bluuebunny/crossref_metadata_2025 huggingface dataset:
EVALUATION OF BEHAVIORAL SELECTION PROCESSES IN CONFLICT SCENARIOS USING A NEWLY DEVELOPED MOUSE BEHAVIORAL PARADIGM
Authors: Honshuku *Yuki , Hitora-Imamura Natsuko , Miyagami Yurika , Nomura Hiroshi , Katsuki Hiroshi , Minami Masabumi
Published: February 2025

Background

Selecting an appropriate behavior is critical for survival in conflict situations during which animals face both appetitive and aversive stimuli. Animals in conflict situations exhibit several processes. First, they stay still in a safe place (suspension); once they decide to take action, they assess risks at a place where danger may occur (risk assessment) and finally reach the reward. However, most studies have not addressed these conflict processes.

Aims & Objectives

We developed a new experimental paradigm– the three-compartment conflict task– to quantitatively evaluate conflict processes and examine the pharmacological validity of the task.

Method

The experimental apparatus for the three- compartment conflict task consisted of start, flat, and grid compartments. Mice were required to explore the grid compartment where they might receive electric footshocks while trying to obtain sucrose. We injected them with diazepam (1.0 mg/kg) intraperitoneally to evaluate its previously reported anti-conflict effect.

Results

We found that applying foot shocks increased sucrose acquisition latency, time in the start compartment, and the number of retreats in the subsequent trials, reflecting an elevated conflict level throughout the trials, in suspension, and in risk assessment, respectively. Strong footshock changed the location of retreats from near to far from the danger zone, reflecting fear generalization. Treatment with diazepam decreased these parameters.

Discussion & Conclusion

Our new paradigm is a valuable tool for quantitatively evaluating conflict processes and investigating the cognitive and neural basis of such behavior.
KEY FACTORS ASSOCIATED WITH TREATMENT-RESISTANT DEPRESSION- RELATED COGNITIVE DECLINE IN DIFFERENT AGE
Authors: Lee *Chi-Wei , Yang Tzu-Jung , Chu Ming-Chia , Chi Hsiang , Li Cheng-Ta , Lin Hui-Ching
Published: February 2025

Background

Cognitive dysfunction is strongly associate with late-life depression. Previous study further indicated that treatment-resistant depression (TRD) patients, which refers poor responses to adequate antidepressant treatment, have prominent cognitive impairment. Moreover, the depression patients with cognitive impairment could be a risk factor for dementia. Recent study revealed that increase of eIF4E phosphorylation have found highly associate with cognitive dysfunction and depressive symptom. The antidepressant effect of low-dose ketamine, which effective in treating TRD, is involved in regulate eIF4E. Previous study further indicated dramatic increase of eIF4E phosphorylation was observed in post-mortem of Alzheimer's disease patients. As mention above, eIF4E may be considered a potential target crossing the cognitive dysfunction and depressive symptom underlying aging.

Aims & Objectives

We hypothesized that eIF4E phosphorylation may involve in cognitive dysfunction and depression, especially TRD, following aging. In present study, we performed the TRD mice model which induced by traumatic stress in young- and mid-age mice.

Method

We applied the traumatic stress to induce the TRD mice model. The behavior tests were examined the depressive-like behaviors. The synaptic plasticity such as long-term potentiation (LTP) was examine by electrical physiology. The phosphorylation of eIF4E was examine by western blotting.

Results

The results indicated that depressive-like behavior was found after traumatic stress in both young- and mid-age mice. While, the cognitive impairment induced by traumatic stress was worse in mid-age mice. Moreover, the increased eIF4E phosphorylation was greater after traumatic stress in mid-aged mice. The depressive-like behavior was improved by eIF4E phosphorylation inhibition. Furthermore, the cognitive impairment only improved by inhibition of eIF4E phosphorylation.

Discussion & Conclusion

Present study demonstrated the relationship between cognitive dysfunction and depression, especially TRD population, following aging. Our finding further provided the evidences that eIF4E may a key factor which highly associate with cognitive dysfunction and depression following aging. To date, effective therapeutic strategy for cognitive dysfunction with TRD remain urgent. EIF4E may be considered a potential target for this issue.
THE INVOLVEMENT OF SPLENIC IMMUNE CELLS IN THE DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS
Authors: Ogawa *Moeka , Kunisawa Kazuo , Kosuge Aika , Tezuka Hiroyuki , Nabeshima Toshitaka , Mouri Akihiro
Published: February 2025

Background

Accumulating evidences suggest a substantial role of enhanced inflammatory responses in the pathophysiology of major depressive disorder (MDD). The spleen, a pivotal organ in the immune response, may play a role in the enhanced inflammatory responses of MDD. Chronic social defeat stress (CSDS) is well established to develop an animal model of MDD.

Aims & Objectives

In the present study, we investigated the involvement of the spleen in the CSDS-induced depression-like behaviors in mouse.

Method

In the CSDS, the adult C57BL/6J mouse was exposed to an aggressor ICR mouse for 10 consecutive days.

Results

CSDS effectively reduced the social interaction (SI) ratios in the social interaction test (SIT) and the time spent in the open arms in the elevated plus maze test (EPM) in C57BL/6J mouse. A remarkable observation was the significant increase in the spleen weight following CSDS, suggesting enhanced inflammatory response in the splenic immune cells. Splenectomy ameliorated the CSDS-induced social impairment in the SIT but not anxiety-like behavior in the EPM. CSDS elevated the levels of noradrenaline (NA) in the spleen. Interestingly, CSDS reduced the adrenergic β2 receptors, primarily localized on CD4+ T cells. Flow cytometry analysis revealed that CSDS decreased CD4+ T cells, but increased CD11b+Ly6C+ monocytes in the spleen. Antidepressant treatment significantly ameliorated the increase of CD11b+ Ly6C+ monocytes and social impairment induced by CSDS.

Discussion&Conclusion: These findings provide insights into the role of splenic immune cells in depressive-like behavior induced by CSDS. Furthermore, our results suggest that a decreased noradrenergic anti-inflammatory pathway may be implicated in the depression-like behavior induced by CSDS.
METHYLONE PRODUCES ANTIDEPRESSANT-RELEVANT ACTIONS AND PROSOCIAL EFFECTS
Authors: Li Zhenlong , Peng Hsien-Yu , Lee Chau-Shoun , Lin Tzer-Bin , Hsieh Ming-Chun , Lai Cheng-Yuan , Wu Han- Fang , Chen Lih-Chyang , Chen Mei-Ci , Chou *Dylan
Published: February 2025

Background

Methylone (3,4-methylenedioxy-N-methylcathinone) is a rapid-acting entactogen that has been shown to have significant benefits in patients with post-traumatic stress disorder and major depressive disorder and is well tolerated in phase 1 clinical trials. A recent preclinical study reported that methylone produced robust antidepressant-like actions in naï ve rats. However, its antidepressant effects on various stress-related psychopathologies and other neuropsychological actions remain unclear.

Aims & Objectives

In the present study, we examined the antidepressant-relevant effects of methylone in learned helplessness (LH) and social defeat stress C57BL/6J male mouse models and further explored its sociability-relevant neuropsychological actions.

Methods

Tail suspension test, female urine sniffing test, sucrose preference test, social interaction test, three-chamber test, social behavior test, observed fear conditioning, helping behavior, and electrophysiological recording were used.

Results

Our results indicate that methylone produces antidepressant-relevant effects on the helpless phenotype, LH-evoked depressive-like behaviors, and psychosocial stress-induced social avoidance, and induced depressive-like behaviors. In addition, methylone was found to enhance social preference and increase various social behaviors, including social contact, sniffing, allogrooming, and following. Moreover, methylone appeared to elevate empathy-like phenotypes and was also found to increase helping-like behavior.

Discussion & Conclusion

Overall, the present results suggest that methylone plays an antidepressant-like role in various stress-relevant psychopathologies and could be an ideal antidepressant candidate. In addition, novel findings on the elevated tendencies of social preference and empathy-like and helping-like phenotypes reveal that methylone may have potential application in patients with social deficits.
CLINICAL VALUE OF PLASMA SOLUBLE TREM2 IN IDENTIFYING MILD COGNITIVE IMPAIRMENT: A COMMUNITY-BASED STUDY OF THE CHINESE ELDERLY
Authors: Huang Anqi , Wang *Lan
Published: February 2025

Objectives

To clarify that correlation in plasma soluble TREM2 (sTREM2) and cognitive function between mild cognitive impairment (MCI) and normal cognitive function in a Chinese community population, and further to explore whether plasma sTREM2 can be used as a blood biomarker to predict and identify MCI.

Methods

This study included 216 community elderly people in Shijiazhuang and Xingtai City, Hebei Province, including 106 MCI and 110 normal cognitive function (NC) subjects. The Montreal cognitive assessment (MoCA) was used, mini mental state examination (MMSE), Boston naming test (BNT), digit span test (DST) to evaluate the cognitive functions of all subjects. Fasting venous blood was collected at the same time, and ELISA was used to detect Aβ42, Aβ40, P-Tau217, P-Tau231, TREM2, sTREM2 concentration. Use software based on SPSS 26.0 to analyze the data.

Results

1. The level of sTREM2 in the MCI group was higher than that in NC group, and the difference was statistically significant (H=4312.0, P=0.001). There was no statistical significance in the difference of the other index between two groups (P>0.05). 2.Correlation analysis showed that sTREM2 was negatively correlated with P-tau217, education level, MMSE, MoCA, BNT, and DST (P<0.05). TREM2 was positively correlated with P-tau217 and Aβ42 (P<0.05). 3. Incorporate whether it was MCI as the dependent variable, gender, age, education level, living style, and the above blood indicators as independent variables in binary logistic regression analysis. The results showed that sTREM2 was a risk factor for MCI (OR=1.009, 95%CI=1.002-1.016, P=0.015), junior high school education or above was a protective factor for MCI (OR=6.133, 95 % CI=2.651-14.189, P<0.001). 4.The area under the ROC curve of sTREM2 was 0.630 (sensitivity 0.472, specificity 0.782), and the area under the ROC curve of sTREM2 combined with MMSE was 0.849 (sensitivity 0.679, specificity 0.873).

Conclusion

sTREM2 is a risk factor for cognitive function decline in MCI. Plasma sTREM2 levels combined with the cognitive function assessment scale have good clinical value in identifying mild cognitive impairment.
BARRIERS TO AND FACILITATORS OF USER ENGAGEMENT WITH PSYCHOLOGICAL FIRST AID CHATBOT INTERVENTION: FEASIBILITY STUDY
Authors: Frankova *Iryna , Lahutina Sofiia
Published: February 2025

Background

Full-scale war of aggression upon Ukraine (February 2022 – ongoing) has affected millions of people (Poberezhets, 2022). Violence, forced displacement, participation in hostilities, loss of loved ones during military conflicts can directly increase the risk of mental disorders, namely post-traumatic stress disorder, depression and anxiety disorders, as well as significantly reduce the quality of life of victims (Grasser, 2022; Bü rgin et al., 2022). Psychological first aid (PFA) involves the provision of immediate support to survivors of violence and trauma in order to reduce stress, alleviate suffering and accelerate recovery (Figueroa et al., 2022). At the same time, the timing of providing PFA after exposure to a traumatic event plays an important role (Vermetten et al., 2020).The digital format of providing PFA can provide rapid, affordable, scalable and effective solution during war, when there is a limited mental health resources, including insufficient numbers of trained professionals, infrastructural gaps, and financial constraints (Mahmoud et al., 2022).

Aim

to assess the feasibility of a digital PFA micro intervention in chatbot during the golden hours and first months for the adult population of Ukraine affected by the war.

Methods

thematic analysis of users` feedback.

Results

a total of 102,391 activated "Friend" PFA chatbot from the 1st of March 2022 to the 1st October 2023. The specifics of using a chatbot have been carried out through a detailed analysis of qualitative and quantitative users` feedback. 2,207 users were surveyed, most of whom (45.2%) gave it an “Excellent” rating, while another significant portion (39.3%) rated the bot as “Fair”. 9.3% of users rated the bot "Bad", 6.2% saw it as "Terrible". 1,557 written feedback were qualified as valuable reviews that were subjected to qualitative analysis. Factors extracted for coding were related to the end user, the program or content offered by the intervention, and the technology and implementation environment. Common barriers included severe mental health issues that hampered engagement, technical issues, and a lack of personalization. Common facilitators were social connectedness facilitated by the intervention, increased insight into health, and a feeling of being in control of one’ s own health.

Discussion And Conclusion

User feedback analysis has been integrated to optimize and personalize the service. Conducting a feasibility study of user engagement with a digital tool is a proactive approach to ensure that the tool meets its intended purpose, resonates with the target audience, and provides a positive return on investment. It allows to make data-driven decisions, mitigate risks, and optimize the tool's design and functionality to enhance engagement and overall success.
CLINICAL UTILITY OF IMPACT OF EVENT-SCALE-REVISED FOR DSM-5 POSTTRAUMATIC STRESS DISORDER
Authors: Chang So-Yeon , Joo *Yonghee , Bae Jeong-Hoon , Kim Won-Hyoung , Park Joo-Eon
Published: February 2025

Background

The Impact of Event Scale-Revised (IES-R) is one of the most widely used self-report measures of post-traumatic stress disorder (PTSD), though it was based on the DSM-IV Diagnostic criteria.1 The previous studies have suggested a cutoff point of the IES-R according to DSM-IV.2

Aims & Objectives

The aim of this study is to investigate whether the IES-R is applicable within the DSM-5 nomenclature and to determine the cutoff point for DSM-5 PTSD diagnosis.

Methods

A total of 238 subjects, recruited from multiple psychiatric centers, participated in this study, including 67 with PTSD, 72 with psychiatric controls, and 99 with healthy controls. All subjects completed the Korean version of the structured clinical interview for DSM-5 Research Version to confirm the presence of PTSD, the Korean version of the PTSD checklist for DSM-5 (K-PCL-5), the Beck Depression Inventory-II (BDI-II), the Beck Anxiety Inventory (BAI), and the Spielberger State Trait Anxiety Inventory.

Results

The IES-R presented good internal consistency (Cronbach's α = 0.95). The IES-R was correlated highly with K-PCL-5. Factor analysis identified five factors in the IES-R, which we labeled as intrusion, avoidance, hyperarousal, sleep disturbance, and numbness-dissociation. The suggested cutoff score for PTSD was 25 of the IES-R with a sensitivity of 86.57 and a specificity of 82.46.

Discussion & Conclusion

These results demonstrated the good concurrent validity with current DSM-5 PTSD scale and adequate diagnostic utility for screening current DSM-5 PTSD. This study suggests that a cutoff score of 25 on the IES-R should be considered when the scale is used to screen for DSM-5 PTSD diagnosisa

References

1)Weiss, DS 2007, Cross-Cultural Assessment of Psychological Trauma and PTSD, Springer, Boston, MA. Eun H-J 2005, 2) A study on reliability and validity of the Korean version of impact of event scale-revised, J Korean Neuropsychiatr Assoc, 44(3), pp. 303–310.
CELL TYPE-SPECIFIC TRANSCRIPTIONAL CHANGES FOLLOWING CHRONIC TREATMENT OF CLOZAPINE IN MOUSE PREFRONTAL CORTEX
Authors: Park Kyungtaek , Kang Nuree , Huh Seong-Hoo , Won Sungho , Kim *Se Hyun
Published: February 2025

Background

Schizophrenia is a major psychotic disorder with complex genetic underpinnings. Clozapine is one of the representative antipsychotics for its unique and superior efficacy. The current understandings of clozapine’ s mechanism do not fully explain the favorable therapeutic properties of clozapine, in which the differential gene activation related to the pathophysiology of schizophrenia may be involved. Therefore, studying the transcriptomic changes induced by clozapine could contribute to the advancement of schizophrenia treatments.

Aims & Objectives

We aimed to investigate cell type-specific clozapine-induced transcriptional changes in mouse prefrontal cortex through single-cell RNA sequencing (scRNA-seq). The goal of this study was to provide important insights into the mechanism of action of clozapine and examine its associations with genes related to the etiology of schizophrenia.

Method

In this study, clozapine was systemically injected into male C58BL/6 mice for 21 consecutive days, and single-cell RNA sequencing was applied to their prefrontal cortical tissue samples. Differentially expressed genes (DEGs) for each cell type, including microglia, astrocytes, neurons, endothelial cells, and vascular smooth muscle cells, were identified through single-cell RNA sequencing. Pathways and intercellular interactions associated with these DEGs were then analyzed. Additionally, a comparative analysis with human databases was conducted, using the toxicogenomics database (CTD), genetic loci implicated in schizophrenia, and genes with evidence of interaction with clozapine.

Results

Clozapine-induced changes in gene expression were most prominent in microglia, and the cell population clusters within microglia were altered by clozapine exposure. Pathway analyses highlighted TNF-α signaling via NF-κ B, IFN-γ response, IFN-α response, and p53 pathway as particularly engaged by clozapine. Cell-cell interaction analysis demonstrated the clozapine-induced interactive changes among microglia, endothelial cells, and vascular smooth muscle cells. Comparative analysis with human data also revealed enriched clozapine-induced DEGs in microglia. As a result, eleven genes, including Nfkb1, Nfe2l2, Egr1, Fos, and Atp6v1b2, were elucidated to have convergent evidence.

Discussion & Conclusion

By using scRNA-seq, we identified discrete cell types and their alterations in the mouse prefrontal cortex. While microglia are mainly impacted by clozapine exposure, other cell types also display distinct changes. Single-cell RNA sequencing could provide important insights into the mechanisms of action of clozapine, a representative antipsychotic with superior efficacy, which has links to the genetic background of pathogenetic and therapeutic mechanisms in schizophrenia.
ASSOCIATIONS BETWEEN NEUROMELANIN ACCUMULATION IN PATIENTS WITH SCHIZOPHRENIA AND TREATMENT RESPONSIVENESS: A CROSS- SECTIONAL NM-MRI STUDY
Authors: Ueno *Fumihiko , Iwata Yusuke , Honda Shiori , Horga Guillermo , Cassidy Clifford M , Torres-Carmona Edgardo , Song Jianmeng , De Luca Vincenzo , Tsugawa Sakiko , Noda Yoshihiro , Agarwal Mahavir , Gerretsen Philip , Nakajima Shinichiro , Graff-Guerrero Ariel
Published: February 2025

Background

Neuromelanin (NM) is a byproduct of monoamine metabolism, including that of dopamine. NM-sensitive Magnetic Resonance Imaging (NM-MRI) sequences enable the in vivo quantification of NM levels in the substantia nigra (SN). The NM-MRI signal is considered a surrogate marker for the integrity of SN dopamine neurons and, consequently, striatal dopaminergic functioning. Elevated striatal dopamine synthesis is associated with patients responsive to first-line antipsychotics (FLR) in schizophrenia, while normal striatal dopamine synthesis is implicated in the pathophysiology of treatment-resistant schizophrenia (TRS). Clozapine is the only antipsychotic currently approved for TRS. However, no studies have yet explored the relationship between SN accumulations, as measured by NM-MRI, and clozapine response in TRS patients.

Aims & Objectives

The study aims to investigate differences in dopaminergic activities among schizophrenia patients based on their treatment response, using NM-MRI.

Methods

The study enrolled TRS patients who either did not respond to clozapine (ultra-resistant schizophrenia [URS]) or did respond (non-URS), along with FLR patients and healthy controls (HCs). TRS was defined as resistance to at least two first-line antipsychotics and ongoing clozapine treatment at the time of the study. SN-NM levels were measured using 3T-MRI. The Contrast Ratio (CR) was calculated as the relative signal intensity difference between the SN and the crus cerebri. SN-CR values were compared between groups, controlling for age and sex. Associations between SN-CR and symptom severity scores were also explored within patient groups.

Results

A total of 78 participants (URS: n=16; non-URS: n=16; FLR: n=20; HCs: n=26) completed the study. Overall group differences in SN-CR values were significant (F(3,72)=3.80, η2=0.21, p=0.001). Specifically, URS patients (Cohen’ s d=0.86, p=0.049) and FLR patients (Cohen’ s d=1.27, p<0.0001) exhibited higher SN-CR values compared to HCs. No associations were found between SN-CR values and symptom severity scores within each group or the entire patient cohort.

Discussion & Conclusion

This study is the first to assess a proxy measure of mesostriatal dopamine function in schizophrenia patients, stratified by treatment responsiveness, using NM-MRI. We observed elevated SN-NM contrast in URS and FLR patients compared to HCs, and levels similar to HCs in non-URS patients. Longitudinal studies are warranted to determine whether SN-NM levels can serve as a reliable biomarker for predicting treatment response in schizophrenia.
SAFETY AND EFFICACY OF LEMBOREXANT IN PATIENTS WITH INSOMNIA DISORDER: REPORT FROM A POST-MARKETING OBSERVATIONAL STUDY
Authors: Mishima *Kazuo , Fujimoto Kenichi , Endo Akira , Ishi Mika
Published: February 2025

Background

The competitive dual orexin receptor antagonist lemborexant (LEM) has been available in Japan as a treatment for insomnia since July 2020. The most commonly reported adverse event (AE) in phase 3 studies was somnolence. A post-marketing observational study (E2006-M081-501) was conducted to examine the incidence of adverse drug reactions (ADRs) in daily clinical practice.

Aims & Objectives

To report the incidence of somnolence, nightmares, abnormal dreams, sleep paralysis, hypnotic hallucinations, suicidal ideation, and suicidal behavior in patients with insomnia disorder during treatment with LEM in daily clinical practice.

Methods

The enrollment period was from October 1, 2020 to September 30, 2021 with an observation period of 24 weeks. Informed consent was obtained from all subjects participating in the survey. Survey items included patient characteristics (eg, age, prior medication), incidence of AEs, overall improvement, and ADRs. The incidence rates of AEs and percentage of subjects demonstrating global improvement were calculated.

Results

The survey was conducted at 170 sites in 539 subjects. Among the 510 subjects included in the safety analysis, there were 210 males and 300 females; the mean age was 53.7 years and the proportion of subjects aged at least 65 years was 32.9%. The incidence of ADRs was somnolence 7.65% (39/510), nightmares 1.76% (9/510), abnormal dreams 0.59% (3/510), and sleep paralysis 0.20% (1/510). ADR incidence in this survey was similar to that reported in phase 3 studies. There were no ADRs related to hypnotic hallucinations, suicidal ideation, or suicidal behavior. The rate of global improvement in symptoms was 80.83% (371/459), excluding cases in which the evaluation time of global improvement was outside the acceptable range, the evaluation date was unknown, or a determination of improvement could not be made.

Discussion & Conclusion

The safety profile found in this analysis was comparable to that described in the LEM prescribing information, and the efficacy profile supports the clinical utility of LEM in the treatment of insomnia disorder.

Support

Eisai Co., Ltd.
CLINICAL EPIDEMIOLOGY OF THE EFFECT OF NOVEL HYPNOTICS ON PRESCRIBING CHANGES IN PATIENTS USING BENZODIAZEPINE RECEPTOR AGONISTS
Authors: Ayani *Nobutaka John , Kurokawa Takuya , Matsumoto Yoshihiro , Oya Nozomu , Kitaoka Riki , Yokoi Takato , Narumoto Jin
Published: February 2025

Background

Insomnia is one of the most common disorders in the general population. Although non- pharmacologic interventions are the first-line treatment in many cases[1], pharmacotherapy is an important option in treatment. Because of the risk of various adverse events associated with benzodiazepine receptor agonists (BZRAs)[2], the use of newer hypnotics that target orexin and melatonin (novel hypnotics) has been recommended in recent years[3]. In the present study, we investigated the change in prescriptions of patients prescribed BZRAs after the initiation of the novel hypnotics. This study was approved by the institutional review boards of the participating institutions.

Methods

Changes in prescriptions after the initiation of novel hypnotics were investigated in patients who were prescribed both BZRAs and novel hypnotics who visited the outpatient clinics of all departments of the two general hospitals between May 01, 2021 and April 30, 2022.

Results

We enrolled 534 patients in this study. The mean (SD) age was 58.5 (18.1) and 300 (56%) were female. About half of the prescriptions (297/610) were made by non-psychiatric departments. The most commonly prescribed drugs in the BZRAs were brotizolam (13%, 172/1290) and eszopiclone (11%, 138/1290); the most commonly prescribed novel hypnotic was suvorexant (22%, 282/1290). The mean number of drugs prescribed before and after the addition of novel hypnotics was 1.7 (SD: 0.6), respectively, and 17% (90 patients) had a decrease in the number of medications, while 15% (82 patients) had an increase in the number of medications.

Conclusion

In the present study, no change in the number of medications was observed as a result of the initiation of novel hypnotics in patients prescribed BZRAs. Future studies should investigate which patients succeed/fail in reducing their medications and how this relates to patient background:

References

[1]Sateia MJ et al. Clinical Practice Guideline for the Pharmacologic Treatment of ChronicInsomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med, 2017.

[2]Hirschtritt ME et al. Balancing the Risks and Benefits of Benzodiazepines. JAMA, 2021.

[3]Neubauer DN. Pharmacotherapy for insomnia in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.(Accessed on December 16, 2023.)
THE USE OF ZOLPIDEM AND THE RISK OF ARRHYTHMIA: INSIGHTS FROM A NATIONAL SURVEY
Authors: Chen *Tien-Yu , Shen Jia-Ying , Chung Chi-Hsiang , Chien Wu-Chien
Published: February 2025

Background

Insomnia, a prevalent sleep disorder with significant health implications, is commonly treated with medications such as zolpidem. Zolpidem, a non-benzodiazepine medication, has advantages over traditional sedative-hypnotics, but its widespread use raises concerns about potential side effects.

Aims & Objectives

This study focuses on investigating the correlation between zolpidem use and cardiac arrhythmias, considering the increasing prevalence of zolpidem consumption and its association with comorbidities.

Method

This population-based, matched-cohort cohort study used Taiwan’ s National Health Insurance Research Database. Participants included those using zolpidem for at least 7 days between the years January 1, 2000, and December 31, 2015. The study focused on patients who used zolpidem and classified them as the exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:2, matching for sex, age, and index year. We used a logistic regression model to investigate the association between zolpidem exposure and the risk of arrhythmia.

Results

We identified 152,652 zolpidem use cases and 305,304 matched controls. Participants with zolpidem use exhibited higher rates of comorbidities compared to the control group. Cox regression analysis revealed a significant association between zolpidem use and incident cardiac arrhythmia (adjusted hazard ratio [aHR] = 1.983, 95% CI: 1.149 – 2.76, P <0.001). Subgroup analyses confirmed the elevated risk of arrhythmia in zolpidem users across various demographic and comorbidity subgroups. Specific cardiac arrhythmias, including paroxysmal ventricular tachycardia, atrial fibrillation, ventricular fibrillation, and cardiac arrest, showed higher adjusted hazard ratios than other types of arrhythmia in patients who used zolpidem.

Discussion & Conclusion

The study suggests a heightened risk of cardiac arrhythmias associated with zolpidem use. While acknowledging the limitations of observational studies, these findings emphasize the need for further research to elucidate underlying mechanisms and establish causality. Healthcare practitioners should consider these risks when prescribing zolpidem, particularly in individuals with predisposing comorbidities.
EFFECTS OF NEUROTICISM ON SUICIDE RISK IN MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER
Authors: Li *Tian , Xing Yujie , Bo Qijing , Wang Chuanyue
Published: February 2025

Background

Suicide is the primary cause of death in patients with major depressive disorder (MDD) or bipolar disorder (BD). However, the effects of personality traits on suicide risk in MDD or BD have not been examined sufficiently. This study characterized the personality traits of patients with MDD or BD, and analyzed the association between personality traits and suicide risk in these patients.

Methods

The study population comprised 88 MDD patients and 90 BD patients. We assessed lifetime suicide risk by using the SCID-I/P. Additionally, the current suicide risk was judged based on the third item (suicide) of the 17-item Hamilton Depression Rating Scale. Personality traits were determined by the Eysenck Personality Questionnaire.

Results

Lifetime suicide risk was present in 60.7% of the study population. In the entire sample, neuroticism was significantly associated with both lifetime and current suicide risk. Higher scores for neuroticism suggested an increased lifetime suicide risk in the whole cohort. Elevated scores for neuroticism increased the current suicide risk in the MDD group.

Conclusion

For patients with MDD or BD, a higher neuroticism score may indicate a higher lifetime risk of suicide. For patients with MDD, a high neuroticism score signaled an elevated current suicide risk.
ASSOCIATION BETWEEN AUTISTIC SPECTRUM DISORDER AND PRECOCIOUS PUBERTY: A NATIONWIDE COHORT STUDY
Authors: Liu *Yi-Chun , Liao Yin-To , Chen Vincent Chin-Hong , Chen Yi-Lung
Published: February 2025

Background

Limited knowledge is available about the association between autistic spectrum disorder (ASD) and precocious puberty.

Aims & Objectives

Our study examined the association between the two medical conditions, and the effect modification by sex and neuropsychiatric comorbidities in a nationwide population.

Method

To compare the risk of precocious puberty between ASD and non-ASD cases, we conducted Cox regression analysis with ASD as exposure and time-to-precocious puberty as outcomes adjusting for sex, attention-deficit/hyperactivity disorder (ADHD), tics disorder, obsessive– compulsive disorder (OCD), anxiety disorder, intellectual disability, and epilepsy. We performed a moderation analysis to examine the potential moderating effects by sex or comorbidities.

Results

Patients with ASD have a higher risk of precocious puberty compared with non-ASD individuals, with an adjusted hazard ratio (aHR) of 1.80 (95% CI: 1.61-2.01). For the effect modification, sex, specifically female, moderated the association between ASD and precocious puberty, with relative excess risk due to interaction (RERI) 7.35 (95% CI 4.90-9.80). No significant effect modification was found for any of the comorbidities within the scope of additive effect modification.

Discussion & Conclusion

We found that patients with ASD had a higher risk of precocious puberty, regardless of sex or comorbid neuropsychiatric disorders. Girls with ASD are at particularly high risk to develop precocious puberty.
PSYCHOPHARMACOTHERAPY FOR CHILDREN WITH AUTISM SPECTRUM DISORDER CAN IMPROVE THEIR ADAPTIVE FUNCTIONING
Authors: Jung *Hanyong , Lee Jeewon
Published: February 2025

Background

Autism spectrum disorder (ASD) is a neurodevelopmental disorder which shows deficits in social interaction and communication, as well as repetitive and restricted patterns of behaviors and interests. Although there is currently no medication that can treat the core symptoms of ASD, there are many pharmacological treatment options that can help diminish the associated symptoms.

Aims & Objectives

The purpose of the present study was to examine the pharmacological treatment of children with ASD. We investigated how the pharmacological treatment of children with ASD improved their adaptive functioning.

Method

The present study was a cross-sectional study of 112 school-aged children who were diagnosed with ASD (mean age= 8.65±1.66 years, female=17.79%). Demographic information and information about current medications were collected. Parents completed the Parent/Caregiver Form of Vineland Adaptive Behavior Scales, 3rd Edition (Vineland-3).

Results

Among the 112 children diagnosed with ASD, 88 children (78.57%) had received psychopharmacotherapy. The medication that the children with ASD were most treated with was antipsychotics such as aripiprazole and risperidone, followed by ADHD medications such as atomoxetine and methylphenidate. SSRIs such as fluoxetine and sertraline, as well as buspirone were also prescribed. Results of VAPS-3 showed that pharmacological treatment improved child’ s communication skills, daily living skills and socialization.

Discussion & Conclusion

The current study showed that majority of children with ASD received pharmacological treatment which were beneficial for their adaptive functioning. Many parents recognize that there is no cure for ASD and eliminate pharmacological treatment options for their children. It should be emphasized that psychopharmacological treatment can alleviate symptoms of irritability, ADHD, and anxiety in children with ASD which improve their adaptive functioning.
EXPRESSION PATTERNS OF IL-17 RECEPTORS IN THE CEREBRAL CORTEX DURING POSTNATAL DEVELOPMENT AND ITS ALTERATION BY MATERNAL IMMUNE ACTIVATION
Authors: Sasaki *Tetsuya , Kamiya Sara , Kishi Kyoko , Iwata Suguru , Takei Yosuke
Published: February 2025

Background

T-helper 17 (Th17) cells are a subset of CD4+ T cells that produce interleukin (IL)-17A. Recent studies showed that an increase in circulating IL-17A causes cognitive dysfunction, although it is unknown how increased systemic IL-17A affects brain function.

Aims & Objectives

Using transgenic mice overexpressing RORγ t, a transcription factor essential for differentiation of Th17 cells (RORγ t Tg mice), we examined changes in the brain caused by chronically increased IL-17A resulting from excessive activation of Th17 cells.

Methods

To investigate the effect of IL-17 on neuronal and glial cells in the brain, we made use of mutant mice overexpressing RORγ t (RORγ t Tg mice).

Results

RORγ t Tg mice exhibited elevated Rorc and IL-17A mRNA expression in the colon, as well as a chronic increase in circulating IL-17A. We found that the immunoreactivity of Iba1 and density of microglia were lower in the dentate gyrus of RORγ t Tg mice compared with wild-type mice. However, GFAP+ astrocytes were unchanged in the hippocampi of RORγ t Tg mice. Levels of synaptic proteins were not significantly different between RORγ t Tg and wild-type mouse brains. In addition, novel object location test results indicated no difference in preference between these mice.

Discussion & Conclusion

Our findings indicate that a continuous increase of IL-17A in response to RORγ t overexpression resulted in decreased microglia activity in the dentate gyrus, but had only a subtle effect on murine hippocampal functions.

References

Sasaki T, Nagata R, Takahashi S, Takei Y. Effects of RORγ t overexpression on the murine central nervous system. Neuropsychopharmacology Reports. 2021. 41(1): 102-110.

Sasaki T, Tome S, Takei Y. Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex. Mol Brain. 13:93. 2020.

Tome S, Sasaki T, Takahashi S, Takei Y. Elevated maternal retinoic acid-related orphan receptor-γ t enhances the effect of polyinosinic-polycytidylic acid in inducing fetal loss. Exp Animals. 2019. Jun 10.
THE EFFECTS OF REDUCED ENDOGENOUS OXYTOCIN RELEASE ON COGNITIVE FUNCTION IN CAPS2 CKO MICE
Authors: Nagano *Wakana , Takahashi Junpei , Yamada Daisuke , Sano Yoshitake , Furuichi Teiichi , Saitoh Akiyoshi
Published: February 2025

Background & Objectives

Recently, we found that the mice treated with oxytocin (OXT) improved the amyloid-β induced memory dysfunction. In addition, plasma OXT levels have been reported to be lower in Alzheimer’ s disease (AD) patients than in healthy individuals, proposing that decreasing the secretion of OXT could be a risk factor for the development of AD. However, it is unknown whether decreased OXT levels affect cognitive functions. We previously developed mice with OXT neuron-specific deficiency of the Ca2+-dependent activator protein for secretion (CAPS) (Caps2 conditional KO (cKO) mice) and found that plasma OXT level was decreased in these mice. In this study, we examined the effects of reduced OXT release on cognitive function in Caps2 cKO mice.

Results

We firstly investigated the OXT receptors mRNA in hippocampus. OXT receptors mRNA was significantly increased in Caps2 cKO mice compared to Caps2flox/flox mice. In Caps2 cKO mice, object memory in the novel object recognition (NOR) test and fear memory in the passive avoidance (PA) test were impaired, respectively, but short-term spatial memory in the Y-maze test was not. The cognitive dysfunction observed in Caps2 cKO mice observed in the NOR and PA tests was reversed by intracerebroventricular administration of OXT. In addition, hippocampal long-term potentiation (LTP) was reduced in Caps2 cKO mice compared to Caps2flox/flox mice without affecting the paired-pulse ratio or input-output curve. Further, the expression of phosphorylated ERK (pERK) in the ventral hippocampus was reduced in the Caps2 cKO mice compared to Caps2flox/flox mice.

Discussion & Conclusion

These results indicate that deletion of CAPS2 in OXT neurons impairs synaptic plasticity via the ERK signaling pathway in the hippocampus, which may result in impairment of cognitive functions such as object recognition and fear memory. This study is expected to provide insight into the relationship between the activity of the oxytocin nervous system in the brain and cognitive function.
ANALYSIS OF MIXED EPISODES IN BIPOLAR DISORDER AND INFLUENCING FACTORS
Authors: Wang *Hong-Li , Lu Ya-Zhou , Shi Xiao-Ning , Zhao Ying-Ying , Dun Wen-Wen , Zhu Xue-Quan , Zhang Ling
Published: February 2025

Background

Mixed episodes of bipolar disorder typically develop at an earlier age, have more severe symptoms, higher rate of suicide, comorbidities and poorer clinical outcomes[1, 2]. Therefore, it is an urgent clinical problem to explore the risk factors of mixed episodes and reduce the recurrence rate.

Aims & Objectives

To explore the mixed episodes of bipolar disorder and analyze its influencing factors.

Methods

During February 2013 to June 2014, 520 patients with bipolar disorder were selected from 7 hospitals in China by continuous sampling method. The demographic data, medical history information, disease characteristics, treatment and other clinical data were collected. We investigated the number of mixed episodes of bipolar disorder and analyzed the influencing factors by Poisson regression model.

Results

Among 520 patients with bipolar disorder, 75 cases (14.42%) were mixed episodes, including 72 cases type I and 3 cases type II. Poisson regression model analysis showed that the risk factors of mixed episodes included: Type I patients had more episodes than type II (IRR = 0.068, p <0.001). Patients with family history of mental illness had more mixed episodes (IRR = 1.435, p = 0.037). Patients with non- manic polarity at first episode had more mixed episodes than manic patients (IRR = 9.988, p <0.001). Non-depressed patients at first episode had more episodes than depressed patients (IRR = 6.241, p <0.001). Patients taking mood stabilizers had more mixed episodes (IRR = 0.561, p = 0.001).

Discussion & Conclusion

Mixed episodes of bipolar disorder are closely related to the type of bipolar disorder, family history of mental illness, polarity of first episode and use of mood stabilizers.

References

1.Chakrabarty, T., K. Keramatian, and L.N. Yatham, Treatment of Mixed Features in Bipolar Disorder: an Updated View. Curr Psychiatry Rep, 2020. 22(3): p. 15.

2.Isometsä, E., et al., Dangerously mixed. Bipolar Disord, 2017. 19(4): p. 314-315.
CATHEPSIN B MODULATES MICROGLIAL MIGRATION AND PHAGOCYTOSIS OF AMYLOID β THROUGH PI3K-AKT SIGNALS IN ALZHEIMER’ S DISEASE
Authors: Ni *Junjun
Published: February 2025

The approval of anti-Amyloid β (Aβ) monoclonal antibodies (lecanemab) in the treatment of patients with early Alzheimer’ s disease by FDA, suggests the reliability and importance of clearance of brain Aβ in AD therapy. Microglia are the main phagocytes in the brain to clean up Aβ, but the regulatory mechanism has not been fully clarified. Here, we investigated the critical role of cathepsin B (CatB) in modulating microglial clearance of Aβ in the mouse brain. We stereotaxically injected Aβ into the hippocampus of mice to assess the effect of CatB on Aβ clearance. CatB deficiency significantly reduced the Aβ clearance efficiency and aggravated the cognitive decline in mice after Aβ administration for 3 weeks.

Exogenous Aβ increase CatB expression majorly in activated microglia. Transcriptomic analysis indicated that CatB is associated with gene clusters of migration, phagocytosis, and inflammation, which were validated by in vitro cell culture experiments. In addition, KEGG analysis and immunoblotting suggested that CatB modulates microglial Aβ clearance depending on PI3K-AKT activation. These findings indicate that CatB regulated microglial Aβ clearance activity, highlighting CatB as a therapeutic target for AD targeting Aβ clearance.
EVALUATION OF ADOLESCENT SMOKERS WHO CALLED TAIWAN SMOKERS’ HELPLINE
Authors: Chiu *Nan-Ying
Published: February 2025

Background

In 1997, the Legislative Yuan of Taiwan passed the “Tobacco Harm Control Act”, which restricts the intake of addictive substances by smokers. On January 3, 2003, the Department of Health and Welfare established Asia's first smoking cessation hotline - "Taiwan Smokers’ Helpline Service Center". On April 30, 2021, Changhua Christian Hospital took charge the Smokers’ Helpline Service. Objectives The aims of the study were to realize the effectiveness of this smokers’ helpline for young smokers, and explore related factors.

Methods

The author collected the data of adolescent smokers aged under 18 years old who called Taiwan Smokers’ Helpline from May1 to November 30, 2021, and analyzed related data, discussed the factors influencing rate of successfully quit smoking.

Results

The data was compared according to whether the adolescent case had successfully quit smoking (consistent non-smoking for more than 6 months). Totally 312 teenage smokers were enrolled, 83.7% were male, average age was 15.8 (SD 1.3) year-old, 88.8% were student, 31.7% smoked for 2-3 years, 69.2% were daily smoker, 38.8% smoked less than 10 cigarettes per day, 35.6% had experience of using electronic cigarette, 27.6% experienced withdrawal syndrome, 71.2% were low tobacco dependence (according to FTND), 69.6% had quitted smoking for at least 24 hours in the past year. 26.0% successfully quit smoking (continuous smoking cessation rate). The author found relating factors for successfully smoking cessation were gender, area of residence, daily smoker, amount of daily tobacco use, family request for quit tobacco smoking, appearance of physical withdrawal syndrome during quitting smoking or reduce smoking amount, total score of FTND, and whether there had been an attempt not to smoke for at least 24 hour in the past year. The accuracy rate of our prediction model for successfully quit tobacco smoking due to related factors is 70.0 %.

Discussion & Conclusion

The Smokers’ Helpline is helpful for adolescent smokers to quit tobacco smoking, the continuous smoking cessation rate was 26.0% of this study. Some significant relating factors were found, the accuracy of prediction rate is acceptable.

References

W.H.C. Li, S.S.C. Chan, M.P. Wang, K.Y. Ho, Y.T.Y. Cheung, V.W.F. Chan, T.H. Lam. An Evaluation of the Youth Quitline Service Young Hong Kong Smokers. J Adolesc Health. 2017 May; 60(5):584-591.
α6GABAAR POSITIVE ALLOSTERIC MODULATOR AS A NOVEL THERAPY FOR ALCOHOL WITHDRAWAL SYNDROME
Authors: Hung *Hao-Yuan , You Ya-Wun , Chiou Lih-Chu
Published: February 2025

Background

Alcohol use disorder (AUD) is a disease manifested by compulsive use of alcohol, the inability to control intake, and characterized by repeated cycles of intoxication, withdrawal, craving, and relapse. Alcohol withdrawal syndrome (AWS), like anxiety, tremor, and hyperthermia, is the leading cause of the high relapse rate in heavy drinkers. Alcohol can facilitate GABA action and down-regulate GABA receptors after long-term use.

Aims & Objectives

Clinically AWS is usually treated with GABAAR positive allosteric modulators (PAMs), like benzodiazepines and barbiturates. However, the combination of benzodiazepines and alcohol is hazardous, leading to life-threatening consequences. Therefore, developing a safer and more efficient therapy is crucial for treating AWS/AUD, mainly focusing on the GABAergic system.

Method

Here, we employed an AUD animal model well-established previously by giving rats intermittent (every other day) access to ethanol (20%) in a 2-bottle choice (IA2BC) procedure (Fig. 1A). After the eight-week IA2BC test, we performed different behavioral tests to evaluate the AWS in our animal model. The light-dark box, open field test, and marble-burying test were used to assess anxiety-related behaviors in rats. Our international collaborating team identified a series of pyrazoloquinolinones (PQs) as the first α6GABAAR-selective PAMs. Hence, we evaluated whether these PQs could be used as a potential novel therapy for treating AWS/AUD. Statistical significance was determined using a two-way ANOVA followed by a Bonferroni post hoc test on raw data.

Results

The rats exposing to alcohol under the IA2BC procedure for eight weeks gradually increased the intake of alcohol, but not water, with a significant ethanol preference from four weeks (Fig. 1B). In these alcohol- dependent rats after 7 days’ abstinence, we observed significant anxiety-like behaviors in the marble- burying (Fig. 1C) and light-dark box (Fig. 1D). In the open field test (Fig. 1E), the alcohol-dependent rats showed less exploration and hypo-locomotion after alcohol withdrawal. We speculate that the decreased locomotion activity is probably related to depression or stress. In contrast, DK-I-56-1 (one of PQs) significantly alleviated the anxiety-related behaviors in both marble-burying and light/dark box tests (Fig. 1C-D), especially on the first withdrawal day.

Discussion & Conclusion

Our preliminary results showed that DK-I-56-1 could significantly improve AWS. Since the AWS period brings great discomfort and intense cravings to the patient, the patient turned to use alcohol, presumably for symptom relief.

Hence, we believe α6GABAARs may be a therapeutic target of AUD/AWS.