Eight-year nationwide study of the bidirectional association between type 2 diabetes and depression in nearly 8 million German outpatients.

INTRODUCTION: Research linking type 2 diabetes and depression mostly relied on hospital-based diagnoses or prescription data, overlooking many outpatient diagnoses. We aimed to quantify the risks of depression in individuals newly diagnosed with type 2 diabetes, and type 2 diabetes in those newly diagnosed with depression, while exploring potential risk differences depending on age, sex, and follow-up time. RESEARCH DESIGN AND METHODS: We conducted a matched cohort study using German nationwide outpatient claims data from 2012 to 2022. Participants were individuals newly diagnosed with type 2 diabetes (N=294 642) or depression (N=1 271 537) in 2015, matched in a 1:4 ratio to controls without these conditions by age, sex, and region. The bidirectional risk was evaluated over an 8-year period using mixed-effects Cox proportional hazards models, adjusting for the Charlson Comorbidity Index, urbanicity, and area-level deprivation. RESULTS: New type 2 diabetes diagnosis was associated with higher depression risk over 8 years (N=54 561 with depression, HR=1.23, 99% CI=1.21 to 1.24). Similarly, depression diagnosis was linked to an increased type 2 diabetes risk (N=71 848 with type 2 diabetes, HR=1.15, 99% CI=1.14 to 1.17). The association between depression and type 2 diabetes was stronger in younger age groups, especially under 34 years. Findings held across sex-stratified analyses. Time stratification showed a more pronounced association between type 2 diabetes and depression risk during the earlier follow-up quarters, whereas the risk of developing type 2 diabetes after depression diagnosis remained constant throughout the follow-up period. CONCLUSIONS: Our findings confirm a bidirectional link between type 2 diabetes and depression, particularly in younger individuals. As type 2 diabetes and depression are frequent, future research needs to study whether preventive approaches can reduce the risk of developing this comorbidity.

The effects of yohimbine and hydrocortisone on selective attention to fearful faces: An fMRI study.

INTRODUCTION: Selective attention to salient emotional information can enable an advantage in the face of danger. The present study aims to investigate the influence of the stress neuromodulators, norepinephrine and cortisol, on selective attention processes to fearful faces and its neuronal activation. METHODS AND MATERIALS: We used a randomized, double-blind, placebo-controlled design. 167 healthy men between 18 and 35 years (mean [SD] age: 25.23 [4.24] years) participated in the study. Participants received either: (A) yohimbine (n= 41), (B) hydrocortisone (n = 41), (C) yohimbine and hydrocortisone (n = 42) or (D) placebo only (n= 43) and participated in a dot-probe task with fearful and neutral faces in an fMRI scanner. RESULTS: We found an attentional bias toward fearful faces across all groups and related neuronal activation in the left cuneus. We did not find any differences between experimental treatment groups in selective attention and its neuronal activation. DISCUSSION: Our results provide evidence that fearful faces lead to an attentional bias with related neuronal activation in the left cuneus. We did not replicate formerly reported activation in the amygdala, intraparietal sulcus, dorsal anterior cingulate cortex, and thalamus. Suitability of the dot-probe task for fMRI studies and insignificant treatment effects are discussed.

Adipokines in depressed women with and without adverse childhood experiences.

BACKGROUND: Adverse childhood experiences (ACE) elevate the risk of both major depressive disorder (MDD) and metabolic diseases. The underlying pathophysiology might include alterations of adipokine levels as a consequence of ACE. In this study, we used a full-factorial design to investigate the levels of select adipokines in women with ACE-only (n = 23), MDD-only (n = 27), ACE+MDD (n = 25) and healthy controls (HC, n = 29) to identify metabolic makers associated with vulnerability and resilience of developing MDD after ACE exposure. METHODS: Serum levels of adiponectin, leptin, adiponectin-to-leptin (A/L) ratio, and retinol binding protein 4 (RBP4) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Adiponectin levels did not differ between groups. Individuals with vs. without MDD showed higher leptin serum concentrations. As predicted, A/L ratio indicated lower values in individuals with vs. without ACE. RBP4 showed a more nuanced pattern with reduced levels in the ACE-only and MDD-only groups compared to HC. Furthermore, the ACE-only group showed lower RBP4 concentrations compared to ACE+MDD. These results were not accounted by BMI or medication status. CONCLUSION: Our results do not support the utility of adiponectin and leptin as predictors of vulnerability or resilience of developing MDD after ACE. In contrast, RBP4 might play a role in resilience towards the development of MDD following ACE. Further research on this more recently discovered adipokine seems warranted.

Comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) for depression in 43,061 older adults with chronic somatic diseases: A Danish target trial emulation study.

OBJECTIVE: To investigate the comparative effectiveness of commonly used selective serotonin reuptake inhibitors (SSRIs) for comorbid depression in older adults with chronic somatic diseases by applying a target-trial-emulation framework. METHODS: Danish target-trial-emulation study including 43,061 individuals aged ≥65 years (54.1% females, mean age 77.8 years) with a first redeemed prescription for depression with sertraline (n = 6673), escitalopram (n = 7104) or citalopram (n = 29,284) in 2006-2017. Individuals had cancer, cardiovascular diseases (CVD), chronic-obstructive-pulmonary-disease (COPD)/asthma, diabetes, neurodegenerative disorders, or osteoporosis. Outcomes were treatment switching, combination/augmentation, psychiatric hospital contact for depression, and any psychiatric in-patient care. Follow-up was one year and adjusted Cox regression analyses calculated hazard rate ratios (HRR) within each somatic disease. RESULTS: Across all six disease groups and four outcomes, we found that citalopram use, compared with sertraline, was associated with lower risks in several analyses, with statistically significant results in cancer, CVD, COPD/asthma, and diabetes (e.g., HRRs for psychiatric hospital contacts for depression/any psychiatric in-patient care ranging between 0.47 and 0.61). For escitalopram, compared with sertraline, some analyses indicated poorer outcomes with significantly higher risks for combination/augmentation treatment (HRRs ranging between 1.15 and 1.40). CONCLUSIONS: Although observational studies are prone to confounding, these findings indicate clinically relevant differences between the SSRIs, with better outcomes in citalopram users and poorer outcomes in escitalopram users than sertraline, urging the need for clinical studies in this vulnerable patient population.

Depression and fatigue six months post-COVID-19 disease are associated with overlapping symptom constellations: A prospective, multi-center, population-based cohort study.

BACKGROUND: Depression and fatigue are commonly observed sequelae following viral diseases such as COVID-19. Identifying symptom constellations that differentially classify post-COVID depression and fatigue may be helpful to individualize treatment strategies. Here, we investigated whether self-reported post-COVID depression and post-COVID fatigue are associated with the same or different symptom constellations. METHODS: To address this question, we used data from COVIDOM, a population-based cohort study conducted as part of the NAPKON-POP platform. Data were collected in three different German regions (Kiel, Berlin, Würzburg). We analyzed data from >2000 individuals at least six months past a PCR-confirmed COVID-19 disease, using elastic net regression and cluster analysis. The regression model was developed in the Kiel data set, and externally validated using data sets from Berlin and Würzburg. RESULTS: Our results revealed that post-COVID depression and fatigue are associated with overlapping symptom constellations consisting of difficulties with daily activities, perceived health-related quality of life, chronic exhaustion, unrestful sleep, and impaired concentration. Confirming the overlap in symptom constellations, a follow-up cluster analysis could categorize individuals as scoring high or low on depression and fatigue but could not differentiate between both dimensions. LIMITATIONS: The data presented are cross-sectional, consisting primarily of self-reported questionnaire or medical records rather than biometric data. CONCLUSIONS: In summary, our results suggest a strong link between post-COVID depression and fatigue, highlighting the need for integrative treatment approaches.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Evidence of deviant parasympathetic response to social exclusion in women with borderline personality disorder.

Stressful social situations like social exclusion are particularly challenging for patients with borderline personality disorder (BPD) and often lead to dysfunctional reactive behaviour of aggression and withdrawal. The autonomous signature of these core symptoms of BPD remains poorly understood. The present study investigated the parasympathetic response to social exclusion in women with BPD (n = 62) and healthy controls (HC; n = 87). In a between-subjects design, participants experienced objective social exclusion or overinclusion in the Cyberball task, a virtual ball-tossing game. Need threat scores served as individual measures of perceived exclusion and the resulting frustration of cognitive-emotional needs. Five-minute measurements of high-frequency heart rate variability (HF-HRV) at three time points (before, during, after Cyberball) indicated parasympathetic tone and regulation. We observed a trend towards lowered baseline HF-HRV in BPD vs. HC in line with previous findings. Interestingly, the parasympathetic response of patients with BPD to objective and perceived social exclusion fundamentally differed from HC: higher exclusion was associated with increased parasympathetic activation in HC, while this autonomic response was reversed and blunted in BPD. Our findings suggest that during social stress, the parasympathetic nervous system fails to display an adaptive regulation in patients with BPD, but not HC. Understanding the autonomous signature of the stress response in BPD allows the formulation of clinically relevant and biologically plausible interventions to counteract parasympathetic dysregulation in this clinical group.

The influence of pharmacological mineralocorticoid and glucocorticoid receptor blockade on the cortisol response to psychological stress.

The glucocorticoid cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis and crucial for the stress response in humans. Cortisol regulates numerous biological functions by binding to two different types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are found in the brain where they are crucially involved in various mental functions and in feedback inhibition of cortisol release. The precise role of both receptors in the human stress response is not completely understood. In this study, we examined the effects of pharmacological blockade of the MR or the GR on stress-induced cortisol release in a sample of 318 healthy young men (M = 25.42, SD = 5.01). Participants received the MR antagonist spironolactone (300 mg), the GR antagonist mifepristone (600 mg), or a placebo and were subjected 90 min later to a social-evaluative stressor (Trier Social Stress Test) or a non-stressful control condition. We found significantly higher stress-induced cortisol release in the spironolactone group, whereas participants after mifepristone administration did not differ from the control groups. These results suggest that MR blockade results in attenuated fast negative feedback processes and emphasize the important role of the MR during the early phase of the stress response.

Effects of oral contraceptives on intrusive memories: a secondary analysis of two studies using the trauma film paradigm in healthy women.

Background: Women are more likely to develop post-traumatic stress disorder (PTSD) than men. Recent research suggests an impact of oral contraceptive (OC) intake on PTSD and intrusive memories, a hallmark symptom of PTSD. Although a majority of women use OCs at some point in their lives, the effects on PTSD pathogenesis are only poorly understood.Objective: In the current paper, we aimed to investigate the impact of OC intake on the acquisition and consolidation of intrusive memories in healthy women after watching a trauma film paradigm.Methods: We performed a secondary analysis of a pooled dataset (N = 437) of two previously conducted and published studies investigating the effect of oxytocin on the development of intrusive memories.Results: Women taking OCs showed an attenuated decline of intrusive memories over time after having watched the trauma film compared to naturally cycling women (F(2.75, 1167) = 3.79, p = .03, ηp2 = .01).Conclusion: These findings indicate that the intake of OCs is associated with the development of intrusive memories after a trauma film paradigm. This indication emphasizes the need to further investigate the complex impact of OCs and gonadal hormones on fear learning processes and PTSD.

The objective of the current study was to analyze the effect of oral contraceptives on the development of intrusive memories after a trauma film paradigm by conducting a secondary analysis of previously published data.Women taking oral contraceptives show an attenuated decline of intrusive memories after watching a trauma film paradigm compared to naturally cycling women in the luteal phase.Women using oral contraceptives show higher basal saliva cortisol levels.

Causes, clinical characteristics, and outcomes of high lithium levels and intoxications: Retrospective analysis of patient records.

BACKGROUND: The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. METHODS: Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. RESULTS: We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). CONCLUSIONS: Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases.

Patient characteristics, validity of clinical diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D): design, procedures and outcomes.

BACKGROUND: Suicidality, ranging from passive suicidal thoughts to suicide attempt, is common in major depressive disorder (MDD). However, relatively little is known about patient, illness and treatment characteristics in those with co-occurring MDD and suicidality, including the timing of and factors associated with the offset, continuation or reemergence of suicidality. Here, we present the background, rationale, design and hypotheses of the Patient Characteristics, Validity of Clinical Diagnoses and Outcomes Associated with Suicidality in Inpatients with Symptoms of Depression (OASIS-D) study, an investigator-initiated, observational study, funded by Janssen-Cilag GmbH. METHODS/RESULTS: OASIS-D is an eight-site, six-month, cohort study of patients aged 18-75 hospitalized with MDD. Divided into three sub-studies and patient populations (PPs), OASIS-D will (i) systematically characterize approximately 4500 consecutively hospitalized patients with any form of unipolar depressive episode (PP1), (ii) evaluate the validity of the clinical diagnosis of moderate or severe unipolar depressive episode with the Mini-International Neuropsychiatric Interview (M.I.N.I.) and present suicidality (at least passive suicidal thoughts) present ≥ 48 h after admission with the Sheehan-Suicide Tracking Scale (S-STS), assessing also predictors of the diagnostic concordance/discordance of MDD in around 500 inpatients (PP2), and (iii) characterize and prospectively follow for 6 months 315 inpatients with a research-verified moderate or severe unipolar depressive episode and at least passive suicidal thoughts ≥ 48 h after admission, evaluating treatment and illness/response patterns at baseline, hospital discharge, 3 and 6 months. Exploratory objectives will describe the association between the number of days with suicidality and utilization of outpatient and inpatient care services, and structured assessments of factors influencing the risk of self-injurious behavior without suicidal intent, and of continuous, intermittent or remitted suicidality during the 6-month observation period. CONCLUSION: Despite their frequency and clinical relevance, relatively little is known about patient and treatment characteristics of individuals with MDD and suicidality, including factors moderating and mediating the outcome of both MDD and suicidality. Results of the OASIS-D study are hoped to improve the understanding of the frequency, correlates and 6-month naturalistic treatment and outcome trajectories of different levels of suicidality in hospitalized adults with MDD and suicidality. TRIAL REGISTRATION: NCT04404309 [ClinicalTrials.gov].

Efficacy and Safety of Antidepressants in Patients With Comorbid Depression and Medical Diseases: An Umbrella Systematic Review and Meta-Analysis.

Importance: Every third to sixth patient with medical diseases receives antidepressants, but regulatory trials typically exclude comorbid medical diseases. Meta-analyses of antidepressants have shown small to medium effect sizes, but generalizability to clinical settings is unclear, where medical comorbidity is highly prevalent. Objective: To perform an umbrella systematic review of the meta-analytic evidence and meta-analysis of the efficacy and safety of antidepressant use in populations with medical diseases and comorbid depression. Data Sources: PubMed and EMBASE were searched from inception until March 31, 2023, for systematic reviews with or without meta-analyses of randomized clinical trials (RCTs) examining the efficacy and safety of antidepressants for treatment or prevention of comorbid depression in any medical disease. Study Selection: Meta-analyses of placebo- or active-controlled RCTs studying antidepressants for depression in individuals with medical diseases. Data Extraction and Synthesis: Data extraction and quality assessment using A Measurement Tool for the Assessment of Multiple Systematic Reviews (AMSTAR-2 and AMSTAR-Content) were performed by pairs of independent reviewers following PRISMA guidelines. When several meta-analyses studied the same medical disease, the largest meta-analysis was included. Random-effects meta-analyses pooled data on the primary outcome (efficacy), key secondary outcomes (acceptability and tolerability), and additional secondary outcomes (response and remission). Main Outcomes and Measures: Antidepressant efficacy presented as standardized mean differences (SMDs) and tolerability (discontinuation for adverse effects) and acceptability (all-cause discontinuation) presented as risk ratios (RRs). Results: Of 6587 references, 176 systematic reviews were identified in 43 medical diseases. Altogether, 52 meta-analyses in 27 medical diseases were included in the evidence synthesis (mean [SD] AMSTAR-2 quality score, 9.3 [3.1], with a maximum possible of 16; mean [SD] AMSTAR-Content score, 2.4 [1.9], with a maximum possible of 9). Across medical diseases (23 meta-analyses), antidepressants improved depression vs placebo (SMD, 0.42 [95% CI, 0.30-0.54]; I2 = 76.5%), with the largest SMDs for myocardial infarction (SMD, 1.38 [95% CI, 0.82-1.93]), functional chest pain (SMD, 0.87 [95% CI, 0.08-1.67]), and coronary artery disease (SMD, 0.83 [95% CI, 0.32-1.33]) and the smallest for low back pain (SMD, 0.06 [95% CI, 0.17-0.39]) and traumatic brain injury (SMD, 0.08 [95% CI, -0.28 to 0.45]). Antidepressants showed worse acceptability (24 meta-analyses; RR, 1.17 [95% CI, 1.02-1.32]) and tolerability (18 meta-analyses; RR, 1.39 [95% CI, 1.13-1.64]) compared with placebo. Antidepressants led to higher rates of response (8 meta-analyses; RR, 1.54 [95% CI, 1.14-1.94]) and remission (6 meta-analyses; RR, 1.43 [95% CI, 1.25-1.61]) than placebo. Antidepressants more likely prevented depression than placebo (7 meta-analyses; RR, 0.43 [95% CI, 0.33-0.53]). Conclusions and Relevance: The results of this umbrella systematic review of meta-analyses found that antidepressants are effective and safe in treating and preventing depression in patients with comorbid medical disease. However, few large, high-quality RCTs exist in most medical diseases.

Treating nightmares in posttraumatic stress disorder with dronabinol: study protocol of a multicenter randomized controlled study (THC PTSD-trial).

BACKGROUND: Distressing nightmares are a core symptom of posttraumatic stress disorder (PTSD) and contribute to psychiatric comorbidity, impaired physical health and decreased social functioning. No specific pharmacological treatment for PTSD-related nightmares is yet approved. Preliminary clinical data indicate that cannabinoid agonists can improve nightmares and overall PTSD symptoms in patients with PTSD. The primary objective of the study is to examine the efficacy of oral dronabinol (BX-1) versus placebo in reducing nightmares in patients with PTSD. The secondary objectives of the study are to examine the efficacy of oral BX-1 in reducing other PTSD symptoms. METHODS: The study is designed as a multi-centric, double-blind, randomized (1:1), placebo-controlled, parallel group interventional trial. Eligible patients will be randomized to BX-1 or placebo, receiving a once-daily oral dose before bedtime for 10 weeks. Primary efficacy endpoint is the Clinician-Administered PTSD Scale (CAPS-IV) B2 score for the last week, measuring frequency and intensity of nightmares. Secondary efficacy endpoints are other disorder-specific symptoms in patients with PTSD. Further, tolerability and safety of dronabinol will be assessed. DISCUSSION: This randomized controlled trial will provide evidence whether treating patients with PTSD and nightmares with dronabinol is safe and efficacious. TRIAL REGISTRATION: NCT04448808, EudraCT 2019-002211-25.

Childhood trauma and cortical thickness in healthy women, women with post-traumatic stress disorder, and women with borderline personality disorder.

BACKGROUND: Structural brain changes have been associated with childhood trauma (CT) and several trauma-associated mental disorders. It is not known whether specific brain alterations are rather associated with CT as such or with disorders that are common sequelae of CT. In this study, we characterized cortical thickness in three distinct groups with CT: healthy women (HC/CT), women with posttraumatic stress disorder (PTSD/CT) and women with borderline personality disorder (BPD/CT). These three CT-exposed groups were compared with healthy controls not exposed to CT (HC). METHODS: We recruited 129 women (n = 70 HC, n = 25 HC/CT, n = 14 PTSD/CT, and n = 20 BPD/CT) and acquired T1-weighted anatomical images. FreeSurfer was used for conducting whole-brain cortical thickness between-group comparisons, applying separate generalized linear models to compare cortical thickness of each CT-exposed group with HC. RESULTS: The HC/CT group had lower cortical thickness in occipital lobe areas (right lingual gyrus, left lateral occipital lobe) than the HC group. The BPD/CT group showed a broader pattern of reduced cortical thickness compared to the HC group, including the bilateral superior frontal gyrus, and bilateral isthmus, the right posterior, and left caudal anterior of the cingulate cortex as well as the right lingual gyrus of the occipital lobe. We found no differences between PTSD/CT and HC. CONCLUSIONS: Cortical thickness reduction in the right lingual gyrus of the occipital lobe seem to be related to CT but is also present in BPD patients even after adjusting for severity of CT. Possibly, reduced cortical thickness in the lingual gyrus presents a CT-related vulnerability factor for CT-related adult psychopathologies such as BPD. Reduced cortical thickness in the frontal and cingulate cortex may represent unique neuroanatomical markers of BPD possibly related to difficulties in emotion regulation.

Association between baseline dissociation levels and stress-induced state dissociation in patients with posttraumatic-stress disorder, borderline personality disorder, and major depressive disorder.

INTRODUCTION: Dissociative symptoms are highly prevalent in patients with trauma-related disorders such as borderline personality disorder (BPD) and posttraumatic-stress disorder (PTSD), and also occur in patients with depressive disorders. Acute dissociative states are theorized to be stress-related, and some individuals experience recurring patterns of dissociation. The relationship between the intensity of dissociative episodes (trait-like dissociation) and acute dissociative states, however, is incompletely understood. In the present study, we investigated how levels of baseline (trait-like) dissociation relate to changes in dissociative states during a laboratory stress induction. METHODS: Our female sample comprised 65 patients with BPD and/or PTSD, 84 patients with major depressive disorder (MDD) and 44 non-clinical controls (NCC). Baseline dissociation was assessed at the start of the study using the Dissociation Tension Scale past week version (DSS-7). All participants underwent the Trier Social Stress Test (TSST) and a placebo version (P-TSST). Before and after the TSST or P-TSST, state dissociation was assessed using the Dissociation Tension Scale acute (DSS-4). We used structural equation models to estimate changes in state dissociation items (somatoform dissociation, derealization, depersonalization, analgesia), and to test whether these changes relate to levels of baseline dissociation. RESULTS: We found significant increases in all state dissociation items in response to the TSST in patients with BPD and/or PTSD and patients with MDD, but not in NCCs. Increases in somatoform dissociation and derealization during the TSST were significantly related to higher levels of baseline dissociation in patients with BPD and/or PTSD, but not in patients with MDD or NCCs. Results indicate no significant changes in state dissociation during the P-TSST. CONCLUSION: Our results replicate earlier findings that patients with BPD and/or PTSD report higher levels of stress-related state dissociation than NCC and extend them to patients with MDD. In addition, our findings indicate that baseline levels of dissociation relate to stress-induced changes in state dissociation among patients with BPD and PTSD, but not patients with MDD. In clinical applications, measures of baseline dissociation could be used to facilitate the prediction and treatment of stress-related dissociative states in patients with BPD and/or PTSD.

Associations between individual depressive symptoms and immunometabolic characteristics in major depression.

Inflammation and metabolic dysregulations are likely to underlie atypical, energy-related depressive symptoms such as appetite and sleep alterations. Indeed, increased appetite was previously identified as a core symptom of an immunometabolic subtype of depression. The aim of this study was 1) to replicate the associations between individual depressive symptoms and immunometabolic markers, 2) to extend previous findings with additional markers, and 3) to evaluate the relative contribution of these markers to depressive symptoms. We analyzed data from 266 persons with major depressive disorder (MDD) in the last 12 months from the German Health Interview and Examination Survey for Adults and its mental health module. Diagnosis of MDD and individual depressive symptoms were determined by the Composite International Diagnostic Interview. Associations were analyzed using multivariable regression models, adjusting for depression severity, sociodemographic/behavioral variables, and medication use. Increased appetite was associated with higher body mass index (BMI), waist circumference (WC), insulin, and lower high-density lipoprotein. In contrast, decreased appetite was associated with lower BMI, WC, and fewer metabolic syndrome (MetS) components. Insomnia was associated with higher BMI, WC, number of MetS components, triglycerides, insulin, and lower albumin, while hypersomnia was associated with higher insulin. Suicidal ideation was associated with higher number of MetS components, glucose, and insulin. None of the symptoms were associated with C-reactive protein after adjustment. Appetite alterations and insomnia were most important symptoms associated with metabolic markers. Longitudinal studies should investigate whether the candidate symptoms identified here are predicted by or predict the development of metabolic pathology in MDD.

Oxytocin vs. placebo effects on intrusive memory consolidation using a trauma film paradigm: a randomized, controlled experimental study in healthy women.

Oxytocin administration during a trauma analogue has been shown to increase intrusive memories, which are a core symptom of post-traumatic stress disorder (PTSD). However, it is unknown whether oxytocin influences the acquisition or the consolidation of the trauma. The current study investigates the effect of the activation of the oxytocin system during the consolidation of an analogue trauma on the formation of intrusive memories over four consecutive days and whether this effect is influenced by individual neurobiological, genetic, or psychological factors. We conducted a randomized double-blind placebo-controlled study in 217 healthy women. They received either a single dose of intranasal oxytocin (24 IU) or placebo after exposure to a trauma film paradigm, which reliably induces intrusive memories. We used a general random forest to examine a potential heterogeneous treatment effect of oxytocin on the consolidation of intrusive memories. Furthermore, we used a poisson regression to examine whether salivary alpha amylase activity (sAA) as a marker of noradrenergic activity and cortisol response to the film, polygenic risk score (PRS) for psychiatric disorders, and psychological factors influence the number of intrusive memories. We found no significant effect of oxytocin on the formation of intrusive memories (F(2, 543.16) = 0.75, p = 0.51, ηp2 = 0.00) and identified no heterogeneous treatment effect. We replicated previous associations of the PRS for PTSD, sAA and the cortisol response on intrusive memories. We further found a positive association between high trait anxiety and intrusive memories, and a negative association between the emotion regulation strategy reappraisal and intrusive memories. Data of the present study suggest that the consolidation of intrusive memories in women is modulated by genetic, neurobiological and psychological factors, but is not influenced by oxytocin. Trial registration: NCT03875391.

Impact of social exclusion on empathy in women with borderline personality disorder.

Unstable interpersonal relationships and fear of abandonment are core symptoms of borderline personality disorder (BPD) that often intensify during stress. Psychosocial stress, which includes components of social exclusion and increases cortisol secretion, enhances emotional empathy in healthy individuals. Women with BPD, on the contrary, react with reduced emotional empathy. The aim of the present study was to investigate the effects of perceived social exclusion without accompanying cortisol increase on empathy in women with BPD and healthy women. To induce social exclusion, we randomized 98 women with BPD and 98 healthy women to either an exclusion or an overinclusion (control) condition of Cyberball, a virtual ball game. Subsequently, participants underwent the Multifaceted Empathy Test (MET), which assesses cognitive and emotional empathy. There was no increase in cortisol release after Cyberball. Cognitive empathy did not differ between groups or conditions. Women with BPD reported lower emotional empathy for positive emotions (group by valence interaction), but not for negative emotions. Exploratory analyses suggested that this effect might be more pronounced after social exclusion. Our results confirm previous findings that cognitive empathy does not differ between women with BPD and healthy women and extend this evidence to social exclusion. Emotional empathy in women with BPD seems to be more sensitive to the effects of stress or ambiguous social situations. Specifically, emotional empathy seems to be reduced for positive emotions, and might further decline after social exclusion. Empathic reactions to emotional stimuli of different valences and to specific emotions should be further investigated.

Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes.

Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets.Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans.