Real-World Effectiveness and Predictors of Nurse-Led Individual Cognitive Behavioral Therapy for Mental Disorders: An Updated Pragmatic Retrospective Cohort Study.

The importance of nurses integrating effective psychological techniques into their clinical practice is widely recognized. Nevertheless, further evidence from real-world settings is needed to establish nurse-led cognitive behavioural therapy (CBT) as an effective approach in clinical practice. This study aimed to examine the clinical effectiveness and predictors of individual CBT for mental disorders delivered by nurses in various routine clinical settings. This pragmatic retrospective cohort study collected data from participants who received nurse-led individual CBT at four institutions from different prefectures in Japan between April 2015 and March 2023. During the study period, 280 clients were referred to nurses for CBT, 240 of whom received nurse-led individual CBT of at least one session. The common primary diagnoses among participants were major depressive disorder (33.8%), social phobia (12.9%), and obsessive-compulsive disorder (10.0%). Of these, 23 participants were ongoing cases at the end of the observation period, and 217 who had completed the course of therapy or discontinued/dropped out from the therapy were included in the analysis (173 completed and 44 discontinued/dropped out (i.e., dropout rate = 20.3%)). Based on the clinical significance definition (primary outcome), 62.4% of the participants who completed the therapy were judged to demonstrate positive clinical significance (recovered or improved), with only a few participants (6.9%) demonstrating deterioration. Significant improvements were observed before and after nurse-led individual CBT across all secondary outcomes, including depression and anxiety symptoms, health-related quality of life, and functional disability (all ps ≤ 0.001). Univariate logistic regression revealed that clients with higher baseline severity of depression and anxiety symptoms were less likely to achieve positive clinical significance following nurse-led individual CBT. The real-world evidence gained through this study will encourage frontline nurses and motivate institutional/organizational leaders and policymakers to employ nurse-led individual CBT, especially for depression and anxiety-related disorders.

Characteristics of psychiatric patients with hypokalemia after yokukansan administration: A retrospective study.

Aim: Yokukansan is a Japanese herbal medicine used in psychiatry to treat behavioral and psychological symptoms of dementia and other psychiatric symptoms. However, the glycyrrhizic acid included in this medicine can cause pseudoaldosteronism and hypokalemia. We aimed to identify the risk factors for hypokalemia due to yokukansan. Methods: A retrospective cohort study was conducted on patients previously treated with yokukansan. The risk factors were determined by comparing the hypokalemia group with the non-hypokalemia group for each parameter. Results: This study included 304 patients who received yokukansan treatment between April 2009 and March 2019. We found that 17.4% (n = 53) of the patients experienced yokukansan-induced hypokalemia. Risk factors detected as significantly different between patients with and without yokukansan-associated hypokalemia were low serum potassium concentration before yokukansan administration, dose 7.5 g /day or more, and dementia. Hypokalemia occurred earlier in patients with low albumin, low potassium, and dementia. Conclusion: It is necessary to pay attention to hypokalemia onset when administering yokukansan at 7.5 g or more to patients with low potassium levels and dementia. Our findings suggest that potassium levels must be checked early after yokukansan administration, especially in patients with low albumin, low potassium, and dementia.

Case of reversible Mobitz type II atrioventricular block after the use of injectable antipsychotics.

Although Mobitz type II atrioventricular block is typically an arrhythmia arising from a permanent organic disorder of the His-Purkinje system, reversible factors should also be considered. Here, we report the association between a rare reversible Mobitz type II atrioventricular block and antipsychotic medication in a 75-year-old patient with schizophrenia.

Effects of intrathecal administration of newer antidepressants on mechanical allodynia in rat models of neuropathic pain.

Antidepressants, especially tricyclic antidepressants (TCAs) are widely used for the treatment of various types of chronic and neuropathic pain. The antinociceptive effects of TCAs are, however, complicated. Therefore, two kinds of newer antidepressants whose functions have been more fully clarified were selected, milnacipran, a serotonin and noradrenaline reuptake inhibitor (SNRI) and paroxetine and fluvoxamine, which are selective serotonin reuptake inhibitors (SSRIs). The antiallodynic effects of intrathecal administration of these newer antidepressants were examined in two rat models of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve and streptozotocin (STZ)-induced diabetic neuropathy. The antiallodynic effect of these antidepressants was evaluated using the von Frey test. The intrathecal administration of milnacipran had an antiallodynic effect in both CCI and STZ-induced diabetic rats in a dose-dependent manner. On the other hand, the intrathecal administration of either paroxetine or fluvoxamine elicited little antiallodynic effect in CCI rats, while both SSRIs had antiallodynic effects in the STZ-induced diabetic rats in a dose-dependent manner. These results indicate a considerable difference to exist in the development and/or maintenance between these two animal models of neuropathic pain and suggest that each of these three antidepressants may be effective for the treatment of diabetic neuropathic pain.

Development of the School Teachers Job Stressor Scale (STJSS).

AIM: Japanese teachers are not only responsible for students but also for tasks outside the classroom, including engagement with parents and the community, and maintaining safety. They work longer hours and have lower self-efficacy than teachers in other countries. Thus, we aimed to develop an assessment scale for job stress in teachers and to evaluate its psychometric properties. METHODS: We developed the "School Teachers Job Stressor Scale (STJSS) Draft" comprising 45 items, based on previous anonymous self-report questionnaires collected from 98 teachers in four elementary and middle schools in Miyazaki City, Japan. Subsequently, the scale draft and the previously validated Brief Job Stress Questionnaire (23-item abridged version) were distributed to 2276 teachers from 73 elementary and middle schools in Miyazaki City. Finally, we analyzed data from 1300 participants. After excluding inappropriate data based on ceiling and floor effect analysis, we carried out a good-poor, item-total correlation, and exploratory factor analyses. We then verified construct validity, criterion-related validity, and reliability using correlation analysis, confirmatory factor analysis, and Cronbach's alpha, respectively. RESULTS: After item-total correlation analysis, five items were excluded. Exploratory factor analysis extracted five factors: "Time spent outside of work," "Self-assessment of one's ability as a teacher," "Relationship with other teachers," "Social interactions outside of teaching," and "Duties outside of teaching." The final version of the STJSS comprised 23 items and five factors. CONCLUSION: The 23-item STJSS developed to measure specific stressors in Japanese teachers to improve their mental health care could provide an accurate assessment tool with adequate reliability and validity.

Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease.

The goal of this study was to examine the topological specificity of methamphetamine-induced activation of the immediate-early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6-OHDA rats. Lower levels of methamphetamine-induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine-induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6-OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6-OHDA rats. This may suggest that Fos and Zif268 therefore possess gene-specific and region-specific functions in the basal ganglia nuclei.

Psychological prenatal stress reduced the number of BrdU immunopositive cells in the dorsal hippocampus without affecting the open field behavior of male and female rats at one month of age.

We examined whether prenatal psychological stress with little physical stress causes changes in the behavior and neurogenesis of the offspring of Sprague-Dawley rats at one month. Dams in the last trimester of gestation were psychologically stressed by placing them in a social communication box and shocking a rat on the other side of a transparent wall. They suffered little physical stress. Male and female offspring from the dams showed little change in an open field test at postnatal day (PND) 30. To evaluate neurogenesis in the brain, BrdU was intraperitoneally injected at PND 35 into offspring not used in the open field test. Immunohistochemical examinations of BrdU in their dorsal hippocampus at PNDs 42 and 112 revealed that the number of BrdU immunopositive cells in the offspring of prenatally stressed rats was significantly smaller than in the offspring of unstressed ones. These results together with our previous finding that prenatal psychological stress can alter specific behaviors suggest that prenatal psychological stress can suppress neurogenesis in the dorsal hippocampus of rats of both sexes at PND 35 even though impairment in the behavioral task has not yet appeared.

A survey of the effects of ramelteon on benzodiazepine-dependence: Comparison between a ramelteon add-on group and a continuous benzodiazepine administration group.

In general, long-term benzodiazepine hypnotics are prescribed for patients in whom it is difficult to reduce benzodiazepine hypnotics. Unlike benzodiazepine receptor (BZ)-mediated sleep agents, ramelteon induces quasi-natural physiological sleep owing to its mechanism of action. We conducted a survey of ramelteon and BZ-dependence in patients with insomnia. Study subjects were patients with insomnia (42 cases), who were divided into a ramelteon group (22 cases; administered 8 mg/day of ramelteon before sleep in addition to BZ) and a control group (20 cases; continually administered only BZs), with a mean disease duration of 11.3 ±â€¯9.6 years. All data were analyzed using two-way repeated measures analysis of variance. No significant difference was observed between the ramelteon group and the control group when a questionnaire concerning BZ-dependence and withdrawal symptoms was used. A significant improvement in scores at Week 16 from those at Week 0 was observed in the Pittsburgh Sleep Quality Index excerpt and in the Global Assessment of Functioning in the ramelteon group [corrected].The Wilcoxon rank-sum test showed that the number of concomitantly used BZ hypnotics decreased significantly in the ramelteon group after Week 16, while no such change was observed in the control group. Thus, by adding ramelteon to therapy for patients with long-term insomnia, we were able to reduce the number of benzodiazepine hypnotics that were used concomitantly.

Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis.

In humans, stressful events during pregnancy may raise the risk of psychiatric disorders in offspring, and studies with rodents have found that physical prenatal stress can cause changes in the physiology, neurobiology, and behavior of offspring. In the present study, we examined whether psychological prenatal stress with little physical stress could cause changes in the neurobiology and behavior of offspring in Sprague-Dawley rats, as physical prenatal stress did. Dams received psychological stress by observing a rat being electrically shocked behind a transparent wall in the social communication box during the last trimester of gestation but were not exposed to any physical stress. Male offspring from the dams exposed to psychological stress showed enhanced emotionality in an open field test, depression-like behavior in a forced swim test, and enhanced activity in the hypothalamo-pituitary-adrenal axis, compared with rats from untreated dams. However, the prenatally stressed rats showed intact ability to acquire context conditioning. This is the first report that psychological prenatal stress in the communication box can cause changes in the neurobiology and behavior of offspring in rodents.

Partial regimen replacement with aripiprazole reduces serum prolactin in patients with a long history of schizophrenia: A case series.

AIM: Aripiprazole (ARP) is a popular antipsychotic drug that has demonstrated ameliorative effects on hyperprolactinemia. However, no study to date has studied the utility of ARP in patients with a long history of schizophrenia and antipsychotic treatment. We therefore examined the effect of partial antipsychotic regimen replacement with ARP on hyperprolactinemia induced by chronic antipsychotic use in patients with schizophrenia. METHODS: Sixteen patients with a schizophrenia diagnosis (F2) based on the International Classification of Diseases (version 10) were recruited. At months 0, 1, 3, and 6 of the study, serum prolactin, body weight, and blood glucose were measured, and QOL and psychotic symptoms were assessed using Global Assessment of Functioning scores and Clinical Global Impressions of Improvement (CGI-I) scores. RESULTS: Nine patients with an average age of 46.7±9.6 years and mean disease duration of 15.9±10.4 years were included in the final analysis. Serum prolactin levels significantly decreased and GAF and CGI-I scores improved significantly over the 6-month period after partial replacement with ARP. Additionally, no changes were observed in body weight or blood glucose over the 6-month period. CONCLUSION: Partial antipsychotic regimen replacement with ARP improves hyperprolactinemia, and may improve the QOL of patients with a long history of schizophrenia. CLINICAL TRIAL REGISTRATION NUMBER: Japan Medical Association, Center for clinical trials D: JMA-IIA00245.

Burnout in Japanese residents and its associations with temperament and character.

AIM: High risk of burnout in healthcare workers has long been recognized. However, there are no methods to predict vulnerability to burnout. METHODS: We examined whether temperament and character are associated with burnout and depressive state in residents by using the Temperament and Character Inventory (TCI). The TCI was used for residents at the beginning of clinical training and then the Maslach Burnout Inventory-General Survey (MBI-GS) and the Self-Rating Depression Scale (SDS) were administered at the beginning of clinical training and after four and ten months. Participants were 85 residents who started clinical training after graduating from the University of Miyazaki Hospital in April 2012 and 2013. RESULTS: After ten months, 23.5% of participants were newly identified with burnout using the MBI-GS and 15.3% of participants were newly diagnosed with depressive state using the SDS. We found that residents with high Cooperativeness were significantly more prone to burnout and that residents with high Harm Avoidance and low Self-Directedness were significantly more prone to depressive states. CONCLUSIONS: Our results suggest that the TCI can predict not only the risk for future depressive state but also the risk for future burnout. We feel it is important for the resident education system to identify residents with these temperament and character traits and to help high-risk residents avoid burnout and depressive state.

Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation.

To investigate the role mesostriatal dopamine system plays in pain processing, we examined the withdrawal response of rat hindpaws to mechanical stimulus at 1, 4, and 12 weeks after unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathway. In all of the 6-OHDA rats examined, almost no tyrosine hydroxylase (TH) immunoreactivity was detected in the substantia nigra, ventral tegmental area, and striatum ipsilateral to 6-OHDA lesions. Alteration in the withdrawal response in this model animal was evaluated by comparing the latency of withdrawal reflex following the mechanical stimulus to the hindpaw. The latency of withdrawal response in the 6-OHDA rats was significantly reduced in the side ipsilateral to 6-OHDA lesions at all times observed, whereas that was not changed through the period observed in the contralateral side, indicating that dopamine depletion in the mesostriatal system has the influence on withdrawal response to the mechanical stimulus. These results show that the unilateral dopamine depletion causes hypersensitivity to the mechanical stimulus in the ipsilateral side, suggesting that, at least in part, dopamine in the mesostriatal system may be involved in sensory processing including pain sensation induced by mechanical stimulation.

Alteration of striatal [11C]raclopride and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine uptake precedes development of methamphetamine-induced rotation following unilateral 6-hydroxydopamine lesions of medial forebrain bundle in rats.

We studied the positron emission tomography (PET) tracer distributions of ligands for dopamine D1 receptors ([11C]SCH23390) and D2 receptors ([11C]raclopride) and of the dopamine precursor analog 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the brain after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher at 14 days than at 3 days after the 6-OHDA lesions. The brains of 6-OHDA-treated rats were analyzed by tissue dissection following i.v. bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [11C]Raclopride, but not [11C]SCH23390, showed higher accumulation in the striatum on the lesion side than on the non-lesion (intact) side both at 3 days and 3 weeks postlesion. On the other hand, lower accumulation of [18F]FDOPA was observed in the striatum on the lesion side at 3 days postlesion and in both the striatum and cerebral cortex on the lesion side at 3 weeks postlesion. Our studies demonstrate that an increase in [11C]raclopride and a decrease in [18F]FDOPA uptake in the denervated striatum is evident even at 3 days after the 6-OHDA lesions when the methamphetamine-induced rotational behavior is not established.

Morphological changes in immunopositive cells of ionotropic glutamate receptor subunits during the development of transplanted fetal ventral mesencephalic neurons.

To elucidate the morphological changes in immunopositive cells of ionotropic glutamate receptors within intrastriatal 'developing' grafts of fetal ventral mesencephalon (VM) in 6-hydroxydopamine-lesioned rats, immunohistochemistry was performed to detect cells expressing N-methyl-D-aspartate (NMDA) receptor subunit 1 (NR1), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunits (GluR1, GluR2/3, and GluR4), or tyrosine hydroxylase (TH) in the intrastriatal VM grafts at 1, 4, and 12 weeks following transplantation. One week after transplantation, TH-positive cells were detected without any immunoreactivity of the NMDA and AMPA receptor subunits in the grafts. Four weeks after transplantation, TH-positive cells, distributed homogeneously in the grafts, appeared to be multipolar and larger compared to those at 1 week post-grafting. At this stage, we could observe immunopositive cells of NMDA and AMPA receptors distributed homogeneously in the grafts. Twelve weeks after transplantation, the numbers of NR1- and GluR1-positive cells were smaller than that at 4 weeks post-grafting, whereas TH-positive cells appeared to be more matured in shape and size. On the other hand, the numbers of GluR2/3- and GluR4-positive cells were not changed as compared with those at 4 weeks post-grafting. These results suggest that the ionotropic glutamate receptors have differential roles during the developmental period of the intrastriatal VM grafts.

Intrastriatal grafts of fetal ventral mesencephalon improve allodynia-like withdrawal response to mechanical stimulation in a rat model of Parkinson's disease.

We previously reported that a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease showed allodynia-like withdrawal response to mechanical stimulation of the ipsilateral side of the rat hindpaw. The goal of this study was to investigate the effect of intrastriatal grafts of fetal ventral mesencephalon (VM) on the withdrawal response in 6-OHDA rats. The withdrawal threshold in response to the mechanical stimulation of the rat hindpaw was measured using von Frey filaments. In the ipsilateral side of the 6-OHDA lesions, the withdrawal threshold in response to mechanical stimulation significantly increased in 6-OHDA rats with VM grafts compared with those with sham grafts, but did not change in the contralateral side at 5 weeks after transplantation. The present results suggest that the intrastriatal grafts of fetal VM may relieve pain sensation induced by mechanical stimulation in 6-OHDA rats.

The role of spinal serotonin receptor and alpha adrenoceptor on the antiallodynic effects induced by intrathecal milnacipran in chronic constriction injury rats.

Milnacipran, a reuptake inhibitor of noradrenaline (NA) and serotonin (5-HT), elicits an antiallodynic effect in rats with neuropathic pain; however, the role of NA and 5-HT receptors in the induction of the antiallodynic effect of milnacipran remains unclear. Thus, we examined the effects of prazosin as an α1 adrenoceptor antagonist, yohimbine as an α2 adrenoceptor antagonist, metergoline as a 5-HT1, 5-HT2 and 5-HT7 receptor antagonist, cyanopindolol as a 5-HT1A/1B receptor antagonist, ketanserin as a 5-HT2 receptor antagonist, and ondansetoron as a 5-HT3 receptor antagonist on the antiallodynic effect of milnacipran in neuropathic rats with chronic constriction injury (CCI). The CCI rats expressed mechanical and thermal allodynia, which was attenuated by intrathecal injection of milnacipran. Yohimbine, but not prazosin, reversed the milnacipran-induced antiallodynic effect. The antiallodynic effect of milnacipran was also reversed by metergoline, ketanserin and ondansetron, while cyanopindolol reversed the antiallodynic effect on mechanical, but not thermal stimulation. Furthermore, c-Fos expression in lamina I/II of the spinal dorsal horn was enhanced by thermal stimulation and the enhanced expression of c-Fos was suppressed by milnacipran. This effect of milnacipran was reversed by yohimbine, metergoline, katanserin and ondansetron, but not prazosin. These results indicate that the effect of milnacipran on mechanical and thermal allodynia and c-Fos expression is elicited through the α2 adrenoceptor, but not α1 adrenoceptor, and 5-HT2 and 5-HT3 receptors; furthermore, the 5-HT1A/1B receptor is involved in mechanical allodynia, but not thermal allodynia.

Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats.

To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin.

Differential expression of FosB, c-Fos, and Zif268 in forebrain regions after acute or chronic L-DOPA treatment in a rat model of Parkinson's disease.

A study was carried out to examine the effects of acute and chronic L-DOPA treatment on the distribution of the immediate-early gene (IEG) proteins (FosB, c-Fos, and Zif268) in forebrain regions in a unilateral 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. During a course of chronic L-DOPA treatment (15 mg/day, 15 days), rats with a 6-OHDA lesion developed abnormal involuntary movements. Compared with the rats in the acute L-DOPA treatment group, those in the chronic treatment group had significantly more FosB-immunopositive cells in the anterior cingulate (Cg) and the dorsolateral caudate-putamen ipsilateral to the lesion and significantly fewer c-Fos-immunopositive cells in the Cg, the nucleus accumbens shell, and the basolateral nucleus of amygdala ipsilateral to the lesion. No significant difference was observed in the number of Zif268-immunopositive cells between the acute and chronic L-DOPA groups. In summary, differential expression of three IEG proteins was observed in the forebrain regions during a course of chronic L-DOPA treatment of 6-OHDA-treated hemiparkinsonian rats.

Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model.

The objective of the present study was to examine whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, has an analgesic effect in rats with neuropathic pain. In addition, the c-Fos expression was investigated in the supraspinal sites of the brain and in the spinal dorsal horn in association with the nociceptive processing in rats with neuropathic pain produced by chronic constriction injury (CCI) in the sciatic nerve. In the CCI-induced neuropathic rats, behavioral testing for determining the change in the withdrawal threshold to mechanical stimulation and immunohistochemical detection of c-Fos were both performed. The anti-allodynic effect derived from milnacipran gradually increased over the observation period, indicating that the delayed-onset analgesia might be elicited by the continuous administration of milnacipran. The increased level of c-Fos expression in the anterior cingulate cortex (ACC) induced by noxious mechanical stimulation was significantly inhibited by the continuous administration of milnacipran, indicating that milnacipran might cause a functional modification in the nociceptive processing in the ACC.