[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.

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.

Anorectic effect of calcitonin, neurotensin and bombesin infused in the area of the rostral part of the nucleus of the tractus solitarius in the rat.

The three neuropeptides calcitonin, neurotensin and bombesin can decrease food intake in the rat when injected into the cerebral ventricles or into the paraventricular nucleus of the hypothalamus. The paraventricular nucleus of the hypothalamus is an important site for the integration of visceral and endocrine systems, and has connections with the nucleus of the tractus solitarius which is a major locus for visceral afferents. Since calcitonin, neurotensin and bombesin, or their receptors, have been found to be present in the nucleus of the tractus solitarius, we tested the effects of local infusions of these peptides on food intake. The peptides were microinjected in a 0.25 microliter volume in rats trained to eat for only 3 hours per day. The injections were made in the rostral part of the nucleus and surrounding areas, through the lateral vestibular nuclei, to avoid leakage of the peptides into the cerebrospinal fluid. In the nucleus of the tractus solitarius the three peptides decreased food intake by more than 50%. The peptides were also active in the spinal trigeminal nucleus oralis, and, for calcitonin and bombesin, in the reticular formation under the nucleus of the tractus solitarius. A local diffusion from the point of injection may explain some of these results. Therefore, the area of the nucleus of the tractus solitarius is a nonhypothalamic site where these peptides can act to produce anorexia.

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.

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.

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.

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.

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.

Electrophysiological investigation of cells in the region of the anterior hypothalamus firing in relation to blood pressure and volaemic changes.

The anterior hypothalamus has been implicated in the higher centre control of blood pressure and more recently in hydromineral balance regulation. Using a glass recording electrode with and without a 7-barrelled iontophoretic electrode we investigated this region for blood pressure-sensitive cells. We used a ventral approach through the optic chiasma. We found 36 cells out of 91 tested that increased their firing rate in response to a spontaneous or induced decrease in blood pressure. Of these 19 increased firing in response to angiotensin II (AII) injected into the lateral cerebral ventricle and 10 of these increased firing in response to local iontophoretic application of AII. Cells responsive to an increase in blood pressure were never found. Thus cells in this area respond to hypovolaemia and hypotension as well as to AII, which could link this area with higher centre responsiveness to stimuli of extracellular thirst.

Anatomical mapping of brain sites involved in the antinociceptive effects of ketoprofen.

Ketoprofen, a non-steroidal anti-inflammatory drug, has analgesic effects in animals and humans through a peripheral as well as a central action. This study was designed to determine which brain sites are involved in the central analgesic action of ketoprofen, by using the hot-plate test. Latencies to the first hindpaw lick were recorded in animals receiving local cerebral injections of ketoprofen (10 micrograms in 0.3 microliters) or a control solution (saline). Nineteen brain sites were tested. A significant analgesia was obtained in the 8 following sites: central gray, centro-medial nucleus of the thalamus, nucleus reuniens, dorso-lateral geniculate nucleus, medial geniculate nucleus, dorso-medial and ventro-medial nuclei of the hypothalamus, posterior hypothalamic nucleus and lateral vestibular nucleus. A slight analgesia, which did not reach significance, was observed in three structures: dorsal raphé, raphé magnus and ventral postero-medial thalamic nucleus. No analgesia was observed in other sites: centro-lateral nucleus of the thalamus, posterior thalamic nuclear group, parafascicular nucleus, bed nucleus of the stria terminalis, mesencephalic tegmentum, nucleus of the tractus solitarius, spinal trigeminal complex, and brainstem reticular formation. Therefore ketoprofen seems to be centrally active mostly at the level of several integrative and non-specific structures.

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 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.

Unit activity in the nucleus triangularis septi of the rat following blood pressure changes or vasoactive peptides, and electrically stimulated blood pressure decreases.

The nucleus Triangularis Septi (TS) of anesthetized rats was studied using iontophoretic application of various vasoactive peptides (vasopressin and angiotensin) to a small number of the cells in this nucleus and blood pressure recordings during electrical stimulation of the nucleus. In the iontophoretic study 83% of the cells investigated were found to be sensitive to iontophoretic application or intracerebroventricular infusion of angiotensin II and vasopressin and that 40% of these cells were sensitive to spontaneous or induced increases of blood pressure. Electrical stimulation of the nucleus produced a reliable and reproducible decrease in blood pressure without any change in heart rate. Therefore the possible role of the TS in blood pressure regulation is discussed.

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)

Iontophoretic application of angiotensin II, vasopressin and oxytocin in the region of the anterior hypothalamus in the rat.

The anterior hypothalamus has been implicated in the regulation of hydromineral balance, drinking, vasopressin release, sodium excretion and blood pressure control. Using anaesthetized rats, we have looked at the activity of cells in this region through using a recording electrode cemented to a 7 barrelled iontophoretic electrode inserted ventrally. Cells were tested for their responsiveness to iontophoretic application (Io) of angiotensin II (AII), vasopressin (AVP) and oxytocin (Ox). Of the 47 cells found to responsive to Io glutamate, 23 increased firing to AII, 18 to AVP and 6 to Ox. Nine cells responsive to AVP also responded to AII. Two cells responded to both Ox and AII. It appears that this rostral diencephalic area has neurons sensitive to more than one of the hormones implicated in the various responses involved in hydromineral regulation.

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.

Iontophoretic investigation of identified SFO angiotensin responsive neurons firing in relation to blood pressure changes.

Activity of 29 histologically identified units in the SFO was recorded in parallel to blood pressure monitoring. The responsiveness of these units to angiotensin II (AII) applied either iontophoretically or via the carotid artery (IC) was investigated together with the capacity of the vasodilator substance NO2- to block the AII response. Fifty-five% of the SFO units responded to iontophoretic application of AII (vs. 27% in the surrounding areas). SFO units were also activated by blood pressure depressions, either as a mirror image (type B) or only restricted to the initial descendent phase of the hypotensive wave (type A). But 8 of the 29 units responded in a mixed A and B fashion, i.e., dramatic firing in the very beginning of the hypotension followed by a sustained moderate response until recovery. Hypertensive spontaneous fluctuations rarely and inconsistently elicited an inhibitory response. An unexpected phenomenon of a hypotensive response following IC injections of low doses of AII was observed and used in this investigation. These observations together with the finding that vasoplegics inhibited unit firing suggest that the SFO is equipped with units able to sense a reduction in local vessels' calibre and fire in relation to it. When activated chemically, electrically or mechanically these units may then trigger hypertensive, antidiuretic and drinking responses.

Antibiotics and morphinomimetic injections prevent automutilation behavior in rats after dorsal rhizotomy.

Unilateral section of dorsal roots C5 to T1 were performed in rats, and the automutilation behavior was measured by the extent of the limb lesions expressed in arbitrary units. Changes in the scores of automutilation were studied after the injection of four substances: a morphinomimetic (pethidine) and three antibiotics, chloramphenicol, amoxicillin, and doxycycline. Effects were tested on groups of at least eight rats that were compared with another group of eight animals operated on in the same way but injected with distilled water. The animals of the group treated with pethidine performed significantly less autotomy than did the animals in the control group. The same effect was found when the animals were injected with chloramphenicol and amoxicillin. On the contrary, doxycycline was found less efficacious. These results are discussed using the hypothesis of autotomy caused by an abnormal painful sensation felt in the deafferented forelimb.

Anatomical mapping of the rat hypothalamus for calcitonin-induced anorexia.

The primary physiological function of calcitonin, a peptide hormone secreted by the thyroid gland, is to modulate plasma calcium concentrations. Calcitonin also has several effects on the central nervous system including an inhibition of feeding behavior. In the present study synthetic salmon calcitonin (15 ng in 0.3 microliter) was found to produce a marked suppression of eating when infused in several hypothalamic areas. The greatest inhibition was produced by infusions into the paraventricular nucleus of the hypothalamus, the perifornical area and several areas on the floor of the hypothalamus. A less marked inhibition of eating was produced by infusions in the nucleus accumbens. Infusions in the olfactory tubercule, the ventrolateral hypothalamus, the medial forebrain bundle and the posterior nucleus of the hypothalamus had no effect. It is concluded that the anorectic effects of calcitonin on the central nervous system are mediated by several hypothalamic and extrahypothalamic sites.

Regional localization of the antagonism of amphetamine-induced hyperactivity by intracerebral calcitonin injections.

Calcitonin receptors are found in the brain, and intracerebral infusions of calcitonin can produce behavioral effects. Among these behavioral effects are decreases in food intake and decreases in amphetamine-induced locomotor activity. In previous experiments we found that decreases in food intake were induced by local administration of calcitonin into several hypothalamic sites and into the nucleus accumbens. In the present experiment calcitonin decreased locomotor activity when locally injected into the same sites where it decreases food intake. The areas where calcitonin is most effective in decreasing locomotor activity are located in the hypothalamus and nucleus accumbens, suggesting that these areas are the major sites of action of calcitonin in inhibiting amphetamine-induced locomotor activity.