Higher immune-related gene expression in major depression is independent of CRP levels: results from the BIODEP study.

Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case-control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP <1, n = 33 with CRP 1-3 and n = 36 with CRP >3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.

Thyroidectomy in dogs with thyroid tumors: Survival analysis in 144 cases (1994-2018).

BACKGROUND: Few studies have assessed predictors of outcome in dogs with thyroid tumors undergoing thyroidectomy. OBJECTIVE: To estimate the survival and identify prognostic factors in dogs with thyroid tumors treated by thyroidectomy. ANIMALS: A total of 144 client-owned dogs with thyroid neoplasia that underwent thyroidectomy. METHODS: Retrospective study. Data for analysis included hospital attended and year of surgery, signalment, thyroxine concentration, thyroid tumor features (lobe involvement, size, invasiveness, histopathological type), thrombosis, metastasis, additional surgery and therapy, administration of adjuvant chemotherapy. The association of predictors with survival (time from surgery to death) were assessed by calculating cause-specific hazard ratios (HRcs ) and 95% confidence intervals (CI). Causes of death were classified as thyroid-related or because of other cause. RESULTS: Overall median survival time was 802 days (CI95% = 723-1015 days); 89 dogs (77.4%) survived >500 days. Metastases were identified at admission in 12 (8.3%) dogs and were associated with higher thyroid cancer-related fatality (HR = 5.83, CI95% = 1.56-21.78; P = .009). Thrombosis occurred in 40 dogs and was associated with increased risk of death because of other cause (HR = 2.73, CI95% = 1.18-6.35; P = .019). Nonfollicular carcinoma (HR = 4.17, CI95% = 1.27-13.69; P = .018) and administration of chemotherapy (HR = 3.45, CI95% = 1.35-8.82; P = .01) were associated with higher risk of thyroid cancer-related death. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with thyroid tumors undergoing thyroidectomy have a long life expectancy. Despite the rare presence of nonfollicular carcinoma and metastases, thyroidectomy should still be considered in some of these dogs.

Translational potential of synaptic alterations in Alzheimer's disease patients and amyloid precursor protein knock-in mice.

Synaptic dysfunction is an early event in Alzheimer's disease. Post-mortem studies suggest that alterations in synaptic proteins are associated with cognitive decline in Alzheimer's disease. We measured the concentration of three synaptic proteins, zinc transporter protein 3, dynamin1 and AMPA glutamate receptor 3 in cerebrospinal fluid of subjects with mild cognitive impairment (n = 18) and Alzheimer's disease (n = 18) and compared the levels to cognitively and neurologically healthy controls (n = 18) by using ELISA assay. In addition, we aimed to assess the translational potential of these synaptic proteins in two established amyloid precursor protein knock-in Alzheimer's disease mouse models by assessing the cerebrospinal fluid, hippocampal and cortical synaptic protein concentrations. Using ELISA, we measured in parallel these three proteins in cerebrospinal fluid and/or brain of 12- and 24-month-old AppNL-F and AppNL-G-F knock-in mice and AppWt control mice. The regional distribution and expression of these proteins were explored upon aging of the App knock-in models by quantitative immunofluorescence microscopy. Notably, we found a significant increase in concentrations of zinc transporter protein 3 and AMPA glutamate receptor 3 in cerebrospinal fluid of both patient groups compared with cognitively healthy controls. Dynamin1 concentration was significantly higher in Alzheimer's disease patients. Remarkably, patients with mild cognitive impairment who converted to Alzheimer's disease (n = 7) within 2 years exhibited elevated baseline cerebrospinal fluid zinc transporter protein 3 concentrations compared with mild cognitive impairment patients who did not convert (n = 11). Interestingly, similar to the alterations in Alzheimer's disease subjects, cerebrospinal fluid AMPA glutamate receptor 3 concentration was significantly higher in AppNL-G-F knock-in mice when compared with wild-type controls. Furthermore, we have detected age and brain regional specific changes of the three synaptic proteins in the hippocampus and prefrontal cortex of both AppNL-F and AppNL-G-F knock-in mice. Notably, all the three cerebrospinal fluid synaptic protein concentrations correlated negatively with concentrations in hippocampal lysates. The elevated zinc transporter protein 3 concentrations in the cerebrospinal fluid of converter versus non-converter mild cognitive impairment patients suggests a prospective role of zinc transporter 3 in differentiating dementia patients of the biological continuum of Alzheimer's disease. The increased cerebrospinal fluid concentrations of synaptic proteins in both patient groups, potentially reflecting synaptic alterations in the brain, were similarly observed in the amyloid precursor protein knock-in mouse models highlighting the translational potential of these proteins as markers for synaptic alterations. These synaptic markers could potentially help reduce the current disparities between human and animal model-based studies aiding the translation of preclinical discoveries of pathophysiological changes into clinical research.

Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response.

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline - the Minocycline in Depression (MINDEP) study. Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP <3 mg/L). Additionally, we investigated the role of serum IL-6 in predicting treatment response to minocycline, using sex-specific medians of IL-6, in novel exploratory analyses. Results: Sex differences in Δ-HAMD-17 indicate that only females (F = 10.49, p = 0.005), but not males (F = 1.64, p = 0.22), presented an effect of CRP levels on the response to minocycline. Also, we detected sex differences in the relationship between serum CRP and IL-6 levels: CRP was strongly correlated with IL-6 in females (Spearman's ρ = 0.658, P < 0.001) but not in males (ρ = 0.007, p = 0.979). Exploratory analyses found that IL-6 was indeed a better predictor of response than minocycline than CRP, as we found an interaction between study arms and IL-6 groups (above and below the IL-6 sex-specific median) in females (F = 4.435 p = 0.050) and, at trend statistical level, in males (F = 4.258 p = 0.060). Moreover, Δ-HAMD-17 was numerically comparable in the two high-IL-6 group taking minocycline (females, mean 9.20 ± SD 7.80; males, mean 8.80 ± SD 5.97), confirming that high IL-6, differently from high CRP, identified responders to minocycline both in males and females. Conclusion: Our findings highlight the need of sex-specific inflammatory biomarkers in predicting antidepressant response to anti-inflammatories in TRD patients, with the possibility of CRP being a relevant predictor of treatment response only for females, and IL-6 being relevant for both sexes.

The influence of comorbid depression and overweight status on peripheral inflammation and cortisol levels.

BACKGROUND: Depression and overweight are each associated with abnormal immune system activation. We sought to disentangle the extent to which depressive symptoms and overweight status contributed to increased inflammation and abnormal cortisol levels. METHODS: Participants were recruited through the Wellcome Trust NIMA Consortium. The sample of 216 participants consisted of 69 overweight patients with depression; 35 overweight controls; 55 normal-weight patients with depression and 57 normal-weight controls. Peripheral inflammation was measured as high-sensitivity C-Reactive Protein (hsCRP) in serum. Salivary cortisol was collected at multiple points throughout the day to measure cortisol awakening response and diurnal cortisol levels. RESULTS: Overweight patients with depression had significantly higher hsCRP compared with overweight controls (p = 0.042), normal-weight depressed patients (p < 0.001) and normal-weight controls (p < 0.001), after controlling for age and gender. Multivariable logistic regression showed that comorbid depression and overweight significantly increased the risk of clinically elevated hsCRP levels ⩾3 mg/L (OR 2.44, 1.28-3.94). In a separate multivariable logistic regression model, overweight status contributed most to the risk of having hsCRP levels ⩾3 mg/L (OR 1.52, 0.7-2.41), while depression also contributed a significant risk (OR 1.09, 0.27-2). There were no significant differences between groups in cortisol awakening response and diurnal cortisol levels. CONCLUSION: Comorbid depression and overweight status are associated with increased hsCRP, and the coexistence of these conditions amplified the risk of clinically elevated hsCRP levels. Overweight status contributed most to the risk of clinically elevated hsCRP levels, but depression also contributed to a significant risk. We observed no differences in cortisol levels between groups.

Using quantitative MRI to study brain responses to immune challenge with interferon-α.

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivo central response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation. Quantitative relaxation times (T1 & T2) and Proton Density (PD) were measured in n â€‹= â€‹6 healthy males (mean age â€‹= â€‹30.5 â€‹± â€‹6.8 years) in two MRI assessments collected before and 24 â€‹hours after a subcutaneous injection of the proinflammatory cytokine and immune activator, interferon-alpha (IFN-α). Serum levels of immune markers and markers of blood-brain barrier integrity (S100B) were also measured before and after the injection. Region of interest and histogram-based analyses (optimized for the small sample size) showed a statistically significant increase of both T1 (t(5) â€‹= â€‹3.78, p â€‹= 0.013) and PD (t(5) â€‹= â€‹2.91, p â€‹= â€‹0.033) parameters in the bilateral hippocampus after IFN-α administration. T1 peak values in bilateral hippocampus were positively correlated with serum Tumour Necrosis Factor-alpha levels at 24 â€‹h after the injection, when this cytokine peaked (Spearman's rho â€‹= â€‹0.67, p â€‹= â€‹0.018) and negatively correlated with S100B levels (Spearman's rho â€‹= â€‹-0.826, p â€‹= â€‹0.001). Our data suggest that peripheral administration of IFN-α produces acute changes in brain qMRI which might indicate a brain immune response. This is supported by the association of such changes with low-grade peripheral inflammation.

Peripheral immune markers and antipsychotic non-response in psychosis.

BACKGROUND: Peripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with psychosis. METHODS: This cross-sectional study recruited 94 patients with schizophrenia and other psychoses, of whom 47 were defined as antipsychotic responders and 47 as antipsychotic non-responders. In all subjects we measured plasma levels of cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, and IFN-γ), complement markers (C1-inhibitor, C3, C4, C3a, C3b, Bb, factor D, C5a, terminal complement complex) and high sensitivity C-reactive protein (hsCRP). Symptom severity was recorded using the Positive and Negative Syndrome scale for Schizophrenia (PANSS). Binary logistic regression tested each immune marker as predictor of response status while covarying for relevant socio-demographic variables. Correlation analyses tested the association between immune markers and the severity of symptoms. RESULTS: Interleukin (IL)-8 significantly predicted antipsychotic non-response (OR=24.70, 95% CI, 1.35-453.23, p = 0.03). Other immune markers were not associated with antipsychotic response. IL-6, IL-8, IL-10 and TNF-α significantly positively correlated with negative psychotic symptoms. CONCLUSIONS: Higher levels of IL-8 are associated with a poor response to antipsychotic treatment. Increased cytokines levels are specifically associated with more severe negative symptoms in patients with schizophrenia and other psychoses.

Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial.

This study aimed to investigate the role of baseline levels of peripheral inflammation when testing the efficacy of antidepressant augmentation with minocycline in patients with treatment-resistant depression. We conducted a 4-week, placebo-controlled, randomised clinical trial of minocycline (200 mg/day) added to antidepressant treatment in 39 patients selected for elevated levels of serum C-reactive protein (CRP ≥ 1 mg/L), n = 18 randomised to minocycline (M) and n = 21 to placebo (P). The main outcome was the change in Hamilton Depression Rating Scale (HAM-D-17) score from baseline to week 4, expressed both as mean and as full or partial response, in the overall sample and after further stratification for baseline CRP≥3 mg/L. Secondary outcomes included changes in other clinical and inflammatory measures. Changes in HAM-D-17 scores and the proportion of partial responders did not differ between study arms. After stratification for CRP levels <3 mg/L (CRP-) or ≥3 mg/L (CRP+), CRP+/M patients showed the largest changes in HAM-D-17 scores (mean ± SD = 12.00 ± 6.45) compared with CRP-/M (2.42 ± 3.20, p < 0.001), CRP+/P (3.50 ± 4.34, p = 0.003) and CRP-/P (2.11 ± 3.26, p = 0.006) patients, and the largest proportion (83.3%, p = 0.04) of partial treatment response at week 4. The threshold point for baseline CRP to distinguish responders from non-responders to minocycline was 2.8 mg/L. Responders to minocycline had higher baseline IL-6 concentrations than non-responders (p = 0.03); IFNγ was significantly reduced after treatment with minocycline compared with placebo (p = 0.03). Our data show some evidence of efficacy of add-on treatment with minocycline in MDD patients but only in those with low-grade inflammation defined as CRP ≥3 mg/L.

Gastrointestinal ultrasonographic findings in cats with Feline panleukopenia: a case series.

BACKGROUND: Feline panleukopenia virus (FPV) is very resistant and highly contagious and infects domestic cats and other felids. FPV is particularly widespread among sheltered cats, and is associated with high morbidity and mortality, causing severe gastroenteritis characterized by anorexia, lethargy, fever, dehydration, hemorrhagic diarrhea, and vomiting. There is currently no data on the ultrasonographic features of cats affected with FPV. This case series describes abdominal ultrasonographic findings in shelter cats with naturally-occurring FPV, and assesses whether are associated with clinical and laboratory findings. Cats affected by FPV were enrolled in the study if an abdominal ultrasound was performed within 12 hours of diagnosis. Clinical, laboratory and survival data were collected from medical records. Ultrasonographic examinations were reviewed for gastrointestinal abnormalities and their associations with the above data were explored. RESULTS: Twenty-one cats were included. Nine cats (42.9%) died and 12 (57.1%) recovered. Based on ultrasonography, the duodenum and jejunum showed thinning of the mucosal layer in 70.6% and 66.6% of cats, thickening of the muscular layer in 52.9% and 57.1% of cats, and hyperechogenicity of the mucosa in 41.2% and 33.3%. Jejunal hyperechoic mucosal band paralleling the submucosa and irregular luminal surface were both observed in 33.3% of the cats. Survival was positively associated with increased jejunal mucosal echogenicity (P = 0.003) and hyperechoic mucosal band (P = 0.003). Peritoneal free fluid was positively associated with vomiting (P = 0.002). CONCLUSIONS: This study provides ultrasonographic features of naturally-occurring FPV in cats, which, as expected, are compatible with gastroenteropathy. The most frequent findings were diffuse small intestine mucosal layer thinning, muscular layer thickening and mucosal hyperechogenicity, jejunal hyperechoic mucosal band and irregular luminal surface. Ultrasonographic features may be useful to complete the clinical picture and assess the severity of the gastroenteropathy in FPV cats. Prospective studies are needed to confirm ultrasonographic prognostic factors.

Correction: Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

We have corrected this Article post-publication, because Dr. Cattaneo's affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article.

Increased Cerebrospinal Fluid Concentration of ZnT3 Is Associated with Cognitive Impairment in Alzheimer's Disease.

BACKGROUND: Cognitive deficits arising in the course of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. OBJECTIVE: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). METHODS: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N = 24), PDD (N = 18), DLB (N = 27), and SCD (N = 28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). RESULTS: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p = 0.002) and of ZnT3 and Dynamin 1 in DLB (p = 0.001, p = 0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p = 0.011), and with depressive symptoms in SCD (p = 0.041). CONCLUSION: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.

Treatment with Class A CpG Oligodeoxynucleotides in Cats with Naturally Occurring Feline Parvovirus Infection: A Prospective Study.

Feline parvovirus (FPV) causes severe gastroenteritis and leukopenia in cats; the outcome is poor. Information regarding specific treatments is lacking. Class A CpG oligodeoxynucleotides (CpG-A) are short single-stranded DNAs, stimulating type I interferon production. In cats, CpG-A induced an antiviral response in vivo and inhibited FPV replication in vitro. The aim was to prospectively investigate the effects of CpG-A on survival, clinical score, hematological findings, antiviral response (cytokines), viremia, and fecal shedding (real-time qPCR) in cats naturally infected with FPV. Forty-two FPV-infected cats were randomized to receive 100 µg/kg of CpG-A (n = 22) or placebo (n = 20) subcutaneously, on admission and after 48 h. Blood and fecal samples were collected on admission, after 1, 3, and 7 days. All 22 cats showed short duration pain during CpG-A injections. The survival rate, clinical score, leukocyte and erythrocyte counts, viremia, and fecal shedding at any time-point did not differ between cats treated with CpG-A (50%) and placebo (40%). Antiviral myxovirus resistance (Mx) gene transcription increased in both groups from day 1 to 3 (p = 0.005). Antibodies against FPV on admission were associated with survival in cats (p = 0.002). In conclusion, CpG-A treatment did not improve the outcome in cats with FPV infection. FPV infection produced an antiviral response.

Childhood trauma, HPA axis activity and antidepressant response in patients with depression.

Childhood trauma is among the most potent contributing risk factors for depression and is associated with poor treatment response. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been linked to both childhood trauma and depression, but the underlying mechanisms are poorly understood. The present study aimed to investigate the link between childhood trauma, HPA axis activity and antidepressant response in patients with depression. As part of the Wellcome Trust NIMA consortium, 163 depressed patients and 55 healthy volunteers were included in this study. Adult patients meeting Structured Clinical Interview for Diagnostic and Statistical Manual Version-5 criteria for major depression were categorised into subgroups of treatment responder (n = 42), treatment non-responder (n = 80) and untreated depressed (n = 41) based on current depressive symptom severity measured by the 17-item Hamilton Rating Scale for Depression and exposure to antidepressant medications established by Antidepressant Treatment Response Questionnaire. Childhood Trauma Questionnaire was obtained. Baseline serum C-reactive protein was measured using turbidimetric detection. Salivary cortisol was analyzed at multiple time points during the day using the ELISA technique. Glucocorticoid resistance was defined as the coexistence of hypercortisolemia and inflammation. Our results show that treatment non-responder patients had higher exposure to childhood trauma than responders. No specific HPA axis abnormalities were found in treatment non-responder depressed patients. Untreated depressed showed increased diurnal cortisol levels compared with patients on antidepressant medication, and higher prevalence of glucocorticoid resistance than medicated patients and controls. The severity of childhood trauma was associated with increased diurnal cortisol levels only in individuals with glucocorticoid resistance. Therefore, our findings suggest that the severity of childhood trauma experience contributes to a lack of response to antidepressant treatment. The effects of childhood trauma on increased cortisol levels are specifically evident in patients with glucocorticoid resistance and suggest glucocorticoid resistance as a target for the development of personalized treatment for a subgroup of depressed patients with a history of childhood trauma rather than for all patients with resistance to antidepressant treatment.

Baseline cortisol and the efficacy of antiglucocorticoid treatment in mood disorders: A meta-analysis.

INTRODUCTION: Hyperactivity of the Hypothalamic-Pituitary-Adrenal (HPA) axis and high cortisol levels have been widely reported in patients with mood disorders but previous clinical trials investigating the efficacy of antiglucocorticoid treatment in this population have reported inconsistent findings. The inconsistencies among these studies may be because not all patients with mood disorders have increased HPA axis activity and therefore might not benefit from antiglucocorticoid treatment. The aim of this meta-analysis was to investigate whether baseline cortisol levels influence the efficacy of antiglucocorticoid drugs in patients with mood disorders. METHODS: PubMed and Scopus databases were searched systematically up to October 2018. We included studies using metyrapone, ketoconazole or mifepristone in patients with major depressive disorder, bipolar disorder and major depressive disorder with psychotic symptoms. We tested for a difference in cortisol levels between responders (a reduction equal to or greater than 30% on depression scales following antiglucocorticoid treatment) and non-responders (a reduction of less than 30% on depression scales). We performed a meta-analysis to look specifically at differences in cortisol levels in the sample of patients treated with cortisol synthesis inhibitors (metyrapone and ketoconazole) and in those treated with glucocorticoid receptor (GR) antagonist (mifepristone). RESULTS: We were able to retrieve data from 11 of the 16 selected studies and to include 9 studies in the meta-analysis. In the overall sample (N = 846), responders had similar baseline cortisol levels compared with non-responders (standardised mean difference, SMD = -0.03, 95% CI [-0.17, 0.12], p = 0.75). In the group of patients treated with cortisol synthesis inhibitors, responders (N = 109) had significantly higher peripheral baseline cortisol levels compared with non-responders (SMD = 0.42, 95% CI [0.01, 0.83], p = 0.047). In the group of patients treated with a GR antagonist (N = 737), both responders and non-responders had similar baseline cortisol levels (SMD = -0.09, 95% CI [-0.25, 0.07], p = 0.26). CONCLUSION: Our data suggest that only patients with higher cortisol levels at baseline benefit from treatment with cortisol synthesis inhibitors and support a potential role for cortisol as a predictive biomarker for treatment with cortisol synthesis inhibitors in patients with mood disorders.

Markers of central inflammation in major depressive disorder: A systematic review and meta-analysis of studies examining cerebrospinal fluid, positron emission tomography and post-mortem brain tissue.

BACKGROUND: Increased peripheral inflammation has been consistently reported in patients with major depressive disorder (MDD). However, only few studies have explored markers of central (brain) inflammation in patients with MDD. The aim of this study is to systematically review in vivo and post-mortem markers of central inflammation, including studies examining cerebrospinal fluid (CSF), positron emission tomography, and post-mortem brain tissues in subjects suffering with MDD compared with controls. METHODS: PubMed and Medline databases were searched up to December 2018. We included studies measuring cerebrospinal fluid (CSF) cytokines and chemokines, positron emission tomography (PET) studies; and post-mortem studies measuring cytokines, chemokines and cell-specific markers of microglia and astrocytes, all in MDD. A meta-analysis was performed only for CSF and PET studies, as studies on post-mortem markers of inflammation had different cell-specific markers and analysed different brain regions. RESULTS: A total of 69 studies met the inclusion criteria. CSF levels of IL-6 and TNF-α were higher in patients with MDD compared with controls (standardised mean difference SMD 0.37, 95%CI: 0.17-0.57 and SMD 0.58, 95%CI 0.26-0.90, respectively). CSF levels of IL-6 were increased in suicide attempters regardless of their psychiatric diagnosis. Translocator protein, a PET marker of central inflammation, was elevated in the anterior cingulate cortex and temporal cortex of patients with MDD compared with controls (SMD 0.78, 95%CI: 0.41-1.16 and SMD 0.52, 95%CI: 0.19-0.85 respectively). Abnormalities in CSF and PET inflammatory markers were not correlated with those in peripheral blood. In post-mortem studies, two studies found increased markers of microglia in MDD brains, while four studies found no MDD related changes. Of the studies investigating expression of cell-specific marker for astrocytes, thirteen studies reported a decreased expression of astrocytes specific markers, two studies reported increased expression of astrocytes specific markers, and eleven studies did not detect any difference. Four out of six studies reported decreased markers of oligodendrocytes in the prefrontal cortex. Post-mortem brain levels of tumor necrosis alpha (TNF-α) were also found increased in MDD. CONCLUSIONS: Our review suggests the presence of an increase in IL-6 and TNF-alpha levels in CSF and brain parenchyma, in the context of a possible increased microglia activity and reduction of astrocytes and oligodendrocytes markers in MDD. The reduced number of astrocytes may lead to compromised integrity of blood brain barrier with increased monocyte recruitment and infiltration, which is partly supported by post-mortem studies and by PET studies showing an increased TSPO expression in MDD.

CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients without dementia.

The aim of this study was to explore cross-sectional associations between Cardiovascular Risk Factors, Aging and Dementia Study (CAIDE) Dementia Risk Score and dementia-related cerebrospinal fluid and neuroimaging biomarkers in 724 patients without dementia from the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden. We additionally evaluated the score's capacity to predict dementia. Two risk score versions were calculated: one including age, gender, obesity, hyperlipidemia, and hypertension; and one additionally including apolipoprotein E (APOE) ε4 carrier status. Cerebrospinal fluid was analyzed for amyloid ß (Aß), total tau, and phosphorylated tau. Visual assessments of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale, and Fazekas scale for white matter changes (WMC) were performed. Higher CAIDE Dementia Risk Score (version without APOE) was significantly associated with higher total tau, more severe MTA, WMC, and global cortical atrophy-frontal subscale. Higher CAIDE Dementia Risk Score (version with APOE) was associated with reduced Aß, more severe MTA, and WMC. CAIDE Dementia Risk Score version with APOE seemed to predict dementia better in this memory clinic population with short follow-up than the version without APOE.

Medial temporal lobe atrophy and depressive symptoms in elderly patients with and without Alzheimer disease.

OBJECTIVE: To determine whether depressive symptoms are associated with medial temporal lobe atrophy in older people with and without Alzheimer disease (AD). METHOD: A total of 368 memory clinic patients with AD, mild cognitive impairment, and subjective cognitive impairment (SCI) were included. Depressive symptoms were defined as a score of 8 or higher on Cornell Scale for Depression in Dementia or use of antidepressant medications. Magnetic resonance imaging and computer tomography scans were rated for medial temporal lobe atrophy (MTA), using the Scheltens scale. For a subsample (n = 57 patients), hippocampal volume was manually traced. RESULTS: Based on visual assessment, AD patients with depressive symptoms had less atrophy of the right medial temporal lobe (odds ratio [OR] for having MTA: 0.39; 95% confidence interval [CI] 0.16-0.99) and decreased scores on Scheltens scale for the left medial temporal lobe (OR: 0.43, 95% CI 0.19-0.96) in comparison to AD patients without depressive symptoms. In the subgroup where manual tracing was used to measure hippocampal volume, people with SCI experiencing depressive symptoms had smaller right (mean difference: 0.28 cm(3); P = .005) and left (mean difference 0.32 cm(3); P = .002) hippocampal volumes compared to people with SCI who did not have depressive symptoms. CONCLUSION: Hippocampal atrophy was more pronounced among patients having SCI with depressive symptoms, while the medial temporal lobe was less atrophic in patients having AD with depressive symptoms than those without depressive symptoms. These findings suggest that different mechanisms underlie depression in older people with and without AD and may explain some of the inconsistent observations in previous studies.

Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer's Disease.

BACKGROUND: The aim of this study was to explore the relationship between cerebrospinal fluid Alzheimer's disease (AD) markers and depression in elderly people. METHOD: We included subjects with AD as well as persons with subjective cognitive impairment and normal cognition. Depression was assessed with the Cornell Scale for Depression in Dementia, and a cut-off score of >6 was used to define depression. Cerebrospinal fluid was analyzed using commercially available assays for ß-amyloid 1-42, total tau, and phosphorylated tau 181. RESULTS: A total of 183 participants (66.7% female) were included (92 with AD and 91 with subjective cognitive impairment), with a mean age (±SD) of 67.6 ± 7.4 years, a Mini-Mental State Examination score of 26.0 ± 4.0, and a median Cornell Scale for Depression in Dementia score of 5 (range 0-19). Depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced ß-amyloid 1-42 in AD or non-demented subjects. CONCLUSIONS: These results suggest that AD pathology does not contribute to depression, indicating that other factors may be more important. Further studies of the aetiology of depression in elderly people with and without AD are warranted.