[Retrospective study of clozapine use in Ile-de-France]. / Etude rétrospective sur l'utilisation de la clozapine en Ile-de-France.

INTRODUCTION: Clozapine, synthesized in the sixties, is an atypical antipsychotic drug whose history has been marked by its haematological toxicity. The purpose of this study was, ten years after it had been replaced at French psychiatrists' disposal, to gather data on the prescription modalities of clozapine, assess whether some factors could affect its efficacy, and describe the population of schizophrenic patients concerned. METHODOLOGY: Psychiatrists in the Paris region were asked to answer a questionnaire about their patients treated with clozapine. The information collected was about socio-demographic data, history of psychiatric disorder and the way clozapine was used. It was a retrospective study concerning 98 patients. RESULTS: Subjects were 57 men and 41 women, with a mean age of 38 years. The majority of patients came from metropolitan France. Patients suffered from various clinical subtypes of schizophrenia, as assessed according to DSM IV criteria. Predominant symptomatology during lifetime was most often auditory hallucinations (41%). Mean duration of lifetime neuroleptic treatment was 10.3 years and breaks in follow-up were rare. Mean number of hospitalisations was 6.9 and a little less than half of the patients had been committed involuntarily. Lastly, 38% of patients had attempted suicide at least once and 35% had expressed hetero-agressive behavior. Main indication of clozapine was resistant schizophrenia (88.5% of patients) and mean duration of treatment was 2 years and 4 months. Treatment efficacy was assessed as good or medium in 77.9% of patients, at mean doses (322 mg per day) in keeping with data from the literature. Tolerance was considered on the whole as satisfactory by half of the clinicians. Among the 98 patients of the study, 21.6% had stopped taking clozapine. The reasons for withdrawal were: inefficacy (6.2%), granulopenia (5.2%), epilepsy (1%) and 8.2% for various reasons (half of these cases being non-compliance with treatment). The study of the 5 cases of granulopenia showed that 3 patients had another associated psychotropic medication: 1 patient received only clozapine as monotherapy, 1 data was missing. Two thirds of all patients were receiving another psychotropic drug in association with clozapine, mainly benzodiazepines (18.4%), antidepressants (15.3%) or mood stabilizers (7.1%). The "therapeutic efficacy" variable was compared with some variables in order to isolate factors possibly associated with a better efficacy of clozapine or, on the contrary, with a population of patients poorly responding to treatment. However, no statistically significant difference appeared according to the variables studied, such as gender or lifetime duration of neuroleptic treatment. Moreover, there was no statistically significant difference in efficacy according to schizophrenia subtype, main symptomatology during the course of illness or substance abuse. We studied whether any factor could affect the occurrence of granulopenia. No statistically significant difference was found. The mean age of patients having stopped the treatment because of granulopenia was higher than in the group with other reasons for interruption, but did not reach statistical significance. A trend also appeared towards female predominance (60% of women in the granulopenia group) and 3/4 of patients who had stopped their treatment because of agranulocytosis received another psychotropic drug in association with clozapine. CONCLUSION: As expected, the main indication for prescribing clozapine was resistant schizophrenia, but contrary to data from the international literature, the efficacy profile was the same whatever the clinical subtype of schizophrenia. The tolerance to clozapine was considered on the whole as satisfactory, but the high proportion of granulopenias leading to treatment withdrawal (5.2% of patients) confirms the need to remain cautious and stresses the importance of regular haematological monitoring. Furthermore, the study of the prescription modalities of clozapine shows that contrary to the guidelines, clozapine is often associated with other psychotropic drugs. In this study, it is striking to note that 75% of granulopenias occurred in a coprescription situation.

Increased in vivo release of calcitonin gene-related peptide-like material from the spinal cord in arthritic rats.

Possible alterations in spinal systems containing calcitonin gene-related peptide (CGRP) due to polyarthritis were assessed in rats 3-4 weeks after an intradermal injection of Freund's adjuvant in the low back. The tissue levels of CGRP-like material (CGRPLM) were approximately 50% higher in the dorsal zone of the spinal cord and dorsal root ganglia at both the cervical and lumbar (but not thoracic) segments in polyarthritic rats than in age-paired control animals. In addition the rate of the spinal release of CGRPLM determined through an intrathecal perfusion procedure in halothane-anaesthetized animals was approximately 15-fold higher in polyarthritic rats than in controls. The blockade of mu-opioid receptors by intrathecal perfusion with 10 microM naloxone produced a larger increase in the spontaneous CGRPLM outflow in polyarthritic rats than in age-paired controls. Furthermore, the stimulation of mu-opioid receptors by intrathecal perfusion with 10 microM DAGO significantly inhibited the spinal outflow of CGRPLM only in polyarthritic rats. These data indicate that CGRP-containing primary afferent fibres are markedly activated in chronic suffering polyarthritic rats. This activation occurs in spite of an increased tonic inhibitory control by endogenous opioids acting at mu receptors.

Kappa-/mu-receptor interactions in the opioid control of the in vivo release of substance P-like material from the rat spinal cord.

The possible involvement of mu and kappa receptors in the opioid control of the spinal release of substance P-like material was assessed in vivo, in halothane-anaesthetized rats whose intrathecal space was continuously perfused with an artificial cerebrospinal fluid supplemented with various opioid receptor agonists and antagonists. Whereas the intrathecal perfusion with the mu agonist DAGO (10 microM) significantly enhanced (approximately + 50%) the spontaneous release of substance P-like material, that with the kappa agonist U 50488 H (10 microM) produced no change in the peptide outflow. The respective antagonists naloxone (10 microM) for the mu receptors and nor-binaltorphimine (10 microM) for the kappa receptors did not affect the spontaneous release of substance P-like material, indicating that endogenous opioids acting at mu and kappa receptors do not exert a tonic control on substance P-containing neurons in the spinal cord of halothane-anaesthetized rats. However, as expected from the involvement of mu receptors, the stimulatory effect of DAGO on the peptide outflow could be prevented by naloxone but not norbinaltorphimine. Furthermore, instead of an increase with DAGO alone, a significant decrease in the spinal release of substance P-like material was observed upon the intrathecal perfusion with DAGO plus U 50488 H. Additional experiments with the respective mu and kappa antagonists naloxone and nor-binaltorphimine demonstrated that this effect actually resulted from the simultaneous stimulation of mu and kappa receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Feedback inhibition of met-enkephalin release from the rat spinal cord in vivo.

The possible existence of a feedback control by endogenous opioids of the spinal release of met-enkephalin-like material was assessed in vivo, in halothane-anesthetized rats whose intrathecal space was continuously perfused with an artificial cerebrospinal fluid supplemented with various opioid-related drugs. Both the intrathecal perfusion of the mu agonist D-Ala2-D-MePhe4-Gly-ol5-enkephalin (DAGO) (10 microM) and the delta agonist Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) (10 microM) produced a significant inhibition of the spinal outflow of met-enkephalin-like material. The effect of DAGO, but not that of DTLET, could be prevented by naloxone (10 microM), and, conversely, the effect of DLTET, but not that of DAGO, was no longer observed in the presence of naltrindole (10 microM). Therefore naloxone and naltrindole acted as potent and selective mu and delta antagonists, respectively, when perfused at 10 microM in the intrathecal space of halothane-anesthetized rats. As expected from the lack of a tonic opioid control of spinal enkephalinergic neurones, neither naloxone nor naltrindole alone affected the spontaneous outflow of met-enkephalin-like material. However, naltrindole, but not naloxone, markedly increased the spinal overflow of met-enkephalin-like material due to intrathecal administration of either porcine calcitonin (10 microM) or the peptidase inhibitors thiorphan (10 microM) plus bestatin (20 microM). These data suggest that delta, but not mu, receptors are involved in a phasic opioid inhibitory control of the release of met-enkephalin-like material in the rat spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)