Inflammatory depression is associated with selective glomerular hypofiltration.

BACKGROUND: Systemic low-grade inflammation may be a pathophysiological mechanism in a subtype of depression. In this study we investigate a novel candidate mechanism of inflammatory depression - Selective Glomerular Hypofiltration Syndromes (SGHS) - which are characterized by a reduced estimated glomerular filtration rate (eGFR) based on cystatin C (cysC) relative to eGFR based on creatinine (crea). SGHS have been associated with increased blood levels of pro-inflammatory markers, but have never been investigated in a sample of depressed individuals. METHOD: The prevalence of SGHS was compared between 313 patients with difficult-to-treat depression and 73 controls. Since there is no single established eGFRcysC/eGFRcrea-ratio cut-off to define SGHS, several cut-offs were investigated in relation to a depression diagnosis, inflammation, and symptom severity. Plasma inflammatory markers tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6, IL-8, and IL-10 were available from 276 depressed patients. We examined mediation effects of IL-6 on the relationship between SGHS and depression. RESULTS: Depressed patients were more likely to have SGHS compared to controls defining SGHS as either eGFRcysC/eGFRcrea-ratio < 0.9 (33.2 % vs 20.5 %, p = 0.035) or < 0.8 (15.7 % vs 5.5 %, p = 0.023). Lower eGFRcysC/eGFRcrea-ratio was associated with higher levels of inflammatory markers in depressed patients. IL-6 partly mediated the relationship between SGHS and depression. CONCLUSION: This is the first study to demonstrate a link between SGHS and inflammatory depression. If replicated in independent and longitudinal cohorts, this may prove to be a relevant pathophysiological mechanism in some cases of depression that could be targeted in future intervention and prevention studies.

An inflamed subtype of difficult-to-treat depression.

BACKGROUND: Chronic low-grade inflammation may play a role in the pathophysiology of depression, at least in a subset of patients. High-sensitivity C-reactive protein (hs-CRP) has been used to define an inflamed subgroup of depression with specific clinical characteristics and symptoms. In this study we investigated biochemical and clinical characteristics in patients with difficult-to-treat depression with and without chronic low-grade inflammation. METHOD: We assayed plasma levels of interferon-gamma, tumor necrosis factor-alpha, Interleukin (IL)-10, IL-6, IL-8, and vitamin D in a clinically well-characterized sample of patients with difficult-to-treat depression (n = 263) and healthy controls (n = 46). Serum hs-CRP levels were available in the patient group and were used to define "inflamed depression" (hs-CRP > 3 mg/L). Based on previous studies correlating specific depressive symptoms to inflammatory markers, we calculated a composite score of inflammatory depressive symptoms (Infl-Dep score). A principal component analysis (PCA) was performed to identify patterns of variance in cytokines and vitamin D among patients. RESULTS: Mean levels of IL-6 and IL-8 were significantly higher in depressed patients compared to controls, also after adjusting for sex, smoking, BMI, and age. None of the other inflammatory markers differed significantly between depressed patients and controls. Two components were extracted using PCA; one showed general cytokine elevations and one represented a pattern where IL-6 and IL-8 were inversely related to vitamin D (IL6-IL8-VitD component). The inflamed subgroup (hs-CRP > 3, n = 51) exhibited significantly higher BMI, higher Infl-Dep scores and higher IL6-IL8-VitD component scores than uninflamed patients (hs-CRP ≤ 3, n = 212). There were no significant differences in overall depression severity or suicidality between the inflamed and uninflamed groups. CONCLUSION: Our results support the hypothesis of an inflamed subgroup of depression as a meaningful construct. This subgroup may have certain biological and clinical characteristics and more studies are needed to determine potential clinical implications.

Decreasing Psychiatric Emergency Visits, but Stable Addiction Emergency Visits, During COVID-19-A Time Series Analysis 10 Months Into the Pandemic.

Background: The COVID-19 pandemic has been suspected to increase mental health problems, but also to possibly lead to a decreased treatment seeking, for example due to fear of attending hospital. Early findings demonstrate decreased treatment seeking for mental health, which may differ across diagnostic groups. This study aimed to examine treatment uptake at a general psychiatry emergency unit and at an addiction psychiatry emergency unit in Malmö, Sweden, separately. In addition, the study aimed to investigate treatment uptake for different diagnostic groups-during and prior to the COVID-19 pandemic. Methods: Monthly data for number of unique patients and number of contacts were extracted for the three-year period of January 2018 through December 2020. Data from each facility were analyzed separately for women, men and patients with psychotic, affective, anxiety and substance use-related disorders. Interrupted time series were used to demonstrate possible effects of COVID-19. Results: COVID-19 was associated with a marked decrease in treatment contacts, both for women and men, in the general psychiatry emergency unit-driven by a significant decrease in anxiety-related disorders (p < 0.001) and affective disorders (p < 0.01)-but not in psychotic or substance use disorders (SUDs). Also, in the addiction psychiatry emergency unit, no significant impact of COVID-19 was seen. Conclusions: COVID-19 may decrease treatment uptake for acute affective and anxiety-related disorders. Given the hypothesized increase in the population regarding these conditions, societal efforts are needed to facilitate adequate treatment for these patients during the COVID-19 pandemic. Society should also remain vigilant with respect to SUDs during the pandemic.

No Apparent Increase in Treatment Uptake for Gambling Disorder during Ten Months of the COVID-19 Pandemic-Analysis of a Regional Specialized Treatment Unit in Sweden.

The COVID-19 pandemic and its impact on society has been suspected to affect gambling behaviors. Potentially, the pandemic crisis may result in increased problem gambling, for example, due to COVID-19-related psychological distress, unemployment, and financial difficulties. In addition, the cancellation of sports in early parts of the crisis has been suspected to alter gambling behaviors. Policy makers have called for action and, in some cases, have changed regulations, and media have reported possible increases in treatment seeking. However, research data are hitherto lacking. The present study assessed the treatment uptake at a regional specialized gambling-disorder unit in the healthcare system of Region Skåne, Sweden. Number of patients, treatment contacts, and patterns of rescheduling or cancellations of appointments were quantified for each month, January-December 2020, and compared to corresponding months of 2018 and 2019. Possible trends were analyzed, using an interrupted time-series analysis. Results did not indicate an increase in treatment uptake for gambling disorder during the months of COVID-19 impact in Sweden. The proportion of digital treatment increased, but total treatment uptake was unaffected by the pandemic. In conclusion, during the first ten months of the pandemic in Sweden, no obvious increase in treatment uptake for gambling disorder could be seen. Moreover, longer follow-up may be necessary in order to see if effects of worsening socioeconomic conditions may be a possible long-term risk factor of increased gambling after COVID-19.

Impact of the COVID-19 Pandemic on the General Mental Health in Sweden: No Observed Changes in the Dispensed Amount of Common Psychotropic Medications in the Region of Scania.

Some first investigations have focused on the consequences of the COVID-19 pandemic for the general mental health after its outbreak in 2020. According to multiple self-reporting surveys, symptoms of stress, anxiety, and depression have risen worldwide. Even some studies based on health care records start to be published, providing more objective and statistically reliable results. Additionally, concerns have been raised, to what extend the access to mental health care has been compromised by the COVID-19 outbreak. The aim of this study was to detect changes in prescription trends of common psychotropic medications in the Swedish region of Scania. The monthly dispensed amounts of selected pharmaceuticals were compared from January 2018 until January 2021, regarding the prescription trends before and after the outbreak of COVID-19. Using an interrupted time series analysis for each medication, no general trend changes were observed. On the one hand, a possible deterioration of the general mental health could not be confirmed by these results. On the other hand, the access to mental health care did not seem to be impaired by the pandemic. When interpreting findings related to the COVID-19 pandemic, regional differences and country-specific approaches for coping with the pandemic should be considered. The Swedish population, for instance, never experienced a full "lock-down" and within Sweden the time point of the outbreak waves differed regionally. In general, the effects of the COVID-19 outbreak on mental health are still unclear and need to be investigated further in an international comparison.

Plasma circulating cell-free mitochondrial DNA in depressive disorders.

BACKGROUND: Plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) is an immunogenic molecule and a novel biomarker of psychiatric disorders. Some previous studies reported increased levels of ccf-mtDNA in unmedicated depression and recent suicide attempters, while other studies found unchanged or decreased ccf-mtDNA levels in depression. Inconsistent findings across studies may be explained by small sample sizes and between-study variations in somatic and psychiatric co-morbidity or medication status. METHODS: We measured plasma ccf-mtDNA in a cohort of 281 patients with depressive disorders and 49 healthy controls. Ninety-three percent of all patients were treated with one or several psychotropic medications. Thirty-six percent had a personality disorder, 13% bipolar disorder. All analyses involving ccf-mtDNA were a priori adjusted for age and sex. RESULTS: Mean levels in ccf-mtDNA were significantly different between patients with a current depressive episode (n = 236), remitted depressive episode (n = 45) and healthy controls (n = 49) (f = 8.3, p<0.001). Post-hoc tests revealed that both patients with current (p<0.001) and remitted (p = 0.002) depression had lower ccf-mtDNA compared to controls. Within the depressed group there was a positive correlation between ccf-mtDNA and "inflammatory depression symptoms" (r = 0.15, p = 0.02). We also found that treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower ccf-mtDNA (f = 8.1, p = 0.005). DISCUSSION: Decreased plasma ccf-mtDNA in difficult-to-treat depression may be partly explained by concurrent psychotropic medications and co-morbidity. Our findings suggest that ccf-mtDNA may be differentially regulated in different subtypes of depression, and this hypothesis should be pursued in future studies.

Vitamin D and inflammation in major depressive disorder.

BACKGROUND: Increased inflammation is reported in Major Depressive Disorder (MDD), which may be more pronounced in suicidal subjects. Vitamin D deficiency may drive this pro-inflammatory state due to vitamin D's anti-inflammatory effects. METHODS: We quantified plasma 25-hydroxyvitamin D (25(OH)D) and inflammatory markers interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and other inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and white blood cell count (WBC) in 48 un-medicated MDD subjects (n = 17 with mild-to-moderate suicidal ideation [SI]) and 54 controls. IL-6 and TNF-α were combined into a composite inflammation score. RESULTS: There were no significant differences in 25(OH)D levels between MDD and controls (p = 0.24) or between MDD with and without SI (p = 0.61). However, 25(OH)D was negatively correlated with all measured inflammatory markers; these correlations were stronger in MDD subjects, and particularly in those with SI. MDD status significantly moderated the relationships between 25(OH)D and NLR (p = 0.03), and 25(OH)D and WBC (p < 0.05), and SI significantly moderated the relationship between 25(OH)D and NLR (p = 0.03). LIMITATIONS: The study was cross-sectional, thereby limiting causal inference, and had a small sample size. Only seventeen of the MDD subjects had SI. CONCLUSION: While 25(OH)D levels did not significantly differ in MDD vs. controls, or in MDD with or without SI, lower 25(OH)D was associated with indices of immune activation in MDD, especially in cases with SI. Although our findings do not address causality, they are consistent with findings that relatively low 25(OH)D levels in MDD are associated with a pro-inflammatory state.

Six autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters.

Previous findings suggest a link between neuroinflammatory processes and suicidality. Despite several lines of evidence supporting this link, including increased pro-inflammatory markers in blood-, cerebrospinal fluid (CSF)- and in post-mortem brain samples from suicidal individuals, the underlying mechanisms remain poorly understood. In this pilot study, we explored the possibility that autoimmune encephalopathies might be found among suicide attempters. We analysed the presence of six different autoantibodies (N-methyl-D-aspartate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid receptor, the γ-amino-butyric acid B-receptor, the leucine-rich, glioma-inactivated 1, the contactin-associated protein-like 2, and the dipeptidyl-peptidase-like protein-6), all previously associated with psychopathology, in CSF samples from 29 unmedicated suicide attempters. Five of these subjects had high CSF/serum albumin ratio, indicative of increased blood-brain-barrier permeability. We were not able to detect any of these autoantibodies in the CSF samples. These pilot data do not support a role for autoimmune encephalopathies in suicidal behaviour, although the presence of lower levels of these autoantibodies cannot be ruled out in these patients.

Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood.

BACKGROUND: Low levels of vitamin D may play a role in psychiatric disorders, as cross-sectional studies show an association between vitamin D deficiency and depression, schizophrenia and psychotic symptoms. The underlying mechanisms are not well understood, although vitamin D is known to influence the immune system to promote a T helper (Th)-2 phenotype. At the same time, increased inflammation might be of importance in the pathophysiology of depression and suicide. We therefore hypothesized that suicidal patients would be deficient in vitamin D, which could be responsible for the inflammatory changes observed in these patients. METHODS: We compared vitamin D levels in suicide attempters (n=59), non-suicidal depressed patients (n=17) and healthy controls (n=14). Subjects were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and went through a structured interview by a specialist in psychiatry. 25(OH)D2 and 25(OH)D3 were measured in plasma using liquid-chromatography-mass-spectrometry (LC-MS). We further explored vitamin D's association with plasma IL-1ß, IL-6 and TNF-α. RESULTS: Suicide attempters had significantly lower mean levels of vitamin D than depressed non-suicidal patients and healthy controls. 58 percent of the suicide attempters were vitamin D deficient according to clinical standard. Moreover, there was a significant negative association between vitamin D and pro-inflammatory cytokines in the psychiatric patients. Low vitamin D levels were associated with higher levels of the inflammatory cytokines IL-6 and IL-1ß in the blood. CONCLUSION: The suicide attempters in our study were deficient in vitamin D. Our data also suggest that vitamin D deficiency could be a contributing factor to the elevated pro-inflammatory cytokines previously reported in suicidal patients. We propose that routine clinical testing of vitamin D levels could be beneficial in patients with suicidal symptoms, with subsequent supplementation in patients found to be deficient.