[Predictive factors of seclusion duration in patients hospitalized in psychiatry settings. A prospective multisite study in the DTRF Paris-Sud]. / Facteurs prédictifs de la durée d'isolement chez les patients hospitalisés en psychiatrie. Une étude prospective multicentrique au sein du DTRF Paris-Sud.

INTRODUCTION: In psychiatric inpatient settings seclusion is a last resort to ensure the safety of the patient, other patients, and staff from disturbed behaviors. Despite its major interest for patients, seclusion could negatively impact treatment adherence and patient/staff relationships. Indeed, some secluded patients report a feeling of guilt during the measure and do not consider seclusion to be a healthcare intervention. To be more beneficial and to reduce the feeling by patients of being forced, seclusions should be as short and rare as possible. In other words, measures to reduce seclusion are available and have been clearly identified. Such measures could be applied, in the first instance, in patients with longer duration. In this way, the aim of this study was to investigate predictive factors of a seclusion of long duration. METHODS: Our study was based on the dataset of the EPIC study, an observational prospective French multicenter study of seclusion and restraint. The EPIC study occurred in seven French psychiatric hospitals in the southern region of Paris. Inclusions were realized for 73days and allowed a data collection of 302 seclusion measures. Of these measures 236 were effectively a seclusion in a standardized room. Because the median duration was 7days, we defined two groups of patients: duration<7days and duration ≥ 7 days. Our variable to be explicated was duration ≥ 7 days. Explicative variables available in EPIC study were age, sex, forced hospitalization, autoagressivity, heteroagressivity, use of sedative treatment (oral or intramuscular), history of seclusion and patient diagnoses. We used bivariate and multivariate analyses to explore the association between a seclusion duration ≥ 7 days and explicative variables. Diagnoses were classified as psychotic disorders, mood disorders and others diagnoses. To be included in multivariate logistic regressions, diagnoses were treated as dummy variables (mood disorder vs psychotic disorders; psychotic disorders vs others; mood disorders vs others). Statistical analyses were performed using SPSS software 20.0 and R 3.4.0. RESULTS: Of the 236 measures of seclusion the mean age was 38.2 (±12.8), 196 (83%) patients were forcibly hospitalized prior to their seclusion, 147 (62%) had a diagnosis of psychotic disorder, 43 (18%) a diagnosis of mood disorder and 33 (14%) an "other diagnosis". Mean duration was 10.2 (1.5) days and median was 7.1 days. One hundred and thirty-five (47%) patients were in the group of duration ≥ 7 days. In bivariate analyses, variables associated with a duration ≥ 7 days were: being in forced hospitalization prior to the seclusion (P=0.04), administration of a sedative treatment (P=0.01) and against the group of others diagnoses the diagnosis of mood disorders (P<0.0005) and psychotic disorders (P=0.001). Multivariate analyses showed that, against the group of other diagnoses, the group of psychotic disorders [OR=3.3, CI 95% (1.3-8.4), P=0.01], the group of mood disorder [OR=2.7, CI 95% (1.4-4.9), P=0.002] and administration of sedative treatment [OR=8.1, CI 95% (2.0-32.5), P=0.003] were significantly associated with a duration ≥ 7 days. These results were independent from other confusion variables. Considering the hospitalization status, psychotic disorders was the only diagnosis which showed an association between duration ≥ 7 days and forced hospitalization [OR=2.9 CI 95% (1.1-7.8), P=0.03]. CONCLUSION: Our study highlighted two profiles of higher risk to remain ≥ 7days in seclusion. The first one is patients with a diagnosis of mood disorder who needed sedative treatment. The second one is patients with a diagnosis of psychotic disorder who needed sedative treatment and forced hospitalized before seclusion. Thus, these two profiles could be a good target to practice, in the first instance, measures to reduce seclusion duration in psychiatry settings.

Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment.

Although antipsychotics are established drugs in schizophrenia treatment, they are admittedly known to induce side effects favoring the onset of obesity and worsening its complications. Despite potential involvement of histamine receptor antagonism, or of other neurotransmitter systems, the mechanism by which antipsychotic drugs increase body weight is not elucidated. The aim of the present study was to investigate whether chronic antipsychotic treatments can directly alter the regulation of two main functions of white adipose tissue: lipolysis and glucose utilization. The influence of a classical antipsychotic (haloperidol) was compared to that of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (ziprasidone). Cell size, lipolytic capacity and glucose transport activity were determined in white adipocytes of rats subjected to 5-week oral treatment with these antipsychotics. Gene expression of adipocyte proteins involved in glucose transport or fat storage and mobilization, such as glucose transporters (GLUT1 and GLUT4), leptin, matrix metallo-proteinase-9 (MMP9), hormone-sensitive lipase (HSL) and fatty acid synthase (FAS) was also evaluated. Adipocytes from chronic olanzapine-treated rats exhibited decreased lipolytic activity, lowered HSL expression and increased FAS expression. These changes were concomitant to enlarged fat deposition and adipocyte size. Alterations were observed in adipocytes from olanzapine-treated rats whereas the other antipsychotics did not induce any notable disorder. Our results therefore show evidence of an effect of chronic antipsychotic treatment on rat adipocyte metabolism. Thus, impairment of fat cell lipolysis should be considered as a side effect of certain antipsychotics, leading, along with the already documented hyperphagia, to the excessive weight gain observed in patients under prolonged treatment..

Calcitonin microinjection into the periaqueductal gray impairs contextual fear conditioning in the rat.

We have previously proposed that behavioral alterations induced by salmon calcitonin in the rat provide an animal model of depression. As depression is characterized by context-related anxiety, behavioral inhibition and alterations in memory processing, we tested the effects of microinjections of salmon calcitonin into the periaqueductal gray matter (PAG) on contextual fear conditioning in the rat. In a first experiment, calcitonin or saline were microinjected into the PAG before the training phase and before the testing phase of a conditional fear testing procedure. In a second experiment, calcitonin or saline were injected before and immediately after the training phase. When given before the training phase, calcitonin had no effects on immediate postshock freezing but produced significant deficits in contextual freezing (24 h after footshock) in comparison with controls. When given immediately after the footshocks, calcitonin impaired contextual fear. These results suggest that calcitonin receptor stimulation in the PAG can alter the acquisition and consolidation of contextual fear behavior processes.

Interleukin-1beta and calcitonin, but not corticotropin-releasing factor, alter sleep cycles when injected into the rat hypothalamic lateral paraventricular area.

Interleukin-1beta (II-1beta) is a cytokine known to have somnogenic properties. We have previously shown that II-1beta decreases food intake when injected into the lateral part of the paraventricular nucleus of the hypothalamus (PVH), and, because food intake and sleep are closely related behaviors, we tested the hypothesis that II-1beta could alter sleep when injected into the lateral PVH area. We compared the effects of II-1beta with those of two other peptides involved in feeding behavior and known to act in the PVH area, the corticotropin-releasing factor (CRF) and salmon calcitonin (sCT). The EEG of rats was recorded for 48 h after the injection. The results showed that CRF had no effects, II-1beta reduced significantly sleep duration during the first 5 h following the injection, and sCT profoundly affected sleep cycles, producing an almost 30-h long insomnia, with a major reduction of slow wave sleep and a long period of alternation of REM sleep and wakening. It is concluded that (i) the area between the lateral part of the PVH and the fornix is a brain site involved in sleep regulation, (ii) II-1beta, a peptide generally considered as somnogenic, decreases sleep when administered in this area, and (iii) sCT is an extremely potent suppressor of slow wave sleep.

Calcitonin-induced impairment in conditioning is antagonized by chronic antidepressant drug treatment.

The purpose of this study was to test the effect of calcitonin, when injected into the lateral ventricle, on conditioning behaviour and to see whether antidepressant drug treatment can antagonize calcitonin-induced impairment of this behaviour. Conditioned response by conditional stimulus (CS) was compared in control rat (CO) and in rats that received intraventricular perfusion of calcitonin (CA), acute antidepressant drug treatment (ADa), acute antidepressant drug treatment + calcitonin (ADa + CA), chronic antidepressant drug treatment (21 days) + calcitonin the day after (ADc + CA). Control rats acquired easily the conditioned response, the CA group and ADa + CA had problems in making the correlation between CS and unconditional stimulus (US), and consequently did not acquire a conditioned response, but in the ADc + CA group, rats exhibited more conditioned responses. The results indicate that calcitonin disrupts conditioning processes and chronic but not acute antidepressant drug treatment can reverse the effects of calcitonin.

Calcitonin increases 5-HT1A binding site densities in the brain of adrenalectomized rats.

Calcitonin is a peptide which acts in the brain to modulate behavior and hormone release, possibly through an interaction with serotonergic systems. We investigated the effects of chronic systemic injections of salmon calcitonin on the [3H]-8-OHDPAT binding to 5-HT1A receptors in the frontal cortex and hippocampus in adrenalectomized and intact (non adrenalectomized) rats. The results show that salmon calcitonin increases the maximal density of 5-HT1A binding sites in both structures in adrenalectomized animals (and decreases the affinity in the frontal cortex only). Calcitonin does not alter this binding in intact rats. These results demonstrate the existence of interactions between calcitonin, serotonin and glucocorticoids, and raise the hypothesis of a neurotrophic effect of calcitonin on serotonergic neurons.

Hypothermic effects of dopamine D3 receptor agonists in the island of Calleja Magna. Potentiation by D1 activation.

The selective functions of D3 receptors in the brain are still poorly understood, mainly because all the ligands active at dopamine D3 receptors have also a high affinity for the D2 receptors. However, it is possible to study selectively D3 receptor function because some brain structures, such as the islands of Calleja, contain D3 and not D2 receptors. The position of the island of Calleja Magna in the rat brain makes it possible to inject dopamine D3 ligands into the vicinity of these D3 receptors, and to study their behavioral role, with no concomitant action on D2 receptors. We studied the effects on body temperature and on locomotion of unilateral microinjections of D2/D3 receptors ligands into the island of Calleja Magna and into the adjacent nucleus accumbens. The results show that D3 agonists injected into the island of Calleja Magna decrease body temperature and that this effect is potentiated by simultaneous injection of the D1 agonist SKF 38393. D3 agonists have no effect on locomotor activity in the island of Calleja Magna. In the nucleus accumbens, the D3 agonists have only weak effects on body temperature, but, when associated with a D1 agonist, strongly stimulate locomotor activity. The effects on body temperature of unilateral microinjections of dopamine agonists into unilaterally dopamine-depleted animals are the same as those in nondepleted ones. This indicates that the D3 receptors are localized postsynaptically in the island of Calleja Magna.

Evidence for a functional role of the dopamine D3 receptors in the cerebellum.

It has recently been shown that the lobules 9 and 10 of the cerebellum contain high densities of dopamine D3 receptors (and almost no D2 receptors [Bouthenet, M.L., Souil, E., Martres, M.P., Sokoloff, P., Giros, B. and Schwartz, J.C., Brain Res., 564 (1991) 203-219; Sokoloff, P., Giros, B., Martres, M.P., Bouthenet, M.L. and Schwartz, J.C., Nature, 347 (1990) 146-151]), and the functional role of this cerebellar dopamine system is unknown. In this study, using microinjections of dopamine receptor ligands into the lobules 9 and 10 of the cerebellum and into the nucleus accumbens, we show that the cerebellar dopamine D3 receptors have a functional role in the regulation of locomotor activity. When microinjected into the lobules 9 and 10 of the cerebellum, amisulpride (a dopamine D2 and D3 antagonist) and nafadotride (a preferential D3 antagonist) dose-dependently alter locomotor activity. At low doses, both agents stimulate locomotor activity, while inhibition is observed at higher doses. Haloperidol (a D2 antagonist) and apomorphine (a dopamine agonist) have no effects at low doses, but decrease locomotor activity at high doses. Similar effects are found in the nucleus accumbens, however the effects are stronger in the nucleus accumbens than in the cerebellum. Therefore, the dopamine D3 receptor system in lobules 9 and 10 of the cerebellum has a functional role, similar but weaker than the D3 receptor system in the nucleus accumbens.

Low doses of neurotensin in the preoptic area produce hyperthermia. Comparison with other brain sites and with neurotensin-induced analgesia.

High amounts of neurotensin (NT) are found in the preoptic area of the hypothalamus, an area known to be involved in the regulation of body temperature. It is generally believed that NT is a peptide that produces hypothermia, and several sites in the brain have been proposed to mediate NT-induced hypothermia, including the preoptic area. However, the doses of NT used in these experiments were always very high (microgram order) whereas, according to Goedert, the total brain content of NT in the rat does not exceed 10 ng. We therefore reinvestigated the effects of microinjections of NT in the brain, using high (5 micrograms) and low (50 and 5 ng) doses, into the preoptic area and other brain sites (cerebral ventricles, posterior hypothalamus, and nucleus accumbens), and we also studied, as a comparison, the effects of high and low doses of NT on pain sensitivity in the same sites. The results show that the preoptic area has unique properties in the regulation of body temperature: low doses of NT in the preoptic area produce a hyperthermic response, whereas high doses produce hypothermia. In comparison, NT produces hypothermia in the posterior hypothalamus whatever the dose, and NT has analgesic effects in the preoptic area only at high doses. Besides, NT has no thermic effect, but does have an analgesic effect, in the nucleus accumbens. The selectivity of the actions of high doses of NT, as well as the mechanism of action of NT (possibly an endogenous neuroleptic), are discussed.

An open trial of the D1 antagonist SCH 39166 in six cases of acute psychotic states.

Six psychotic patients were included in a four-week study of the effects of the D1 selective antagonist SCH 39166 given as monotherapy. Four had a diagnosis of schizophrenia, and two suffered from a schizoaffective disorder. All presented with an acute psychotic exacerbation at the beginning of the trial. SCH 39166 was progressively increased from 50 mg/day to 600 mg/day. In the four schizophrenic patients, the BPRS worsened, and three out of the four failed to complete the study because of this. Three schizophrenic patients were aggressive or violent after abrupt discontinuation of treatment. In the two patients with schizoaffective disorder the BPRS improved during the trial, but they had an acute relapse immediately after treatment discontinuation. Extrapyramidal symptoms improved in three of the six patients, and worsened in one.

Hypothalamic and thalamic sites of action of interleukin-1 beta on food intake, body temperature and pain sensitivity in the rat.

Interleukin-1beta (IL-1beta ) has anorectic, hyperthermic, and analgesic or hyperalgesic (depending on the studies) effects in the rat. These effects appear to be mediated by the central nervous system; however, the exact localization of action of IL-1beta in the brain has never been delineated with precision. The purpose of this study was to determine precisely where IL- IO acts in the hypothalamus and in the thalamus to modulate food intake, body temperature, and pain sensitivity. Animals were tested after local intracerebral microinjections of 5 ng of IL-1beta dissolved in 0.3 microl of saline, or of 0.3 microl saline alone. The results show that IL-1beta has anorectic effects in 3 diencephalic sites (the perifornical area, an area above the optic chiasma, and an area internal to the mamillo-thalamic tract), and not in 9 other sites tested. IL-1beta has hyperthermic effects in 7 sites (the media] and lateral preoptic area, the hypothalamic periventricular substance, the dorso-medial and arcuate nuclei of the hypothalamus, and the centro-medial and gelatinosus nuclei of the thalamus), and not in 6 other sites. IL-1beta has analgesic effects in the centro-medial and gelatinosus nuclei of the thalamus, and not in 7 other sites. IL-1beta also increases food intake and decreases pain sensation thresholds in the paraventricular nucleus of the hypothalamus. Therefore IL-1beta has very selective anatomical sites of action in the brain, and the paraventricular nucleus of the hypothalamus appears to have special properties regarding the effects of IL-1beta on food intake and pain sensation regulation.

Extensive brain mapping of calcitonin-induced anorexia.

The purpose of this study was to compare the localization in the brain of calcitonin-induced anorexia to the distribution of calcitonin binding sites (as described by others). We, thus, performed an extensive mapping of brain structures to determine those involved in calcitonin-induced anorexia. A significant anorexia is found after injection of calcitonin (15 ng in 0.3 microliters) into several brain areas. Forebrain: lateral septum, lateral part of the anterior commissure, and bed nucleus of the stria terminalis; hypothalamus: floor of the anterior part of the hypothalamus, paraventricular nucleus and adjacent perifornical area; thalamus: nucleus reuniens, an area internal to the mamillo-thalamic tract, and medial geniculate body; other areas: amygdala, lateral hippocampus, and central gray. No significant effect is found in the following areas: forebrain: nucleus accumbens, striatum, and medial septum; hypothalamus: lateral, ventro-medial, dorso-medial, and posterior nuclei; thalamus: centro-medial nucleus, lateral part of the zona incerta, and lateral geniculate body; hippocampus: dorsal and ventral parts; midbrain: central tegmentum, ventral tegmental area, and substantia nigra. When these results are compared to the distribution of calcitonin binding sites in the brain, two types of discrepancies are found. The first is the absence of effect in areas containing receptors: these areas may be involved in calcitonin-induced behaviors other than food intake. The second is the occurrence of anorexia in areas where no receptors are found: this finding is not easy to explain and raises some speculative hypotheses. In conclusion, calcitonin is active to decrease food intake in several brain areas, the strongest effect occurring in the paraventricular/perifornical area.(ABSTRACT TRUNCATED AT 250 WORDS)

[Humoral and cellular immunologic reactions in various forms of chronic psychiatric diseases]. / Etude des réactions immunitaires humorales et cellulaires dans diverses formes de pathologies psychiatriques chroniques.

Studies on the status of the immune system in mental disorders have mostly provided contradictory results. For example, some authors have reported dramatic increases of immunoglobulin G in schizophrenic patients, and others a decrease of immunoglobulin G in the same patients. This prompted us to undertake a study on a large cohort of psychiatric patients (120 schizophrenics, 30 manic-depressives, 8 epileptics, 48 cases of Alzheimer and vascular dementia, 23 cases of alcoholic dementia, 14 cases of childhood psychosis, 47 encephalopaths, and 21 chronic alcoholics), all chronically hospitalized. Plasma antitetanus antibodies were assayed in 238 previously immunized patients, the tuberculin test was performed on 302 patients, and the candidine test on 287 patients. Furthermore, 21 patients had an antitetanus vaccine booster injection with antibodies assayed before the injection and one month later, and 31 patients had 2 tuberculin tests with a year or more between them. The results show no major abnormal immune disorders in the patients. Nevertheless some particular features have been found. The first is a very significant relation between the age and the weakness of the immune defences. The second is a large scattering of the blood tetanus antibodies titers in schizophrenic patients, specially in the paranoid subgroup (20.6% of abnormally high or low titers). And the third is the existence of inpredictable variations in the responses when stimulations, or tests, are repeated. These results can raise the hypothesis of a state-dependent component of the immune response in mentally ill patients, but further in, depth studies are needed for better understanding the nature of our findings.

Analgesic effects of antibiotics in rats.

Studies in forelimb-deafferented rats suggest that treatment with certain antibiotics can decrease pain sensation. To test this hypothesis, the analgesic effects of nine randomly selected antibiotics were studied in rats by using a constant-temperature hotplate. The results show that several antibiotics have antinociceptive properties, and two of them, chloramphenicol and ampicillin, can produce analgesia in a dose range used in human therapy (100 mg/kg). This analgesia is comparable to salicylate and ketoprofen analgesia but lower than pethidine's one. The analgesia is long lasting with chloramphenicol (10 h or more). These antinociceptive properties cannot be attributed to sedation because amphetamine-induced hyperactivity, measured in an open field, is not sensitive to injection of the most sensitive antibiotics.

Medial diencephalic sites involved in calcitonin-induced hyperthermia and analgesia.

Calcitonin is a peptide hormone which can act centrally to decrease food intake and locomotor activity, and increase body temperature and nociceptive thresholds. In a previous study we showed that the brain sites involved in the food intake and locomotion decreases were mostly the paraventricular nucleus, the perifornical area and the preoptic area above the optic chiasma. We now study the diencephalic sites involved in calcitonin-induced increases in body temperature and nociceptive thresholds. Salmon calcitonin (15 ng in 0.3 microliters) was injected in several diencephalic sites, and the effects on body temperature and nociceptive thresholds compared with a saline injection. The results show that the sensitive sites are the dorsomedial nucleus of the hypothalamus, the preoptic area and the centromedial nucleus of the thalamus, and not the paraventricular nucleus and adjacent perifornical area. Therefore, different kinds of central effects of calcitonin can be differentiated on an anatomical basis.

Antagonism of calcitonin-induced anorexia by chronic, but not acute, tricyclic antidepressants in the rat.

Intraperitoneal or intracerebral injections of calcitonin in the rat produce several behavioral and hormonal effects which have some analogies with the human depressive syndrome. To determine if calcitonin effects are sensitive to antidepressant drugs, the ability of antidepressants and other psychotropic drugs to interact with calcitonin-induced anorexia was tested. The results show that chronic treatments (21 days) with tricyclic, or with tetracyclic, antidepressants significantly tend to neutralize the anorectic effect of calcitonin. Other antidepressants and other psychotropic drugs had no significant effect. The acute administration (24 h) of clomipramine did not antagonize the effect of calcitonin, and even significantly enhanced it. These results allow the author to propose the effects of calcitonin in the rat as a new animal model of depression, and to raise the hypothesis that a possible mechanism of action of tricyclic antidepressant treatments is to counteract the effects of certain brain peptides.