bluuebunny/crossref_metadata_2025_split huggingface dataset:
DRUG-RESPONSE RELATIONSHIP OF ESCITALOPRAM IN OBSESSIVE COMPULSIVE DISORDER BASED ON TREATMENT OUTCOME: A PHARMACOKINETIC-PHARMACODYNAMIC MODELING APPROACH
Authors: Kim *Seoyoung , Kim Bo-Hyung , Kim Euitae , Kwon Jun Soo 
Published: February 2025

Abstract

Background
While selective serotonin reuptake inhibitors (SSRIs) are the established first-line treatment for obsessive compulsive disorder (OCD), substantial number of patients show unsatisfactory response. Effectiveness of high dose SSRIs has been reported, but evidences from randomized clinical trial is still limited. In the meantime, population pharmacokinetic-pharmacodynamic (PK-PD) model approach and model-based simulation might be useful in establishing time course of the dose-response relationship, whichthen can be utilized to predict treatment response.

Aim and Objectives
This study aimed to evaluate the time course of the relationship between plasma escitalopram concentration and treatment response measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS) score by a simulation based on population PK-PD model.

Methods
The steady-state plasma escitalopram concentrations and YBOCS scores from 91 patients who were enrolled in the prior escitalopram clinical trial were used in this analysis. Subjects were randomly assigned to two groups with different maintenance dose of escitalopram, 20 or 40mg. The serial plasma escitalopram concentrations from 12 healthy volunteers were also used for the development of escitalopram PK model. The changes in YBOCS score after escitalopram treatment were described sequentially by a PD model using the predicted concentrations from the patient PK model. All the PK-PD models were developed using NONMEM®

Results
The escitalopram PK data from the patients and healthy volunteers were modeled using two- compartment model with a first-order absorption (Ka). The clearance of escitalopram for patients was estimated to be 43% lower than healthy subjects. The relationship between exposure to escitalopram and YBOCS score was described by an inhibitory Emax model with effect compartment model. Simulated relationship between escitalopram concentrations in effect compartment and YBOCS score of treatment responders and non-responders showed difference in dose-response relationship.

Discussion and Conclusions
The developed PK-PD model adequately describes the dose-response relationship of escitalopram and the improvement in YBOCS score in OCD adequately. The model-based simulation shows that the drug trial of adequate dose for sufficient duration and monitoring the plasma drug level is important when determining treatment response to escitalopram. The difference in dose-response relationship of escitalopram in patients with OCD according to treatment responsiveness imply the possibility of different neurobiologic mechanism underlying OCD patients who are not responding to the SSRI treatment.
HUMAN MICROBIOTA FROM DRUG-NAIVE PATIENTS WITH OBSESSIVE- COMPULSIVE DISORDER DRIVES BEHAVIORAL SYMPTOMS AND NEUROINFLAMMATION VIA SUCCINIC ACID IN MICE
Authors: Shi *Dong-Dong , Zhang Ying-Dan , Wang Zhen 
Published: February 2025

Abstract

Background
Emerging evidence suggests that the gut microbiota is closely related to psychiatric disorders. However, little is known about the role of the gut microbiota in the development of obsessive- compulsive disorder (OCD).

Aims & Objectives
Here, to investigate the contribution of gut microbiota to the pathogenesis of OCD, we transplanted fecal microbiota from first-episode, drug-naive OCD patients or demographically matched healthy individuals into antibiotic-treated specific pathogen-free (SPF) mice.

Method & Results
Our study showed that colonization with OCD microbiota is sufficient to induce core behavioral deficits, including abnormal anxiety-like and compulsive-like behaviors. The fecal microbiota was analyzed using 16S rRNA full-length sequencing, and the results demonstrated a clear separation of the fecal microbiota of mice colonized with OCD and control microbiota. Notably, microbiota from OCD- colonized mice resulted in injured neuronal morphology and function in the mPFC, with inflammation in the mPFC and colon. Unbiased metabolomic analyses of the serum and mPFC region revealed the accumulation of succinic acid (SA) in OCD-colonized mice. SA impeded neuronal activity and induced an inflammatory response in both the colon and mPFC, impacting intestinal permeability and brain function, which act as vital signal mediators in gut microbiota– brain– immune crosstalk. Manipulations of dimethyl malonate (DM) have been reported to exert neuroprotective effects by suppressing the oxidation of accumulated succinic acid, attenuating the downstream inflammatory response and neuronal damage, and can help to partly improve abnormal behavior and reduce neuroinflammation and intestinal inflammation in OCD-colonized mice.

Discussion & Conclusion
We propose that the gut microbiota likely regulates brain function and behaviors in mice via succinic acid signaling, which contributes to the pathophysiology of OCD through gut-brain crosstalk and may provide new insights into the treatment of this disorder.
DORSAL CA3 NEURAL ACTIVITY MEDIATES WITNESSING STRESS- INDUCED RECOGNITION MEMORY DEFICITS IN ADOLESCENT MALE MICE
Authors: Liu *Xiao , Li Ji-Tao , Si Tian-Mei 
Published: February 2025

Abstract

Background
Witnessing traumatic events is a common adverse life experience in children or adolescents and is associated with several adverse effects. The role of hippocampus in adolescent witnessing stress needs to be uncovered.

Aims & Objectives
To establish the CWSD model in adolescent male mice and reveal the involvement of hippocampus in CWSD-induced cognitive and emotional problems.

Method
Cognitive and anxiety-like behaviors were assessed in adolescent male mice exposed to chronic witnessing social defeat (CWSD) stress. Immediate early gene c-fos immunostaining was used to examine the neuronal functional activity of hippocampus. Chemogenetic and pharmacological experiments were performed to investigate the causal involvement of dorsal and ventral CA3 neurons in CWSD-induced behavioral deficits.

Results
CWSD impaired cognitive function and increased anxiety levels in adolescent male mice and the behavioral deficits persisted into adulthood. Stressed mice had more dCA3 neurons activated during the spatial object recognition test and fewer vCA3 neurons activated during the light- dark box task. Chemogenetic activation and inhibition of dCA3 neuron activity specifically mimicked and reversed CWSD-induced recognition memory deficits, not anxiety-like behaviors. In comparison, both inhibiting and activating vCA3 neurons increased anxiety-like behaviors in adolescent mice. Chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dCA3 neurons and impaired recognition memory in CWSD mice.

Discussion & Conclusion
These results suggest that dorsal CA3 neural activity mediates CWSD-induced recognition memory deficits in adolescent male mice, which shed light on the pathophysiology of adolescent CWSD-induced adverse effects and provide preclinical evidence for early treatment of stress-induced cognitive deficits.
FACTORS ASSOCIATED WITH THE INITIATION OF LAXATIVE USE IN THE SAME PATIENTS WITH SCHIZOPHRENIA OVER A 20-YEAR PERIOD: RETROSPECTIVE COHORT STUDY
Authors: Kawamata *Yasushi , Sugawara Norio , Sasaki Taro , Yokoyama Saaya , Okayasu Hiroaki , Shinozaki Masataka , Takeuchi Yoshitaka , Sato Aoi , Ishikawa Takaaki , Komahashi-Sasaki Hazuki , Miyazaki Kensuke , Fukasawa Takashi , Furukori Hanako , Yasui-Furukori Norio 
Published: February 2025

Abstract

Background
Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period.

Methods
We enrolled patients with schizophrenia attending each hospital (n=14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran– Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period.

Results
Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated magnesium oxide, lubiprostone and elobixibat were differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period.

Conclusions
Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.

References
Kawamata Y, Sugawara N, Sasaki T, Yokoyama S, Okayasu H, Shinozaki M, Takeuchi Y, Sato A, Ishikawa T, Komahashi-Sasaki H, Miyazaki K, Fukasawa T, Furukori H, Yasui-Furukori N. Factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period: Retrospective cohort study. Neuropsychopharmacol Rep. 2023 Sep 12. doi: 10.1002/npr2.12378. Epub ahead of print. PMID: 37698084.
IDENTIFYING THE UNIQUE GENETIC ARCHITECTURE OF SCHIZOPHRENIA DISTINGUISHED FROM BIPOLAR DISORDER USING GENOMIC STRUCTURAL EQUATION MODELING
Authors: Jang *Yoonjeong , Park Sanghyeon , Won Hong-Hee , Myung Woojae 
Published: February 2025

Abstract

Background
Schizophrenia (SCZ) and bipolar disorder (BIP) exhibit considerable overlap in symptomatology and genetic components. The pharmacological treatments and clinical differential diagnosis between these disorders present significant challenges due to their shared characteristics. Unraveling the specific genetic architecture of SCZ, independent of BIP, could significantly advance the identification of therapeutic targets and the development of biomarkers for SCZ.

Methods
This study aimed to explore the unique genetic architecture of SCZ. We employed Genomic Structural Equation Modeling (Genomic SEM) on genome-wide association study (GWAS) data for SCZ and BIP. It integrates the results of schizophrenia GWAS analysis and bipolar disorder GWAS analysis to construct a genetic structure, including factors, as a multivariate model, enabling the validation of associated genetic variants for each factor. GWAS-by-Subtraction is a technique used with the Genomic SEM method to elucidate the specific genetic composition of a particular trait by removing the genetic influence of other traits. Our approach focused on identifying the unique genetic pathways of SCZ by subtracting the genetic variance attributable to BIP.

Results
From the initial 205 SCZ-associated single nucleotide polymorphisms (SNPs) identified in GWAS, conditioning on BIP resulted in the attenuation of 13 signals, leaving 192 SCZ-specific signals (p &lt;5 x 10- 8, r2 = 0.2). Notably, the SNP-based heritability for SCZ GWAS was 40% (s.e. = 1.8%), but it was estimated to be 9% (s.e. = 0.4%) when SCZ conditioned on BIP.

Conclusion
These findings enhance our understanding of the pathophysiology of SCZ and indicate distinct genetic underpinnings that differentiate it from BIP. This study paves the way for more targeted SCZ treatments and the development of specific biomarkers, contributing to precision medicine in psychiatric disorders.
GENDER DIFFERENCES IN THE OCCURRENCE OF NEUROPSYCHIATRIC DISORDERS INDUCED BY DIPEPTIDYL PEPTIDASE-4 INHIBITORS
Authors: Shishido *Masataka , Noguchi Yoshihiro , Yosimura Tomoaki 
Published: February 2025

Abstract

Background
Neuropsychiatric comorbidities in diabetic patients are becoming an increasingly significant concern. Although gender differences have been identified in the development of neuropsychiatric disorders, the association between gender differences and neuropsychiatric disorders induced by dipeptidyl peptidase- 4 (DPP-4) inhibitors, the most commonly used drugs in the treatment of type 2 diabetes in Japan, has not been fully elucidated.

Aims and Objectives
In this study, the association between gender differences and neuropsychiatric disorders induced by DPP-4 inhibitors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) was explored.

Methods
In this study, we analyzed 10,676,525 cases registered in the FAERS during the third quarter of FY2021. The targeted neuropsychiatric disorders were defined as psychiatric disorders within the System Organ Class of the Medical Dictionary for Regulatory Activities. To assess the association between gender differences and neuropsychiatric disorders caused by DPP-4 inhibitors, signal scores were used (the frequentist statistical index: relative reporting odds ratio; rROR, and the Bayesian statistical index: information component delta; ICΔ) in the disproportionality analysis. We applied previously reported signal detection criteria, which included having a minimum of 3 reports, a lower limit of the 95 % confidence interval for rROR (rROR025) &gt;1, and a lower limit of the 95 % credible interval for ICΔ (ICΔ 025) &gt;0.

Results
Two signals associated with males were detected. In contrast, nine signals linked to females, including confusion (rROR025: 1.16, ICΔ025: 0.24), aphasia (rROR025: 1.93, ICΔ025: 1.09), and personality disorder (rROR025: 8.34, ICΔ025: 3.74), were identified.

Discussion and Conclusion
This study elucidated gender differences in DPP-4 inhibitor-induced neuropsychiatric disorders through pharmacoepidemiological analysis based on the FAERS. Notably, gender differences were identified in DPP-4 inhibitor-induced neuropsychiatric disorders, particularly warranting special attention in females. Consequently, it is crucial to assess the mental status of female patients with diabetes during treatment with a DPP-4 inhibitor.
CB2 RECEPTOR IS ONE OF THE REGULATORY FACTORS OF THE AGE- RELATED CHANGES IN IMMUNE MECHANISM
Authors: Hosoki *Haruka , Asahi Toru , Nozaki Chihiro 
Published: February 2025

Abstract

Background
Aging is one of the important factor which regulates immunity. It is established in adolescence, whereas immunosenescence occurs in the old age. It is necessary to examine the changes in immune mechanisms during each period to consider what effects the immunity-decline in old age. Cannabinoid type 2 (CB2) receptor is known to be expressed throughout immune-related cells, and it has been reported to act as an inhibitory regulator of immune response. However, contribution of CB2 receptors to immunosenescence still remains unknown.

Aims & Objectives
This study focus on clarifying what CB2 signaling will do in context of systemic immune regulation from the perspective of age, by comprehensive analysis of immune cell behavior under presence or absence of CB2 activity.

Methods
We chose LPS-induced systemic inflammatory model to evoke immune activation. LPS (10 mg/kg) was given by i.p. to CB2-KO and WT controls of 5 different ages: 2 month-old to 6 month-old, one month apart. Spleen has been harvested from these mice 2 hours after the administration, and immunophenotyping by flow cytometry has been conducted. As a result, T/NKT and NK cell populations particularly increased in LPS-treated CB2-KO, whereas B cells and CD11chigh cell populations significantly decreased in same animals. Interestingly, such population change has only been seen in particular ages, which are between 2 and 4 months (Fig 1). This particular age range in mouse is equivalent to the 10s to 20s in human.

Discussion & Conclusion
Altogether, we found that CB2 signaling may affect LPS-mediated immune cell population change, particularly in specific age range that is young to mature adult. These results further suggest that CB2 signaling could be one of the key modulator of the immune system transition among age. Identification of the possibly-affected immune cells will be required, to confirm the detailed mechanism between CB2 activation and cell population fluctuations under aging.
IN VITRO METABOLISM OF THE STRUCTURALLY SIMILAR FENTANYL ANALOGS, 3-PHENYLPROPANOYLFENTANYL AND BENZOYLFENTANYL
Authors: Abe *Konosuke , Itoh Kosuke , Iwai Kosei , Shimada Momoka , Soda Midori , Oida Yasuhisa , Kitaichi Kiyoyuki 
Published: February 2025

Abstract

Background
Opioid addiction and toxicity due to overdose by fentanyl analogs (FAs) are a serious problem worldwide. Predicting the pharmacological effect of FAs is very difficult because many new FAs with slight structural alterations frequently appear in the market. The investigation of in vitro metabolism of FAs is an easy and quick method to predict their pharmacological effects.

Aims and Objectives
In this study, we examined the in vitro metabolism of structurally similar FAs with N-acyl group modification, N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl]-3-phenylpropanamide (3- phenylpropanoylfentanyl, 3-PPF) and N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl]benzamide (benzoylfentanyl, BZF), using human liver microsomes (HLMs).

Methods
3-PPF and BZF were incubated with HLMs for 2 and 3 h, respectively (Kadomura et al. 2021). Samples were collected at the designated time points. These FAs and their metabolites were detected by LC-MS/MS and LC-MS IT-TOF.

Results
The metabolic half-life of 3-PPF was less than 10 min, whereas that of BZF was more than 80 min. Time-course metabolic profiles of these FAs demonstrated that 3-PPF was rapidly metabolized to 3- PPF monohydroxylate, whereas BZF was gradually metabolized into several metabolites. A detailed analysis using LC-MS IT-TOF showed that 3-PPF was primarily monohydroxylated at the N-acyl group. Oxidative N-dealkylated metabolites of 3-PPF and BZF, nor-3-PPF and nor-BZF, were predominantly observed at the end of the experiment, rather than other metabolites.

Discussion and Conclusion
The relatively longer metabolism of BZF suggests that it may exhibit more significant pharmacological effects than 3-PPF. The rapid metabolism of 3-PPF suggests that FAs with a longer N-acyl group are susceptible to rapid hydroxylation at the N-acyl group. Although various studies have already demonstrated that nor-FAs are inactive metabolites, the detection of nor-3-PPF and nor- BZF may be a useful surrogate for drug intake.

References
Kadomura N, Ito T, Kawashima H, Matsuhisa T, Kinoshita T, Soda M, Kohyama E, Iwaki T, Nagai H & Kitaichi K (2021) In vitro metabolic profiles of adamantylpositional isomers of synthetic cannabinoids. Forensic Toxicology vol no. 39, pp 26-44.
COMORBIDITY OF MENTAL ILLNESS, NON-COMMUNICABLE DISEASES AND POLYPHARMACY IN HOME MEDICAL CARE USING MEDICAL BIG DATA
Authors: Arai *Shun , Iida Makoto , Yoshinaga Yasunori , Sakagami Ryuji , Shoji Yoshihisa , Morikawa Nagisa , Nohara Yume , Nohara Shoichiro , Fukumoto Yoshihiro , Ishii Kazuo 
Published: February 2025

Abstract

Background
According to the progress of super-aging society in Japan, the number of patients with non- communicable diseases (NCDs) and the number of people requiring medical care and nursing care is rapidly increasing. The number of receiving home medical care (HMC) is also rapidly increasing. In HMC, most of patients are elderly people and a lot of patients with NCDs, such as diabetes mellitus, hypertension, cardiovascular disease, and cerebrovascular disorders, and mental illnesses, such as dementia and depression, are containing. At the same time, polypharmacy such as psychotropic drugs was often recognized.

Aims & Objectives
In this study, using NDB (National Database of Health Insurance Claims and Specific Health Checkups of Japan) established by the Ministry of Health, Labour and Welfare, comorbidity of mental Illness, NCDs and polypharmacy in HMC were analyzed.

Method
This study was conducted using the NDB Sampling Dataset in NDB provided by the Ministry of Health, Labor and Welfare. Medical Non-Hospitalization Receipts and Prescription Receipts were linked by patient ID. Based on the Injury/Disease Code and Drug Code, the disease prevalence and drug prescription status of patients receiving HMC were summarized. Patients receiving HMC were counted as patients containing the phrase "home medical care (zaitaku)" in Prescription Codes.

Results
When investigating the status of polypharmacy in patients receiving HMC, polypharmacy was observed almost 90% of patients, most of whose possessing NCDs and mental illness. The peak of patients receiving HMC with polypharmacy was around 85 years of age. In the Injury/Disease Codes, among patients receiving HMC, many of patients with mental illnesses were found to suffer from diseases that showed neurocognitive disorders, such as unspecified dementia, delirium, and Parkinson's disease. Polypharmacies were recognized to include psychotropic drugs and drugs related to NCDs such as diabetes mellitus and hypertension. These results were visualized using various methods such as word clouds and co-occurrence networks to understand the overall trends of comorbidities.

Discussion & Conclusion
Analysis of NDB reveals that in HMC, there are many elderly patients, many patients with comorbidities with mental illnesses and NCDs, and polypharmacy of psychotropic drugs and drugs related to NCDs such as diabetes mellitus and hypertension is significant. These findings suggest the need to reduce the adverse events of polypharmacy by optimizing drug prescriptions.
PREVALENCE OF MANAGED AND UNMANAGED METABOLIC SYNDROME COMPONENTS AMONG ADULT PATIENTS ADMITTED IN THE PSYCHIATRIC WARD OF THE PHILIPPINE GENERAL HOSPITAL FROM 2018-2020: A RETROSPECTIVE CROSS-SECTIONAL STUDY
Authors: Cammayo *Tyrone Paul Baylon 
Published: February 2025

Abstract
The risk of psychiatric patients developing metabolic syndrome greatly increases with the psychiatric diagnoses and use of certain psychotropic medications; hence, psychiatrists must be alert in addressing the syndrome.
The primary objective of this study is to describe how the adult psychiatric patients with metabolic syndrome components admitted at Ward 7 of PGH Department of Psychiatry and Behavior Medicine are managed while they were admitted. A retrospective cross-sectional study was employed. Ninety patient charts were reviewed from the admitted patients in 2018-2020. The demographic profile, anthropometric measurements, highest BP, FBS, and lipid profile results were obtained. Charts were reviewed for any interventions done regarding observed metabolic syndrome components.
There were 7 (7.78%) patients with increased FBG or known diabetic. Anti-diabetic prescription was given to 71.42% of these patients. There were 16 (17.78%) patients found to have increased blood pressure or had previous anti-hypertensive medication. Anti-hypertensive medication was given to 56.25%. There were 55 (61.11%) patients who had increased triglycerides, decreased HDL-C, or had anti- dyslipidemic medications. Only 7 (12.73%) of these patients were given anti-dyslipidemic medication while diet modification was advised in 13 (23.64%) patients. Of the total patients, only seven (7.78%) were referred to other services for management of their co-morbidities.
This study shows that while MS components were detected during admission, disparity between the number of managed and unmanaged patients were observed.