Comparative analysis of salivary cortisol measurements using different assay methods in relation to serum-free cortisol measurement.

Objectives: Salivary cortisol reflects the biologically active form of serum cortisol, offering a noninvasive evaluation method for the diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis. While liquid chromatography-tandem mass spectrometry (LC-MS/MS) is known for its specificity, immunoassays (IA) are commonly used because of their simplicity. This study aimed to assess the performance of salivary cortisol measurement using both IA and LC-MS/MS in comparison to serum-free cortisol measurement. Methods: Assay results for 188 saliva and 94 serum samples from 47 participants were analyzed. Salivary samples collected at different time points were analyzed using IA and LC-MS/MS. Serum samples were analyzed for cortisol, cortisol-binding globulin, and free cortisol. The statistical analyses included correlations and method comparisons. Results: The diurnal salivary cortisol profiles exhibited a comparable circadian rhythm pattern; however, the concentrations measured using IA were consistently higher than those measured using LC-MS/MS. The correlation analysis revealed robust associations among salivary cortisol (IA), salivary cortisol (LC-MS/MS), and serum-free cortisol levels (LC-MS/MS). However, the method comparison revealed a systematic bias between IA and LC-MS/MS in salivary cortisol measurement. Conclusions: This study contributes to the ongoing debate on assay techniques by affirming the suitability of IA and LC-MS/MS for salivary cortisol measurement to assess dynamic changes in HPA axis activity. The identified systematic bias emphasizes the importance of selecting methods based on specific research or clinical requirements.

Exploratory Clinical Trial of a Depression Diagnostic Software That Integrates Stress Biomarkers and Composite Psychometrics.

OBJECTIVE: This study evaluated the clinical effectiveness of Minds.NAVI, a depression screening kit combining psychometric measures and stress hormone biomarkers, in a prospective clinical trial. The objective was to assess its potential as a depression screening tool and investigate the associations between psychological assessments, salivary hormone staging, and depression severity. METHODS: Thirty-five participants with major depressive disorder and 12 healthy controls (HCs) were included. The Minds.NAVI software, utilizing the PROtective and Vulnerable factors battEry Test (PROVE) and salivary cortisol/dehydroepiandrosterone (DHEA) analysis, was employed. The PROVE test is a comprehensive self-report questionnaire that assesses depressive symptoms, suicide risk, attachment style, adverse childhood experiences, mentalization capacity, and resilience. In addition, salivary cortisol and DHEA levels were measured to evaluate the functional stage of the hypothalamic-pituitary-adrenal (HPA) axis. RESULTS: Minds.NAVI exhibited 100% sensitivity, 91.7% specificity, and 97.9% accuracy in distinguishing depression from HCs within an exploratory small group. Salivary stress hormone phases showed changes with depression stage (p=0.030), and the proportion of patients with "adrenal exhaustion stage" was higher in the moderate/severe depression group (p=0.038). Protective/vulnerable factors differed significantly between controls and depressed groups (p<0.001). Cortisol awakening response inversely correlated with depressive symptom severity (r=-0.31, p=0.034). CONCLUSION: This study suggested possible clinical effectiveness of Minds.NAVI, a depression screening tool that integrates psychometric measures and stress hormone biomarkers. The findings support the potential association between depression, chronic stress, and HPA axis hyporesponsiveness.

Resting-state functional connectivity and cognitive performance in aging adults with cognitive decline: A data-driven multivariate pattern analysis.

BACKGROUND: Cognitive impairments occur on a continuous spectrum in multiple cognitive domains showing individual variability of the deteriorating patterns; however, often, cognitive domains are studied separately. METHODS: The present study investigated aging individual variations of cognitive abilities and related resting-state functional connectivity (rsFC) using data-driven approach. Cognitive and neuroimaging data were obtained from 62 elderly outpatients with cognitive decline. Principal component analysis (PCA) was conducted on the cognitive data to determine patterns of cognitive performance, then data-driven whole-brain connectome multivariate pattern analysis (MVPA) was applied on the neuroimaging data to discover neural regions associated with the cognitive characteristic. RESULTS: The first component (PC1) delineated an overall decline in all domains of cognition, and the second component (PC2) represented a compensatory relationship within basic cognitive functions. MVPA indicated rsFC of the cerebellum lobule VIII and insula with the default-mode network, frontoparietal network, and salience network inversely correlated with PC1 scores. Additionally, PC2 score was related to rsFC patterns with temporal pole and occipital cortex. CONCLUSIONS: The featured primary cognitive characteristic depicted the importance of the cerebellum and insula connectivity patterns in of the general cognitive decline. The findings also discovered a secondary characteristic that communicated impaired interactions within the basic cognitive function, which was independent from the impairment severity.

Association and interaction between clinician-rated measures of depression and anxiety with heart rate variability in elderly patients with psychiatric disorders.

Background: Older adults are vulnerable to comorbid depression and anxiety symptoms; however, these conditions are widely underrecognized and often untreated. Understanding their combined manifestation using objective measurements, such as clinician-rated scales and heart rate variability (HRV), can help refine the diagnosis and select a treatment strategy for geriatric patients. Methods: This study included patients over 65 years who were mainly diagnosed with either category of depressive or anxiety disorders from the psychiatric outpatient clinic in a university hospital. A total of 114 patients met eligibility with a completed collection of electrocardiograms, the Hamilton Depression Rating Scale (HDRS; clinician-rated depression), and the Hamilton Anxiety Scale (HAS; clinician-rated anxiety) to assess the severity of symptoms. Both main and interaction effects between HDRS and HAS on HRV parameters were examined. Results: Significant interaction effects between clinician-rated depression and anxiety (HDRS × HAS) on HRV reduction in frequency parameters (i.e., nuLF, nuHF, LF/HF ratio) were found, which consistently indicated autonomic nervous system dysregulation. Findings imply that HRV could reflect synergistic effects of comorbid depressive and anxiety symptoms, perhaps due to the amplification of individual symptoms in geriatric patients. Conclusions: The results imply that using objective measurements can improve diagnostic accuracy, particularly in geriatric patients with comorbid status, and the normalization of the autonomic nervous system might be a candidate target for prevention and treatment.

The Prevalence and Clinical Characteristics of Borderline Personality Disorder in South Korea Using National Health Insurance Service Customized Database.

PURPOSE: The purpose of the present study was to identify the prevalence and clinical characteristics of borderline personality disorder (BPD) in South Korea using the Korean National Health Insurance database (DB). MATERIALS AND METHODS: We used the National Health Insurance Service (NHIS)'s research DB (NHIS-2021-1-790) from January 1, 2010 to December 31, 2019, to make customized DB including sociodemographic information and absence or presence of BPD and other psychiatric disorders. The prevalence and the age of onset of BPD was estimated. To compare medical service utilization between the BPD group and the control group, a 1:1:1 propensity score matching was employed, and the regression analysis was conducted. RESULTS: The prevalence of BPD per 10000 people was 0.96 in 2010 and 1.06 in 2019. The prevalence ratio of males to females was 1:1.38 in 2010 and 1:1.65 in 2019, showing that BPD was more prevalent in females. The patients' overall average age of onset was 33.19±14.6 years, with the highest prevalence shown in 8503 people in their 20s. By administrative district, the highest prevalence of BPD per 10000 people was shown in Seoul with 8.71 and the lowest in Jeollanam-do with 2.35. The BPD patients showed a pattern of extensive use of general and mental healthcare services. CONCLUSION: This study identified the prevalence of BPD on a national DB set in South Korea. Although the prevalence of BPD in South Korea was relatively low compared to other countries, there was a steady increase in the number of BPD patients over a decade, which may be possibly due to an increased awareness of mental health and campaigns among healthcare providers and users in the country.

Differential relationship of observer-rated and self-rated depression and anxiety scales with heart rate variability features.

Heart rate variability (HRV) is a known psychophysiological marker for diverse psychiatric symptoms. In this study, we aimed to explore the potential for clinical use of HRV by investigating the interrelationship between HRV indices and clinical measures mainly used to assess depressive and anxious symptoms. Participants who reported depressive and anxious symptoms were designated into the following groups: group 1, clinician-rated and self-rated depression; group 2, only self-rated depression; group 3, clinician-rated and self-rated anxiety; group 4, only self-rated anxiety. Statistical comparisons were performed between these groups to investigate the association between HRV and clinical measures. As a result, HRV variables showed significant correlations only with the clinician-rated assessments. Moreover, both time and frequency domain HRV indices were significantly different between groups 1 and 2, but groups 3 and 4 showed significant differences only in frequency domain HRV indices. Our study showed that HRV is an objective indicator for depressive or anxious symptoms. Additionally, it is considered a potential indicator for predicting the severity or state of depressive symptoms rather than of anxious symptoms. This study will contribute to increasing the diagnostic utility of discriminating those symptoms based on HRV in the future.

Effect of developmental stress on the in vivo neuronal circuits related to excitation-inhibition balance and mood in adulthood.

Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.

Risk of Secondary Cancer after Adjuvant Tamoxifen Treatment for Ductal Carcinoma In Situ: A Nationwide Cohort Study in South Korea.

Endocrine therapy is the mainstay treatment for hormone receptor-positive ductal carcinoma in situ. The aim of this study was to examine the long-term secondary malignancy risk of tamoxifen therapy. The data of patients diagnosed with breast cancer between January 2007 and December 2015 were retrieved from the database of the Health Insurance Review and Assessment Service of South Korea. The International Classification of Diseases, 10th revision, was used to track all-site cancers. Age at the time of surgery, chronic disease status, and type of surgery were considered covariates in the propensity score matching analysis. The median follow-up duration was 89 months. Forty-one patients in the tamoxifen group and nine in the control group developed endometrial cancer. The Cox regression hazard ratio model showed that tamoxifen therapy was the only significant predictor of the development of endometrial cancer (hazard ratio, 2.791; 95% confidence interval, 1.355-5.747; p = 0.0054). No other type of cancer was associated with long-term tamoxifen use. In consonance with the established knowledge, the real-world data in this study demonstrated that tamoxifen therapy is related to an increased incidence of endometrial cancer.

Marked Reduction in the Risk of Dementia in Patients with Breast Cancer: A Nationwide Population-Based Cohort Study.

PURPOSE: An inverse relationship between cancer and neurodegenerative disease, which presents the possibility of a reduced risk of dementia in cancer patients, has been suggested previously. However, a nationwide longitudinal population-based study of specific types of cancer with due consideration of treatment effects has not been conducted. Materials and Methods: This nationwide population-based cohort study used data obtained in a 12-year period (January 2007- December 2018) in the Korean National Health Insurance claims database. All female breast cancer patients (age ≥ 50 years) diagnosed between 2009 and 2010 were included after excluding those with physician visits for any cancer during a 2-year period (2007-2008). Patients with senile cataract constituted the control group. The main study outcome was the risk of developing dementia. RESULTS: From a total of 90,396 and 85,906 patients with breast cancer and cataract, respectively, patients without behavior codes were excluded. Data for 15,407 breast cancer patients and 7,020 controls were analyzed before matching. After matching for comorbidities and age, either group comprised 2,252 patients. The median follow-up time was 104.1±24.0 months after matching. After matching, breast cancer was a predictor of a lower risk of for dementia (hazard ratio, 0.091; 95% confidence interval, 0.075 to 0.111; p < 0.001). In breast cancer patients, receiving chemotherapy and endocrine therapy did not significantly affect the incidence of dementia. CONCLUSION: Breast cancer was associated with a remarkably decreased risk of dementia. The findings strongly suggest an inverse relationship between cancer and neurodegeneration, regardless of the adverse effects of cancer treatment on cognitive function.

Neurophysiological insights into impaired mentalization in borderline personality disorder an electroencephalography study.

Introduction: Borderline personality disorder (BPD) is characterized by interpersonal and emotional instabilities, recurring suicidal tendencies, and feelings of emptiness. Childhood adverse event is reported in 70%-80% of cases involving BPD. Furthermore, the deficiency in mentalization capacity plays a significant role in emotion dysregulation and social interaction problems within individuals with BPD. This study explored the relationship among childhood adverse experiences, mentalization capacity, and neurophysiological activity in patients with BPD. Methods: Resting-state electroencephalography was used to identify the neural correlates associated with childhood adversity and mentalization deficits. The participants included 45 patients with BPD and 15 healthy controls. Results: The BPD group exhibited reduced alpha activity during eyes-closed rest, indicating heightened arousal even during relaxation. Correlations were found between the power spectral density (PSD) and mentalization capacity in the delta and theta ranges, suggesting an association between PSD and emotional awareness and expression. Gamma activity negatively correlated with psychic equivalence, implying a blurring of the boundaries between internal mental experiences and the external world. Conclusion: These findings offer insights into the pathophysiology of BPD, provide potential diagnostic markers, and suggest personalized treatment approaches based on mentalization traits.

Advancing ecological validity and clinical utility in virtual reality-based continuous performance test: exploring the effects of task difficulty and environmental distractors.

Introduction: Researchers have highlighted concerns regarding the limited diagnostic utility and ecological validity of the Continuous Performance Test (CPT). Recent advancements in VR-based CPTs have attempted to address these concerns by simulating real-life scenarios and enhancing attention deficit hyperactivity disorder (ADHD) diagnosis; however, certain areas require improvement for obtaining reliable data from both healthy individuals and those with ADHD. To tackle these issues, we developed an enhanced VR-based CPT program featuring four distinct difficulty levels, advancing toward home-based assessment. Method: Our feasibility study involved subjects without ADHD to establish a normative profile for VR-based CPT before extending it to ADHD assessment. Our sample included 20 Korean adults. They received a VR device with the VR-based CPT program installed and were asked to perform 1-2 blocks per day at home. Participants were instructed to complete 12 blocks over the subsequent 2 weeks. Psychological assessments and electroencephalograms (EEGs) were administered before and after the program. Post-study usability measures were also collected. Result: Higher commission errors were notably evident in the "very high" difficulty level which featured complex stimuli and increased distraction. A notable correlation emerged between the overall distraction level and CPT accuracy, along with a significant link between intensity scores and commission errors. No significant differences were found in psychological assessment and there were no significant changes in the Theta-Beta Ratio (TBR) index before and after the program. The usability of our program was fair. Discussion: The study reveals that the newly designed VR-CPT program, simulating diverse real-life environments and offering varying task difficulty levels, proved acceptable and feasible. The key point of our study was that the adjustment and segmentation of difficulty levels in the VR-based CPT were achieved, and that this effort was validated by examining the impact of different levels of difficulty on CPT measures. Implementing this experimental setup in a home-based environment increased ecological validity, as well as clinical utility. Limitations and suggested directions for further investigation are described in detail.

Risk of developing depression from endocrine treatment: A nationwide cohort study of women administered treatment for breast cancer in South Korea.

Background: Although previous studies demonstrated no association between depression and tamoxifen in patients with breast cancer, there is still a limited amount of long-term follow-up data. This study aimed to evaluate the relationship between endocrine treatment and the risk of depression. Methods: This nationwide population-based cohort study used data obtained over a 14-year period (January 2007 to December 2021) from the Korean National Health Insurance claims database. All female patients with breast cancer were included. We examined the incidence of depression in patients who underwent endocrine treatment, and those who did not undergo endocrine treatment constituted the control group. Results: The data from 11,109 patients who underwent endocrine treatment and 6,615 control patients between 2009 and 2010 were analyzed. After performing matching for comorbidities and age, both groups comprised 6,532 patients. The median follow-up were 119.71 months. Before and after matching was performed, the endocrine treatment was not a significant risk factor for developing depression (p=0.7295 and p=0.2668, respectively), nor was it a significant factor for an increased risk for suicide attempt (p=0.6381 and p=0.8366, respectively). Conclusions: Using a real-world population-based cohort, this study demonstrated that there is no evidence that the endocrine treatment increases the risk of depression.

Relationship of Resilience Factors With Biopsychosocial Markers Using a Comprehensive Home Evaluation Kit for Depression and Suicide Risk: A Real-World Data Analysis.

Objectives: Adverse childhood experiences (ACEs) are fundamental factors in developing depression with increased suicide risk. Resilience is considered an important protective factor that can prevent trauma survivors from developing depression. We developed a home evaluation kit for a comprehensive assessment of bio-psycho-social factors related to depression and suicide. This kit contained a psycho-social evaluation battery, named the Protective and Vulnerable factors battery questionnaire (PROVE) comprising depressive symptoms and suicide risk, as well as various depression-related psychosocial factors, such as ACE, resilience, mentalization capacity, and attachment, via online survey tools. Furthermore, salivary cortisol levels were used as biological indicators to assess the hypothalamus-pituitary-adrenal axis function. Methods: Real-world data analysis was made out of data collected from participants who visited CHEEU Counseling center or Gangnam Severance hospital for mental health check-ups. The participants were put into three mental state groups (green-normal, yellow-borderline, and red-risk) depending on the result of PROVE battery. The difference between psychosocial factors and salivary cortisol indicators by the group was identified by analysis of covariance with sex and age as covariates. Linear regression analysis was conducted to find a significant association of resilience score with other bio-psycho-social variables, such as ACE, attachment, mentalization, or post-awakening cortisol concentrations (area under the curve with respect to ground, AUCg). A partial correlation analysis was performed to evaluate the relationship of AUCg with psychosocial factors. Results: Depression-related psycho-social indicators were significantly different among groups. Insecure attachment and the mentalization problem are negatively influencing factors to resilience. Furthermore, the severity of depression in participants with ACE was also influenced by mentalization problems. AUCg was different according to the PROVE group, presence of ACE, or resilience level. In addition, AUCg showed a positive correlation with resilience score but negative correlations with depressive symptoms, ACE, mentalization problems, and anxiety or avoidance attachment. Conclusion: This study suggests that there are some key factors negatively affecting resilience: insecure attachment and mentalization problems. In groups with ACE, a mentalization problem was suggested as a factor that can increase depressive symptoms. AUCg was associated with resilience as well as several other vulnerable factors of depression, showing its potential as a promising biomarker.

Association between social phobia and the risk of arrhythmia using the Korean National Sample Cohort: a retrospective cohort study.

BACKGROUND: Social phobia shares symptoms with arrhythmias, such as palpitations and chest discomfort. However, it is unclear how social phobia is associated with the actual risk of arrhythmia. This study aimed to investigate whether social phobia is associated with the risk of arrhythmia using a nationally representative sample cohort. METHODS: This retrospective cohort study assessed data from the 2002-2013 Korean National Health Insurance Service National Sample Cohort. Using 1:3 propensity score matching for sex, age, income, and insurance status, 1514 patients with social phobia and 4542 control group patients were included in the study. Social phobia and arrhythmia were defined per the International Classification of Diseases, 10th revision. Using cox proportional hazard regression, hazard ratios (HRs) were calculated to estimate the risk of arrhythmia in patients with social phobia. RESULTS: There were statistically significant associations between social phobia history and elevated risks of arrhythmia. Patients with social phobia had a higher risk of arrhythmia after adjusting with covariates (HR = 1.78, 95%CI = 1.25-2.55). Among different types of arrhythmias, atrial fibrillation and flutter presented the highest risk (HR = 2.20, CI = 1.06-4.57) compared to paroxysmal tachycardia (HR = 1.07, CI = 0.39-2.91) and other cardiac arrhythmias (HR = 1.83, CI = 1.16-2.89). CONCLUSION: This study identified the association between social phobia and the risk of arrhythmia in a South Korean representative cohort. These results suggest that social phobia should be treated properly to reduce arrhythmia risks.

Virtual reality-based monitoring test for MCI: A multicenter feasibility study.

Objectives: As the significance of the early diagnosis of mild cognitive impairment (MCI) has emerged, it is necessary to develop corresponding screening tools with high ecological validity and feasible biomarkers. Virtual reality (VR)-based cognitive assessment program, which is close to the daily life of the older adults, can be suitable screening tools for MCI with ecological validity and accessibility. Meanwhile, dehydroepiandrosterone (DHEA) has been observed at a low concentration in the older adults with dementia or cognitive decline, indicating its potential as a biomarker of MCI. This study aimed to determine the efficacy and usability of a VR cognitive assessment program and salivary DHEA for screening MCI. Methods: The VR cognitive assessment program and the traditional Montreal Cognitive Assessment (MOCA) test were performed on 12 patients with MCI and 108 healthy older adults. The VR program operates in a situation of caring for a grandchild, and evaluates the memory, attention, visuospatial, and executive functions. An analysis of covariance (ANCOVA), a partial correlation analysis, and receiving operating characteristic (ROC) curve analysis were conducted for statistical analysis. Results: According to the ANCOVA, no significant difference in MOCA scores was found between the normal and MCI groups (F = 2.36, p = 0.127). However, the VR total score of the MCI group was significantly lower than that of the normal group (F = 8.674, p = 0.004). There was a significant correlation between the MOCA and VR scores in the total and matched subdomain scores. The ROC curve analysis also showed a larger area under the curve (AUC) for the VR test (0.765) than for the MOCA test (0.598), and the sensitivity and specificity of the VR program were 0.833 and 0.722, respectively. Salivary DHEA was correlated with VR total (R 2 = 0.082, p = 0.01) and attention scores (R 2 = 0.086, p = 0.009). Conclusion: The VR cognitive test was as effective as the traditional MOCA test in the MCI classification and safe enough for older adults to perform, indicating its potential as a diagnostic tool. It has also been shown that salivary DHEA can be used as a biomarker for MCI.

Neutrophil-Lymphocyte Ratio as a Potential Biomarker for Delirium in the Intensive Care Unit.

Background: Recognition and early detection of delirium in the intensive care unit (ICU) is essential to improve ICU outcomes. To date, neutrophil-lymphocyte ratio (NLR), one of inflammatory markers, has been proposed as a potential biomarker for brain disorders related to neuroinflammation. This study aimed to investigate whether NLR could be utilized in early detection of delirium in the ICU. Methods: Of 10,144 patients who admitted to the ICU, 1,112 delirium patients (DE) were included in the current study. To compare among inflammatory markers, NLR, C-reactive protein (CRP), and white blood cell (WBC) counts were obtained: the mean NLR, CRP levels, and WBC counts between the initial day of ICU admission and the day of initial delirium onset within DE were examined. The inflammatory marker of 1,272 non-delirium patients (ND) were also comparatively measured as a supplement. Further comparisons included a subgroup analysis based on delirium subtypes (non-hypoactive vs. hypoactive) or admission types (elective vs. emergent). Results: The NLR and CRP levels in DE increased on the day of delirium onset compared to the initial admission day. ND also showed increased CRP levels on the sixth day (the closest day to average delirium onset day among DE) of ICU admission compared to baseline, while NLR in ND did not show significant difference over time. In further analyses, the CRP level of the non-hypoactive group was more increased than that of the hypoactive group during the delirium onset. NLR, however, was more significantly increased in patients with elective admission than in those with emergent admission. Conclusion: Elevation of NLR was more closely linked to the onset of delirium compared to other inflammatory markers, indicating that NLR may play a role in early detection of delirium.

Evaluation of the Effects of Developmental Trauma on Neurotransmitter Systems Using Functional Molecular Imaging.

Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems.

Association between BDNF Polymorphism and Depressive Symptoms in Patients Newly Diagnosed with Type 2 Diabetes Mellitus.

PURPOSE: Little is known about the relationship between brain-derived neurotrophic factor (BDNF) gene polymorphisms and psychiatric symptoms in diabetes patients. We investigated the effects of BDNF Val/66/Met polymorphism, glucose status, psychological susceptibility, and resilience on anxiety and depression symptoms in patients newly diagnosed with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We examined biochemical factors and BDNF polymorphism in 89 patients who were newly diagnosed with T2DM. Psychiatric symptoms were investigated with the Hospital Anxiety and Depression Scale (HADS), and the Connor-Davidson Resilience Scale (CD-RISC) and Impact of Event Scale (IES) were used to assess psychological resilience and susceptibility to psychological distress, respectively. Logistic regression analyses were conducted to investigate factors associated with psychiatric symptoms. RESULTS: We determined that 62 patients (70%) were Met-carriers. No significant differences were found between the Val/Val homozygous and Met-carrier groups regarding age, sex, body mass index, and clinical factors related to glycemic control and lipid profiles. HADS-anxiety and HADS-depression scores and IES factor scores were higher in the Met-carrier than the Val/Val homozygous group. Hemoglobin A1c (HbA1c) level was significantly inversely correlated with the severity of depressive symptoms. Resilience factors showed significant inverse correlations, and IES factors showed positive correlations with depressive symptom severity. In the logistic regression analysis model, depressive symptoms were significantly associated with HbA1c and BDNF polymorphism, whereas only the hyperarousal factor of the IES scale was associated with anxiety. CONCLUSION: Depressive symptoms are associated with the presence of the Met-carriers and lower HbA1c in patients newly diagnosed with T2DM.

Rapid Symptom Improvement in Major Depressive Disorder Using Accelerated Repetitive Transcranial Magnetic Stimulation.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has contributed to increase in the remission rate for patients with major depressive disorder (MDD). However, current rTMS treatment is practically inconvenient because it requires daily treatment sessions for several weeks. Accelerated rTMS treatment is as efficient and safe for MDD patients as conventional rTMS. METHODS: Fifty-one patients with MDD participated in this study; they were randomized into accelerated rTMS (n = 21), conventional rTMS (n = 22), and sham-treatment (n = 8) groups. The accelerated and conventional rTMS groups received 15 sessions for 3 days and 3 weeks, respectively. The sham-treatment group received 15 sham rTMS sessions for 3 days. Primary outcome was assessed using self-report and clinician-rated Korean Quick Inventory of Depressive Symptomatology (KQIDS-SR and KQIDS-C, respectively). Adverse effects were monitored using the Frequency, Intensity, and Burden of Side Effects Rating scale. Changes in depressive symptoms were compared among the three groups using mixed model analyses. RESULTS: For the KQIDS-SR score, there was a significant main effect of "time" (F3,47 = 11.05, p < 0.001), but no effect of "group" (F2,47 = 2.04, p = 0.142), and a trend-level interaction effect of "group × time" (F6,47 = 2.26, p = 0.053). Improvement in depressive symptoms, based on the KQIDS-SR score 3 weeks after treatment, was more prominent in the accelerated rTMS group than in the sham-treatment group (p = 0.011). Tolerability was comparable among the three groups. CONCLUSION: The accelerated rTMS treatment group showed rapid improvement of depressive symptoms compared with the sham-treatment and conventional rTMS treatment groups. Therefore, accelerated rTMS treatment could be a viable option for MDD, with improved accessibility.

Maladaptive Alterations of Defensive Response Following Developmental Complex Stress in Rats.

OBJECTIVE: Despite the etiological significance of complex developmental trauma in adult personality disorders and treatment-resistant depression, neurobiological studies have been rare due to the lack of useful animal models. As a first step, we devised an animal model to investigate the effects of multiple trauma-like stress during different developmental periods. METHODS: Twenty-one male Sprague-Dawley rats were classified into 3 groups based on the stress protocol: fear conditioning control (FCC, n = 6), complex stress (ComS, n = 9), and control (n = 6). While the ComS experienced three types of stress (maternal separation, juvenile isolation, electric foot shock), the FCC only experienced an electric foot shock stress and the control never experienced any. We compared fear responses at postnatal day (PND) 29 and PND 56 through freezing time per episode (FTpE), total freezing time (TFT), total freezing episodes (TFE), and ultrasonic vocalization (USV). RESULTS: ComS showed the longest FTpE in the conditioned fear response test. ComS and FCC exhibited the longer TFT and these two groups only displayed USV. ComS show difference TFE between PND 29 and PND 56. CONCLUSION: The results of this investigation show that complex stress may affect not quantity of fear response but characteristics of fear response. Longer FTpE may be associated with tonic immobility which could be considered as a failed self-protective reaction and might be analogous to a sign of inappropriate coping strategy and self-dysregulation in complex trauma patients.