bluuebunny/crossref_metadata_2025 huggingface dataset:
ASSOCIATION BETWEEN PROOPIOMELANOCORTIN GENE VARIATION AND ALCOHOL DEPENDENCE IN JAPANESE
Authors: Kasai *Shinya , Nishizawa Daisuke , Higuchi Susumu , Ikeda Kazutaka
Published: February 2025

Background & Objectives

The contribution of genetic factors in alcohol dependence is approximately 0.4- 0.6, indicating that genetic variations can be markers for individual vulnerability to alcohol dependence. Racial and ethnic differences in genetic backgrounds lead to different effect sizes of each genetic variation in the analyses and would be expected to affect the results of association studies. The endogenous opioid system has been reportedly implicated in addiction including alcohol dependence. In the present study, we focused on the Proopiomeranocortin (POMC) gene which encodes an endogenous opioid, β-Endorphin and examined the effects of genetic variations on alcohol dependence in Japanese.

Method

This study included 425 Japanese patients diagnosed with alcohol abuse/dependence by DSM-III- R and 339 control subjects matched to alcoholic patients on gender and age. The statistical significance of associations between genetic variations in alcohol-dependent patients and control subjects was evaluated with non-parametric analyses. Linkage disequilibrium (LD) was examined with the SNVs identified by direct sequencing around the POMC gene.

Result

The POMC C-1802T variation was significantly different between patients with alcohol dependence and control subjects. The significant difference in the recessive model was confirmed after correction by ALDH2 rs672 variation. Three LD blocks were constructed around the POMC gene, but no one including the variation was identified in Japanese.

Discussion & Conclusion

A genetic variation in 5 flanking region of the POMC gene appears to be associated with alcohol dependence in Japanese. This genetic variation may alter the expression of the POMC gene and affect vulnerability to alcohol dependence. Nalmefene, an inverse agonist of the μ-opioid receptor and a partial agonist of the κ-opioid receptor, is used in the treatment of alcohol dependence in Japan. The frequency of this genetic variation varies widely among racial groups around the world and is expected to influence the efficacy of alcoholism medications such as naltrexone and nalmefene.
MITOCHONDRIAL DYSFUNCTION IN BONE DENSITY METABOLISM IN PATIENTS WITH OPIOID USE DISORDER UNDER METHADONE MAINTENANCE TREATMENT
Authors: Hsu *Wenyu
Published: February 2025

Background

Recent studies have also shown that mitochondrial function and oxidative stress might play important roles in bone metabolism. Whether patients with opioid use disorder (OUD) experienced a decrease in bone density and an increased risk of osteoporosis and fractures through this mechanism is still unknown. Therefore, we examined the mitochondrial function between health control subjects the OUD patients under methadone maintenance treatment.

Methods

We conducted a cross-sectional cohort study. Patients with OUD receiving methadone maintenance treatment in Changhua Christian Hospital in Taiwan were recruited. We compared the difference between patients with OUD and without OUD in Mitochondrial DNA (mtDNA) copy number, oxidative modification of mtDNA index(mtDNA(DeltaCT)), and 8-hydroxy-2'-deoxyguanosine.

Results

Finally, 29 patients from MMT were allocated in opioid group. 37 health control subjects were allocated in control group. Patients in opioid group had significantly lower mtDNA than those in control group. Besides, patients in opioid group also had significantly lower DeltaCT and 8-hydroxy-2'-deoxyguanosine than those in control group.

Conclusions

Mitochondrial dysfunction was found in patients with OUD in our study. The precise role of mitochondrial dysfunction in bone density metabolism in this population should be further investigated.

References

Wen-Yu Hsu, et al. (2019) Association between opioid use disorder and fractures: a population-based study. Addiction. 114(11):2008-2015.

Wen-Yu Hsu, et al. (2018) Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease. Frontiers in Psychiatry. 9:91.
ASSOCIATION OF NEUROFILAMENT LIGHT CHAIN WITH THE ANTIDEPRESSANT EFFECTS OF LOW-DOSE KETAMINE INFUSION AMONG PATIENTS WITH TREATMENT-RESISTANT DEPRESSION
Authors: Wu Hui-Ju , Chen *Mu-Hong , Lin Wei-Chen
Published: February 2025

Background

The role of neurofilament light chain (NFL) in treatment-resistant depression (TRD) is unclear. Whether baseline NFL concentrations are associated with the antidepressant effects of low- dose ketamine infusion has not been determined.

Methods

The NFL concentrations of 71 patients with TRD and 17 healthy controls were assessed. Patients with TRD were randomly administered a single infusion of 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were assessed prior to infusion and sequentially at postinfusion timepoints (after 240 min and 2–7 and 14 days after infusion) using the Hamilton Depression Rating Scale (HDRS).

Results

After adjustment for age, sex, and body mass index, patients with TRD were more likely to have higher concentrations of NFL than healthy controls (p <0.001). A generalized estimating equation model with adjustments for infusion group, age, sex, body mass index, and baseline HDRS scores showed that baseline NFL concentrations were positively associated with subsequent HDRS scores following low-dose ketamine infusion (p = 0.038).

Discussion

Higher concentrations of NFL were observed among patients with TRD compared with healthy controls. Baseline NFL concentrations may predict the antidepressant effects of low-dose ketamine infusion.

References

1.Chen et al. Int J Neuropsychopharmacol 25(2): 99-105.

2.Lin et al. Int J Neuropsychopharmacol. 2023 Jul 25;pyad045.
MODULATION OF THE ANTIDEPRESSANT RESPONSE OF KETAMINE BY AN IMMUNOSUPPRESSANT RAPAMYCIN: A PROSPECTIVE RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN THE PATIENTS WITH REFRACTORY DEPRESSION
Authors: Su *Tungping , Chen Mu-Hong
Published: February 2025

Background

Our ketamine studies on the refractory depression (TRD) in the past 10 years have observed a short effect of a single dose of ketamine infusion lasting less than14 days. The antidepressant effect of ketamine was believed to activate the mechanistic target of rapamycin complex 1 (mTORC1), and produce synaptogenesis. Theoretically, inhibition of mTORC1 by an immunosuppressant rapamycin, prior to ketamine infusion, its antidepressant effect by ketamine would be diminished. However, in a comparison study using rapamycin plus ketamine vs. placebo plus ketamine, Abdallah found the antidepressant effect of the former was 47% whereas the later was 13 %, indicating that rapamycin might have other mechanisms beyond activation of mTORC1. To assess the role of rapamycin in ketamine treatment of TRD patients and to test if rapamycin might enhance and prolong the antidepressant effect of ketamine, we will conduct a parallel, randomized, double blind and placebo controlled study.

Method

The clinical trial has two study phases: in phase 1 study, 48 subjects with TRD will be enrolled. Two group of patients with each 24 subjects, randomly sampled, will receive either oral rapamycin 6 mg or placebo 2 hours before ketamine (0.5mg/kg) infusion once every two weeks for three times. Ratings for depression, anxiety and suicidality will be assessed at baseline, 2nd week, 4th week and 6th week.

Response is defined by 50% reduction of the baseline mood symptoms at each timepoint and 2 out of 3 - timepoint response is defined as clinical responder. The outcome is to compare the number of responder between these two parallel trial groups. The responder obtained from phase 1 trial will be enrolled for the phase 2 open-label study. These subjects will continue to receive oral rapamycin 6 mg, 2 hours prior to a single dose of ketamine 0.5mg/kg infusion at the timepoint of the end of 6th week.

Result

Our initial results revealed 24 subjects (50%) received oral rapamycin 6mg + ketamine (0.5mg/kg) infusion while another 24 subjects received oral placebo + ketamine (0.5mg/kg) infusion. Response rate was found equally in the rapamycin ketamine group and placebo ketamine group. The effect of rapamycin ketamine group was not superior to that of the placebo ketamine group.

Conclusion

The initial finding was not compatible with the previous result from Abdallah’ s study, and did not show that rapamycin might prolong the duration of efficacy of ketamine.. Further detailed analysis might answer the differences.
PREDICTING RELAPSE FROM THE TIME TO REMISSION DURING THE ACUTE TREATMENT OF DEPRESSION: A RE-ANALYSIS OF THE STAR*D DATA
Authors: Kubo *Kaoruhiko , Sakurai Hitoshi , Tani Hideaki , Watanabe Koichiro , Uchida Hiroyuki
Published: February 2025

Background

Major depressive disorder (MDD) is a recurrent illness. However, there is still lack of clinical data to predict relapse at an early point in patients with depression.

Aims and Objectives

The objective of this analysis was to investigate the association between the time taken to achieve remission in the acute phase, and the subsequent relapse rate or time to relapse using the Sequenced Treatment Alternatives to Relieve Depression dataset.

Method

Data of 1,296 outpatients with nonpsychotic depression who entered a 12-month naturalistic follow-up period after achieving remission with citalopram for up to 14 weeks were analyzed. One-way analysis of variance and the Jonckheere-Terpstra trend test were performed to compare the relapse rates and days to relapse during the follow-up period among those who achieved remission at weeks 2, 4, 6, 9, 12, and 14. Remission and relapse were defined as scores of <=5 and >=11, respectively, on the 16- Item Quick Inventory of Depressive Symptomatology and Self-Report. Multivariate logistic regression analysis was also performed in order to examine other demographic and clinical characteristics which are associated with subsequent relapse.

Results

A total of 1,093 participants achieved remission during Step 1 treatment and received at least one assessment during the follow-up period. The mean± SD weeks taken to achieve remission were 6.4±3.8. Among them, 362 (33.1%) patients relapsed during the follow-up period. The mean± SD days to subsequent relapse after remission were 160.0±99.8. The relapse rates were significantly different among those who achieved remission each week (F(5, 1087)=4.995, p <0.001). The lowest and highest relapse rates were observed in those who achieved remission at weeks 4 (25.7%) and 12 (42.4%), respectively, with a significant difference (p =0.006). There was also a significant negative trend between the weeks taken to achieve remission and the days to relapse (z=-6.13, p <0.001). In the multivariate logistic regression analysis, weeks at achieving remission status were associated subsequent relapse in the follow-up phase (OR=1.05±0.03, p=0.02). Older age, longer current episodes and baseline severity of depression were also significantly associated with subsequent relapses during the follow-up period.

Discussion & Conclusions

The present findings demonstrated that achieving remission at earlier weeks during treatment was associated with a lower relapse rate and a longer time to relapse during the one- year follow-up period. These results indicate that patients with depression who show a faster response to antidepressant treatment are more likely to maintain remission in the long term. Thus, to prevent relapse, it is critical to closely monitor patients who take a longer time to achieve remission.
NEURAL MECHANISMS OF ACCELERATED ITBS FOR TREATMENT- RESISTANT DEPRESSION: A DOUBLE-BLIND SHAM-CONTROLLED NEUROIMAGING STUDY
Authors: Li *Cheng-Ta , Cheng Chih-Ming , Wu Hui-Ting , Bai Ya-Mei , Su Tung-Ping
Published: February 2025

Background

Intermittent theta-burst stimulation (iTBS), as an updated form of repetitive transcranial magnetic stimulation (rTMS), was effective in treating treatment-resistant depression (TRD)1,2,3. 10-Hz rTMS at left prefrontal cortex (PFC) was reported to have antidepressant effects by modulating the activities in bilateral frontal-cingulo-temporal circuit2. Although both 10-Hz rTMS and iTBS were found to be effective, iTBS (80% motor threshold, 1800 pulses) acted differently by modulating the activities in midline structures, such as cingulate cortex and precuneus. Although the clinical effects were not enhanced compared to single session of iTBS treatment per day, we recently reported that 2 uninterrupted sessions of iTBS were also effective4. However, it remains elusive whether accelerated protocols (i.e., two uninterrupted sessions per day: prolonged iTBS x 2, piTBS*2) may also be effective through modulation in the midline structures.

Methods

Patients with antidepressant-resistant major depressive disorder were randomly assigned and to the piTBS*2 group, rTMS*2 group (10Hz, 120% motor threshold, 3000pulses/session, 2 sessions/day), and sham treatment group. Before and after the trials, 18F-FDG PET was applied and depression severity by 17-item Hamilton Depression Rating Scale (HDRS- 17) was evaluated.

Results

HDRS-17 scores decreased significantly in all three groups. Voxel-based analysis revealed that the piTBS*2 group showed increased activities after treatment in the midline structures including anterior and middle cingulate cortex and precuneus. By contrast, rTMS increased the bilateral frontal and temporal lobe activities.

Conclusion

Accelerated iTBS modulated the metabolism in the midline structures, but the direction of modulation is opposite to the findings reported in the singles-session iTBS protocol. Findings in the rTMS*2 group were similarr with past studies. Our results suggested that neural mechanisms of iTBS was not linear and dose-dependent.

References

Cheng-Ta Li* et al. Efficacy of Prefrontal Theta-Burst Stimulation in Refractory Depression: A Randomized Sham-Controlled Study. Brain, 2014 Jul;137(Pt 7):2088-98. Cheng-Ta Li* et al. Effects of prefrontal theta-burst stimulation on brain function in treatment-resistant depression. Brain Stimulation. 2018;11(5):1054-1062.

Cheng-Ta Li* et al. Antidepressant Efficacy of Prolonged Intermittent Theta Burst Stimulation Monotherapy for Recurrent Depression and Comparison of Methods for Coil Positioning: A Randomized, Double-Blind, Sham-controlled Study. Biological Psychiatry, Mar. 2020

Cheng-Ta Li* et al. The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder. Asian J Psychiatry. 2023
BEHAVIORAL ANALYSES OF ANTIDEPRESSANT-LIKE EFFECT OF SEROTONERGIC PSYCHEDELICS IN MICE
Authors: Ibi *Daisuke , Takaba Rika , Yoshida Keisuke , Mamiya Takayoshi , Kitagaki Shinji , Hiramatsu Masayuki
Published: February 2025

Background

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through the serotonin 5-HT2A receptor (5-HT2A). Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders.

Aims & Objectives

The involvement of 5-HT2A in mediating the therapeutic effects of serotonergic psychedelics remains unclear. In this study, we analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h after treatment.

Method

Male C57BL/6J mice (7–9 weeks old) were utilized in this study. The forced-swimming test (FST) and tail-suspension test (TST) were performed to investigate the antidepressant-like effect of psychedelics in mice. The anxiolytic-like effect of psychedelics was assessed using the novelty-suppressed feeding test (NSFT). Mice subjected to either chronic unpredictable mild stress (CUMS) or chronic corticosterone (CORT) treatment were employed as animal models of depression. All drugs were administered intraperitoneally.

Results

Mice with acute psychedelic treatment exhibited significantly shorter immobility times in the FST and TST than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the NSFT, the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not antagonize this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. Lastly, we observed that mice subjected to either CUMS or CORT treatment exhibited a decrease in immobility time in the FST, which was reversed by a single dose of DOI.

Discussion & Conclusion

These results suggest that 5-HT2A plays a central role in the antidepressant effects of serotonergic psychedelics, which may contribute to the therapeutic effects of psychedelics in animal models of depression.
USING MULTI-SCALE ENTROPY ANALYSIS IN FMRI DATA TO EXAMINE THE COGNITIVE FUNCTION IN PATIENTS OF LATE-LIFE DEPRESSION AFTER ONE-YEAR FISH OIL SUPPLEMENT
Authors: Lin *Chemin , Lee Shwu-Hua , Huang Chih-Mao , Wu Yu-Wen , Chang You-Xun , Liu Ho-Ling , Ng Shu-Hang , Cheng Ying-Chih , Chiu Chih-Chiang , Wu Shun-Chi Wu
Published: February 2025

Background

Late-life depression (LLD) is a risk factor for dementia and cognitive decline. Fish oil supplement is efficacious for depressive symptoms with cognitive protective benefits. While there is limited strategy to deter cognitive decline in older adults, examining the cognitive protection in LLD by using fish oil can potentially provide a new promise.

Aims & Objectives

In addition to using double-blind randomized controlled trial to examine the clinical effects of fish oil in LLD, we also explore the neural mechanism by using pre-and post fMRI scans.

Method

A 52-week trial was conducted. Complexity analysis (multi-scale sample entropy) was employed to analyze rs-fMRI data. We also correlate the MRI changes with changes in cognitive function and inflammatory profiles.

Results

Limited by the pandemic, we only included 20 patients with 11 u nder fish oil and nine under placebo. Only marginal improvement in processing speed was found in fish oil group. We found decreased brain entropy in left posterior cingulate gyrus (PCG), multiple visual areas, the orbital part of the right middle frontal gyrus, and the left Rolandic operculum. Brain entropy changes in PCG in the fish oil group was associated with language function improvement and decrease in interleukin-6 levels.

Discussion & Conclusion

Our results confirm the anti-inflammatory effects of fish oil in LLD could be the underlying mechanism of cognitive protective effects. Also, fish oil may exert its function through modulation of brain entropy changes in key area in default-mode network, a network strategic both in depression and dementia.
EXPLORING MOLECULAR CHANGES IN THE EXTENDED AMYGDALA INDUCED BY CHRONIC CORTICOSTERONE ADMINISTRATION
Authors: Ueda *Shuhei , Hosokawa Masahito , Kakita Manami , Arikawa Koji , Matsunaga Hiroko , Takeyama Haruko , Takemoto-Kimura Sayaka
Published: February 2025

Chronic stress is a significant risk factor for multiple psychiatric disorders, including depression. When exposed to social and/or environmental stressors, the hypothalamic-pituitary-adrenal (HPA) axis becomes activated, leading to the release of glucocorticoids (cortisol in humans, corticosterone in rodents) from the adrenal glands into the blood. This activation works to regulate various physiological processes such as metabolism, blood pressure, and immunity, allowing the body to cope with stress.

Subsequently, negative feedback on the HPA axis lead to its deactivation and terminates the stress response. While, severe chronic stress can disrupt the normal functioning of the HPA axis and is believed to contribute to the development of psychiatric disorders. However, it is still unclear what kind of changes at molecular level occur in the brain due to dysfunction of the HPA axis, leading to various psychiatric symptoms. In the present study, we employed mice that were continuously administered corticosterone for 24 days as a model of chronic stress-induced HPA axis dysfunction. These mice exhibited depression-like symptoms, including body weight loss, decreased spontaneous activity, diminished sucrose preference (anhedonia), and increased immobility time during the forced swim test (despair). Next, we focused on the extended amygdala, a pivotal brain region of emotions and stress responses, and performed subnuclei-targeted tissue collection using microdissection punching system, followed by gene expression analysis by RNA-seq. As a result, we found that in the extended amygdala with complex subnuclear structures, different molecular changes were observed in each subnucleus due to chronic corticosterone administration. These findings represent a significant step toward elucidating the neural circuit alterations induced by chronic stress.
BRAIN PH IS DECREASED IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A META-ANALYSIS OF POSTMORTEM STUDIES
Authors: Hagihara *Hideo , Miyakawa Tsuyoshi
Published: February 2025

Background

Major depressive disorder (MDD) is a prevalent and debilitating mental disorder that shares symptoms, genetics, and molecular changes in the brain with other psychiatric disorders, such as schizophrenia and bipolar disorder. Decreased brain pH, associated with increased lactate levels due to altered energy metabolism and neuronal hyperexcitation, has consistently been observed in individuals with schizophrenia and bipolar disorder compared with healthy controls. We have recently demonstrated that similar brain alterations are common in a wide range of animal models of neuropsychiatric disorders, including MDD. However, our understanding of brain pH alterations in human patients with MDD remains limited.

Aims & Objectives

In this study, we aimed to evaluate postmortem brain pH in patients with MDD in comparison to control subjects.

Method

We utilized publicly available data on brain pH to conduct a quantitative meta-analysis.

Results

The results of the random effects model, using 43 available datasets, indicated a decrease in brain pH in patients with MDD (Hedges’ g = -0.22, p = 0.0056). We also conducted a two-way analysis of covariance, with the dataset and diagnosis as the main factors, and postmortem interval, age at death, and sex as covariates. While significant effects were observed for the covariates, the effect of diagnosis remained significant.

Discussion & Conclusion

This study suggests a decrease in brain pH in patients with MDD, which could be a potential clue in understanding the pathophysiology. When combined with insights from animal model studies, it suggests that altered brain energy metabolism leading to decreased brain pH may serve as a potential transdiagnostic endophenotype for MDD and other neuropsychiatric disorders.
UTILIZING STRUCTURAL EQUATION MODELING TO ANALYZE POLYGENIC RISK AND ENVIRONMENTAL INFLUENCES ON LATE-LIFE DEPRESSION
Authors: Elsheikh *Samar Salah Mohamedahmed , Marshe Victoria , Kennedy James , Paré Guillaume , Fischer Corinne , Felsky Daniel , Mueller Daniel
Published: February 2025

Background

Our understanding of the interplay between genetic and environmental factors (Gene x Environment Interaction, or GxE) determining mental health disorders has improved through the proliferation of genome-wide interaction association studies (GWIAS) and targeted GxE analyses.

Moreover, multivariate modelling approaches, such as structural equation modelling (SEM) and polygenic risk scores (PRS), offer opportunities for the integration of clinical and genome-wide genotype data in building improved biopsychosocial models of mental illness aetiology and their response to treatment.

Aims & Objectives

We propose to construct a SEM framework to uncover the inter-correlation and directed structure of mental health phenotypes by leveraging the joint predictive capacity of PRS for comorbid traits that share underlying biological and environmental risk pathways. The proposed model will be capable of linking latent constructs to their observed measurements; these will include disease severity, comorbidities and clinical histories, and behaviours and lifestyle factors such as physical and social activity.

Method

Our gene-by-environment SEM (GESEM) will be initially developed and tested using four well- characterized clinical cohorts for older adults diagnosed with late-life depression and treated with antidepressants (CAN-BIND, IRL-GREY, STOP-PD II and IMPACT; n =1,238). The primary outcome will be antidepressant remission. Multiple PRS will be calculated to capture underlying genetic risk across vulnerable pathways which contribute to comorbidities. This selection will be made based on new, largely unpublished work from our group on the impact of PRS and targeted GxE studies on psychiatric outcomes across the lifespan. Each PRS will be calculated using both clumping and thresholding (PRSice-2) and continuous shrinkage (PRS-CS-auto) methods across selected cohorts using well-powered publicly available GWAS summary statistics. The multilevel GESEM model will include interactions between symptoms and comorbidities (i.e., observed measurements), which are caused by unobserved factors (i.e.,latent constructs), and are subject to modification by background PRS. We will compare our GESEM model against existing SEM-based approaches to GxE, including local SEM (LOSEM).

Discussion & Conclusion

An open-source R package of the analytical code will be created and shared with the research community. This work has the potential to improve upon existing PRS-based predictive models in a clinical setting.
HIGH-DEFINITION TRANSCRANIAL DIRECT CURRENT STIMULATION IN HOARDING DISORDER: A CASE REPORT
Authors: Mondino *Marine , Neige Cécilia , Bation Rémy , Brunelin Jérôme
Published: February 2025

Background

Hoarding disorder, characterized by excessive acquisition of possessions and difficulty in discarding them, is a major treatment challenge. At the brain level, hoarding disorder has been associated with increased activity in the right dorsolateral prefrontal cortex (DLPFC).

Aims & Objectives

In a case report, we explored a therapeutic strategy using high-definition transcranial direct current stimulation (HD-tDCS) to alleviate symptoms in a patient with hoarding disorder. HD-tDCS is an emerging neuromodulation technique for patients with treatment-resistant psychiatric symptoms.

Method

A 63-year-old patient with severe, treatment-resistant hoarding disorder received 15 sessions of 20-min HD-tDCS (3 sessions per day for 5 consecutive days), with the cathode placed over the right DLPFC using a 4x1 ring electrode montage. Hoarding symptoms were assessed before at baseline, after HD-tDCS, and at 1 and 3 months follow-up using the Saving Inventory-Revised (SI-R) scale. Mood was assessed using the Montgomery-Å sberg Depression Rating Scale (MADRS).

Results

The treatment was well tolerated with no adverse events. We observed a reduction in the SI-R total score from 80 to 66 at 1-month follow-up (-18.5 %). This improvement was mainly in the excessive acquisition subscale (-50%), while the difficulty discarding subscale showed a modest decrease (-22%), and there was no change in the clutter subscale. Depressive symptoms decreased by 27% (MADRS) at 1 month, but returned to baseline at 3 months. Nevertheless, a 38% decrease in the SI-R acquisition subscale persisted at 3-month follow-up (-12.5% for the SI-R total score).

Discussion & Conclusion

Cathodal HD-tDCS over the right DLPFC appears to be a safe and promising intervention for hoarding disorder. Further validation through randomized, sham-controlled trials is needed to confirm these encouraging findings.
DEEP TRANSCRANIAL MAGNETIC STIMULATION TREATMENT FOR TREATMENT-RESISTANT OBSESSIVE-COMPULSIVE DISORDER: A CASE SERIES FROM THAILAND
Authors: Wongsaisuwan *Waewwan , Virotjanakood Vasuthorn , Jarassaeng Nittaya , Chaiudomsom Kusalaporn , Piyavhatkul Nawanant , Paholpak Pongsatorn
Published: February 2025

Background

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder. The first-line treatment of OCD is either pharmacological or psychotherapy. However, the rate of treatment resistant OCD after the treatment is still high (van Roessel et al., 2023). Deep Transcranial Magnetic Stimulation (dTMS) with H-7 coil has been recently approved for resistant OCD in the USA but has not been used widely in Asia.

Aims & Objectives

To report case series of the first 4 patients with resistant OCD who received dTMS in Thailand.

Cases

All 4 patients were males and they have received at least 2 antidepressants with inadequate improvement of symptoms. The mean dose of antidepressants was 85 mg/day of fluoxetine equivalent. Three of four were taking antipsychotics (2 risperidone & 1 aripiprazole)., and two of four were taking benzodiazepine. Duration of OCD varied from 1 – 6.5 years with psychiatric comorbidity ranging from insomnia disorder to post-autoimmune encephalitis. One patient underwent electroconvulsive therapy with unsatisfactory outcomes. All patients received at least 20 sessions of FDA-approved protocol of dTMS for OCD five days a week: Frequency = 20 Hz, Duration = 2 s, Wait time = 20 s, 50 trains per session, Intensity = 60% - 100% motor threshold. All patients continued taking the medications without changing the dosages. All patients reported an improvement of clinical outcomes after dTMS, reducing the overall subjective severity of the obsessive-compulsive symptoms. Minimal, transient, but tolerable adverse effects were reported without any serious events in this case series.

Discussion and Conclusion

This is the first report from Thailand on using dTMS as an add-on treatment with pharmacological treatments. Subjective clinical outcomes from all patients were favorable with good safety and tolerability.

References

1.van Roessel PJ, Grassi G, Aboujaoude EN, Menchó n JM, Van Ameringen M, Rodrí guez CI. Treatment- resistant OCD: Pharmacotherapies in adults. Compr Psychiatry. 2023 Jan;120:152352. doi: 10.1016/j.comppsych.2022.152352. Epub 2022 Oct 25. PMID: 36368186.
ELUCIDATION OF THE INVOLVEMENT OF ASTROCYTE FUNCTION IN THE PATHOGENESIS OF GLUT1 DEFICIENCY SYNDROME
Authors: Hirai *Shinobu , Tamura Shoko , Shimbo Hiroko , Park Jonghyuk , Okado Haruo
Published: February 2025

Background

Glucose is a main energy source to support healthy brain function. Glucose transporter-1 (GLUT1) is the most important transport protein that transports glucose from the blood to the brain parenchyma and is reported to be expressed mainly in vascular endothelial cells and astrocyte endfeet. GLUT1 deficiency syndrome (GLUT1-DS) is a metabolic encephalopathy caused by impaired glucose transport into the brain. GLUT1-DS is a congenital disorder and heterozygous de novo mutations in the GLUT1 gene (SLC2A1) have been found in the majority of patients with GLUT1-DS, hypoglycaemia within the central nervous system, resulting in a range of CNS dysfunctions, including cognitive and motor dysfunction. Several papers have reported that Glut1 expressed in vascular endothelial cells (ECs) is important in neurological symptoms, and Adeno-associated virus (AAV)-based GLUT1 replacement therapy targeting vascular ECs is under development.

Methods

Astrocyte- and vascular EC-specific and systemic Glut1 haploinsufficient mice were used to attempt to identify the cells involved in the development of GLUT1-DS symptoms. Specifically, Aldh1l1-cre; Glut1 fl/+ mice were selected to analyze the contribution of astrocytes to GLUT1-DS symptoms and Tie2-cre; Glut1 fl/+ mice to analyze the contribution of ECs. Each mouse strain was used to measure glucose concentrations in cerebrospinal fluid (CSF) and interstitial fluid (ISF). These mice were also used in behavioral tests to assess cognitive and motor function, followed by evaluation of inflammation in the brain.

Results

First, Glut1 was found to be expressed throughout the astrocytic branches, not only in the endfeet. Next, compared to wild-type mice, all Glut1-deficient mouse strains showed reduced glucose levels in both CSF and ISF in addition to reduced cognitive and motor function. (All Glut1-deficient mouse strains: Aldh1l1-cre; Glut1 fl/+ mice, Tie2-cre; Glut1 fl/+ mice, Glut1 haploinsafficient mice).

Conclusion

These results suggest that Glut1 in astrocytes plays an important role in glucose uptake into CSF and ISF and in cognitive and motor functions. The two facts that Glut1 is expressed throughout astrocytes and the glucose concentration in ISF as well as CSF was reduced in Aldh1l1-cre; Glut1 fl/+ mice suggests that astrocytes may play a role in actively transporting glucose from blood to ISF. From this study, in addition to vascular ECs, GLUT1 in astrocytes is implicated in the pathogenesis of GLUT1-DS, suggesting that astrocytes may be a promising therapeutic target for GLUT1-DS.
MINOCYCLINE PREVENTS PREMATURE COGNITIVE DECLINE IN A MOUSE MODEL OF INTELLECTUAL DISABILITY INDUCED BY ZBTB18/RP58 HAPLOINSUFFICIENCY
Authors: Tanaka *Tomoko , Hirai Shinobu , Manabe Hiroyuki , Shimbo Hiroko , Yoshitane Hikari , Okado Haruo
Published: February 2025

Transcriptional repressor ZBTB18/RP58 haploinsufficiency, consisting of heterozygous ZBTB18/RP58 missense and truncated variants, causes intellectual disability. However, the pathogenesis of intellectual disability and whether this disorder can be prevented or treated are unknown. Heterozygous Zbtb18/Rp58 knockout mice were used as a model of ZBTB18/RP58 haploinsufficiency. Multiple behaviors and local potentials were assessed, and histochemical analyses in the hippocampus was performed to assess microglial status and DNA fragmentation. Object location memory was similar in wild-type mice at 2 and 4-5-months-old mice, but it decreased at 12-18-months-old mice. In contrast, in Zbtb18/Rp58 heterozygous knockout mice, object location memory at 2-months-old was similar to that of age-matched wild-type mice but decreased at 4-5-months-old. In Zbtb18/Rp58 heterozygous knockout mice, DNA damage accumulation and activation of microglia in the dentate gyrus increased early, associated with defects in DNA repair. In particular, in Zbtb18/Rp58 heterozygous knockout mice, chronic administration of minocycline suppressed age-related phenotypes such as accumulation of DNA damage and impaired object location memory. In conclusion, Zbtb18/Rp58 heterozygous knockout mice exhibit early onset of cognitive decline related to defects in DNA repair, and minocycline suppressed this abnormality, suggesting that minocycline may be a potential therapeutic agent for cognitive dysfunction caused by ZBTB18/Rp58 haploinsufficiency.
IS THERE A DIFFERENCE IN VESTIBULAR SYSTEM REACTIVITY BETWEEN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY CONTROL PARTICIPANTS?
Authors: Kambari *Yasaman , Song Jianmeng , Amaev Aron , Abdolizadeh Ali , Torres-Carmona Edgardo , Ueno Fumihiko , Koizumi Teruki , Rutka John , Leblanc Emma , Bailie Neil , Dillon Wanda , Harvey Kaitlin , Palmer Laurel , Graff-Guerrero Ariel , Gerretsen Philip
Published: February 2025

Background

Conventional caloric vestibular stimulation (CVS), which involves the irrigation of cold or warm water into the external ear canal induces a temperature gradient across the semicircular canals of the vestibular apparatus stimulating the vestibular nerve and eliciting the vestibulo-ocular reflex. It is commonly used in both otolaryngology to assess vestibular function and neurology to test brain stem function. In schizophrenia, there is no conclusive link between psychopathology and vestibular dysfunction. Initial data from another CVS study by our group suggests that individuals with schizophrenia may have greater reactivity to body temperature (37° C) CVS, as measured by the peak slow phase velocity of the resulting nystagmus (PSPV), than would be expected for healthy participants1. However, we are unaware of any studies that have investigated the differential effects of CVS temperature gradients on individuals with schizophrenia versus healthy control participants.

Aim & Objective

In the current study we aimed to examine if individuals with schizophrenia have greater reactivity to caloric vestibular stimulation than healthy control (HC) participants.

Methods

Patients with schizophrenia and HC participants received three conditions bilaterally: (1) body temperature (37° C) CVS; (2) warm CVS (44° C), and (3) cold CVS (30° C). All conditions were performed by an audiologist. The physiological response of vestibular stimulation was assessed with videonystagmography, which provides a measure of the intensity of the nystagmus via PSPV. Independent sample t-tests were conducted to compare vestibular reactivity (i.e., nystagmus) between patients and HC participants for each CVS condition.

Results

A total of 20 patients (mean age 39.2, SD=12.6, 25% female) and 20 HC participants (mean age 37.9, SD=13.1; 25% female) completed the study. There was no statistically significant difference between patients and HC participants in body temperature, warm or cold CVS (p>0.05).

Discussion & Conclusion

In schizophrenia, there is no conclusive link between psychopathology and vestibular dysfunction, and we are not aware of any data that exists on the range of responses to CVS in persons with schizophrenia. We did not find any differences in vestibular reactivity between patients with schizophrenia and HC participants in response to CVS.

References

Gerretsen, P.et al.(2017) ‘Vestibular stimulation improves insight into illness in schizophrenia spectrum disorders’, Psychiatry Research, 251, pp. 333–341. doi:10.1016/j.psychres.2017.02.020.
THE EFFECT OF FOOD ON THE PHARMACOKINETICS OF A SINGLE ORAL DOSE OF ICLEPERTIN (BI 425809), A GLYCINE TRANSPORTER 1 INHIBITOR, IN HEALTHY VOLUNTEERS: A PHASE I OPEN-LABEL, RANDOMIZED, CROSSOVER TRIAL
Authors: Harada *Akiko , Madari Shilpa , Jungnik Arvid , Breithaupt-Groegler Kerstin , Hohl Kathrin
Published: February 2025

Background

Iclepertin (BI 425809) is a glycine transporter 1 inhibitor being developed for the treatment of cognitive impairment associated with schizophrenia (CIAS).

Aims and Objectives

To investigate the effect of food on the pharmacokinetics (PK) of iclepertin in healthy volunteers (HV).

Methods

This Phase I, open-label, two-period, two-sequence crossover trial included Caucasian HV (18–55 years of age). HV were randomized (1:1) to a single oral dose of iclepertin 10 mg (film-coated tablet) when fasted (reference, R) and following a standard high-fat, high-calorie meal (test, T), or received T then R. Iclepertin administrations were separated by a wash-out period of at least 14 days. The primary endpoints were area under the concentration– time curve over the time interval from 0 to the last quantifiable data point (AUC0-tz) and maximum measured concentration (Cmax) of iclepertin in plasma. The secondary endpoint was area under the concentration– time curve over the time interval from 0 extrapolated to infinity (AUC0-∞) of iclepertin in plasma. Relative bioavailability was estimated by calculating a geometric mean (gMean) T/R ratio using an analysis of variance. Safety and tolerability assessments included adverse event (AE) reporting; HVs with AEs were analysed descriptively.

Results

The 16 enrolled HV (9 women, 7 men) had a mean (standard deviation) age of 37.1 (10.1) years. The treatment adjusted gMean AUC0-tz, Cmax and AUC0-∞ and the adjusted gMean T/R ratios for the PK endpoints were higher following iclepertin 10 mg administration in the fed versus the fasted state (Table). Overall, 8/16 HV (50.0%) reported at least 1 AE; 6/16 HV (37.5%) reported drug-related AEs (fasted: 4/16 HV [25%]; fed: 3/15 HV [20.0%]) and headache was reported most frequently.

Discussion and Conclusion

Although the exposure (AUC0-tz, Cmax and AUC0-∞) and relative bioavailability of a single oral dose of iclepertin 10 mg was higher in the fed versus the fasted state, increases were deemed minor and not clinically meaningful. Further, iclepertin was generally well tolerated by Caucasian HV participating in this trial and no new safety signals were identified. These findings may be relevant to the Asian population (Rosenbrock et al., 2023).

Funding

Boehringer Ingelheim (1346-0053; NCT05347004).

References

Rosenbrock, H., Desch, M. and Wunderlich, G. (2023). Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci, 273(7), pp.1557–1566.
SYSTEMATIC REVIEW OF INDUCED PLURIPOTENT STEM CELL THERAPY IN TRAUMATIC BRAIN INJURY
Authors: Amalakanti *Sridhar , Avula Vijaya Chandra Reddy , Singh Sachin
Published: February 2025

Background

Traumatic brain injury (TBI) is a major global health problem with limited treatment options. Induced pluripotent stem cells (iPSCs) have emerged as a promising therapy for neural regeneration and repair after TBI.

Aims & Objectives

This systematic review aimed to evaluate preclinical studies on the efficacy of iPSC- based therapies for functional recovery after TBI.

Method

From, PubMed, Ovid Medline, Cochrane Library, SCOPUS, and Web of Science 102 studies were found for studies on iPSCs in TBI animal models. Included studies (n=9) used neural stem cells derived from iPSCs transplanted into rodent models of TBI. Outcome measures were brain injury volume, functional recovery, and tissue repair biomarkers. Study quality was assessed using a 10-point scale.

Results

The majority of studies showed significant improvement in motor function, cognition, and social behavior with iPSC therapy. Transplanted iPSC-neural stem cells migrated to injury sites, differentiated into neurons and glia, reduced lesion size, and increased neural repair markers. Higher quality scores were noted for studies reporting randomization, blinded assessment, and temperature control.

Discussion & Conclusions

Preclinical evidence demonstrates the potential of iPSC-derived neural stem cell transplantation to improve functional outcomes after TBI through neuroregenerative effects. Further research is warranted to evaluate safety, optimize protocols, and translate findings to clinical trials for TBI patients. iPSC-based therapies may offer new hope for recovery after this devastating injury.
DEVELOPMENT OF AN AUTOMATION SYSTEM OF CULTURE AND LONGITUDINAL EVALUATION OF PATIENT IPS CELL-DERIVED ORGANOIDS (ASCLEPIOS)
Authors: Shiraishi *Atsushi , Inoue Takahito , Takaba Junji , Futamura Takashi
Published: February 2025

Background

Misfolding and aggregation of neurodegenerative disease proteins induce synaptic loss and neuronal cell death in specific regions of central nervous system (CNS). Although discoveries in rodent models have led to a better understanding of the mechanisms leading to neurodegeneration, differences between the rodent and human genomes may have profound effects for developing rodent models. For example, binding sites of RNA binding proteins and single nucleotide variants (SNV) associated with neurodegeneration are less conserved in rodent models.

Method

Human induced pluripotent stem cells (iPSCs) contain donor genetic background and have the potential to generate any type of cells or tissues. Therefore, the iPSC-derived neurons and tissues, called brain organoids, are expected to be useful for establishing CNS disease models and drug discovery. We have generated several brain region-specific organoids from various patient iPS cell lines.

Aims & Objectives

There are three challenges in drug discovery using iPSCs; (i) reproducibility of experiments, (ii) coordination of differentiation status among different iPSC lines and (iii) adequate cell supply.

Results

To overcome these challenges, we are developing an automation system of culture and longitudinal evaluation of patient iPS cell-derived organoids named ASCLEPiOs. ASCLEPiOs includes two robotic arms, a liquid handling system, two automated CO2 incubators and a confocal image cytometer.

Discussion & Conclusion

ASCLEPiOs will enable us to execute cell culture experiments and image processing analyses to an accurate schedule. We expect that cell-based assays using vulnerable human neuronal cells and organoids produced by ASCLEPiOs will accelerate the discovery of drug candidates including small-molecules and new modalities for neurodegenerative diseases.
BARRIERS IN ACCESS TO MENTAL HEALTH CARE SERVICES BY KEY POPULATIONS IN POLAND
Authors: Kowalczyk *Katarzyna Kinga
Published: February 2025

The mental health of Poles has been deteriorating for many years, with a particularly critical situation concerning children and teenagers. Recent events, such as the COVID pandemic and war in Ukraine, have further exacerbated this issue. According to the Comprehensive survey of the mental health status of the population and its determinants (EZOP II), almost 25% of adults, have experienced at least one mental health disorder in their lifetime within the 2016-2020 period. One of the key groups that are facing mental health problems are people who use drugs, however, the existing mental health services are incapable of addressing their needs, particularly those with dual diagnosis. The presented study is part of a Eurasian Harm Reduction Association project run in 2022 aimed at assessing the Barriers in Access To Mental Health Care Services by Key Populations in four countries: Czech Republic, Estonia, Moldova and Poland. The poster presentation will focus on Poland and Polish opioid users. To assess the barriers desk research and semi-structured interviews with 12 Polish experts (professionals working in drug treatment facilities and people who use drugs) were conducted. Some of the key findings include lack of a holistic, client-centered approach to drug dependence and mental health treatment, lack of mental health professional personnel, low accessibility of mental health services, dominance of medical treatment methods in comparison to psychotherapy options, insufficient funding for mental health care services, language barriers, stigmatization, self-stigma and discrimination based on drug and psychiatry registry. The study provides several crucial recommendations, including improving the primary health care system to ensure optimal access to mental health care, integrating harm reduction and mental health services, moving the professional community to client-centered evidence-based approaches, preparing information campaigns aimed at raising awareness of the availability of mental health services for people who use drugs, and combating stigma.