapine) au centre hospitalier Charles Perrens de Bordeaux.

Schizophrenia disorders afflict approximately 1% of the population during their lifetime. Conventional antipsychotic agents show therapeutic limitations because of their side-effects and inefficacy among some patients. A novel antipsychotic class, named atypical neuroleptics, among Léponex is the leader, constitutes a hope in treatment-resistant schizophrenia. However, because the drug involves a 1% to 2% risk of agranulocytosis, an haematological oversees has been established. Moreover, the acquisition cost of clozapine is high in comparison with that of standard antipsychotics. The purpose of this study was to observe the management of 72 patients suffering from resistant schizophrenia, to assess the cost of this treatment in medical and social terms, and to realize cost-effectiveness study in Charles Perrens Hospital (Bordeaux). The survey based on three questionnaires (Clinical informations, Quality of Life, Epidemiological information) was sent to psychiatrists practising in this hospital. The results confirm efficacy (overall functioning measured by CGI which is significant, p < 0.0001) and tolerance of Léponex (no side effects in 33.3% patients, no agranulocytosis, only one neutropenia and only 4.2% neurologic side effects). We found a significant reduction of the annual mean number of days of full time hospitalization (214 days versus 135 after two years, p < 0.0005) associated with the significant reduction of direct cost mainly related to shorter length of hospitalization; and 45.8% versus 8.3% adjust to life in the community (p < 0.0004). Clozapine produced a marked improvement (p < 0.0001) in Quality of Life measured by two self-rating scales (SWN and TEAQV). The estimated total two-years cost decreased from 31,108 Francs/month/patient to 22,950 Francs/month/patient, a saving of 8,158 Francs/month/patient (a decrease of 26.2%). Although the acquisition cost of clozapine is high, cost effectiveness estimates in patients with treatment resistant schizophrenia suggest that the clinical benefits (improved psychopathology, social functioning and quality of life) of this drug may confer medium to long term economic benefits, primarily by reducing the need for psychiatric hospital service.

Comparison of the metabolism and pharmacokinetics of metbufen and itanoxone and their analogues in rats.

Metbufen, II, itanoxone, I, and two other derivatives of gamma-aryl-gamma-keto-substituted butyric acids labelled with 14C in their carbonyl group were synthesized for a metabolic investigation in rats. Profound changes in pharmacokinetic parameters, most specifically in the distribution, elimination, and metabolic pathways, were induced by substitution in the aromatic nucleus or changes in saturation of the aliphatic chain. The metabolites isolated from plasma and urine were identified by gas chromatography and mass spectrometry, by comparison with chemical controls, revealing the processes of metabolism of these structural analogues. This difference in metabolism further understanding of the diversity of biological effects inherent in these compounds.